Faculty Bibliography

Tourette syndrome is a childhood onset neurodevelopmental disorder characterized by multiple motor and vocal tics. Although many youth experience attenuation or even remission of tics in adolescence and young adulthood, some individuals experience persistent tics, which can be debilitating or disabling. Most patients also have 1 or more psychiatric comorbid disorders, such as attention-deficit/hyperactivity disorder or obsessive-compulsive disorder. Treatment is multimodal, including both pharmacotherapy and cognitive-behavioral treatment, and requires disentanglement of tics and the comorbid symptoms.

Tourette syndrome is a childhood onset neurodevelopmental disorder characterized by multiple motor and vocal tics. Although many youth experience attenuation or even remission of tics in adolescence and young adulthood, some individuals experience persistent tics which can be debilitating or disabling. The majority of patients also have one or more psychiatric comorbid disorders, such as attention deficit hyperactivity disorder and/or obsessive-compulsive disorder. Treatment is multimodal, including both pharmacotherapy and cognitive behavioral treatment, and requires disentanglement of tics and the comorbid symptoms. Although the only two formally approved medications in the United States are haloperidol and pimozide, these treatments are generally not used as first-line interventions due to their significant potential for adverse effects. The alpha-adrenoceptor agonists guanfacine and clonidine have an established evidence base for both efficacy and tolerability, and are usually recommended as initial pharmacotherapy. Atypical neuroleptics, such as aripiprazole or risperidone, are typically used if the alpha-adrenoceptor agonists are ineffective or intolerable. However, many other pharmacological agents reviewed in this manuscript have been studied as treatment alternatives.

OBJECTIVE: To examine the role of 17beta-estradiol in the regulation of the autoantigen tripartite motif-containing protein 21 (TRIM-21) in patients with systemic lupus erythematosus (SLE). METHODS: Monocytes isolated from healthy control subjects and patients with SLE were stimulated with 17beta-estradiol and/or the estrogen receptor alpha (ERalpha) antagonist methyl-piperidino-pyrazole dihydrochloride. TRIM-21, ERalpha, and CREMalpha expression was determined by real-time polymerase chain reaction (PCR) analysis. MatInspector software was used to identify putative binding sites within the TRIM-21 promoter. ERalpha binding to the TRIM-21 gene promoter region in monocytes was analyzed by chromatin immunoprecipitation (ChIP) assay. TRIM-21 and interferon regulatory factor 3 protein levels were analyzed by Western blotting. RESULTS: Real-time PCR analysis demonstrated a role of estrogen in the regulation of TRIM-21 expression in monocytes, which correlated positively with ERalpha gene expression in patients with SLE. Investigations into the human TRIM-21 promoter revealed the presence of an estrogen response element, with ChIP assays confirming ERalpha binding to this site. Studies into estrogen-induced TRIM-21 expression revealed a hyperresponsiveness of SLE patients to 17beta-estradiol, which led to the enhanced levels of TRIM-21 observed in these individuals. CONCLUSION: Our results demonstrate a role of estrogen in the regulation of TRIM-21 expression through an ERalpha-dependent mechanism, a pathway that we observed to be overactive in SLE patients. Treatment of monocytes with an ERalpha antagonist abrogated estrogen-induced TRIM-21 expression and, as a consequence, decreased the expression of interleukin-23. These findings identify TRIM-21 as a novel ERalpha-regulated gene and provide novel insights into the link between estrogen and the molecular pathogenesis of SLE.

To explore behavioral differences as possible cultural factors in presentation of psychiatric comorbidity in two clinically referred, consecutively ascertained samples of youth with Tourette's disorder (TD) from New York and Buenos Aires. Subjects were evaluated between 2002 and 2010 at the Tics and Tourette's Clinical and Research Program at the New York University Child Study Center in New York and the Interdisciplinary Center for Tourette's, Obsessive Compulsive Disorder (OCD) and Associated Disorders (CITTTA)/Institute of Cognitive Psychology (INECO) in Buenos Aires. Demographic, diagnostic, tic severity (Yale Global Tic Severity Scale; YGTSS), clinical (Child Behavior Check List-Parent version; CBCL), and global functioning (Global Assessment of Functioning; GAF) data were compared using descriptive statistics. The sample included 111 subjects ages 6-17 years, who met DSM-IV-TR diagnostic criteria for TD. Findings revealed that the BA sample (n = 35) was significantly older at initial evaluation at the tic specialty clinic, and had higher frequency of oppositional defiant disorder (ODD), mood and non-OCD anxiety disorders than the NY sample (n = 76). There were no differences in gender distribution, age at tic onset or TD diagnosis, tic severity, proportion with current diagnoses of OCD/OC behavior or attention deficit hyperactivity disorder (ADHD), CBCL internalizing, externalizing, or total problems scores, YGTSS scores, or GAF scores. The observed similarities in demographic features, clinical presentation, rates of ADHD and OCD/OCB, and global impairment may reflect similar phenomenology and illness-related characteristics of TD in these referred youth. Differences in age at initial specialty clinic evaluation and rates of ODD, mood and non-OCD anxiety disorders may need further exploration before they may be considered to reflect cultural factors. Because of these limitations (e.g. small sample size), these results can be regarded only as preliminary.