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1.  Tolosa-Hunt syndrome masquerading as a carotid artery dissection 
To demonstrate the difficulties of diagnosing a patient with Tolosa-Hunt syndrome (THS) due to its complicated presentation and extensive diagnostic testing, and how to manage the treatment of a patient in an emergent setting.
Patients and methods
A female patient with THS affecting the left eye was examined using two magnetic resonance imaging (MRI) scans. The patient was treated with high-dose methylprednisolone (Solu-Medrol®) and prednisone. A follow-up MRI and magnetic resonance angiogram (MRA) was also performed 4 months later.
The second MRI scan disclosed a 5×9×10 mm lesion in the left superior orbital fissure/cavernous sinus. After administration of methylprednisolone and prednisone, the patient’s pain completely resolved, and the left eye regained full duction and eyelid mobility. The MRI and MRA obtained after the treatment showed no abnormalities.
The rarity of THS makes it difficult to diagnose, especially when there is a question of accuracy and reproducibility of the testing performed. An ophthalmologic consultation in such cases is crucial.
PMCID: PMC3984061  PMID: 24741291
granulomatous lesion; painful ophthalmoplegia; idiopathic orbital inflammation; multiple cranial nerve palsies
2.  Merely Misunderstood? Receptive, Expressive, and Pragmatic Language in Young Children With Disruptive Behavior Disorders 
Children with disruptive behavior disorders (DBDs) often seem to have poorer language skills compared to same-age peers; however, language as an early risk factor for DBD has received little empirical attention. The present study provides an empirical examination of associations between normal language variation and DBD by investigating receptive, expressive, and pragmatic language skills and preschool DBD symptoms. The sample consisted of 109 preschoolers ages 3 to 6 (M = 4.77 years, SD = 1.10, 59% boys; 73% with DBD, including oppositional defiant disorder [ODD] and attention-deficit/hyperactivity disorder [ADHD]) along with their primary caregivers, who completed a clinician-administered interview, symptom questionnaires, and a questionnaire measure of pragmatic language, and teacher and/or daycare providers completed symptom questionnaires. Children completed objective tests of receptive and expressive vocabulary. Preschoolers with DBD showed poorer receptive, expressive, and pragmatic skills compared to preschoolers without DBD. Preschoolers with ADHD-only or ADHD+ODD exhibited poorer language skills, compared to ODD and non-DBD groups. Specificity analyses suggested that parent-rated hyperactivity-impulsivity were particularly associated with poorer language skills. Thus, preschoolers with DBD exhibited poorer language skills compared to preschoolers without DBD, and preschoolers with increased hyperactivity-impulsivity exhibited particular problems with language skills. This work suggests the need for early assessment of language in preschoolers, particularly those with ADHD, as well as the possible utility of tailored interventions focused on improving language skills, particularly for those with high hyperactivity-impulsivity.
PMCID: PMC4311524  PMID: 23924073
3.  Conscientiousness as a mediator of the association between masculinized finger-length ratios and attention-deficit/hyperactivity disorder (ADHD) 
One often-overlooked biological risk factor that may help explain sex-biased prevalence rates in psychopathology is sex hormones. Personality traits, which also show sex differences, may mediate relations between biological risk factors like hormones and childhood psychopathology such as ADHD (or, alternatively, be independent risk factors).
Three hundred and twelve children/adolescents (178 boys, 134 girls) between the ages of 8 and 17 completed a comprehensive, multistage, clinical diagnostic procedure; 168 children were diagnosed with ADHD and 144 were classified as non-ADHD comparison controls. Primary caregivers completed the California Q-sort in order to provide a measure of conscientiousness. Finger-length ratios (specifically right 2D:4D) served as a proxy of prenatal testosterone exposure (relative to estrogen).
Lower levels of conscientiousness statistically mediated the relationship between more masculine right 2D:4D (i.e., increased prenatal testosterone exposure) and increased ADHD inattentive symptoms.
More masculinized finger-length ratios show associations with ADHD symptoms, possibly acting through the trait mechanism of conscientiousness.
PMCID: PMC4311552  PMID: 19298468
ADHD; hormones; personality; mediation
4.  Dispositional Trait Types of ADHD in Young Children 
Journal of attention disorders  2012;10.1177/1087054712466915.
This study evaluated a novel person-centered approach to parsing ADHD heterogeneity using dispositional traits.
Participants were one hundred nine 3- to 6-year-olds, and their primary caregivers and day care providers/teachers who completed a multi-informant diagnostic procedure with longitudinal follow-up.
Based on latent profile analysis, young children with ADHD could be divided into low control, high surgency, and high negative affect subgroups. The low control and high surgency groups exhibited increased parent- and teacher-rated hyperactive-impulsive and oppositional-defiant disorder (ODD) symptoms. Although the low control group exhibited the worst response inhibition, the high surgency group exhibited the worst working memory. Furthermore, the high surgency group exhibited high aggression and increasing levels of hyperactivity-impulsivity and ODD symptoms over time.
A subgroup of young children with ADHD with high surgency may be at particular risk for comorbid psychopathology and longitudinal worsening of symptoms.
PMCID: PMC4308572  PMID: 23239785
ADHD; maladaptive traits; cognitive control
5.  Emerging Control and Disruptive Behavior Disorders During Early Childhood 
Developmental neuropsychology  2013;38(3):153-166.
The current study evaluates associations between control processes and Oppositional Defiant Disorder (ODD) and attention deficit hyperactivity disorder (ADHD) during early childhood. Participants were 98 children between ages 3 and 6 and their primary caregivers. Diagnostic information on ODD and ADHD symptoms was available from parents and teachers/caregivers via standardized rating forms. Affective, effortful, and cognitive control processes were measured using parent and examiner ratings via standardized questionnaires, observational ratings, and child performance on laboratory tasks of cognitive control. Affective control, but not effortful control, was significantly associated with cognitive control. A latent factor of control was significantly associated with ADHD, but not ODD, symptoms.
PMCID: PMC4307392  PMID: 23573794
6.  Revisiting the latent structure of ADHD: is there a ‘g’ factor? 
Attention-deficit/hyperactivity disorder (ADHD) is presumed to be heterogeneous, but the best way to describe this heterogeneity remains unclear. Considerable evidence has accrued suggesting that inattention versus hyperactivity-impulsivity symptom domains predict distinct clinical outcomes and may have partially distinct etiological influence. As a result, some conceptualizations emphasize two distinct inputs to the syndrome. Yet formal testing of models that would accommodate such assumptions using modern methods (e.g., second-order factor and bifactor models) has been largely lacking.
Participants were 548 children (321 boys) between the ages of 6 and 18 years. Of these 548 children, 302 children met DSM-IV criteria for ADHD, 199 were typically developing controls without ADHD, and 47 were classified as having situational or subthreshold ADHD. ADHD symptoms were assessed via parent report on a diagnostic interview and via parent and teacher report on the ADHD Rating Scale.
A bifactor model with a general factor and specific factors of inattention and hyperactivity-impulsivity fit best when compared with one-, two-, and three-factor models, and a second-order factor model.
A bifactor model of ADHD latent symptom structure is superior to existing factor models of ADHD. This finding is interpreted in relation to multi-component models of ADHD development, and clinical implications are discussed.
PMCID: PMC4307590  PMID: 20331490
ADHD; structural equation modeling; development
7.  The Structure of Childhood Disruptive Behaviors 
Psychological assessment  2010;22(4):816-826.
Attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) frequently co-occur. Comorbidity of these 2 childhood disruptive behavior domains has not been satisfactorily explained at either a structural or etiological level. The current study evaluated a bifactor model, which allows for a “g” factor in addition to distinct component factors, in relation to other models to improve understanding of the structural relationship between ADHD and ODD. Participants were 548 children (321 boys, 227 girls) between the ages of 6 years and 18 years who participated in a comprehensive diagnostic assessment incorporating parent and teacher ratings of symptoms. Of these 548 children, 153 children were diagnosed with ADHD (without ODD), 114 children were diagnosed with ADHD + ODD, 26 children were diagnosed with ODD (without ADHD), and 239 children were classified as non-ADHD/ODD comparison children (including subthreshold cases). ADHD symptoms were assessed via parent report on a diagnostic interview and via parent and teacher report on the ADHD Rating Scale. ODD symptoms were assessed via teacher report. A bifactor model of disruptive behavior, comprising a “g” factor and the specific factors of ADHD and ODD, exhibited best fit, compared to 1-factor, 2-factor, 3-factor, and 2nd-order factor models of disruptive behaviors. It is concluded that a bifactor model of childhood disruptive behaviors is superior to existing models and may help explain common patterns of comorbidity between ADHD and ODD.
PMCID: PMC4307591  PMID: 21133546
disruptive behavior; ADHD; ODD; bifactor model
8.  Developmental differences in structure of attention-deficit/hyperactivity disorder (ADHD) between childhood and adulthood 
The current paper utilizes a bifactor modeling approach to evaluate the structure of attention-deficit/hyperactivity disorder (ADHD) in adulthood and assess developmental continuity of ADHD structure between childhood and adulthood. The study compared traditional one-factor, two-factor, three-factor, and second-order factor models of ADHD with a bifactor model of ADHD. Developmental differences in ADHD structure were examined using an extension of the bifactor model: a two-group model comparing children and adults. Participants were 406 adults (49% male; 145 of 406 with ADHD), (18 to 37) years old, and 548 children (58% male; 302 of 548 with ADHD), 6 to 18 years old. A bifactor model of ADHD exhibited the best fit in adults and children compared to traditional models, suggesting continuity in the ADHD latent construct across development. However, significant differences in the factor loadings were evident between children and adults in the two-group bifactor model, suggesting changes in the relative importance of particular symptoms over time. Namely, hyperactivity symptoms appear to decline in importance relative to the ADHD phenotype between childhood and adulthood.
PMCID: PMC4307607  PMID: 25635150
attention problems; children; development; developmental psychopathology
9.  The Dopamine Receptor D4 Gene (DRD4) Moderates Family Environmental Effects on ADHD 
Attention-Deficit/Hyperactivity Disorder (ADHD) is a prime candidate for exploration of gene-by-environment interaction (i.e., G × E), particularly in relation to dopamine system genes, due to strong evidence that dopamine systems are dysregulated in the disorder. Using a G × E design, we examined whether the DRD4 promoter 120-bp tandem repeat polymorphism, previously associated with ADHD, moderated the effects of inconsistent parenting and marital conflict on ADHD or Oppositional-Defiant Disorder (ODD). Participants were 548 children with ADHD and non-ADHD comparison children and their parents. Homozygosity for the DRD4 promoter 120-bp tandem repeat insertion allele increased vulnerability for ADHD and ODD only in the presence of inconsistent parenting and appeared to increase susceptibility to the influence of increased child self-blame for marital conflict on ADHD inattention. DRD4 genotypes may interact with these proximal family environmental risk factors by increasing the individual’s responsivity to environmental contingencies.
PMCID: PMC4306231  PMID: 20644990
Attention; ADHD; Genetics; Environmental effects
10.  Individual Differences in Attention Deficit Hyperactivity Disorder Symptoms and Associated Executive Dysfunction and Traits: Sex, Ethnicity, and Family Income 
The American journal of orthopsychiatry  2013;83(2 0 3):165-175.
The goal of the present investigation was to investigate sex, ethnic, and socioeconomic status (SES) influences on attention deficit hyperactivity disorder (ADHD) symptoms and risk markers, including executive dysfunction and temperament traits. Participants were 109 children who were 3 to 6 years old (64% male; 36% ethnic minority) and their primary caregivers and teachers who completed a multistage, multi-informant screening, and diagnostic procedure. Parents completed a diagnostic interview and diagnostic and temperament questionnaires, teachers completed questionnaires, and children completed cognitive control tasks. Because of targeted overrecruitment of clinical cases, 56% of children in the sample were diagnosed with ADHD. Results suggested minimal sex differences, but prominent ethnic differences, in ADHD symptoms and temperament and executive function risk markers. Further, low family income was associated with increased ADHD symptoms and more temperament and executive function risk markers, and low family income explained many ethnic differences in ADHD symptoms and these risk markers. There were prominent interactions among child sex, ethnicity, and family income. Thus, study results suggest that children with multiple individual difference demographic risk factors (e.g., such as being male and ethnic minority) are at highly increased risk of ADHD symptoms and associated risk markers in the temperament and executive function domains.
PMCID: PMC4306561  PMID: 23889009
ethnic minority children; attention deficit hyperactivity disorder; ethnicity; socioeconomic status; family income; negative affect; surgency; effortful control; executive function; additive risk
11.  Personality Mediation of Genetic Effects on Attention-Deficit/Hyperactivity Disorder 
Personality traits may be viable candidates for mediators of the relationship between genetic risk and ADHD. Participants were 578 children (331 boys; 320 children with ADHD) between the ages of six and 18. Parents and teachers completed a comprehensive, multistage diagnostic procedure to assess ADHD and comorbid disorders. Mother completed the California Q-Sort to assess child Big Five personality traits. Children provided buccal samples of DNA which were assayed for selected markers on DRD4, DAT1, and ADRA2A. An additive genetic risk composite was associated with ADHD symptoms and maladaptive personality traits; maladaptive personality traits were associated with ADHD symptoms. Low conscientiousness and high neuroticism partially mediated the relationship between genetic risk and ADHD symptoms. Mediation effects for conscientiousness were specific to inattentive symptoms; effects for neuroticism generalized to all disruptive behaviors. High neuroticism and low conscientiousness may be useful as early markers for children at risk for ADHD.
PMCID: PMC4303410  PMID: 20146095
ADHD; Genetics; Personality; Disruptive behaviors
12.  Prenatal Testosterone and Preschool Disruptive Behavior Disorders 
Disruptive Behaviors Disorders (DBD), including Oppositional-Defiant Disorder (ODD) and Attention-Deficit/Hyperactivity Disorder (ADHD), are fairly common and highly impairing childhood behavior disorders that can be diagnosed as early as preschool. Prenatal exposure to testosterone may be particularly relevant to these early-emerging DBDs that exhibit a sex-biased prevalence rate favoring males. The current study examined associations between preschool DBD symptom domains and prenatal exposure to testosterone measured indirectly via right 2D:4D finger-length ratios. The study sample consisted of 109 preschool-age children between ages 3 and 6 (64% males;72% with DBD) and their primary caregivers. Primary caregivers completed a semi-structured interview (i.e., Kiddie Disruptive Behavior Disorder Schedule), as well as symptom questionnaires (i.e., Disruptive Behavior Rating Scale, Peer Conflict Scale); teachers and/or daycare providers completed symptom questionnaires and children provided measures of prenatal testosterone exposure, measured indirectly via finger-length ratios (i.e., right 2D:4D). Study results indicated a significant association of high prenatal testosterone (i.e., smaller right 2D:4D) with high hyperactive-impulsive ADHD symptoms in girls but not boys, suggesting that the effect may be driven by, or might only exist in, girls. The present study suggests that prenatal exposure to testosterone may increase risk for early ADHD, particularly hyperactivity-impulsivity, in preschool girls.
PMCID: PMC4295489  PMID: 25598567
Preschool children; ADHD; Prenatal; Testosterone; Hyperactivity; Impulsivity
13.  Learning-induced and stathmin-dependent changes in microtubule stability are critical for memory and disrupted in ageing 
Nature communications  2014;5:4389.
Changes in the stability of microtubules regulate many biological processes, but their role in memory remains unclear. Here we show that learning causes biphasic changes in the microtubule-associated network in the hippocampus. In the early phase, stathmin is dephosphorylated, enhancing its microtubule-destabilizing activity by promoting stathmin-tubulin binding, whereas in the late phase these processes are reversed leading to an increase in microtubule/KIF5-mediated localization of the GluA2 subunit of AMPA receptors at synaptic sites. A microtubule stabilizer paclitaxel decreases or increases memory when applied at the early or late phases, respectively. Stathmin mutations disrupt changes in microtubule stability, GluA2 localization, synaptic plasticity and memory. Aged wild-type mice show impairments in stathmin levels, changes in microtubule stability, and GluA2 localization. Blocking GluA2 endocytosis rescues memory deficits in stathmin mutant and aged wild-type mice. These findings demonstrate a role for microtubules in memory in young adult and aged individuals.
PMCID: PMC4137320  PMID: 25007915
14.  Comparison of Five Bacteriophages as Models for Viral Aerosol Studies 
Applied and Environmental Microbiology  2014;80(14):4242-4250.
Bacteriophages are perceived to be good models for the study of airborne viruses because they are safe to use, some of them display structural features similar to those of human and animal viruses, and they are relatively easy to produce in large quantities. Yet, only a few studies have investigated them as models. It has previously been demonstrated that aerosolization, environmental conditions, and sampling conditions affect viral infectivity, but viral infectivity is virus dependent. Thus, several virus models are likely needed to study their general behavior in aerosols. The aim of this study was to compare the effects of aerosolization and sampling on the infectivity of five tail-less bacteriophages and two pathogenic viruses: MS2 (a single-stranded RNA [ssRNA] phage of the Leviviridae family), Φ6 (a segmented double-stranded RNA [dsRNA] phage of the Cystoviridae family), ΦX174 (a single-stranded DNA [ssDNA] phage of the Microviridae family), PM2 (a double-stranded DNA [dsDNA] phage of the Corticoviridae family), PR772 (a dsDNA phage of the Tectiviridae family), human influenza A virus H1N1 (an ssRNA virus of the Orthomyxoviridae family), and the poultry virus Newcastle disease virus (NDV; an ssRNA virus of the Paramyxoviridae family). Three nebulizers and two nebulization salt buffers (with or without organic fluid) were tested, as were two aerosol sampling devices, a liquid cyclone (SKC BioSampler) and a dry cyclone (National Institute for Occupational Safety and Health two-stage cyclone bioaerosol sampler). The presence of viruses in collected air samples was detected by culture and quantitative PCR (qPCR). Our results showed that these selected five phages behave differently when aerosolized and sampled. RNA phage MS2 and ssDNA phage ΦX174 were the most resistant to aerosolization and sampling. The presence of organic fluid in the nebulization buffer protected phages PR772 and Φ6 throughout the aerosolization and sampling with dry cyclones. In this experimental setup, the behavior of the influenza virus resembled that of phages PR772 and Φ6, while the behavior of NDV was closer to that of phages MS2 and ΦX174. These results provide critical information for the selection of appropriate phage models to mimic the behavior of specific human and animal viruses in aerosols.
PMCID: PMC4068686  PMID: 24795379
15.  The association between negative affect and prescription opioid misuse in patients with chronic pain: The mediating role of opioid craving 
Over the past decade, considerable research has accumulated showing that chronic pain patients experiencing high levels of negative affect (i.e., anxiety, depression) are at increased risk for prescription opioid misuse. The primary objective of the present study was to examine the factors that underlie the association between negative affect (NA) and prescription opioid misuse among patients with chronic pain. In this study, 82 patients with chronic musculoskeletal pain being prescribed opioid medication completed the Current Opioid Misuse Measure (COMM), a well-validated self-report questionnaire designed to assess prescription opioid misuse. Patients were also asked to complete self-report measures of pain intensity, NA, and opioid craving. A bootstrapped multiple mediation analysis was used to examine the mediating role of patients’ pain intensity and opioid craving in the association between NA and prescription opioid misuse. Consistent with previous research, we found a significant association between NA and prescription opioid misuse. Interestingly, results revealed that opioid craving, but not pain intensity, mediated the association between NA and opioid misuse. Discussion addresses the potential psychological and neurobiological factors that might contribute to the inter-relationships between NA, opioid craving, and prescription opioid misuse in patients with pain. The clinical implications of our findings are also discussed.
PMCID: PMC3877217  PMID: 24295876
Chronic pain; prescription opioid misuse; negative affect; opioid craving
16.  Reliability and Validity of the Assessment for Disaster Engagement with Partners Tool (ADEPT) for Local Health Departments 
Public Health Reports  2014;129(Suppl 4):77-86.
This study presents reliability and validity findings for the Assessment for Disaster Engagement with Partners Tool (ADEPT), an instrument that can be used to monitor the frequency and nature of collaborative activities between local health departments (LHDs) and community-based organizations (CBOs) and faith-based organizations (FBOs) for disaster preparedness, response, and recovery.
We used formative research to develop the instrument by ranking LHDs according to their disaster outreach and engagement activities. We validated the scale through a 2011 national survey of disaster preparedness coordinators (n=273) working in LHDs. We reduced the original measure of 25 items to a final measure comprising 15 items with four dimensions: (1) communication outreach and coordination, (2) resource mobilization, (3) organizational capacity building, and (4) partnership development and maintenance. We used internal consistency reliability m correlation and factor analysis to validate the measure.
Using internal consistency reliability, we found reasonable inter-item reliability for the four hypothesized dimensions (Cronbach's alpha: 0.71–0.88). These four dimensions were confirmed through correlation and factor analysis (Varimax rotation).
Higher scores on all four dimensions of ADEPT for organizational respondents suggest that more activities were conducted for inter-organizational preparedness in those organizations than in organizations whose respondents had lower scores. This finding implies that organizations with higher ADEPT scores have more active relationships with CBOs/FBOs in the realm of preparedness, a key element for creating community resilience for emergencies and disaster preparedness.
PMCID: PMC4187310  PMID: 25355978
17.  The accurate assessment of small-angle X-ray scattering data 
A set of quantitative techniques is suggested for assessing SAXS data quality. These are applied in the form of a script, SAXStats, to a test set of 27 proteins, showing that these techniques are more sensitive than manual assessment of data quality.
Small-angle X-ray scattering (SAXS) has grown in popularity in recent times with the advent of bright synchrotron X-ray sources, powerful computational resources and algorithms enabling the calculation of increasingly complex models. However, the lack of standardized data-quality metrics presents difficulties for the growing user community in accurately assessing the quality of experimental SAXS data. Here, a series of metrics to quantitatively describe SAXS data in an objective manner using statistical evaluations are defined. These metrics are applied to identify the effects of radiation damage, concentration dependence and interparticle interactions on SAXS data from a set of 27 previously described targets for which high-resolution structures have been determined via X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy. The studies show that these metrics are sufficient to characterize SAXS data quality on a small sample set with statistical rigor and sensitivity similar to or better than manual analysis. The development of data-quality analysis strategies such as these initial efforts is needed to enable the accurate and unbiased assessment of SAXS data quality.
PMCID: PMC4304685  PMID: 25615859
SAXS data quality; SAXStats
18.  Mice lacking epidermal PPARγ exhibit a marked augmentation in photocarcinogenesis associated with increased UVB-induced apoptosis, inflammation and barrier dysfunction 
Recent studies suggest that peroxisome proliferator-activated receptor gamma (PPARγ) agonists may have cancer chemopreventive activity. Other studies have shown that loss of epidermal PPARγ results in enhanced chemical carcinogenesis in mice via unknown mechanisms. However, ultraviolet B (UVB) exposure represents the primary etiological agent for skin cancer formation and the role of PPARγ in photobiology and photocarcinogenesis is unknown. In previous studies, we demonstrated that UVB irradiation of cells results in the formation of oxidized glycerophosphocholines that exhibit PPARγ ligand activity. We therefore hypothesized that PPARγ would prove to be a chemopreventive target in photocarcinogenesis. We first showed that UVB irradiation of mouse skin causes generation of PPARγ agonist species in vivo. We then generated SKH-1 hairless, albino mice deficient in epidermal Pparg (Pparg−/−epi) using a cytokeratin 14 driven Cre-LoxP strategy. Using a chronic model of UVB photocarcinogenesis, we next showed that Pparg−/−epi mice exhibit an earlier onset of tumor formation, increased tumor burden, and tumor progression. Increased tumor burden in Pparg−/−epi mice was accompanied by a significant increase in epidermal hyperplasia and p53 positive epidermal cells in surrounding skin lacking tumors. Following acute UVB irradiation, Pparg−/−epi mice exhibited an augmentation of both UVB-induced caspase 3/7 activity and inflammation. Increased apoptosis and inflammation was also observed following treatment with the PPARγ antagonist GW9662. With chronic UVB irradiation, Pparg−/−epi mice exhibited a sustained increase in erythema and transepidermal water loss relative to wildtype littermates. This suggests that PPARγ agonists could have possible chemopreventive activity in non-melanoma skin cancer.
PMCID: PMC4280796  PMID: 22467332
19.  Semantic Language as a Mechanism Explaining the Association between ADHD Symptoms and Reading and Mathematics Underachievement 
Journal of abnormal child psychology  2012;40(8):1339-1349.
ADHD is associated with academic underachievement, but it remains unclear what mechanism accounts for this association. Semantic language is an underexplored mechanism that provides a developmental explanation for this association. The present study will examine whether semantic language deficits explain the association between ADHD and reading and mathematics underachievement, taking into account alternative explanations for associations, including verbal working memory (WM) impairments, as well as specificity of effects to inattentive and hyperactive-impulsive ADHD symptom domains. Participants in this cross-sectional study were 546 children (54% male) ages six to twelve (M=9.77, SD=1.49). ADHD symptoms were measured via maternal and teacher report during structured interviews and on standardized rating forms. Children completed standardized semantic language, verbal WM, and academic testing. Semantic language fully mediated the ADHD-reading achievement association and partially mediated the ADHD-mathematics achievement association. Verbal WM also partially mediated the ADHD-mathematics association but did not mediate the ADHD-reading achievement association. Results generalized across inattentive and hyperactive-impulsive ADHD symptom domains. Semantic language explained the association between ADHD and reading underachievement and partially explained the association between ADHD and mathematics underachievement. Together, language impairment and WM fully explained the association between ADHD and reading underachievement, in line with developmental models suggesting that language and WM conjointly influence the development of attention and subsequent academic achievement. This work has implication for the development of tailored interventions for academic underachievement in children with ADHD.
PMCID: PMC4278425  PMID: 22661106
ADHD; academic achievement; semantic language; working memory
20.  Diversity in Pathways to Common Childhood Disruptive Behavior Disorders 
Journal of abnormal child psychology  2012;40(8):1223-1236.
Oppositional-Defiant Disorder (ODD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are highly comorbid, a phenomenon thought to be due to shared etiological factors and mechanisms. Little work has attempted to chart multiple-level-of-analysis pathways (i.e., simultaneously including biological, environmental, and trait influences) to ODD and ADHD, the goal of the present investigation. 559 children/adolescents (325 boys) between the ages of 6 and 18 participated in a multi-stage, comprehensive diagnostic procedure. 148 were classified as ODD; 309 were classified as ADHD, based on parent, teacher, and clinician ratings. Children provided buccal or salivary samples of DNA, assayed for select markers in DRD4 and 5HTT. Parents completed the Alabama Parenting Questionnaire and the California Q-Sort. Children completed the Child Perception of Interparental Conflict Scale. Correlational associations consistent with multiple-level-of-analysis pathways to ODD and ADHD emerged. For ODD, children with the short allele of the 5HTT promoter polymorphism had higher neuroticism and ODD symptoms regardless of level of self-blame in relation to inter-parental conflict, whereas children without this allele had more ODD symptoms only in the context of more self-blame for inter-parental conflict. For ADHD (and ODD), children homozygous for the long allele of DRD4 120bp insertion polymorphism had lower conscientiousness when exposed to inconsistent parenting, whereas children without this genotype were more resilient to effects of inconsistent discipline on conscientiousness. Thus, ODD and ADHD appear to demonstrate somewhat distinct correlational associations between etiological factors and mechanisms consistent with pathway models using a multiple-level-of-analysis approach.
PMCID: PMC4274781  PMID: 22584505
disruptive behavior disorders; ODD; ADHD; mediation; gene by environment interaction
21.  Autovaccination Confers Protection against Devriesea agamarum Associated Septicemia but Not Dermatitis in Bearded Dragons (Pogona vitticeps) 
PLoS ONE  2014;9(12):e113084.
Devrieseasis caused by Devriesea agamarum is a highly prevalent disease in captive desert lizards, resulting in severe dermatitis and in some cases mass mortality. In this study, we assessed the contribution of autovaccination to devrieseasis control by evaluating the capacity of 5 different formalin-inactivated D. agamarum vaccines to induce a humoral immune response in bearded dragons (Pogona vitticeps). Each vaccine contained one of the following adjuvants: CpG, incomplete Freund's, Ribi, aluminium hydroxide, or curdlan. Lizards were administrated one of the vaccines through subcutaneous injection and booster vaccination was given 3 weeks after primo-vaccination. An indirect ELISA was developed and used to monitor lizard serological responses. Localized adverse effects following subcutaneous immunization were observed in all but the Ribi adjuvanted vaccine group. Following homologous experimental challenge, the incomplete Freund's as well as the Ribi vaccine were observed to confer protection in bearded dragons against the development of D. agamarum associated septicemia but not against dermatitis. Subsequently, two-dimensional gelelectrophoresis followed by immunoblotting and mass spectrometry was conducted with serum obtained from 3 lizards that showed seroconversion after immunisation with the Ribi vaccine. Fructose-bisphosphate aldolase and aldo-keto reductase of D. agamarum reacted with serum from the latter lizards. Based on the demonstrated seroconversion and partial protection against D. agamarum associated disease following the use of formalin-inactivated vaccines as well as the identification of target antigens in Ribi vaccinated bearded dragons, this study provides promising information towards the development of a vaccination strategy to control devrieseasis in captive lizard collections.
PMCID: PMC4257540  PMID: 25479609
22.  l-Methionine Placental Uptake 
Reproductive Sciences  2013;20(12):1492-1507.
Our aim was to investigate the influence of gestational diabetes mellitus (GDM) and GDM-associated conditions upon the placental uptake of 14C-l-methionine (14C-l-Met). The 14C-l-Met uptake by human trophoblasts (TBs) obtained from normal pregnancies (normal trophoblast [NTB] cells) is mainly system l-type amino acid transporter 1 (LAT1 [L])-mediated, although a small contribution of system y+LAT2 is also present. Comparison of 14C-l-Met uptake by NTB and by human TBs obtained from GDM pregnancies (diabetic trophoblast [DTB] cells) reveals similar kinetics, but a contribution of systems A, LAT2, and b0+ and a greater contribution of system y+LAT1 appears to exist in DTB cells. Short-term exposure to insulin and long-term exposure to high glucose, tumor necrosis factor-α, and leptin decrease 14C-l-Met uptake in a human TB (Bewo) cell line. The effect of leptin was dependent upon phosphoinositide 3-kinase, extracellular-signal-regulated kinase 1/2 (ERK/MEK 1/2), and p38 mitogen-activated protein kinase. In conclusion, GDM does not quantitatively alter 14C-l-Met placental uptake, although it changes the nature of transporters involved in that process.
PMCID: PMC3817665  PMID: 23653387
gestational diabetes; placenta; transport; l-methionine
23.  Can the presence of endoscopic high-risk stigmata be predicted before endoscopy? A multivariable analysis using the RUGBE database 
Medical management of acute nonvariceal upper gastrointestinal bleeding begins with appropriate risk stratification based on currently validated clinical and pre-endoscopic scoring tools. Although these tools have contributed to advances in diagnostic accuracy and shorter hospital stays, data supporting their utility in predicting high-risk stigmata (HRS) have been lacking. Patients with HRS would benefit most from early endoscopy; accordingly, the authors attempted to identify laboratory and clinical predictors of HRS using information from a national registry.
Many aspects in the management of acute upper gastrointestinal bleeding rely on pre-esophagogastroduodenoscopy (EGD) stratification of patients likely to exhibit high-risk stigmata (HRS); however, data predicting the presence of HRS are lacking.
To determine clinical and laboratory predictors of HRS at the index EGD in patients presenting with acute upper gastrointestinal bleeding using retrospective data from a validated national database – the Canadian Registry in Upper Gastrointestinal Bleeding and Endoscopy registry.
Relevant clinical and laboratory parameters were evaluated. HRS was defined as spurting, oozing, nonbleeding visible vessel or adherent clot after vigorous irrigation. Multivariable modelling was used to identify predictors of HRS including age, sex, hematemesis, use of antiplatelet agents, American Society of Anesthesiologists (ASA) classification, nasogastric tube aspirate, hemoglobin level and elapsed time from the onset of bleeding to EGD.
Of the 1677 patients (mean [± SD] age 66.2±16.8 years; 38.3% female), 28.7% had hematemesis, 57.8% had an ASA score of 3 to 5, and the mean hemoglobin level was 96.8±27.3 g/L. The mean time from presentation to endoscopy was 22.2±37.5 h. The best fitting multivariable model included the following significant predictors: ASA score 3 to 5 (OR 2.16 [95% CI 1.71 to 2.74]), a shorter time to endoscopy (OR 0.99 [95% CI 0.98 to 0.99]) and a lower initial hemoglobin level (OR 0.99 [95% CI 0.99 to 0.99]).
A higher ASA score, a shorter time to endoscopy and lower initial hemoglobin level all significantly predicted the presence of endoscopic HRS. These criteria could be used to improve the optimal selection of patients requiring more urgent endoscopy.
PMCID: PMC4072229  PMID: 24945183
Bleeding; Endoscopy; High-risk; Stigmata; Stratification
24.  Three-Dimensional Holographic Refractive-Index Measurement of Continuously Flowing Cells in a Microfluidic Channel 
Physical review applied  2014;1:014002.
Refractive index of biological specimens is a source of intrinsic contrast that can be explored without any concerns of photobleaching or harmful effects caused by extra contrast agents. In addition, RI contains rich information related to the metabolism of cells at the cellular and subcellular levels. Here, we report a no-moving parts approach that provides three-dimensional refractive index maps of biological samples continuously flowing in a microfluidic channel. Specifically, we use line illumination and off-axis digital holography to record the angular spectra of light scattered from flowing samples at high speed. Applying the scalar diffraction theory, we obtain accurate RI maps of the samples from the measured spectra. Using this method, we demonstrate label-free 3-D imaging of live RKO human colon cancer cells and RPMI8226 multiple myeloma cells, and obtain the volume, dry mass and density of these cells from the measured 3-D refractive index maps. Our results show that the reported method, alone or in combination with the existing flow cytometry techniques, promises as a quantitative tool for stain-free characterization of large number of cells.
PMCID: PMC4236915  PMID: 25419536
25.  Tenascin-X promotes epithelial-to-mesenchymal transition by activating latent TGF-β 
The Journal of Cell Biology  2014;205(3):409-428.
The matrix glycoprotein tenascin-X regulates the bioavailability of mature TGF-β through an α11β1 integrin–dependent mechanism that promotes epithelial-to-mesenchymal transition.
Transforming growth factor β (TGF-β) isoforms are secreted as inactive complexes formed through noncovalent interactions between the bioactive TGF-β entity and its N-terminal latency-associated peptide prodomain. Extracellular activation of the latent TGF-β complex is a crucial step in the regulation of TGF-β function for tissue homeostasis. We show that the fibrinogen-like (FBG) domain of the matrix glycoprotein tenascin-X (TNX) interacts physically with the small latent TGF-β complex in vitro and in vivo, thus regulating the bioavailability of mature TGF-β to cells by activating the latent cytokine into an active molecule. Activation by the FBG domain most likely occurs through a conformational change in the latent complex and involves a novel cell adhesion–dependent mechanism. We identify α11β1 integrin as a cell surface receptor for TNX and show that this integrin is crucial to elicit FBG-mediated activation of latent TGF-β and subsequent epithelial-to-mesenchymal transition in mammary epithelial cells.
PMCID: PMC4018787  PMID: 24821840

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