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BACKGROUND: Recording of event-related potentials (ERPs) from the scalp is a noninvasive technique reflecting the sensory and cognitive processes associated with attention tasks. Attention deficit hyperactivity disorder (ADHD) is a disorder involving deficits in attention and behavioral control. The aim of this study was to investigate the difference in ERPs between normal children and those with ADHD. METHODS: We examined 50 children with ADHD and 51 age-matched controls. All children with ADHD met the full criteria for ADHD according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). The auditory oddball paradigm was applied, and event-related long-latency components (N1, P2, N2 and P3) from Fz, Cz and Pz were measured in each test subject. RESULTS: Children with ADHD showed a significantly longer latency and a lower amplitude of P3 compared to normal control children (p < 0.01). Delayed N2 latency at the Pz electrode was shown in children with ADHD compared to normal controls (p < 0.01). No differences in other ERP indices were found between children with ADHD and controls. When divided into four age groups, the latency of P3 was significantly increased in all age groups and a significantly smaller amplitude in P3 over the central region was found in children with ADHD > 10 years of age (p < 0.05). CONCLUSION: We found that the endogenous ERPs (P3 and N2) were significantly affected in children with ADHD, compared to exogenous ERPs (N1 and P2). Increased latency of P3 suggests a slower processing speed, and decreased P3 amplitude is interpreted as disruption of inhibitory control in children with ADHD. These results indicate a neurocognitive abnormality in ADHD, as presented by a reduction in ERP response.

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OBJECTIVES: To identify the determinants of adherence to immediate-release (IR) methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder (ADHD); to examine the impact of adherence on ADHD-related symptoms; and to compare the efficacy, adherence, and side effects of IR methylphenidate and osmotic release oral system (OROS) methylphenidate. METHOD: This national survey, involving 12 hospitals, consisted of 2 phases of assessment. Treatment adherence in 240 (39.5%) of the 607 children aged 5 to 16 years with a clinical diagnosis of DSM-IV ADHD enrolled in the study was poor (defined as missing >or= 1 dose of ADHD medication a day and on 2 days or more during school days). Children with poor adherence at phase 1 were able to switch to OROS methylphenidate, while adherents remained on the IR variant. We reassessed 124 poor adherents who switched to OROS methylphenidate. The global ADHD severity, parent-child interaction, classroom behavior, academic performance, and side effects of the child subjects were evaluated by investigators. Parents completed the rating scales about the ADHD-related symptoms. The study began in April 2005 and was completed in February 2006. RESULTS: Determinants for poor adherence included older age, later onset of ADHD, family history of ADHD, higher paternal education level, and multi-dose administration. Mental retardation and treatment at medical centers were inversely related to poor adherence. Overall, poor adherence was associated with more severe ADHD-related symptoms by comparison to good adherence. Similar side effect profile, superior adherence, and improved efficacy were demonstrated in intra-individual comparison of the OROS and IR methylphenidate forms. CONCLUSION: Given that poor adherence to medication may be an important reason for suboptimal outcome in ADHD treatment, physicians should ensure adherence with therapy before adjusting dosage or switching medication. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00460720.

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Hepatitis C virus (HCV) is a positive-strand RNA virus that encodes a helicase required for viral replication. Although HCV does not replicate through a DNA intermediate, HCV helicase unwinds both RNA and DNA duplexes. An X-ray crystal structure of the HCV helicase complexed with (dU)(8) has been solved, and the substrate-amino acids interactions within the catalytic pocket were shown. Among these, residues W501 and V432 were reported to have base stacking interactions and to be important for the unwinding function of HCV helicase. It has been hypothesized that specific interactions between the enzyme and substrate in the catalytic pocket are responsible for the substrate specificity phenotype. We therefore mutagenized W501 and V432 to investigate their role in substrate specificity in HCV helicase. Replacement of W501, but not V432, with nonaromatic residues resulted in complete loss of RNA unwinding activity, whereas DNA unwinding activity was largely unaffected. The loss of unwinding activity was fully restored in the W501F mutant, indicating that the aromatic ring is crucial for RNA helicase function. Analysis of ATPase and nucleic acid binding activities in the W501 mutant enzymes revealed that these activities are not directly responsible for the substrate specificity phenotype. Molecular modeling of the enzyme-substrate interaction at W501 revealed a putative pi-facial hydrogen bond between the 2'-OH of ribose and the aromatic tryptophan ring. This evidence correlates with biochemical results suggesting that the pi-facial bond may play an important role in the RNA unwinding activity of the HCV NS3 protein.

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Poliovirus proteinase 2A(pro) is an essential enzyme involved in cleavages of viral and cellular proteins during the infectious cycle. Evidence has been obtained that 2A(pro) is also involved in genome replication. All enteroviruses have a negatively charged cluster of amino acids at their C terminus (E(E)/(D)(E)/(D)AMEQ-NH(2)), a common motif suggesting function. When aligned with enterovirus sequences, the 2A(pro) proteinase of human rhinovirus type 2 (HRV2) has a shorter C terminus (EE.Q:-NH(2)) and, indeed, the HRV2 2A(pro) cannot substitute for poliovirus 2A(pro) to yield a viable chimeric virus. Here evidence is provided that the C-terminal cluster of amino acids plays an unknown role in poliovirus genome replication. Deletion of the EEAME sequence from poliovirus 2A(pro) is lethal without significantly influencing proteinase function. On the other hand, addition of EAME to HRV2 2A(pro), yielding a C terminus of this enzyme of EEEAMEQ:, stimulated RNA replication of a poliovirus/HRV2 chimera 100-fold. The novel role of the C-terminal sequence motif is manifested at the level of protein function, since silent mutations in its coding region had no effect on virus proliferation. Poliovirus type 1 Mahoney 2A(pro) could be provided in trans to rescue the lethal deletion EEAME in the poliovirus variant. Encapsidation studies left open the question of whether the C terminus of poliovirus 2A(pro) is involved in particle formation. It is concluded that the C terminus of poliovirus 2A(pro) is an essential domain for viral RNA replication but is not essential for proteolytic processing.

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