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1.  The Concentration of Glutathione in Human Erythrocytes is a Heritable Trait 
Free radical biology & medicine  2013;65:10.1016/j.freeradbiomed.2013.08.002.
Glutathione (GSH) is a ubiquitous, redox active, small molecule that is critical to cellular and organism health. In red blood cells (RBCs), the influence of the environment (e.g. diet and lifestyle) on GSH levels has been demonstrated in numerous studies. However, it remains unknown if levels of GSH are determined principally by environmental factors, or if there is a genetic component, i.e. heritability. To investigate this we conducted a twin study. Twin studies are performed by comparing the similarity in phenotypes between mono- and di-zygotic twin pairs. We determined the heritability of GSH, as well as its oxidation product glutathione disulfide (GSSG), the sum of GSH equivalents (tGSH), and the status of the GSSG/2GSH couple (marker of oxidation status, Ehc) in RBCs. In our study population we found that the estimated heritability for the intracellular concentration of GSH in RBCs is 57 %; GSSG is 51 %, tGSH is 63 %, and Ehc is 70 %. We conclude that a major portion of the phenotype of these traits is controlled genetically. We anticipate that these heritabilities will also be reflected in other cell types. The discovery that genetics play a major role in the innate levels of redox active species in RBCs is paradigm-shifting and opens new avenues of research in the field of redox biology. Inherited RBC anti-oxidant levels may be important disease modifiers. By identifying the relative contributions of genes and the environment to anti-oxidant variation between individuals, new therapeutic strategies can be developed. Understanding the genetic determinants of these inherited traits may allow personalized approaches to relevant therapies.
doi:10.1016/j.freeradbiomed.2013.08.002
PMCID: PMC3859832  PMID: 23938402
Glutathione; Red blood cells; Heritability; Twin study
2.  Proteoglycan 4: A Dynamic Regulator of Skeletogenesis and Parathyroid Hormone Skeletal Anabolism 
Proteoglycan 4 (Prg4), known for its lubricating and protective actions in joints, is a strong candidate regulator of skeletal homeostasis and parathyroid hormone (PTH) anabolism. Prg4 is a PTH-responsive gene in bone and liver. Prg4 null mutant mice were used to investigate the impact of proteoglycan 4 on skeletal development, remodeling, and PTH anabolic actions. Young Prg4 mutant and wild-type mice were administered intermittent PTH(1–34) or vehicle daily from 4 to 21 days. Young Prg4 mutant mice had decreased growth plate hypertrophic zones, trabecular bone, and serum bone formation markers versus wild-type mice, but responded with a similar anabolic response to PTH. Adult Prg4 mutant and wild-type mice were administered intermittent PTH(1–34) or vehicle daily from 16 to 22 weeks. Adult Prg4 mutant mice had decreased trabecular and cortical bone, and blunted PTH-mediated increases in bone mass. Joint range of motion and animal mobility were lower in adult Prg4 mutant versus wild-type mice. Adult Prg4 mutant mice had decreased marrow and liver fibroblast growth factor 2 (FGF-2) mRNA and reduced serum FGF-2, which were normalized by PTH. A single dose of PTH decreased the PTH/PTHrP receptor (PPR), and increased Prg4 and FGF-2 to a similar extent in liver and bone. Proteoglycan 4 supports endochondral bone formation and the attainment of peak trabecular bone mass, and appears to support skeletal homeostasis indirectly by protecting joint function. Bone- and liver-derived FGF-2 likely regulate proteoglycan 4 actions supporting trabeculae formation. Blunted PTH anabolic responses in adult Prg4 mutant mice are associated with altered biomechanical impact secondary to joint failure.
doi:10.1002/jbmr.508
PMCID: PMC4118835  PMID: 21932346
PTH; PRG4; BONE; LIVER; FGF-2
3.  Hypothesizing that brain reward circuitry genes are genetic antecedents of pain sensitivity and critical diagnostic and pharmacogenomic treatment targets for chronic pain conditions 
Medical hypotheses  2008;72(1):14-22.
SUMMARY
While it is well established that the principal ascending pathways for pain originate in the dorsal horn of the spinal cord and in the medulla, the control and sensitivity to pain may reside in additional neurological loci, especially in the mesolimbic system of the brain (i.e., a reward center), and a number of genes and associated polymorphisms may indeed impact pain tolerance and or sensitivity. It is hypothesized that these polymorphisms associate with a predisposition to intolerance or tolerance to pain. It is further hypothesized that identification of certain gene polymorphisms provides a unique therapeutic target to assist in the treatment of pain. It is hereby proposed that pharmacogenetic testing of certain candidate genes (i.e., mu receptors, PENK etc.) will result in pharmacogenomic solutions personalized to the individual patient, with potential improvement in clinical outcomes.
doi:10.1016/j.mehy.2008.07.059
PMCID: PMC4098664  PMID: 18951726
4.  Survival of patients with cystic fibrosis on ECMO: analysis of the Extracorporeal Life Support Organization Registry 
Progressive respiratory failure is a common cause of death in patients with cystic fibrosis (CF). Although this may be related to the disease process itself, acute infectious problems may lead to respiratory failure requiring mechanical ventilation. Given the progressive nature of the disorder, some have suggested that the use of extracorporeal membrane oxygenation (ECMO) is contraindicated. The current study retrospectively reviewed the Extracorporeal Life Support Organization (ELSO) Registry to evaluate the outcomes following the use of ECMO in patients with CF. A total of 73 ECMO runs were identified in CF patients. There were 33 who received VV ECMO, 32 on VA ECMO, and 8 who received combined VA and VA ECMO. The overall survival rate for the cohort was 52% (38 of 73 patients). There was no difference in survival when comparing VA and VV ECMO. We noted an increasing trend for VV ECMO for this patient population over this time period. These data further support the need for a prospective study to evaluate outcomes following ECMO in this population with standardization of care across multiple centers.
PMCID: PMC4073758  PMID: 24995097
Cystic fibrosis; extracorporeal membrane oxygenation; survival; venoarterial; venovenous
6.  Nutrigenomic targeting of carbohydrate craving behavior: Can we manage obesity and aberrant craving behaviors with neurochemical pathway manipulation by Immunological Compatible Substances (nutrients) using a Genetic Positioning System (GPS) Map? 
Medical hypotheses  2009;73(3):427-434.
SUMMARY
Genetic mediated physiological processes that rely on both pharmacological and nutritional principles hold great promise for the successful therapeutic targeting of reduced carbohydrate craving, body-friendly fat loss, healthy body recomposition, and overall wellness. By integrating an assembly of scientific knowledge on inheritable characteristics and environmental mediators of gene expression, we review the relationship of genes, hormones, neurotransmitters, and nutrients as they correct unwanted weight gain coupled with unhappiness. In contrast to a simple one-locus, one-mechanism focus on pharmaceuticals alone, we hypothesize that the use of nutrigenomic treatment targeting multi-physiological neurological, immunological, and metabolic pathways will enable clinicians to intercede in the process of lipogenesis by promoting lipolysis while attenuating aberrant glucose cravings. In turn, this approach will enhance wellness in a safe and predictable manner through the use of a Genetic Positioning System (GPS) Map. The GPS Map, while presently incomplete, ultimately will serve not only as a blueprint for personalized medicine in the treatment of obesity, but also for the development of strategies for reducing many harmful addictive behaviors and promoting optimal health by using substances compatible with the body’s immune system.
doi:10.1016/j.mehy.2009.02.037
PMCID: PMC3758908  PMID: 19450935
7.  Clostridium difficile MazF Toxin Exhibits Selective, Not Global, mRNA Cleavage 
Journal of Bacteriology  2012;194(13):3464-3474.
Clostridium difficile is an important, emerging nosocomial pathogen. The transition from harmless colonization to disease is typically preceded by antimicrobial therapy, which alters the balance of the intestinal flora, enabling C. difficile to proliferate in the colon. One of the most perplexing aspects of the C. difficile infectious cycle is its ability to survive antimicrobial therapy and transition from inert colonization to active infection. Toxin-antitoxin (TA) systems have been implicated in facilitating persistence after antibiotic treatment. We identified only one TA system in C. difficile strain 630 (epidemic type X), designated MazE-cd and MazF-cd, a counterpart of the well-characterized Escherichia coli MazEF TA system. This E. coli MazF toxin cleaves mRNA at ACA sequences, leading to global mRNA degradation, growth arrest, and death. Likewise, MazF-cd expression in E. coli or Clostridium perfringens resulted in growth arrest. Primer extension analysis revealed that MazF-cd cleaved RNA at the five-base consensus sequence UACAU, suggesting that the mRNAs susceptible to cleavage comprise a subset of total mRNAs. In agreement, we observed differential cleavage of several mRNAs by MazF-cd in vivo, revealing a direct correlation between the number of cleavage recognition sites within a given transcript and its susceptibility to degradation by MazF-cd. Interestingly, upon detailed statistical analyses of the C. difficile transcriptome, the major C. difficile virulence factor toxin B (TcdB) and CwpV, a cell wall protein involved in aggregation, were predicted to be significantly resistant to MazF-cd cleavage.
doi:10.1128/JB.00217-12
PMCID: PMC3434716  PMID: 22544268
8.  Crystal structure and immunogenicity of the class C acid phosphatase from Pasteurella multocida 
Pasteurella multocida is a pathogen of veterinary and medical importance. Here, we report the 1.85 Å resolution crystal structure of the class C acid phosphatase from this organism (denoted rPmCCAP). The structure shows that rPmCCAP exhibits the same haloacid dehalogenase fold and dimeric assembly as the class C enzyme from Haemophilus influenzae. Formation of the dimer in solution is demonstrated using analytical ultracentrifugation. The active site is devoid of a magnesium ion due to the presence of citrate in the crystallization buffer. Absence of the metal ion minimally perturbs the active site structure, which suggests that the main role of the ion is to balance the negative charge of the substrate rather than stabilize the active site structure. The crystal lattice displays unusual crystal packing involving the C-terminal polyhistidine tag mimicking the substrate. Steady-state kinetic constants are determined for the substrates NMN, 5´-AMP, 3´-AMP, 2´-AMP, and p-nitrophenyl phosphate. The highest catalytic efficiency is observed with NMN. The production of polyclonal anti-rPmCCAP antibodies is demonstrated, and these antibodies are shown to cross-react with the H. influenzae class C phosphatase. The antibodies are used to detect PmCCAP in clinical P. multocida and Mannheimia haemolytica strains cultured from infected animals.
doi:10.1016/j.abb.2011.02.021
PMCID: PMC3086075  PMID: 21371420
X-ray crystallography; class C acid phosphatase; analytical ultracentrifugation; steady-state kinetics; polyhistidine affinity tag; haloacid dehalogenase fold
9.  Expression, purification and crystallization of class C acid phosphatases from Francisella tularensis and Pasteurella multocida  
Two members of the class C family of bacterial nonspecific acid phosphatases have been cloned, expressed, purified and crystallized. One of the crystal forms exhibited epitaxial twinning.
Class C nonspecific acid phosphatases are bacterial enzymes that are secreted across the cytoplasmic membrane and hydrolyze a variety of phosphomono­esters at acidic pH. These enzymes are of interest for the development of improved vaccines and clinical diagnostic methods. In one case, the category A pathogen Francisella tularensis, the class C phosphatase plays a role in bacterial fitness. Here, the cloning, expression, purification and crystallization methods for the class C acid phosphatases from F. tularensis and Pasteurella multocida are reported. Crystals of the F. tularensis enzyme diffracted to 2.0 Å resolution and belonged to space group C2221, with one enzyme molecule in the asymmetric unit. Crystals of the P. multocida enzyme diffracted to 1.85 Å resolution and belonged to space group C2, with three molecules in the asymmetric unit. Diffraction patterns from crystals of the P. multocida enzyme exhibited multiple interpenetrating reciprocal-space lattices, indicating epitaxial twinning. Despite this aberrance, autoindexing was robust and the data could be satisfactorily processed to 1.85 Å resolution using MOSFLM and SCALA.
doi:10.1107/S1744309109001511
PMCID: PMC2650447  PMID: 19255471
acid phosphatases; class C nonspecific acid phosphatases; Francisella tularensis; Pasteurella multocida; epitaxial twinning
10.  A functional role for sodium dependent glucose transport across the blood-brain barrier during oxygen glucose deprivation 
In the current study we determined the functional significance of sodium dependent/independent glucose transporters at the neurovasculature during oxygen glucose deprivation (OGD). Confluent brain endothelial cells cocultured with astrocytes were exposed to varying degrees of in vitro stroke conditions. Glucose transporter 1 (GLUT1) and sodium glucose cotransporter (SGLT) activity were investigated by luminal membrane uptake and transport studies using [3H] D-glucose and also by [14C] alpha methyl D-glucopyranoside (AMG), a specific, nonmetabolized substrate of SGLT. In vivo middle cerebral artery occlusion (MCAO) experiments were tested to determine if blood-brain barrier (BBB) SGLT activity was induced during ischemia. Increases in luminal D-glucose and AMG uptake and transport were observed with in vitro stroke conditions. Specific inhibitor experiments suggest a combined role for both SGLT and GLUT1 at the BBB during OGD. A time dependent increase in the uptake of AMG was also seen in mice exposed to permanent focal ischemia and this increase was sensitive to SGLT inhibitor, phlorizin. Infarct and edema ratio during ischemia were significantly decreased by the inhibition of this transporter. These results show that both GLUT1 and SGLT play a role at the BBB in the blood-to-brain transport of glucose during ischemic conditions and inhibition of SGLT during stroke has the potential to improve stroke outcome. Pharmacological modulation of this novel BBB transporter could prove to be a brain vascular target in stroke.
doi:10.1124/jpet.108.146589
PMCID: PMC2630371  PMID: 18981287
11.  Angiotensin II Induces Phosphorylation of Glucose-Regulated Protein-75 in WB Rat Liver Cells 
Studies in vascular smooth muscle cells suggest that, angiotenisn II (Ang II)-mediated cellular response requires transactivation of epidermal growth factor receptor (EGF-R), and involves tyrosine phosphorylation of caveolin-1. Here we demonstrate that, exposure of WB rat liver cells to Ang II does not cause transactivation of EGF-R, but did rapidly activate p42/p44 mitogen-activated protein (MAP) kinases suggesting that it activates MAP kinases independent of EGF-R transactivation. We observed that the phospho-specific anti-caveolin-1 antibody detected a tyrosine phosphorylated, 75 kDa protein in Ang II-treated cells which we identified as glucose regulated protein-75 (GRP-75). Phosphoamino acid analysis showed that Ang II induced its phosphorylation at tyrosine, serine and threonine residues and was localized to the cytoplasm. The ability of Ang-II to induce GRP-75 phosphorylation suggests that it may play a role in the protection of cytoplasmic proteins from the damaging effect of oxidative stress known to be produced during Ang-II induced signaling.
doi:10.1016/j.abb.2006.10.011
PMCID: PMC2577571  PMID: 17109810
Angiotensin II; GRP-75; Phosphorylation; Signal transduction; Oxidative stress; Mitochondria; Chaperone; EGF-R transactivation
12.  Automated analysis of embryonic gene expression with cellular resolution in C. elegans 
Nature methods  2008;5(8):703-709.
We describe a system that permits the automated analysis of reporter gene expression in Caenorhabditis elegans with cellular resolution continuously during embryogenesis and demonstrate its utility by defining the expression patterns of reporters for several embryonically expressed transcription factors. The invariant cell lineage permits the automated alignment of multiple expression profiles, allowing the direct comparison of the expression of different genes' reporters. We have also used the system to monitor perturbations to normal development involving changes both in cell division timing and in cell fate. Systematic application could reveal the gene activity of each cell throughout development.
doi:10.1038/nmeth.1228
PMCID: PMC2553703  PMID: 18587405
13.  Plasma growth hormones, P300 event-related potential and test of variables of attention (TOVA) are important neuroendocrinological predictors of early cognitive decline in a clinical setting: Evidence supported by structural equation modeling (SEM) parameter estimates 
Age  2007;29(2-3):55-67.
A review of the literature in both animals and humans reveals that changes in sex hormone have often been associated with changes in behavioral and mental abilities. Previously published research from our laboratory, and others, provides strong evidence that P300 (latency) event-related potential (ERP), a marker of neuronal processing speed, is an accurate predictor of early memory impairment in both males and females across a wide age range. It is our hypothesis, given the vast literature on the subject, that coupling growth hormones (insulin-like growth factor-I, (IGF-I) and insulin-like growth factor binding protein 3 (IGF-BP3)), P300 event-related potential and test of variables of attention (TOVA) are important neuroendocrinological predictors of early cognitive decline in a clinical setting. To support this hypothesis, we utilized structural equation modeling (SEM) parameter estimates to determine the relationship between aging and memory, as mediated by growth hormone (GH) levels (indirectly measured through the insulin-like growth factor system), P300 latency and TOVA, putative neurocognitive predictors tested in this study. An SEM was developed hypothesizing a causal directive path, leading from age to memory, mediated by IGF-1 and IGF-BP3, P300 latency (speed), and TOVA decrements. An increase in age was accompanied by a decrease in IGF-1 and IGF-BP3, an increase in P300 latency, a prolongation in TOVA response time, and a decrease in memory functioning. Moreover, independent of age, decreases in IGF-1 and IGF-BP3, were accompanied by increases in P300 latency, and were accompanied by increases in TOVA response time. Finally, increases in P300 latency were accompanied by decreased memory function, both directly and indirectly through mediation of TOVA response time. In summary, this is the first report utilizing SEM to reveal the finding that aging affects memory function negatively through mediation of decreased IGF-1 and IGF-BP3, and increased P300 latency (delayed attention and processing speed).
doi:10.1007/s11357-007-9030-3
PMCID: PMC2267660  PMID: 19424831
Structural equation modeling (SEM); P300 latency; TOVA;  IGF-1; IGF-BP3; Age and memory
14.  Intergenerational effects of high socioeconomic status on low birthweight and preterm birth in African Americans. 
As socioeconomic status (SES) increases, the incidence of low birthweight and preterm birth decreases irrespective of social class. However, low birthweight remains twice as high for African-American women as for white women even when SES is controlled. This study examines to what extent second generation high SES African-American women experience improvement in birthweight and gestational age. One hundred eighty-nine former Meharry students were surveyed. Identified were 934 births that are the children and grandchildren of these students who matriculated at Meharry. These infants are compared with a cohort of white mothers from a study in the School of Public Health at Yale University. Low birthweight was reduced in the third generation high SES African-American children (6.9%) from the second generation (11.4%) but remained higher than white children (3.3%). Results showed that African-American third generation children remained at higher risk for low birthweight than were white children (relative risk [RR], 1.78; 95% confidence interval [CI], 1.03, 3.09). Similar results were observed for preterm delivery where the increased risk to third generation African-American children was 3.16 (1.89, 5.27). Persistent strong ethnic differences in birthweight in this high SES cohort (OR = 3.16, 95% CI, 1.89-5.27) support a conclusion that African-American women have birthweight distributions that are somewhat lighter than white women. This may explain a portion of current ethnic differences in birthweight. It is also possible that persistent psychosocial and behavioral factors continue to negatively influence birthweight, even in second generation high SES African-American mothers. This explanation will require identification of powerful risk factors, which are largely unrelated to those presently under investigation.
PMCID: PMC2640563  PMID: 10881470
15.  Physiological and Environmental Studies of Sclerotium Formation and Maturation in Isolates of Morchella crassipes 
Applied and Environmental Microbiology  1989;55(12):3095-3100.
This study provides a set of nutritional and environmental parameters suitable for the growth of morel (Morchella crassipes) sclerotia in the laboratory, using a modification of the jar method of Ower et al. (U.S. patent 4,594,809, June 1986). The optimum nutritional and environmental conditions for morel sclerotium formation and maturation as determined in this study consist of a layer of rye grain supplemented with peptone, yeast extract, trace elements, and Casamino Acids overlaid with perforated aluminum foil and covered with a layer of nutrient-poor soil medium in an 8-oz. (ca. 237-ml) glass jar in the dark. We noted that addition of asparagine or aspartic acid as a nitrogen source to the rye also had a beneficial effect on sclerotium formation, while addition of carbon sources had no significant effect.
Images
PMCID: PMC203229  PMID: 16348070
16.  Respiratory Trace Feature Analysis for Prediction of Respiratory-Gated PET Quantification 
Physics in medicine and biology  2014;59(4):1027-1045.
The benefits of respiratory gating in quantitative PET/CT vary tremendously between individual patients. Respiratory pattern is among many patient-specific characteristics that are thought to play an important role in gating-induced imaging improvements. However, the quantitative relationship between patient-specific characteristics of respiratory pattern and improvements in quantitative accuracy from respiratory-gated PET/CT has not been well established. If such a relationship could be estimated, then patient-specific respiratory patterns could be used to prospectively select appropriate motion compensation during image acquisition on a per-patient basis. This study was undertaken to develop a novel statistical model that predicts quantitative changes in PET/CT imaging due to respiratory gating. Free-breathing static FDG-PET images without gating and respiratory-gated FDG-PET images were collected from twenty-two lung and liver cancer patients on a PET/CT scanner. PET imaging quality was quantified with peak standardized uptake value (SUVpeak) over lesions-of interest. Relative differences in SUVpeak between static and gated PET images were calculated to indicate quantitative imaging changes due to gating. A comprehensive multidimensional extraction of the morphological and statistical characteristics of respiratory patterns was conducted, resulting in 16 features that characterize representative patterns of a single respiratory trace. The 6 most informative features were subsequently extracted using a stepwise feature selection approach. The multiple-regression model was trained and tested based on a leave-one-subject-out cross validation. The predicted quantitative improvements in PET imaging achieved an accuracy higher than 90% using a criterion with a dynamic error-tolerance range for SUVpeak values. The results of this study suggest that our prediction framework could be applied to determine which patients would likely to benefit from respiratory motion compensation when clinicians quantitatively assess PET/CT for therapy target definition and response assessment.
doi:10.1088/0031-9155/59/4/1027
PMCID: PMC4000406  PMID: 24504153
patient classification; respiratory motion; PET/CT; respiratory gating
17.  Flavivirus NS1 crystal structures reveal a surface for membrane association and regions of interaction with the immune system 
Science (New York, N.Y.)  2014;343(6173):881-885.
Flaviviruses, the human pathogens responsible for dengue fever, West Nile fever, tick-borne encephalitis and yellow fever, are endemic in tropical and temperate parts of the world. The flavivirus non-structural protein 1 (NS1) functions in genome replication as an intracellular dimer and in immune system evasion as a secreted hexamer. We report crystal structures for full-length, glycosylated NS1 from West Nile and dengue viruses. The NS1 hexamer in crystal structures is similar to a solution hexamer visualized by single-particle electron microscopy. Recombinant NS1 binds to lipid bilayers and remodels large liposomes into lipoprotein nanoparticles. The NS1 structures reveal distinct domains for membrane association of the dimer and interactions with the immune system, and are a basis for elucidating the molecular mechanism of NS1 function.
doi:10.1126/science.1247749
PMCID: PMC4263348  PMID: 24505133
18.  Characterization of monocyte maturation/differentiation that facilitates their transmigration across the blood–brain barrier and infection by HIV: Implications for NeuroAIDS 
Cellular immunology  2010;267(2):109-123.
The prevalence of human immunodeficiency virus 1 (HIV) associated neurocognitive disorders resulting from infection of the central nervous system (CNS) by HIV continues to increase despite the success of combination antiretroviral therapy. Although monocytes are known to transport HIV across the blood–brain barrier (BBB) into the CNS, there are few specific markers that identify monocyte subpopulations susceptible to HIV infection and/or capable of infiltrating the CNS. We cultured human peripheral blood monocytes and characterized the expression of the phenotypic markers CD14, CD16, CD11b, Mac387, CD163, CD44v6 and CD166 during monocyte/macrophage (Mo/Mac) maturation/differentiation. We determined that a CD14+CD16+CD11b+Mac387+ Mo/Mac subpopulation preferentially transmigrates across our in vitro BBB model in response to CCL2. Genes associated with Mo/Mac subpopulations that transmigrate across the BBB and/or are infected by HIV were identified by cDNA microarray analyses. Our findings contribute to the understanding of monocyte maturation, infection and transmigration into the brain during the pathogenesis of NeuroAIDS.
doi:10.1016/j.cellimm.2010.12.004
PMCID: PMC4335637  PMID: 21292246
NeuroAIDS; Monocytes/macrophages; Transmigration; Maturation/differentiation; Blood; brain barrier; CCL2; CD14; CD16
19.  Patterns of Care Among Patients Receiving Radiation Therapy for Bone Metastases at a Large Academic Institution 
Purpose
This study evaluates outcomes and patterns of care among patients receiving radiation therapy (RT) for bone metastases at a high-volume academic institution.
Methods and Materials
Records of all patients whose final RT course was for bone metastases from April 2007 to July 2012 were identified from electronic medical records. Chart review yielded demographic and clinical data. Rates of complicated versus uncomplicated bone metastases were not analyzed.
Results
We identified 339 patients whose final RT course was for bone metastases. Of these, 52.2% were male; median age was 65 years old. The most common primary was non-small-cell lung cancer (29%). Most patients (83%) were prescribed ≤10 fractions; 8% received single-fraction RT. Most patients (52%) had a documented goals of care (GOC) discussion with their radiation oncologist; hospice referral rates were higher when patients had such discussions (66% with vs 50% without GOC discussion, P=.004). Median life expectancy after RT was 96 days. Median survival after RT was shorter based on inpatient as opposed to outpatient status at the time of consultation (35 vs 136 days, respectively, P<.001). Hospice referrals occurred for 56% of patients, with a median interval between completion of RT and hospice referral of 29 days and a median hospice stay of 22 days.
Conclusions
These data document excellent adherence to American Society for Radiation Oncolology Choosing Wisely recommendation to avoid routinely using >10 fractions of palliative RT for bone metastasis. Nonetheless, single-fraction RT remains relatively uncommon. Participating in GOC discussions with a radiation oncologist is associated with higher rates of hospice referral. Inpatient status at consultation is associated with short survival.
doi:10.1016/j.ijrobp.2014.04.028
PMCID: PMC4332799  PMID: 25035214
20.  The Contribution of Adolescent Effortful Control to Early Adult Educational Attainment 
Journal of educational psychology  2014;106(3):730-743.
Effortful control has been proposed as a set of neurocognitive competencies that is relevant to self-regulation and educational attainment (Posner & Rothbart, 2007). This study tested the hypothesis that a multiagent report of adolescents’ effortful control (age 17) would be predictive of academic persistence and educational attainment (age 23–25), after controlling for other established predictors (family factors, problem behavior, grade point average, and substance use). Participants were 997 students recruited in 6th grade from 3 urban public middle schools (53% males; 42.4% European American; 29.2% African American). Consistent with the hypothesis, the unique association of effortful control with future educational attainment was comparable in strength to that of parental education and students’ past grade point average, suggesting that effortful control contributes to this outcome above and beyond well-established predictors. Path coefficients were equivalent across gender and ethnicity (European Americans and African Americans). Effortful control appears to be a core feature of the self-regulatory competencies associated with achievement of educational success in early adulthood. These findings suggest that the promotion of self-regulation in general and effortful control in particular may be an important focus not only for resilience to stress and avoidance of problem behavior, but also for growth in academic competence.
doi:10.1037/a0035831
PMCID: PMC4191676  PMID: 25308996
educational attainment level; self-regulation; academic achievement; adolescence; family background
21.  Prevalence of Congenital Cardiovascular Malformations in Children of Human Immunodeficiency Virus-Infected Women: The Prospective P2C2 HIV Multicenter Study 
Objectives
The purpose of the study was to assess the effects of maternal HIV-1 (human immunodeficiency virus) infection and vertically transmitted HIV-1 infection on the prevalence of congenital cardiovascular malformations in children.
Background
In the United States, an estimated 7000 children are born to HIV-infected women annually. Previous limited reports have suggested an increase in the prevalence of congenital cardiovascular malformations in vertically transmitted HIV-infected children.
Methods
In a prospective longitudinal multicenter study, diagnostic echocardiograms were performed at 4–6-month intervals on two cohorts of children exposed to maternal HIV-1 infection: 1) a Neonatal Cohort of 90 HIV-infected, 449 HIV-uninfected and 19 HIV-indeterminate children; and 2) an Older HIV-Infected Cohort of 201 children with vertically transmitted HIV-1 infection recruited after 28 days of age.
Results
In the Neonatal Cohort, 36 lesions were seen in 36 patients, yielding an overall congenital cardiovascular malformation prevalence of 6.5% (36/558), with a 8.9% (8/90) prevalence in HIV-infected children and a 5.6% (25/449) prevalence in HIV-uninfected children. Two children (2/558, 0.4%) had cyanotic lesions. In the Older HIV-Infected Cohort, there was a congenital cardiovascular malformation prevalence of 7.5% (15/201). The distribution of lesions did not differ significantly between the groups.
Conclusions
There was no statistically significant difference in congenital cardiovascular malformation prevalence in HIV-infected versus HIV-uninfected children born to HIV-infected women. With the use of early screening echocardiography, rates of congenital cardiovascular malformations in both the HIV-infected and HIV-uninfected children were five- to ten-fold higher than rates reported in population-based epidemiologic studies but not higher than in normal populations similarly screened. Potentially important subclinical congenital cardiovascular malformations were detected.
PMCID: PMC4331099  PMID: 9822105
22.  Incidence of cardiac abnormalities in children with human immunodeficiency virus infection: The Prospective P2C2 HIV Study 
The Journal of pediatrics  2002;141(3):327-334.
Objective
To describe the 5-year cumulative incidence of cardiac dysfunction in human immunodeficiency virus (HIV)-infected children.
Study design
We used a prospective cohort design, enrolling children at 10 hospitals. Group I included 205 vertically HIV-infected children enrolled at a median age of 1.9 years. Group II consisted of 600 HIV-exposed children enrolled prenatally or as neonates, of whom 93 were ultimately HIV-infected. The main outcome measures were echocardiographic indexes of left ventricular dysfunction.
Results
In group I, the 5-year cumulative incidence of left ventricular fractional shortening ≤25% was 28.0%. The 5-year incidence of left ventricular end-diastolic dilatation was 21.7%, and heart failure and/or the use of cardiac medications 28.8%. The mortality rate 1 year after the diagnosis of heart failure was 52.5% [95% CI, 30.5-74.5]. Within group II, the 5-year cumulative incidence of decreased fractional shortening was 10.7% in the HIV-infected compared with 3.1% in the HIV-uninfected children (P = .01). Left ventricular dilation, heart failure, and/or the use of cardiac medications were more common in infected compared with uninfected children.
Conclusions
During 5 years of follow-up, cardiac dysfunction occurred in 18% to 39% of HIV-infected children and was associated with an increased risk of death. We recommend that HIV-infected children undergo routine echocardiographic surveillance for cardiac abnormalities.
PMCID: PMC4331106  PMID: 12219051
23.  Subarachnoid haemorrhage with bilateral intracranial vertebral artery dissecting aneurysms treated by staged endovascular stenting 
BMJ Case Reports  2013;2013:bcr0320126002.
Bilateral vertebral artery dissecting aneurysms (VADAs) presenting with subarachnoid haemorrhage (SAH) are an exceedingly rare and deadly clinical dilemma. Prompt intervention in the case of unilateral VADAs is advocated to prevent rebleed; however, in the case of bilateral VADAs, the optimal therapeutic intervention is unclear. We describe the case of a patient presenting with SAH with bilateral VADAs treated by staged endovascular stenting. This led to resolution of the aneurysms with patency of both vertebral arteries.
Stent-based therapy of the symptomatic aneurysm followed by staged stenting of the asymptomatic, contralateral aneurysm appears to be a viable treatment option. This method allows the ability to preserve flow in both vertebral arteries with minimal changes in flow characteristics that may threaten the contralateral, asymptomatic VADA, and appears to be the ideal treatment in these rare cases.
doi:10.1136/bcr-03-2012-6002
PMCID: PMC3603424  PMID: 23417929
24.  Synthesis and characterization of a porphyrazine–Gd(III) MRI contrast agent and in vivo imaging of a breast cancer xenograft model 
Porphyrazines (Pz), or tetraazaporphyrins, are being studied for their potential use in detection and treatment of cancer. Here, an amphiphilic Cu–Pz–Gd(III) conjugate has been prepared via azide-alkyne Huisgen cycloaddition or ‘click’ chemistry between an azide functionalized Pz and alkyne functionalized DOTA–Gd(III) analog for use as an MRI contrast agent. This agent, Cu–Pz–Gd(III), is synthesized in good yield and exhibits solution-phase ionic relaxivity (r1 = 11.5 mm−1 s−1) that is approximately four times higher than that of a clinically used monomeric Gd (III) contrast agent, DOTA–Gd(III). Breast tumor cells (MDA-MB-231) associate with Cu–Pz–Gd(III) in vitro, where significant contrast enhancement (9.336 ± 0.335 contrast-to-noise ratio) is observed in phantom cell pellet MR images. This novel contrast agent was administered in vivo to an orthotopic breast tumor model in athymic nude mice and MR images were collected. The average T1 of tumor regions in mice treated with 50 mg kg−1 Cu–Pz–Gd (III) decreased relative to saline-treated controls. Furthermore, the decrease in T1 was persistent relative to mice treated with the monomeric Gd(III) contrast agent. An ex vivo biodistribution study confirmed that Cu–Pz–Gd(III) accumulates in the tumors and is rapidly cleared, primarily through the kidneys. Differential accumulation and T1 enhancement by Cu–Pz–Gd(III) in the tumor's core relative to the periphery offer preliminary evidence that this agent would find application in the imaging of necrotic tissue.
doi:10.1002/cmmi.1577
PMCID: PMC4327828  PMID: 24706615
tumor imaging; porphyrazine; MRI contrast agent; click chemistry
25.  A comprehensive analysis of recruitment and transactivation potential of K-Rta and K-bZIP during reactivation of Kaposi's sarcoma-associated herpesvirus 
Virology  2009;387(1):76-88.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma. K-Rta and K-bZIP are two major viral transcription factors that control reactivation of this virus. Here we report a genome-wide analysis of transcriptional capacity by evaluation of a comprehensive library of 83 putative KSHV promoters. In reporter assays, 34 viral promoters were activated by K-Rta, whereas K-bZIP activated 21 promoters. When K-Rta and K-bZIP were combined, 3 K-Rta responsive promoters were repressed by K-bZIP. The occupancy of K-Rta and K-bZIP across KSHV promoters was analyzed by chromatin immunoprecipitation with a viral promoter-chip in BCBL-1 cells. In addition, acetylation of local histones was examined to determine accessibility of promoters during latency and reactivation. Finally, 10 promoters were selected to study the dynamics of transcription factor recruitment. This study provides a comprehensive overview of the responsiveness of KSHV promoters to K-Rta and K-bZIP, and describes key chromatin changes during viral reactivation.
doi:10.1016/j.virol.2009.02.016
PMCID: PMC4327937  PMID: 19269659
Kaposi's sarcoma; KSHV; HHV-8; Transcription; Chromatin immunoprecipitation; Gene expression; K-Rta/ORF50; K-bZIP/K8; Microarray; Chromatin

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