Faculty Bibliography

Antibody (Ab)-dependent cellular cytotoxicity (ADCC) is thought to potentially play a role in vaccine-induced protection from HIV-1. The characteristics of such antibodies remain incompletely understood. Furthermore, correlates between ADCC and HIV-1 immune status are not clearly defined. We screened the sera of 20 HIV-1-positive (HIV-1(+)) patients for ADCC. Normal human peripheral blood mononuclear cells were used to derive HIV-infected CD4(+) T cell targets and autologous, freshly isolated, natural killer (NK) cells in a novel assay that measures granzyme B (GrB) and HIV-1-infected CD4(+) T cell elimination (ICE) by flow cytometry. We observed that complex sera mediated greater levels of ADCC than anti-HIV-1 envelope glycoprotein (Env)-specific monoclonal antibodies and serum-mediated ADCC correlated with the amount of IgG and IgG1 bound to HIV-1-infected CD4(+) T cells. No correlation between ADCC and viral load, CD4(+) T cell count, or neutralization of HIV-1(SF162) or other primary viral isolates was detected. Sera pooled from clade B HIV-1(+) individuals exhibited breadth in killing targets infected with HIV-1 from clades A/E, B, and C. Taken together, these data suggest that the total amount of IgG bound to an HIV-1-infected cell is an important determinant of ADCC and that polyvalent antigen-specific Abs are required for a robust ADCC response. In addition, Abs elicited by a vaccine formulated with immunogens from a single clade may generate a protective ADCC response in vivo against a variety of HIV-1 species. Increased understanding of the parameters that dictate ADCC against HIV-1-infected cells will inform efforts to stimulate ADCC activity and improve its potency in vaccinees.

Knowledge of the long-term course of childhood Attention Deficit Hyperactivity Disorder (ADHD) is limited by the lack of longitudinal studies that extend beyond the third decade. Information about the later adult status of children with ADHD, one of the most common disorders of childhood, is important since the disorder is widely reported to persist through adulthood. Findings from a prospective 30 year longitudinal study addresses the extended course of ADHD. We report on the functional and psychiatric outcome of 135 males at mean age 41, diagnosed with ADHD at mean age of 8 (range, 6-12 years), and 136 non-ADHD males matched for age and SES, interviewed blindly by trained clinicians. As expected, ADHD at follow-up was significantly elevated in probands (P < 0.001). When the number of ADHD criteria is reduced, as recommended for ADHD in adults, rates rise in both groups. Other disorders significantly more prevalent in probands were:antisocial personality disorder (APD), drug (non-alcohol) disorders, and nicotine dependence. Childhood ADHD was not associated with elevated rates of mood or anxiety disorders in adulthood. Findings pertaining to other functional domains also will be presented. The extended clinical course of ADHD appears diagnostically specific, consisting of ADHD, APD and drug (non-alcohol) use disorders, supporting the validity of the ADHD diagnosis

OBJECTIVE:Clinical observations have suggested therapeutic effects for omega-3 fatty acids (O3FA) in Tourette's disorder (TD), but no randomized, controlled trials have been reported. In a placebo-controlled trial, we examined the efficacy of O3FA in children and adolescents with TD.METHODS:Thirty-three children and adolescents (ages 6-18) with TD were randomly assigned, double-blind, to O3FA or placebo for 20 weeks. O3FA consisted of combined eicosapentaenoic acid and docosahexaenoic acid. Placebo was olive oil. Groups were compared by using (1) intent-to-treat design, with the last-observation-carried-forward controlling for baseline measures and attention-deficit/hyperactivity disorder via (a) logistic regression, comparing percentage of responders on the primary Yale Global Tic Severity Scale (YGTSS)-Tic and secondary (YGTSS-Global and YGTSS-Impairment) outcome measures and (b) analysis of covariance; and (2) longitudinal mixed-effects models.RESULTS:At end point, subjects treated with O3FA did not have significantly higher response rates or lower mean scores on the YGTSS-Tic (53% vs 38%; 15.6 +/- 1.6 vs 17.1 +/- 1.6, P > .1). However, significantly more subjects on O3FA were considered responders on the YGTSS-Global measure (53% vs 31%, P = .05) and YGTSS-Impairment measure (59% vs 25%, P < .05), and mean YGTSS-Global scores were significantly lower in the O3FA-treated group than in the placebo group (31.7 +/- 2.9 vs 40.9 +/- 3.0, P = .04). Obsessive-compulsive, anxiety, and depressive symptoms were not significantly affected by O3FA. Longitudinal analysis did not yield group differences on any of the measures.CONCLUSIONS:O3FA did not reduce tic scores, but it may be beneficial in reduction of tic-related impairment for some children and adolescents with TD. Limitations include the small sample and the possible therapeutic effects of olive oil.

CONTEXT: Anhedonia, a core symptom of major depressive disorder (MDD) and highly variable among adolescents with MDD, may involve alterations in the major inhibitory amino acid neurotransmitter system of gamma-aminobutyric acid (GABA). OBJECTIVE: To test whether anterior cingulate cortex (ACC) GABA levels, measured by proton magnetic resonance spectroscopy, are decreased in adolescents with MDD. The associations of GABA alterations with the presence and severity of anhedonia were explored. DESIGN: Case-control, cross-sectional study using single-voxel proton magnetic resonance spectroscopy at 3 T. SETTING: Two clinical research divisions at 2 teaching hospitals. PARTICIPANTS: Twenty psychotropic medication-free adolescents with MDD (10 anhedonic, 12 female, aged 12-19 years) with episode duration of 8 weeks or more and 21 control subjects group matched for sex and age. MAIN OUTCOME MEASURES: Anterior cingulate cortex GABA levels expressed as ratios relative to unsuppressed voxel tissue water (w) and anhedonia scores expressed as a continuous variable. RESULTS: Compared with control subjects, adolescents with MDD had significantly decreased ACC GABA/w (t = 3.2; P < .003). When subjects with MDD were categorized based on the presence of anhedonia, only anhedonic patients had decreased GABA/w levels compared with control subjects (t = 4.08; P < .001; P(Tukey) < .001). Anterior cingulate cortex GABA/w levels were negatively correlated with anhedonia scores for the whole MDD group (r = -0.50; P = .02), as well as for the entire participant sample including the control subjects (r = -0.54; P < .001). Anterior cingulate cortex white matter was also significantly decreased in adolescents with MDD compared with controls (P = .04). CONCLUSIONS: These findings suggest that GABA, the major inhibitory neurotransmitter in the brain, may be implicated in adolescent MDD and, more specifically, in those with anhedonia. In addition, use of a continuous rather than categorical scale of anhedonia, as in the present study, may permit greater specificity in evaluating this important clinical feature

BACKGROUND: Little is known about the prevalence of self-reported photosensitivity (PS) and its effects on quality of life in a US cutaneous lupus population. OBJECTIVE: We sought to determine the prevalence of self-reported PS among a cutaneous lupus population and to examine its impact on quality of life. METHODS: A total of 169 patients with lupus were interviewed about PS symptoms and completed the modified Skindex-29+3, a quality-of-life survey. A complete skin examination was conducted and the Cutaneous Lupus Erythematosus Disease Area and Severity Index was completed. RESULTS: In all, 68% of patients reported some symptoms of PS. The PS group (those who reported a history of and current PS) scored worse on PS-related items of the modified Skindex-29+3 and had higher cutaneous disease activity as determined by the Cutaneous Lupus Erythematosus Disease Area and Severity Index. Patients with PS had worse symptoms and emotions and experienced significant functional impairments compared with patients who had cutaneous lupus without PS. LIMITATIONS: This study was done at a single referral center. CONCLUSIONS: Self-reported PS is very common among patients with cutaneous lupus and is associated with significant impairments related to symptoms, emotions, and daily functioning.

CONTEXT: Volumetric studies have reported relatively decreased cortical thickness and gray matter volumes in adults with attention-deficit/hyperactivity disorder (ADHD) whose childhood status was retrospectively recalled. We present, to our knowledge, the first prospective study combining cortical thickness and voxel-based morphometry in adults diagnosed as having ADHD in childhood. OBJECTIVES: To test whether adults with combined-type childhood ADHD exhibit cortical thinning and decreased gray matter in regions hypothesized to be related to ADHD and to test whether anatomic differences are associated with a current ADHD diagnosis, including persistent vs remitting ADHD. DESIGN: Cross-sectional analysis embedded in a 33-year prospective follow-up at a mean age of 41.2 years. SETTING: Research outpatient center. PARTICIPANTS: We recruited probands with ADHD from a cohort of 207 white boys aged 6 to 12 years. Male comparison participants (n = 178) were free of ADHD in childhood. We obtained magnetic resonance images in 59 probands and 80 comparison participants (28.5% and 44.9% of the original samples, respectively). MAIN OUTCOME MEASURES: Whole-brain voxel-based morphometry and vertexwise cortical thickness analyses. RESULTS: The cortex was significantly thinner in ADHD probands than in comparison participants in the dorsal attentional network and limbic areas (false discovery rate < 0.05, corrected). In addition, gray matter was significantly decreased in probands in the right caudate, right thalamus, and bilateral cerebellar hemispheres. Probands with persistent ADHD (n = 17) did not differ significantly from those with remitting ADHD (n = 26) (false discovery rate < 0.05). At uncorrected P < .05, individuals with remitting ADHD had thicker cortex relative to those with persistent ADHD in the medial occipital cortex, insula, parahippocampus, and prefrontal regions. CONCLUSIONS: Anatomic gray matter reductions are observable in adults with childhood ADHD, regardless of the current diagnosis. The most affected regions underpin top-down control of attention and regulation of emotion and motivation. Exploratory analyses suggest that diagnostic remission may result from compensatory maturation of prefrontal, cerebellar, and thalamic circuitry

Background: Children and adolescents who seek medical treatment for persistent physical distress often suffer from co-occurring anxiety disorders. Treatment options for this impaired population are limited. This study tests the feasibility and potential efficacy of a cognitive-behavioral intervention targeting pain and anxiety for youth with impairing functional physical symptoms and anxiety disorders presenting to pediatricians for medical care. Methods: Children and adolescents (aged 8-16) experiencing somatic complaints, without an explanatory medical disorder (i.e., functional), were recruited from primary care and specialty (gastroenterologists and cardiologists) pediatricians. Forty children, primarily with gastrointestinal symptoms, who met criteria for a co-occurring anxiety disorder, were randomly assigned to a cognitive-behavioral treatment addressing pain and anxiety, Treatment of Anxiety and Physical Symptoms (TAPS), or to a waiting list control. Results: TAPS was found to be an acceptable treatment for this population and was superior to the waiting list condition. Eighty percent of children in TAPS were rated as treatment responders by independent evaluators compared with none of the controls. Overall, self- and parent ratings indicated reductions in children's somatic discomfort and anxiety following intervention. TAPS participants maintained clinical gains 3 months following treatment. Conclusions: The study supports the feasibility and preliminary efficacy of a cognitive-behavioral intervention targeting co-occurring physical distress and anxiety in youth presenting for medical treatment. Such an approach has the potential to exert broad impact on children's dysfunction and to minimize exposure to invasive, ineffective, and costly medical procedures and treatments. Depression and Anxiety, 2011. (c) 2011 Wiley-Liss, Inc

Among adults, anxiety related to asthma has been acknowledged to influence asthma self-management. However, it has not been addressed in pediatric samples and there have been no measures developed to assess asthma-related anxiety in youth or parents. The objective of this study was to develop and test the psychometric properties of novel instruments assessing asthma-related anxiety: the Youth Asthma-Related Anxiety Scale (YAAS) and Parent Asthma-Related Anxiety Scale (PAAS). Scale items were analyzed for content validity. We determined the factor structure using exploratory factor analysis and tested the scales' psychometric properties with 285 Hispanic and African American early adolescents with uncontrolled asthma (mean age=12.8) and their parents (n=230) who participated in a larger randomized control trial testing the efficacy of an asthma intervention; control group families (134 youth and 103 parents) provided follow-up data to assess temporal stability. Both the YAAS and PAAS contained 2 factors with Cronbach alpha coefficients ranging from 0.75 to 0.90. The 2 factors, anxiety about asthma severity and about disease-related restrictions, were highly correlated within each measure. The measures displayed content and construct validity and demonstrated moderate temporal stability over 2-3 months (range: 0.36-0.42). The YAAS and PAAS have adequate psychometric properties and can meaningfully contribute to the assessment of asthma-related anxiety in adolescents and their parents, filling a clinical need in this population.