Applying an Established Exposure Response Prevention Protocol for Young People With Tourette Syndrome in an Intensive, Group Format: A Feasibility Study.

BACKGROUND: The motor and vocal tics that characterise Tourette syndrome are stigmatizing and impact on quality of life. Behavioural interventions such as Exposure Response Prevention or Comprehensive Behavioural Interventions for Tics are first line treatment for Tourette syndrome, but availability is limited. This study is the first to explore the impact of an established manualised Exposure Response Prevention treatment protocol, developed for individual therapy, but here uniquely delivered intensively, to a group. METHODS: A naturalistic study comprised of a consecutive series of children (N = 20), aged 8-16 years (M = 12, SD = 2.17) were offered Exposure Response Prevention in one of two groups, delivered in series within a specialist clinic. Young people received the equivalent of 12 sessions (matching the manualised individual protocol). RESULTS: The YGTSS and Giles de la Tourette Syndrome Quality of Life Scale for Children and Adolescents (Satisfaction Scale) showed significant improvement following treatment with moderate to large effect sizes. Thirty-five percent of children demonstrated a reliable improvement on the YGTSS Global Tic Severity score. CONCLUSIONS: These data suggest an established Exposure Response Prevention protocol can be delivered in an intensive, group setting with a positive clinical outcome. Replication in a randomized controlled trial is an important next step.

Combining nucleoside analogues to achieve recognition of oligopurine tracts by triplex-forming oligonucleotides at physiological pH.

We have used DNase I footprinting to examine DNA triple helix formation at a 12 base pair oligopurine.oligopyrimidine sequence, using oligonucleotides that contain combinations of 2'-aminoethoxy-5-(3-aminoprop-1-ynyl)uridine (bis-amino-U, BAU) and 3-methyl-2-aminopyridine (MeP) in place of T and C, respectively. This combination acts cooperatively to enable high affinity triple helix formation at physiological pH. The affinity depends on the number of substitutions and their arrangement; oligonucleotides in which these analogues are evenly distributed throughout the third strand bind much better than those in which they are clustered together.

Stable recognition of TA interruptions by triplex forming oligonucleotides containing a novel nucleoside.

We have prepared the 2'-aminoethoxy derivative of the S nucleoside ((2AE)S) and incorporated it into triplex-forming oligonucleotides for recognition of TA interruptions within a target oligopurine tract. Fluorescence melting, UV melting, and DNase I footprinting experiments show that (2AE)S has greater affinity than G or S for a single TA interruption. Stable triplexes are formed at pH 6.0 at an 18-mer target site containing two TA interruptions, even though this contains eight C(+).GC triplets. Although (2AE)S and S produce stable triplexes at TA interruptions, they also interact with other base pairs, in particular, CG, although the selectivity for TA improves with increased pH.( 2AE)S is the best nucleoside described so far for recognition of TA within a triple-helix target.

Determining the origin of the stabilization of DNA by 5-aminopropynylation of pyrimidines.

DNA duplexes are stabilized by aminopropynyl modification of pyrimidines at the 5 position. A combination of thermodynamic analyses as a function of ionic strength, NMR, and molecular modeling has been applied to determine the origin of the stabilization. UV melting studies of a dodecamer bearing one, two, or three nonadjacent modified dU and dC and of a single dU(8) in the Dickerson-Drew dodecamer revealed that the modifications are essentially additive in terms of T(m), DeltaG, and DeltaH, and there is little difference between dU and dC. The free energy change was parsed into electrostatic and nonelectrostatic components, which showed a significant contribution from charge interactions at physiological ionic strength but also a nonelectrostatic contribution that arises in part from hydration. NMR spectroscopy of the modified Dickerson-Drew dodecamer revealed that the conformation of the duplexes is not significantly altered by the modifications, though (31)P NMR shows that the positive charge may affect ionic interactions with the oxygen atoms of the neighboring phosphates. The modified duplex showed significant hydration in both major and minor grooves. The single strands were also analyzed by NMR, which showed evidence of significant stacking interactions in the modified oligonucleotide. Parsing the energy contribution has shown that electrostatics and hydration can produce substantial increases in thermodynamic stability without significant changes in the conformation of the duplex state. These considerations have significance for the design of oligonucleotides used for hybridization.

Selectivity and affinity of triplex-forming oligonucleotides containing 2'-aminoethoxy-5-(3-aminoprop-1-ynyl)uridine for recognizing AT base pairs in duplex DNA.

We have used DNase I footprinting, fluorescence and ultraviolet (UV) melting experiments and circular dichroism to demonstrate that, in the parallel triplex binding motif, 2'-aminoethoxy-5-(3-aminoprop-1-ynyl)uridine (bis-amino-U, BAU) has very high affinity for AT relative to all other Watson-Crick base pairs in DNA. Complexes containing two or more substitutions with this nucleotide analogue are stable at pH 7.0, even though they contain several C.GC base triplets. These modified triplex-forming oligonucleotides retain exquisite sequence specificity, with enhanced discrimination against YR base pairs (especially CG). These properties make BAU a useful base analogue for the sequence-specific creation of stable triple helices at pH 7.0.