Biomedical subjects

Kelly Sullivan

Publications and source records attributed to Kelly Sullivan.

7 recordsLinked to original sources

PubMed2007

Behavioural equivalents of anxiety in children with fragile X syndrome: parent and teacher report.

BACKGROUND: Identifying many of the diagnostic criteria for anxiety and depression in individuals with intellectual disability (ID) can be challenging because they may be unable to recognize and communicate their emotional experiences accurately. The purpose of this study is to identify behavioural equivalents of anxiety in children with fragile X syndrome (FXS), the leading inherited cause of ID. METHODS: Parents and teachers of 43 children (aged 6-14 years) with full mutation FXS completed two standardized questionnaires on children's problem behaviour and psychiatric symptoms. Items from the questionnaires thought to be possible behavioural equivalents of anxiety were identified and grouped into four domains: Avoidance Behaviours - Confrontational; Avoidance Behaviours - Non-confrontational; Anxiety Continuum Behaviours; and Behavioural Dysregulation. The mean rating for the four groups of items was used to predict the children's status for exhibiting significant problems with anxiety as defined by the Diagnostic and Statistical Manual of Mental Disorders-oriented Anxiety Subscale from the problem behaviour scale. RESULTS: The predictor variables classified 81% (parent rating) and 86% (teacher rating) of the children correctly. Avoidance Behaviours - Confrontational and Avoidance Behaviours - Non-confrontational (teacher rating) and Anxiety Continuum Behaviours (parent and teacher rating) made unique contributions to the models. CONCLUSIONS: Children who are unable to identify and communicate that they worry about general day-to-day events may exhibit more observable behaviours resembling active and passive avoidance (e.g. arguing, avoiding difficult tasks, staring off) or have specific phobias and compulsions. These findings suggest that there are behavioural equivalents for anxiety disorder in children with FXS and, more generally, support the notion of behavioural equivalents in ID.

Adolescent↗

PubMed2006

ADHD symptoms in children with FXS.

Parent- and teacher-report of attention-deficit/hyperactivity disorder (ADHD) symptoms were examined using problem behavior and DSM-IV symptom inventory questionnaires for 63 children with full mutation fragile X syndrome (FXS) and 56 children without disabilities matched on mental age (MA). Prevalence rates of ADHD symptoms varied depending on type of measure (problem behavior or DSM-IV criteria), subscale (ADHD-inattentive or ADHD-hyperactive), scoring method (continuous T-scores or categorical scores based on DSM-IV algorithm), and rater (parent or teacher). Overall, 54-59% of boys with FXS met diagnostic behavioral criteria for either ADHD-inattentive type only, ADHD-hyperactive type only, or ADHD-combined type based on parent or teacher report. Boys with FXS were rated as having clinically high scores or met diagnostic criteria at higher rates than expected for the general population and had higher raw scores than their MA-matched peers. Parent ratings of boys with FXS resulted in higher ADHD-inattentive type and ADHD-hyperactive type T-scores than teachers. Boys who were rated as meeting DSM-IV criteria were more likely to be taking psychotropic medication and to have younger mental ages. Parents were substantially more likely than teachers to rate boys as meeting DSM-IV criteria for ADHD-inattentive type, while teachers were only slightly more likely than parents to rate boys as meeting DSM-IV criteria for ADHD-hyperactive type. Teachers were more likely than parents to rate boys as meeting DSM-IV criteria for ADHD when boys had lower levels of FMRP.

Adolescent↗

PubMed2006

Aplindore (DAB-452), a high affinity selective dopamine D2 receptor partial agonist.

The pharmacology of aplindore (DAB-452) was characterized in CHO-K1 cells stably transfected with the human dopamine D(2) receptor short isoform (CHO-D(2s)) and in a behavioral model for post-synaptic agonism in rats. In [(3)H]-spiperone competition binding studies, aplindore showed high affinity for dopamine D(2) and D(3) receptors and low affinity for the dopamine D(4), serotonin (5-HT)(1A), 5-HT(2) receptors and the alpha1-adrenoceptor. The high potency partial agonist activity of aplindore was demonstrated in [(35)S]guanosine 5'-O-(3-thiotriphosphate) ([(35)S]GTPgammaS) binding, extracellular signal-regulated kinase (ERK)-phosphorylation and intracellular calcium flux assay using fluorometric plate reader ([Ca(2+)](i)-FLIPR) format. The [Ca(2+)](i)-FLIPR assay was conducted with CHO-D(2S) receptor cells also stably expressing chimeric G(alphaq/o)-proteins. In all assay modalities, the potencies and intrinsic activities of aplindore were lower than dopamine and higher than aripiprazole. In contrast to the [(35)S]GTPgammaS binding and ERK-phosphorylation assays, the [Ca(2+)](i)-FLIPR assay was able to detect the low partial agonist activity of SDZ 208-912. In unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, aplindore induced contralateral turning, which was blocked by the dopamine D(2) receptor antagonist raclopride. The dopamine D(2) receptor selective partial agonist profile of aplindore suggests that it should be effective for the treatment of dopaminergic-based disorders, such as schizophrenia and Parkinson's disease.

Animals↗

PubMed2006

Pituitary adenylate cyclase-activating peptide (PACAP) induces differentiation in the neuronal F11 cell line through a PKA-dependent pathway.

PACAP is a peptide with neuroprotective activity, which induces adenylate cyclase and protein kinase A (PKA) activity. PACAP has also been shown to induce neurite outgrowth in PC12 cells and dorsal root ganglion (DRG) neurons. Here, we report that exogenous PACAP38 promotes neurite outgrowth in the F11 neuroblastoma/dorsal DRG hybrid cell line. Using an automated microscopy system, we show that PACAP38 induces a 170-fold increase in neurite length, with an EC50 of 3.1 nM, compared to 3.7 microM for forskolin and 143.4 microM for dibutyril cyclic AMP (dbcAMP). PACAP38 induced a 4-fold increase in the level of phosphorylation of cAMP-responsive element binding protein (CREB) in F11 cells with an EC50 of 130 pM. In contrast a peptide related to PACAP, vasoactive intestinal peptide (VIP) failed to induce CREB phosphorylation or neurite outgrowth in F11 cells. Addition of the nonselective phosphodiesterase inhibitor, isobutyl methylxanthine (IBMX) increased the potency of PACAP at inducing neurite outgrowth by ten-fold. The PKA inhibitor, H89, was a potent inhibitor of PACAP38-induced neurite outgrowth. The delta-opioid receptor agonist, SNC 80, did not inhibit PACAP-induced neurogenesis even though it did reduce CREB phosphorylation. In contrast to previous studies in PC12 cells, PACAP38 failed to show MEK1 activation in F11 cells. PACAP is upregulated in DRG neurons as a result of injury, and F11 cells provide an easily accessible in vitro model for understanding mechanisms underlying PACAP differentiation and neurogenesis.

1-Methyl-3-isobutylxanthine↗

PubMed2005

Disruption of ShcA signaling halts cell proliferation--characterization of ShcC residues that influence signaling pathways using yeast.

Shc adapter proteins are thought to regulate cellular proliferation, differentiation and apoptosis by activating the SOS-Grb2-RAS-MAPK signaling cascade. Using the small hairpin RNA (shRNA) technique, we found that decreasing ShcA mRNA reduced the proliferative ability of HEK293 mammalian culture cells. We then recapitulated phosphorylation-dependent Shc-Grb2 complex formation in Saccharomyces cerevisiae. Immunoprecipitation followed by Western analysis demonstrated that activated TrkB, composed of the intracellular domain of TrkB fused to glutathione S-transferase (GST-TrkB(ICD)), promoted the association of ShcC and Grb2 in yeast. The Ras-recruitment system (RRS), in which a myristoylated (Myr)-bait and son of sevenless (hSOS)-prey are brought together to complement the defective Ras-cAMP pathway in a thermosensitive cdc25H mutant yeast strain, was used to validate a phenotypic assay. Yeast cells transformed with both Myr-ShcC and hSOS-Grb2 (referred to as scheme 1) or Myr-Grb2 and hSOS-ShcC (scheme 2) did not grow at non-permissive temperature; the additional transformation of GST-TrkB(ICD) enabled growth. GST-TrkB(ICD) also enabled growth with hSOS-Grb2 and either Myr-ShcA or Myr-SHP2. Mutational analysis of TrkB showed that its kinase activity was essential for complementation, while its docking site for Shc proteins was not. Mutational analysis of ShcC showed that the PTB and SH2 domains were not essential for complementation but phosphorylation at Y304 in the CH1 domain was. Phosphorylation at Y304 could not be substituted by an acidic amino acid. The RRS provides a genetic system to probe Shc proteins and potentially identify member specific protein partners and pharmacological reagents.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Mapping nonverbal IQ in young boys with fragile X syndrome.

This study examines the developmental changes in nonverbal intellectual functioning evident in males with fragile X syndrome (FXS) measured by the Leiter International Performance Scales-Revised (Leiter-R). The Leiter-R provides both IQ scores and associated growth scores which permit the examination of both age-based IQ scores and overall intellectual growth. Participants were 45 males with full mutation FXS and ranged in age from 4.0 to 13.8 years. Each child was assessed annually using the Leiter-R as part of a larger longitudinal battery for an average of 3.5 assessments per child and a range of 2-6 assessments, representing a total of 156 assessment occasions. Longitudinal analyzes of Leiter scores consisted primarily of hierarchical linear modeling, with the impact of chronological age, maternal education, fragile X mental retardation 1 protein (FMRP), autistic behaviors also being assessed. Findings revealed a significant linear decline in nonverbal IQ scores, with no effects of maternal education, autistic behaviors, or FMRP on mean level or rate of change in IQ scores over time. The decline slowed significantly around 8 years of age, but scores continued to decline into the 12th year of age. In contrast, a significant linear increase was observed in Leiter-R growth scores, which was negatively influenced by autistic behaviors. The rate of increase did not change over time, and neither mean level nor rate of increase was influenced by maternal education or FMRP levels. These findings suggest that declines in IQ are the result of steady, but suboptimal intellectual growth, rather than a true deterioration in overall intellectual functioning.

Adolescent↗

PubMed2005

Preliminary (3 years) experience with smooth wall silicone gel implants for primary breast augmentation.

The goal of this study is to obtain data concerning the incidence of capsular contracture and reoperation rates in patients having primary breast augmentation utilizing modern low-bleed smooth-wall silicone gel implants. Data were collected retrospectively and consisted of 44 patients who underwent primary breast augmentation using smooth silicone gel implants (Mentor Corporation) in the period between 2001 and 2003. Of the 131 patients identified, 44 patients fit the criteria of primary breast augmentation. Secondary cases and primary augmentation with mastopexy were excluded from this study. This group of patients is still followed, and the data are being updated periodically. A total of 44 patients underwent primary breast augmentation. Average age was 32 years (range, 19-57). Average follow-up was 34 months (range, 28-40). Average operative time was 52 minutes. The inframammary incision was used in 65% of patients and the areolar incision in 35%. The subglandular position was used in 35% of patients versus the submuscular position in 65%. Nine patients (20%) developed capsular contracture. Six patients (13.6%) had Baker 3 capsular contracture, which required revision. Four of the 9 patients with capsular contracture had implants placed in the submuscular space and 5 in the subglandular position. Relative to the implant position, 4 patients (9%) with implants placed in the submuscular position developed capsular contracture. Relative to the subglandular position, 5 patients (11.3%) with implants placed in the subglandular position developed capsular contracture. Eight patients (19%) required implant revision, 6 patients for capsular contracture, and 2 patients requested size change. Preliminary data from this study indicate that the use of the new generation of gel implants yields less capsular contracture, as well as decreased revision rates. Subglandular placement of gel implants did not significantly increase the risk of capsular contracture. Longer follow-up and multicenter studies are still needed to confirm these findings. This cumulative data could challenge the current status of gel implant moratorium imposed by the incidence of capsular contracture and revision rates.

Adult↗