Faculty Bibliography

OBJECTIVE: To evaluate the long-term effects of methylphenidate imediate-release (MPH-IR), and to confirm the efficacy established in previous meta-analyses of short-term studies. METHOD: Published and unpublished studies in which participants were treated with MPH-IR for 12 weeks or more were searched. Pooled effect sizes from these studies were computed with the DerSimonian and Laird random-effect model. Meta-regression analysis was conducted to estimate covariates associated with treatment effects. RESULTS: Seven studies were included. Pooled parents ratings for inattention and hyperactivity/impulsivity resulted in standardized mean difference (SMD) = 0.96 (95% confidence interval [CI] = [0.60, 1.32]) and SMD = 1.12 (95% CI = [0.85, 1.39]), respectively; pooled teachers ratings showed SMD = 0.98 (95% CI = [0.09, 1.86]) for inattention and SMD = 1.25 (95% CI = [0.7, 1.81]) for hyperactivity/impulsivity. No evidence of association of any covariates with treatment effect was detected in the meta-regression. CONCLUSION: MPH-IR is efficacious for childhood ADHD for periods longer than 12 weeks.

Objective: To examine the level of agreement between self- and observer-reported ratings of ADHD symptoms and executive function (EF) behaviors in adults with moderate to severe ADHD and EF deficits. Method: During a 10-week, randomized, double-blind, placebo-controlled study, the effect of lisdexamfetamine dimesylate (LDX) on EF was assessed by self-report and informant report (Behavior Rating Inventory of Executive Function-Adult Version), and ADHD symptoms were assessed by clinician- and informant-rated scales (ADHD Rating Scale IV with adult prompts and Conners' Adult ADHD Rating Scales-Observer Report: Short Version, respectively). Post hoc analysis used Pearson correlations to assess relationships between self- and informant-rated EF and clinician- and informant-rated ADHD symptoms. Results: Correlations between self-ratings versus informant ratings and clinician versus informant ratings were greater at Week 10/early termination (EF: placebo [0.5231-0.6085], LDX [0.3543-0.5167]; ADHD symptoms: placebo [0.4169], LDX [0.4004]) versus baseline (EF: placebo [0.3208-0.5023], LDX [0.2852-0.3439]; ADHD symptoms: placebo [0.1511], LDX [-0.0408]). Conclusion: LDX improved EF and ADHD symptoms, based on participant, informant, and clinician ratings. Increased rater agreement over time may reflect improved symptom awareness. (J. of Att. Dis. XXXX; XX(X) XX-XX).

Objectives: (a) Evaluate the efficacy and duration of effect of lisdexamfetamine dimesylate (LDX) in adult ADHD. (b) Assess the reliability and validity of the Adult ADHD Medication Smoothness of Effect Scale (AMSES) and Adult ADHD Medication Rebound Scale (AMRS). Method: Adults (N = 40) with ADHD were treated with LDX for up to 12 weeks. The primary efficacy measure was the ADHD Rating Scale (ADHD-RS). The psychometric properties of the AMSES and AMRS are analyzed and compared with the ADHD-RS, ADHD Self-Report Scale (ASRS) v1.1 Symptom Checklist, and Time-Sensitive ADHD Symptom Scale (TASS). Results: ADHD-RS scores were significantly improved with LDX. The AMSES and AMRS had high internal consistency and were correlated with the ADHD-RS, ASRS v1.1 Symptom Checklist, and TASS. Conclusion: LDX is effective in treating adult ADHD and has a smooth drug effect throughout the day with limited symptom rebound. The AMSES and AMRS are valid and reliable measures. (J. of Att. Dis. 2013; XX(X) 1-XX).

UNLABELLED:Ketogenic diet is an established and effective non-pharmacologic treatment for drug-resistant epilepsy. Ketogenic diet represents the treatment of choice for GLUT-1 deficiency syndrome and pyruvate dehydrogenase complex deficiency. Infantile spasms, Dravet syndrome and myoclonic-astatic epilepsy are epilepsy syndromes for which ketogenic diet should be considered early in the therapeutic pathway. Recently, clinical indications for ketogenic diet have been increasing, as there is emerging evidence regarding safety and effectiveness. Specifically, ketogenic diet response has been investigated in refractory status epilepticus and encephalopathy with status epilepticus during sleep. New targets in neuropharmacology, such as mitochondrial permeability transition, are being studied and might lead to using it effectively in other neurological diseases. But, inefficient connectivity and impaired ketogenic diet proposal limit ideal availability of this therapeutic option. Ketogenic diet in Italy is not yet considered as standard of care, not even as a therapeutic option for many child neurologists and epileptologists. CONCLUSIONS:The aim of this review is to revisit ketogenic diet effectiveness and safety in order to highlight its importance in drug-resistant epilepsy and other neurological disorders. WHAT IS KNOWN/BACKGROUND:• Ketogenic diet efficacy is now described in large case series, with adequate diet compliance and side effects control. • Ketogenic diet is far from being attempted as a first line therapy. Its availability varies worldwide. What is New: • New pharmacological targets such as mitochondrial permeability transition and new epileptic syndromes and etiologies responding to the diet such as refractory status epilepticus are being pointed out. • Ketogenic diet can function at its best when used as a tailor-made therapy. Fine tuning is crucial.

Touch between mother and infant plays an important role in development starting from birth. Cross-cultural differences surrounding rearing practices have an influence on parent-infant interaction, including types of touch used and the development of emotional regulation. This study was designed to investigate maternal touch and infant emotional regulation in infant-mother dyads from Ecuador (n=25) and Hispanic dyads from the United States (US) (n=26). Mothers and their 4-month-old full-term infants participated in the Still Face Paradigm. Second-by-second coding of maternal touch and infant affect was completed. Overall the analyses showed that Ecuadorian mothers used more nurturing and accompaniment touch and less attention seeking touch than US Hispanic mothers during the pre-stressor (baseline) episode. Lagged multilevel models were used to investigate the effect of the different types of touch on infant emotional regulation in the groups for the episodes. The data suggest that playful touch had a significant increase in infant affect, whereas accompaniment and attention-seeking touch had a significant decrease in infant affect. Overall, this study provides support for the role of touch in mother-infant synchronicity in relation to infant's emotional regulation. Identifying touch that is more calming is important to foster emotional regulation in infancy, which can have important implications for development.

The binding of drugs to metalloenzymes is an intricate process that involves several interactions, including binding of the drug to the enzyme active site metal, as well as multiple interactions between the drug and the enzyme residues. In order to determine the free energy contribution of Zn(2+) binding by known metalloenzyme inhibitors without the other interactions, valid active site zinc structural mimetics must be formed and binding studies need to be performed in biologically relevant conditions. The potential of each of five ligands to form a structural mimetic with Zn(2+) was investigated in buffer using Isothermal Titration Calorimetry (ITC). All five ligands formed strong 1 : 1 (ligand : Zn(2+)) binary complexes. The complexes were used in further ITC experiments to study their interaction with 8-hydroxyquinoline (8-HQ) and/or acetohydroxamic acid (AHA), two bidentate anionic zinc-chelating enzyme inhibitors. It was found that tetradentate ligands were not suitable for creating zinc structural mimetics for inhibitor binding in solution due to insufficient coordination sites remaining on Zn(2+). A stable binary complex, [Zn(BPA)](2+), which was formed by a tridentate ligand, bis(2-pyridylmethyl)amine (BPA), was found to bind one AHA in buffer or a methanol : buffer mixture (60 : 40 by volume) at pH 7.25 or one 8-HQ in the methanol : buffer mixture at pH 6.80, making it an effective structural mimetic for the active site of zinc metalloenzymes. These results are consistent with the observation that metalloenzyme active site zinc ions have three residues coordinated to them, leaving one or two sites open for inhibitors to bind. Our findings indicate that Zn(BPA)X2 can be used as an active site structural mimetic for zinc metalloenzymes for estimating the free energy contribution of zinc binding to the overall inhibitor active site interactions. Such use will help aid in the rational design of inhibitors to a variety of zinc metalloenzymes.

BACKGROUND:The purpose of this study was to investigate whether dependent personality and/or general personality dimensions might explain the strong relationships between separation anxiety disorder (Sep-AD) and three other anxiety disorders (agoraphobia, panic disorder and social anxiety disorder) in individuals with obsessive compulsive disorder (OCD). METHODS:Using data from 509 adult participants collected during the OCD Collaborative Genetic Study, we used logistic regression models to evaluate the relationships between Sep-AD, dependent personality score, general personality dimensions and three additional anxiety disorders. RESULTS:The dependent personality score was strongly associated with Sep-AD and the other anxiety disorders in models adjusted for age at interview, age at onset of OC symptoms and worst ever OCD severity score. Several general personality dimensions, especially neuroticism, extraversion and conscientiousness, were also related to Sep-AD and the other anxiety disorders. Sep-AD was not independently related to these anxiety disorders, in multivariate models including general personality and dependent personality disorder scores. CONCLUSIONS:The results suggest that Sep-AD in childhood and these other anxiety disorders in adulthood are consequences of dependent personality disorder (for agoraphobia and panic disorder) or introversion (for social phobia). It is unknown whether these results would be similar in a non-OCD sample.

PURPOSE:To develop a system prognostic of outcome in those undergoing allogeneic hematopoietic cell transplantation (allo HCT) for myelodysplastic syndrome (MDS). PATIENTS AND METHODS:We examined 2,133 patients with MDS undergoing HLA-matched (n = 1,728) or -mismatched (n = 405) allo HCT from 2000 to 2012. We used a Cox multivariable model to identify factors prognostic of mortality in a training subset (n = 1,151) of the HLA-matched cohort. A weighted score using these factors was assigned to the remaining patients undergoing HLA-matched allo HCT (validation cohort; n = 577) as well as to patients undergoing HLA-mismatched allo HCT. RESULTS:Blood blasts greater than 3% (hazard ratio [HR], 1.41; 95% CI, 1.08 to 1.85), platelets 50 × 10(9)/L or less at transplantation (HR, 1.37; 95% CI, 1.18 to 1.61), Karnofsky performance status less than 90% (HR, 1.25; 95% CI, 1.06 to 1.28), comprehensive cytogenetic risk score of poor or very poor (HR, 1.43; 95% CI, 1.14 to 1.80), and age 30 to 49 years (HR, 1.60; 95% CI, 1.09 to 2.35) were associated with increased hazard of death and assigned 1 point in the scoring system. Monosomal karyotype (HR, 2.01; 95% CI, 1.65 to 2.45) and age 50 years or older (HR, 1.93; 95% CI, 1.36 to 2.83) were assigned 2 points. The 3-year overall survival after transplantation in patients with low (0 to 1 points), intermediate (2 to 3), high (4 to 5) and very high (≥ 6) scores was 71% (95% CI, 58% to 85%), 49% (95% CI, 42% to 56%), 41% (95% CI, 31% to 51%), and 25% (95% CI, 4% to 46%), respectively (P < .001). Increasing score was predictive of increased relapse (P < .001) and treatment-related mortality (P < .001) in the HLA-matched set and relapse (P < .001) in the HLA-mismatched cohort. CONCLUSION:The proposed system is prognostic of outcome in patients undergoing HLA-matched and -mismatched allo HCT for MDS.

Sexual aggression and violence against women (VAM) are not only social problems; they are mental health problems. Women who experience sexual trauma often express disruptions in emotional and cognitive processes, some of which lead to depression and post-traumatic stress disorder (PTSD). Animal models of neurogenesis and learning suggest that social yet aggressive interactions between a pubescent female and an adult male can disrupt processes of learning related to maternal care, which in turn reduce survival of new neurons in the female hippocampus. Mental and Physical (MAP) Training is a novel clinical intervention that was translated from neurogenesis research. The intervention, which combines meditation and aerobic exercise, is currently being used to help women learn to recover from traumatic life experiences, especially those related to sexual violence and abuse.