Search

Importance: Surgical site infections increase patient morbidity and health care costs. The Centers for Disease Control and Prevention emphasize improved basic preventive measures to reduce bacterial transmission and infections among patients undergoing surgery., Objective: To assess whether improved basic preventive measures can reduce perioperative Staphylococcus aureus transmission and surgical site infections., Design, Setting, and Participants: This randomized clinical trial was conducted from September 20, 2018, to September 20, 2019, among 19 surgeons and their 236 associated patients at a major academic medical center with a 60-day follow-up period. Participants were a random sample of adult patients undergoing orthopedic total joint, orthopedic spine, oncologic gynecological, thoracic, general, colorectal, open vascular, plastic, or open urological surgery requiring general or regional anesthesia. Surgeons and their associated patients were randomized 1:1 via a random number generator to treatment group or to usual care. Observers were masked to patient groupings during assessment of outcome measures., Interventions: Sustained improvements in perioperative hand hygiene, vascular care, environmental cleaning, and patient decolonization efforts., Main Outcomes and Measures: Perioperative S aureus transmission assessed by the number of isolates transmitted and the incidence of transmission among patient care units (primary) and the incidence of surgical site infections (secondary)., Results: Of 236 patients (156 [66.1%] women; mean [SD] age, 57 [15] years), 106 (44.9%) and 130 (55.1%) were allocated to the treatment and control groups, respectively, received the intended treatment, and were analyzed for the primary outcome. Compared with the control group, the treatment group had a reduced mean (SD) number of transmitted perioperative S aureus isolates (1.25 [2.11] vs 0.47 [1.13]; P = .002). Treatment reduced the incidence of S aureus transmission (incidence risk ratio; 0.56; 95% CI, 0.37-0.86; P = .008; with robust variance clustering by surgeon: 95% CI, 0.42-0.76; P < .001). Overall, 11 patients (4.7%) experienced surgical site infections, 10 (7.7%) in the control group and 1 (0.9%) in the treatment group. Transmission was associated with an increased risk of surgical site infection (8 of 73 patients [11.0%] with transmission vs 3 of 163 [1.8%] without; risk ratio, 5.95; 95% CI, 1.62-21.86; P = .007). Treatment reduced the risk of surgical site infection (hazard ratio, 0.12; 95% CI, 0.02-0.92; P = .04; with clustering by surgeon: 95% CI, 0.03-0.51; P = .004)., Conclusions and Relevance: Improved basic preventive measures in the perioperative arena can reduce S aureus transmission and surgical site infections., Trial Registration: ClinicalTrials.gov Identifier: NCT03638947.

The mechanisms underpinning attentional deficits are only partially understood. Here we ask if shifts in a child's field of view (FOV) act as a mediator between symptoms of attention deficit hyperactivity disorder (ADHD) and associated cognitive anomalies, particularly in attentional processes. Real time measurement of shifts in FOV were obtained on 85 children (mean age 9.4 (SD 1.9) years; 45 with DSM 5-defined ADHD) as they completed the continuous performance task in a "virtual classroom". We extracted measures reflecting focused and selective attention across the task, along with diffusion modelling of latent cognitive processes of information uptake, response conservativeness and non-decision time. Mediation analyses showed that shifts in FOV partially mediated the relationship between hyperactive impulsive symptoms and both poor focused attention and information uptake. Performance accuracy decreased and shifts in FOV increased during the task, but these changes over time did not differ by symptom severity. Employing virtual reality and mediation analysis, we implicate shifts in FOV as a mechanism linking symptoms of ADHD and deficits in focused attention and in the gathering of information to make decisions. The identification of mediating mechanisms might provide new targets for intervention.

Objective: Since its introduction to the psychiatric nomenclature in 2013, research on avoidant/restrictive food intake disorder (ARFID) has proliferated highlighting lack of clarity in how ARFID is defined., Method: In September 2018, a small multi-disciplinary pool of international experts in feeding disorder and eating disorder clinical practice and research convened as the Radcliffe ARFID workgroup to consider operationalization of DSM-5 ARFID diagnostic criteria to guide research in this disorder., Results: By consensus of the Radcliffe ARFID workgroup, ARFID eating is characterized by food avoidance and/or restriction, involving limited volume and/or variety associated with one or more of the following: weight loss or faltering growth (e.g., defined as in anorexia nervosa, or by crossing weight/growth percentiles); nutritional deficiencies (defined by laboratory assay or dietary recall); dependence on tube feeding or nutritional supplements (≥50% of daily caloric intake or any tube feeding not required by a concurrent medical condition); and/or psychosocial impairment., Conclusions: This article offers definitions on how best to operationalize ARFID criteria and assessment thereof to be tested in existing clinical populations and to guide future study to advance understanding and treatment of this heterogeneous disorder., (© 2019 Wiley Periodicals, Inc.)

Background: While the neuroanatomic substrates of symptoms of attention deficit hyperactivity disorder (ADHD) have been investigated, less is known about the neuroanatomic correlates of cognitive abilities pertinent to the disorder, particularly in adults. Here we define the neuroanatomic correlates of key cognitive abilities and determine if there are associations with histories of psychostimulant medication., Methods: We acquired neuroanatomic magnetic resonance imaging data from 264 members of 60 families (mean age 29.5; s.d. 18.4, 116 with ADHD). Using linear mixed model regression, we tested for associations between cognitive abilities (working memory, information processing, intelligence, and attention), symptoms and both cortical and subcortical volumes., Results: Symptom severity was associated with spatial working memory (t = -3.77, p = 0.0002), processing speed (t = -2.95, p = 0.004) and a measure of impulsive responding (t = 2.19, p = 0.03); these associations did not vary with age (all p &gt; 0.1). Neuroanatomic associations of cognition varied by task but centered on prefrontal, lateral parietal and temporal cortical regions, the thalamus and putamen. The neuroanatomic correlates of ADHD symptoms overlapped significantly with those of working memory (Dice's overlap coefficient: spatial, p = 0.003; verbal, p = 0.001) and information processing (p = 0.02). Psychostimulant medication history was associated with neither cognitive skills nor with a brain-cognition relationships., Conclusions: Diagnostic differences in the cognitive profile of ADHD does not vary significantly with age; nor were cognitive differences associated with psychostimulant medication history. The neuroanatomic substrates of working memory and information overlapped with those for symptoms within these extended families, consistent with a pathophysiological role for these cognitive skills in familial ADHD.

The column in this issue is supplied by Whitney Sharp, D.O., and Juan Jose Olivero, M.D. Dr. Sharp is chief medical resident in internal medicine at Houston Methodist Hospital and earned her Doctor of Osteopathic Medicine degree at Nova Southeastern University in Fort Lauderdale, Florida. Dr. Olivero is a nephrologist at Houston Methodist Hospital and a member of the hospital's Nephrology Training Program. He obtained his medical degree from the University of San Carlos School of Medicine in Guatemala, Central America, and completed his residency and nephrology fellowship at Baylor College of Medicine in Houston, Texas.

Genome-wide association studies (GWASs) are unraveling the genetics of adult brain neuroanatomy as measured by cross-sectional anatomic magnetic resonance imaging (aMRI). However, the genetic mechanisms that shape childhood brain development are, as yet, largely unexplored. In this study we identify common genetic variants associated with childhood brain development as defined by longitudinal aMRI. Genome-wide single nucleotide polymorphism (SNP) data were determined in two cohorts: one enriched for attention-deficit/hyperactivity disorder (ADHD) (LONG cohort: 458 participants; 119 with ADHD) and the other from a population-based cohort (Generation R: 257 participants). The growth of the brain's major regions (cerebral cortex, white matter, basal ganglia, and cerebellum) and one region of interest (the right lateral prefrontal cortex) were defined on all individuals from two aMRIs, and a GWAS and a pathway analysis were performed. In addition, association between polygenic risk for ADHD and brain growth was determined for the LONG cohort. For white matter growth, GWAS meta-analysis identified a genome-wide significant intergenic SNP (rs12386571, P = 9.09 × 10 -9 ), near AKR1B10. This gene is part of the aldo-keto reductase superfamily and shows neural expression. No enrichment of neural pathways was detected and polygenic risk for ADHD was not associated with the brain growth phenotypes in the LONG cohort that was enriched for the diagnosis of ADHD. The study illustrates the use of a novel brain growth phenotype defined in vivo for further study., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

The study of monozygotic twins discordant for attention deficit hyperactivity disorder can elucidate mechanisms that contribute to the disorder, which affects ~7% of children. First, using in vivo neuroanatomic imaging on 14 pairs of monozygotic twins (mean age 9.7, s.d. 1.9 years), we found that discordance for the disorder is mirrored by differing dimensions of deep brain structures (the striatum and cerebellum), but not the cerebral cortex. Next, using whole-blood DNA from the same twins, we found a significant enrichment of epigenetic differences in genes expressed in these 'discordant' brain structures. Specifically, there is differential methylation of probes lying in the shore and shelf and enhancer regions of striatal and cerebellar genes. Notably, gene sets pertaining to the cerebral cortex (which did not differ in volume between affected and unaffected twins) were not enriched by differentially methylated probes. Genotypic differences between the twin pairs-such as copy number and rare, single-nucleotide variants-did not contribute to phenotypic discordance. Pathway analyses of the genes implicated by the most differentially methylated probes implicated γ-aminobutyric acid (GABA), dopamine and serotonin neurotransmitter systems. The study illustrates how neuroimaging can help guide the search for epigenomic mechanisms in neurodevelopmental disorders.

We have a limited understanding of why many children with attention deficit hyperactivity disorder do not outgrow the disorder by adulthood. Around 20-30% retain the full syndrome as young adults, and about 50% show partial, rather than complete, remission. Here, to delineate the neurobiology of this variable outcome, we ask if the persistence of childhood symptoms into adulthood impacts on the brain's functional connectivity. We studied 205 participants followed clinically since childhood. In early adulthood, participants underwent magnetoencephalography (MEG) to measure neuronal activity directly and functional MRI (fMRI) to measure hemodynamic activity during a task-free period (the "resting state"). We found that symptoms of inattention persisting into adulthood were associated with disrupted patterns of typical functional connectivity in both MEG and fMRI. Specifically, those with persistent inattention lost the typical balance of connections within the default mode network (DMN; prominent during introspective thought) and connections between this network and those supporting attention and cognitive control. By contrast, adults whose childhood inattentive symptoms had resolved did not differ significantly from their never-affected peers, both hemodynamically and electrophysiologically. The anomalies in functional connectivity tied to clinically significant inattention centered on midline regions of the DMN in both MEG and fMRI, boosting confidence in a possible pathophysiological role. The findings suggest that the clinical course of this common childhood onset disorder impacts the functional connectivity of the adult brain., Competing Interests: The authors declare no conflict of interest., (Published under the PNAS license.)

Objective: Understanding the neural processes tied to the adult outcome of childhood attention deficit hyperactivity disorder (ADHD) could guide novel interventions to improve its clinical course. It has been argued that normalization of prefrontal cortical activity drives remission from ADHD, while anomalies in subcortical processes are "fixed," present even in remission. Using multimodal neuroimaging of inhibitory processes, the authors tested these hypotheses in adults followed since childhood, contrasting remitted against persistent ADHD., Method: Adult participants (persistent ADHD, N=35; remit-ted ADHD, N=47; never affected, N=99) were scanned with functional MRI (fMRI) (N=85), magnetoencephalography (N=33), or both (N=63) during a response inhibition task., Results: In fMRI analyses, during inhibition, right caudate anomalies reflected a childhood ADHD history and were present even among those who remitted. By contrast, differences related to adult outcome emerged in cortical (right inferior frontal and inferior parietal/precuneus) and cerebellar regions. The persistent ADHD group showed under-activation, whereas the remitted ADHD group did not differ significantly from the never-affected group. Magnetoencephalography showed that the association between adult symptom severity and prefrontal neuronal activity was confined to the time window covering the act of inhibition (300 ms-350 ms). Group differences in cerebellar and parietal neuronal activity occurred during the time window of performance monitoring processes (500 ms-600 ms)., Conclusions: By combining fMRI and magnetoencephalography, the location and time window of neuronal activity that underpins the adult outcome of ADHD was pinpointed. Thus, the cortico-cerebellar processes tied to the clinical course of ADHD are separated from the subcortical processes that are not.

Importance: Despite its high heritability, few risk genes have been identified for attention-deficit/hyperactivity disorder (ADHD). Brain-based phenotypes could aid gene discovery. There is a myriad of structural and functional connections that support cognition. Disruption of such connectivity is a key pathophysiologic mechanism for ADHD, and identifying heritable phenotypes within these connections could provide candidates for genomic studies., Objective: To identify the structural and functional connections that are heritable and pertinent to ADHD., Design, Setting, and Participants: Members of extended multigenerational families enriched for ADHD were evaluated. Structural connectivity was defined by diffusion tensor imaging (DTI) of white matter tract microstructure and functional connectivity through resting-state functional magnetic resonance imaging (rsfMRI). Heritability and association with ADHD symptoms were estimated in 24 extended multigenerational families enriched for ADHD (305 members with clinical phenotyping, 213 with DTI, and 193 with rsfMRI data). Findings were confirmed in 52 nuclear families (132 members with clinical phenotypes, 119 with DTI, and 84 with rsfMRI). The study and data analysis were conducted from April 1, 2010, to September 1, 2016., Results: In the 52 nuclear families, 86 individuals (65.2%) were male and the mean (SD) age at imaging was 20.9 (15.0) years; in the 24 multigenerational extended families, 145 individuals (47.5%) were male and mean age at imaging was 30.4 (19.7) years. Microstructural properties of white matter tracts connecting ipsilateral cortical regions and the corpus callosum were significantly heritable, ranging from total additive genetic heritability (h2) = 0.69 (SE, 0.13; P = .0000002) for radial diffusivity of the right superior longitudinal fasciculus to h2 = 0.46 (SE, 0.15; P = .0009) for fractional anisotropy of the right inferior fronto-occipital fasciculus. Association with ADHD symptoms was found in several tracts, most strongly for the right superior longitudinal fasciculus (t = -3.05; P = .003). Heritable patterns of functional connectivity were detected within the default mode (h2 = 0.36; SE, 0.16; cluster level significance, P < .002), cognitive control (h2 = 0.32; SE, 0.15; P < .002), and ventral attention networks (h2 = 0.36; SE, 0.16; P < .002). In all cases, subregions within each network showed heritable functional connectivity with the rest of that network. More symptoms of hyperactivity/impulsivity (t = -2.63; P = .008) and inattention (t = -2.34; P = .02) were associated with decreased functional connectivity within the default mode network. Some cross-modal correlations were purely phenotypic, such as that between axial diffusivity of the right superior longitudinal fasciculus and heritable aspects of the default mode network (phenotypic correlation, ρp = -0.12; P = .03). A genetic cross-modal correlation was seen between the ventral attention network and radial diffusivity of the right inferior fronto-occipital fasciculus (genetic correlation, ρg = -0.45, P = .02)., Conclusions: Analysis of data on multigenerational extended and nuclear families identified the features of structural and functional connectivity that are both significantly heritable and associated with ADHD. In addition, shared genetic factors account for some phenotypic correlations between functional and structural connections. Such work helps to prioritize the facets of the brain's connectivity for future genomic studies.

Background: When children have marked problems with motor coordination, they often have problems with attention and impulse control. Here, we map the neuroanatomic substrate of motor coordination in childhood and ask whether this substrate differs in the presence of concurrent symptoms of attention-deficit/hyperactivity disorder (ADHD)., Method: Participants were 226 children. All completed Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5)-based assessment of ADHD symptoms and standardized tests of motor coordination skills assessing aiming/catching, manual dexterity and balance. Symptoms of developmental coordination disorder (DCD) were determined using parental questionnaires. Using 3 Tesla magnetic resonance data, four latent neuroanatomic variables (for the cerebral cortex, cerebellum, basal ganglia and thalamus) were extracted and mapped onto each motor coordination skill using partial least squares pathway modeling., Results: The motor coordination skill of aiming/catching was significantly linked to latent variables for both the cerebral cortex (t = 4.31, p < 0.0001) and the cerebellum (t = 2.31, p = 0.02). This effect was driven by the premotor/motor cortical regions and the superior cerebellar lobules. These links were not moderated by the severity of symptoms of inattention, hyperactivity and impulsivity. In categorical analyses, the DCD group showed atypical reduction in the volumes of these regions. However, the group with DCD alone did not differ significantly from those with DCD and co-morbid ADHD., Conclusions: The superior cerebellar lobules and the premotor/motor cortex emerged as pivotal neural substrates of motor coordination in children. The dimensions of these motor coordination regions did not differ significantly between those who had DCD, with or without co-morbid ADHD.

Doxorubicin (Doxo) is a chemotherapeutic drug widely used to treat variety of cancers. One of the most serious side effects of Doxo is its dose-dependent and delayed toxicity to the heart. Doxo is known to induce cardiac mitochondrial damage. Recently, the mitochondrial sirtuin SIRT3 has been shown to protect mitochondria from oxidative stress. Here we show that overexpression of SIRT3 protects the heart from toxicity of Doxo by preventing the drug-induced mitochondrial DNA (mtDNA) damage. Doxo treatment caused depletion of Sirt3 levels both in primary cultures of cardiomyocytes and in mouse hearts, which led to massive acetylation of mitochondrial proteins. Doxo-induced toxicity to cardiomyocytes was associated with increased reactive oxygen species (ROS) production, mitochondrial fragmentation, and cell death. Overexpression of SIRT3 helped to attenuate Doxo-induced ROS levels and cardiomyocyte death. Sirt3 knockout (Sirt3.KO) mice could not endure the full dose of Doxo treatment, developed exacerbated cardiac hypertrophy, and died during the course of treatment, whereas Sirt3 transgenic (Sirt3.tg) mice were protected against Doxo-induced cardiotoxicity. Along with Sirt3, we also observed a concomitant decrease in levels of oxoguanine-DNA glycosylase-1 (OGG1), a major DNA glycosylase that hydrolyzes oxidized-guanine (8-oxo-dG) to guanine. Depletion of OGG1 levels was associated with increased mtDNA damage. Sirt3.KO mice and Doxo-treated mice showed increased 8-oxo-dG adducts in DNA and corresponding increase in mtDNA damage, whereas, 8-oxo-dG adducts and mtDNA damage were markedly reduced in Sirt3 overexpressing transgenic mice hearts. These results thus demonstrated that Sirt3 activation protects the heart from Doxo-induced cardiotoxicity by maintaining OGG1 levels and protecting mitochondria from DNA damage., (Copyright © 2016 the American Physiological Society.)

Endophentoypes, quantifiable traits lying on the causal chain between a clinical phenotype and etiology, can be used to accelerate genomic discovery in obsessive-compulsive disorder (OCD). Here we identify the neuroanatomic changes that are shared by 22 OCD adult and adolescent patients and 25 of their unaffected siblings who are at genetic risk for the disorder. Comparisons were made against 47 age and sex matched healthy controls. We defined the surface morphology of the striatum, globus pallidus and thalamus, and thickness of the cerebral cortex. Patients with OCD show significant surface expansion compared with healthy controls, following adjustment for multiple comparisons, in interconnected regions of the caudate, thalamus and right orbitofrontal cortex. Their unaffected siblings show similar, significant expansion, most marked in the ventromedial caudate bilaterally, the right pulvinar thalamic nucleus and the right orbitofrontal cortex. These regions define a network that has been consistently implicated in OCD. In addition, both patients with OCD and unaffected siblings showed similar increased thickness of the right precuneus, which receives rich input from the thalamic pulvinar nuclei and the left medial temporal cortex. Anatomic change within the orbitofrontostriatal and posterior brain circuitry thus emerges as a promising endophenotype for OCD.

Changes in cerebral cortical anatomy have been tied to the clinical course of attention deficit hyperactivity disorder (ADHD). We now ask if alterations in white matter tract microstructure are likewise linked with the adult outcome of childhood ADHD. Seventy-five young adults, 32 with ADHD persisting from childhood and 43 with symptom remission were contrasted against 74 never-affected comparison subjects. Using diffusion tensor imaging, we defined fractional anisotropy, a metric related to white matter microstructure, along with measures of diffusion perpendicular (radial) and parallel (axial) to the axon. Analyses were adjusted for head motion, age and sex, and controlled for multiple comparisons and medication history. Tract-based analyses showed that greater adult inattention, but not hyperactivity-impulsivity, was associated with significantly lower fractional anisotropy in the left uncinate (standardized β=-0.37, t=3.28, p=0.002) and inferior fronto-occipital fasciculi (standardized β=-0.37, t=3.29, p=0.002). The ADHD group with symptoms persisting into adulthood had significantly lower fractional anisotropy than the never-affected controls in these tracts, differences associated with medium to large effect sizes. By contrast, the ADHD group that remitted by adulthood did not differ significantly from controls. The anomalies were found in tracts that connect components of neural systems pertinent to ADHD, such as attention control (inferior fronto-occipital fasciculus) and emotion regulation and the processing of reward (the uncinate fasciculus). Change in radial rather than axial diffusivity was the primary driver of this effect, suggesting pathophysiological processes including altered myelination as future targets for pharmacological and behavioral interventions.

Helping children to use words to express their thoughts and feelings is the goal of psychodynamic group therapy. The subject of this paper was a group of boys in a weekly school-based counseling group. The article explores ways in which the boys could only discharge psychic tension in action and uncovers a fear of using words as a mode of expression. By conceptualizing what he calls "action-talk," a stage between the use of action and talk which sounds like talk, but is not, the author resolved resistances to progressive communication. The importance of being aware of the therapist's own need to control the direction of the group, tendency to avoid negative feelings, and the importance of open-ended, talk-based therapy approaches (versus curriculum-based or psychoeducational groups) are discussed.

Objective: The basal ganglia are implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD), but little is known of their development in the disorder. Here, we mapped basal ganglia development from childhood into late adolescence using methods that define surface morphology with an exquisite level of spatial resolution., Method: Surface morphology of the basal ganglia was defined from neuroanatomic magnetic resonance images acquired in 270 youth with DSM-IV-defined ADHD and 270 age- and sex-matched typically developing controls; 220 individuals were scanned at least twice. Using linear mixed model regression, we mapped developmental trajectories from age 4 through 19 years at approximately 7,500 surface vertices in the striatum and globus pallidus., Results: In the ventral striatal surfaces, there was a diagnostic difference in developmental trajectories (t = 5.6, p < .0001). Here, the typically developing group showed surface area expansion with age (estimated rate of increase of 0.54 mm(2) per year, standard error [SE] 0.29 mm(2) per year), whereas the ADHD group showed progressive contraction (decrease of 1.75 mm(2) per year, SE 0.28 mm(2) per year). The ADHD group also showed significant, fixed surface area reductions in dorsal striatal regions, which were detected in childhood at study entry and persisted into adolescence. There was no significant association between history of psychostimulant treatment and developmental trajectories., Conclusions: Progressive, atypical contraction of the ventral striatal surfaces characterizes ADHD, localizing to regions pivotal in reward processing. This contrasts with fixed, nonprogressive contraction of dorsal striatal surfaces in regions that support executive function and motor planning., (Published by Elsevier Inc.)

Background: Childhood attention-deficit/hyperactivity disorder (ADHD) persists into adulthood in around half of those affected, constituting a major public health challenge. No known demographic, clinical, or neuropsychological factors robustly explain the clinical course, directing our focus to the brain. Herein, we link the trajectories of cerebral cortical development during childhood and adolescence with the severity of adult ADHD., Methods: Using a longitudinal study design, 92 participants with ADHD had childhood (mean 10.7 years, SD 3.3) and adult clinical assessments (mean 23.8 years, SD 4.3) with repeated neuroanatomic magnetic resonance imaging. Contrast was made against 184 matched typically developing volunteers., Results: Attention-deficit/hyperactivity disorder persisted in 37 (40%) subjects and adult symptom severity was linked to cortical trajectories. Specifically, as the number of adult symptoms increased, particularly inattentive symptoms, so did the rate of cortical thinning in the medial and dorsolateral prefrontal cortex. For each increase of one symptom of adult ADHD, the rate of cortical thinning increased by .0018 mm (SE = .0004, t = 4.2, p < .0001), representing a 5.6% change over the mean rate of thinning for the entire group. These differing trajectories resulted in a convergence toward typical dimensions among those who remitted and a fixed, nonprogressive deficit in persistent ADHD. Notably, cortical thickening or minimal thinning (greater than -.007 mm/year) was found exclusively among individuals who remitted., Conclusions: Adult ADHD status is linked with the developmental trajectories of cortical components of networks supporting attention, cognitive control, and the default mode network. This informs our understanding of the developmental pathways to adult ADHD., (Published by Elsevier Inc on behalf of Society of Biological Psychiatry.)

Background: Delineation of the cortical anomalies underpinning attention-deficit/hyperactivity disorder (ADHD) can powerfully inform pathophysiological models. We previously found that ADHD is characterized by a delayed maturation of prefrontal cortical thickness. We now ask if this extends to the maturation of cortical surface area and gyrification., Methods: Two hundred thirty-four children with ADHD and 231 typically developing children participated in the study, with 837 neuroanatomic magnetic resonance images acquired longitudinally. We defined the developmental trajectories of cortical surfaces and gyrification and the sequence of cortical maturation, as indexed by the age at which each cortical vertex attained its peak surface area., Results: In both groups, the maturation of cortical surface area progressed in centripetal waves, both lateral (starting at the central sulcus and frontopolar regions, sweeping toward the mid and superior frontal gyrus) and medial (descending down the medial prefrontal cortex, toward the cingulate gyrus). However, the surface area developmental trajectory was delayed in ADHD. For the right prefrontal cortex, the median age by which 50% of cortical vertices attained peak area was 14.6 years (SE = .03) in ADHD, significantly later than in typically developing group at 12.7 years (SE = .03) [log-rank test χ(¹)² = 1300, p < .00001]. Similar, but less pronounced, delay was found in the left hemispheric lobes. There were no such diagnostic differences in the developmental trajectories of cortical gyrification., Conclusions: The congruent delay in cortical thickness and surface area direct attention away from processes that selectively affect one cortical component toward mechanisms controlling the maturation of multiple cortical dimensions., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Factors that affect water loss rates (WLRs) are poorly known for organisms in natural habitats. Seed-harvester ant queens provide an ideal system for examining such factors because WLRs for mated queens excavated from their incipient nests are twofold to threefold higher than those of alate queens. Indirect data suggest that this increase results from soil particles abrading the cuticle during nest excavation. This study provides direct support for the cuticle abrasion hypothesis by measuring total mass-specific WLRs, cuticular abrasion, cuticular transpiration, respiratory water loss and metabolic rate for queens of the ant Messor pergandei at three stages: unmated alate queens, newly mated dealate queens (undug foundresses) and mated queens excavated from their incipient nest (dug foundresses); in addition we examined these processes in artificially abraded alate queens. Alate queens had low WLRs and low levels of cuticle abrasion, whereas dug foundresses had high WLRs and high levels of cuticle abrasion. Total WLR and cuticular transpiration were lowest for alate queens, intermediate for undug foundresses and highest for dug foundresses. Respiratory water loss contributed ~10% of the total WLR and was lower for alate queens and undug foundresses than for dug foundresses. Metabolic rate did not vary across stages. Total WLR and cuticular transpiration of artificially abraded alate queens increased, whereas respiratory water loss and metabolic rate were unaffected. Overall, increased cuticular transpiration accounted for essentially all the increased total water loss in undug and dug foundresses and artificially abraded queens. Artificially abraded queens and dug foundresses showed partial recovery after 14 days.

Background: It was recently found that the development of typical patterns of prefrontal, but not posterior, cortical asymmetry is disrupted in right-handed youth with attention-deficit/hyperactivity disorder (ADHD). Using longitudinal data, we tested the hypothesis that there would be a congruent disruption in the growth of the anterior corpus callosum, which contains white matter tracts connecting prefrontal cortical regions., Methods: Areas of five subregions of the corpus callosum were quantified using a semiautomated method from 828 neuroanatomic magnetic resonance scans acquired from 236 children and adolescents with ADHD (429 scans) and 230 typically developing youth (399 scans), most of whom had repeated neuroimaging. Growth rates of each diagnostic group were defined using mixed-model linear regression., Results: Right-handed participants with ADHD showed a significantly higher rate of growth in the anterior-most region of the corpus callosum (estimated annual increase in area of .97%, SEM .12%) than their typically developing peers (annual increase in area of .32% SEM .13%; t = 3.64, p = .0003). No significant diagnostic differences in growth rates were found in any other regions in right-handed participants, and no significant diagnostic differences were found in non-right-handed participants., Conclusions: As hypothesized, we found anomalous growth trajectories in the anterior corpus callosum in ADHD. This disrupted anterior callosal growth may reflect, or even drive, the previously reported disruption in the development of prefrontal cortex asymmetry. The finding documents the dynamic, age-dependent nature of callosal and congruent prefrontal cortical abnormalities characterizing ADHD., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: There is considerable epidemiological and neuropsychological evidence that attention deficit hyperactivity disorder (ADHD) is best considered dimensionally, lying at the extreme end of a continuous distribution of symptoms and underlying cognitive impairments. The authors investigated whether cortical brain development in typically developing children with symptoms of hyperactivity and impulsivity resembles that found in the syndrome of ADHD. Specifically, they examined whether a slower rate of cortical thinning during late childhood and adolescence, which they previously found in ADHD, is also linked to the severity of symptoms of hyperactivity and impulsivity in typically developing children., Method: In a longitudinal analysis, a total of 193 typically developing children with 389 neuroanatomic magnetic resonance images and varying levels of symptoms of hyperactivity and impulsivity (measured with the Conners' Parent Rating Scale) were contrasted with 197 children with ADHD with 337 imaging scans. The relationship between the rates of regional cortical thinning and severity of symptoms of hyperactivity/impulsivity was determined., Results: Youth with higher levels of hyperactivity/impulsivity had a slower rate of cortical thinning, predominantly in prefrontal cortical regions, bilaterally in the middle frontal/premotor gyri, extending down the medial prefrontal wall to the anterior cingulate; the orbitofrontal cortex; and the right inferior frontal gyrus. For each increase of one point in the hyperactivity/impulsivity score, there was a decrease in the rate of regional cortical thinning of 0.0054 mm/year (SE=0.0019 mm/year). Children with ADHD had the slowest rate of cortical thinning., Conclusions: Slower cortical thinning during adolescence characterizes the presence of both the symptoms and syndrome of ADHD, providing neurobiological evidence for dimensionality of the disorder.

Context: Just as typical development of anatomical asymmetries in the human brain has been linked with normal lateralization of motor and cognitive functions, disruption of asymmetry has been implicated in the pathogenesis of neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD). No study has examined the development of cortical asymmetry using longitudinal neuroanatomical data., Objective: To delineate the development of cortical asymmetry in children with and without ADHD., Design: Longitudinal study., Setting: Government Clinical Research Institute., Participants: A total of 218 children with ADHD and 358 typically developing children, from whom 1133 neuroanatomical magnetic resonance images were acquired prospectively., Main Outcome Measures: Cortical thickness was estimated at 40 962 homologous points in the left and right hemispheres, and the trajectory of change in asymmetry was defined using mixed-model regression., Results: In right-handed typically developing individuals, a mean (SE) increase in the relative thickness of the right orbitofrontal and inferior frontal cortex with age of 0.011 (0.0018) mm per year (t(337) = 6.2, P < .001) was balanced against a relative left-hemispheric increase in the occipital cortical regions of 0.013 (0.0015) mm per year (t(337) = 8.1, P < .001). Age-related change in asymmetry in non-right-handed typically developing individuals was less extensive and was localized to different cortical regions. In ADHD, the posterior component of this evolving asymmetry was intact, but the prefrontal component was lost., Conclusions: These findings explain the way that, in typical development, the increased dimensions of the right frontal and left occipital cortical regions emerge in adulthood from the reversed pattern of childhood cortical asymmetries. Loss of the prefrontal component of this evolving asymmetry in ADHD is compatible with disruption of prefrontal function in the disorder and demonstrates the way that disruption of typical processes of asymmetry can inform our understanding of neurodevelopmental disorders.

There is controversy over the nature of the disturbance in brain development that underpins attention-deficit/hyperactivity disorder (ADHD). In particular, it is unclear whether the disorder results from a delay in brain maturation or whether it represents a complete deviation from the template of typical development. Using computational neuroanatomic techniques, we estimated cortical thickness at >40,000 cerebral points from 824 magnetic resonance scans acquired prospectively on 223 children with ADHD and 223 typically developing controls. With this sample size, we could define the growth trajectory of each cortical point, delineating a phase of childhood increase followed by adolescent decrease in cortical thickness (a quadratic growth model). From these trajectories, the age of attaining peak cortical thickness was derived and used as an index of cortical maturation. We found maturation to progress in a similar manner regionally in both children with and without ADHD, with primary sensory areas attaining peak cortical thickness before polymodal, high-order association areas. However, there was a marked delay in ADHD in attaining peak thickness throughout most of the cerebrum: the median age by which 50% of the cortical points attained peak thickness for this group was 10.5 years (SE 0.01), which was significantly later than the median age of 7.5 years (SE 0.02) for typically developing controls (log rank test chi(1)(2) = 5,609, P < 1.0 x 10(-20)). The delay was most prominent in prefrontal regions important for control of cognitive processes including attention and motor planning. Neuroanatomic documentation of a delay in regional cortical maturation in ADHD has not been previously reported.

Background: There are, to date, no pre-post onset longitudinal imaging studies of bipolar disorder at any age. We report the first prospective study of cortical brain development in pediatric bipolar illness for 9 male children, visualized before and after illness onset., Method: We contrast this pattern with that observed in a matched group of healthy children as well as in a matched group of 8 children with 'atypical psychosis' who had similar initial presentation marked by mood dysregulation and transient psychosis (labeled as 'multi-dimensionally impaired' (MDI)) as in the bipolar group, but have not, to date, developed bipolar illness., Results: Dynamic maps, reconstructed by applying novel cortical pattern matching algorithms, for the children who became bipolar I showed subtle, regionally specific, bilaterally asymmetrical cortical changes. Cortical GM increased over the left temporal cortex and decreased bilaterally in the anterior (and sub genual) cingulate cortex. This was seen most strikingly after the illness onset, and showed a pattern distinct from that seen in childhood onset schizophrenia. The bipolar neurodevelopmental trajectory was generally shared by the children who remained with MDI diagnosis without converting to bipolar I, suggesting that this pattern of cortical development may reflect affective dysregulation (lability) in general., Conclusions: These dynamic trajectories of cortical development may explain age-related disparate findings from cross-sectional studies of bipolar illness, and suggest the importance of mood disordered non-bipolar control group in future studies.

Context: Attention-deficit/hyperactivity disorder (ADHD) is one of the most heritable neuropsychiatric disorders, and a polymorphism within the dopamine D4 receptor (DRD4) gene has been frequently implicated in its pathogenesis., Objective: To examine the effects of the 7-repeat microsatellite in the DRD4 gene on clinical outcome and cortical development in ADHD. We drew comparisons with a single nucleotide polymorphism in the dopamine D1 receptor (DRD1) gene, which was associated with ADHD within our cohort, and a polymorphism within the dopamine transporter (DAT1) gene, reported to have additive effects with the DRD4 7-repeat allele., Design: Longitudinal cohort study., Setting: National Institutes of Health, Bethesda, Maryland., Participants: One hundred five children (with 222 neuroanatomical magnetic resonance images) with ADHD (mean age at entry, 10.1 years) and 103 healthy controls (total of 220 magnetic resonance images). Sixty-seven subjects with ADHD (64%) had follow-up clinical evaluations (mean follow-up, 6 years)., Main Outcome Measures: Cortical thickness across the cerebrum and presence of DSM-IV-defined ADHD at follow-up., Results: Possession of the DRD4 7-repeat allele was associated with a thinner right orbitofrontal/inferior prefrontal and posterior parietal cortex. This overlapped with regions that were generally thinner in subjects with ADHD compared with controls. Participants with ADHD carrying the DRD4 7-repeat allele had a better clinical outcome and a distinct trajectory of cortical development. This group showed normalization of the right parietal cortical region, a pattern that we have previously linked with better clinical outcome. By contrast, there were no significant effects of the DRD1 or DAT1 polymorphisms on clinical outcome or cortical development., Conclusions: The DRD4 7-repeat allele, which is widely associated with a diagnosis of ADHD, and in our cohort with better clinical outcome, is associated with cortical thinning in regions important in attentional control. This regional thinning is most apparent in childhood and largely resolves during adolescence.

Background: Impaired neurocognitive functioning is one increasingly recognized long-term consequence of childhood ALL treatment. However, research findings have been inconsistent regarding the domains affected and the degree to which they are compromised., Procedure: A comprehensive meta-analytic review of the long-term neurocognitive effects of childhood ALL was conducted. Studies were included if they were published in English, reported original quantitative data on the post-treatment neurocognitive functioning of childhood ALL patients in first remission and control groups, and used neurocognitive measures with adequate psychometric properties and published normative data., Results: Data from 28 empirical studies yielding 13 effect sizes across nine domains were extracted and analyzed. All effects were negative (g = -0.34 to -0.71), demonstrating that ALL survivors consistently experienced significant deficits in intellectual functioning, academic achievement, and specific neurocognitive abilities compared to control groups. The role of potential moderators, including treatment with cranial irradiation, age at time of diagnosis, and time since treatment ended, was examined. However, no effects emerged as clearly and consistently moderated by these variables., Conclusions: The results from this meta-analysis suggest that declines in both global and specific areas of areas of neurocognitive functioning occur as a result of contemporary ALL treatment. Such deficits have significant implications for survivors' academic achievement and overall quality of life. Neurocognitive assessment plays a critical role in determining what remedial or specialized instruction is needed in childhood ALL survivors and should be included as a standard part of long-term follow-up care.

Context: Cortical gray matter (GM) loss is marked and progressive in childhood-onset schizophrenia (COS) during adolescence but becomes more circumscribed by early adulthood. Nonpsychotic siblings of COS probands could help evaluate whether the cortical GM abnormalities are familial/trait markers., Objective: To map cortical development in nonpsychotic siblings of COS probands., Design: Using an automated measurement and prospectively acquired anatomical brain magnetic resonance images, we mapped cortical GM thickness in healthy full siblings (n = 52, 113 scans; age 8 through 28 years) of patients with COS, contrasting them with age-, sex-, and scan interval-matched healthy controls (n = 52, 108 scans). The false-discovery rate procedure was used to control for type I errors due to multiple comparisons., Setting: An ongoing COS study at the National Institute of Mental Health., Participants: Fifty-two healthy full siblings of patients with COS, aged 8 through 28 years, and 52 healthy controls., Main Outcome Measures: Longitudinal trajectories of cortical GM development in healthy siblings of patients with COS compared with matched healthy controls and exploratory measure of the relationship between developmental GM trajectories and the overall functioning as defined by the Global Assessment Scale (GAS) score., Results: Younger, healthy siblings of patients with COS showed significant GM deficits in the left prefrontal and bilateral temporal cortices and smaller deficits in the right prefrontal and inferior parietal cortices compared with the controls. These cortical deficits in siblings disappeared by age 20 years and the process of deficit reduction correlated with overall functioning (GAS scores) at the last scan., Conclusions: Prefrontal and temporal GM loss in COS appears to be a familial/trait marker. Amelioration of regional GM deficits in healthy siblings was associated with higher global functioning (GAS scores), suggesting a relationship between brain plasticity and functional outcome for these nonpsychotic, nonspectrum siblings.

Polymorphisms of the dopamine receptor D4 gene DRD4, 11p15.5, have previously been associated with attention-deficit/hyperactivity disorder (ADHD) [Bobb et al., 2005; Am J Med Genet B Neuropsychiatr Genet 132:109-125; Faraone et al., 2005; Biol Psychiatry 57:1313-1323; Thapar et al., 2005; Hum Mol Genet 14 Spec No. 2:R275-R282]. As a follow up to a pilot study [see Castellanos et al., 1998; Mol Psychiatry 3:431-434] consisting of 41 probands and 56 controls which found no significant association between the DRD4 7-repeat allele in exon 3 and ADHD, a greatly expanded study sample (cases n = 166 and controls n = 282) and long term follow-up (n = 107, baseline mean age n = 9, follow-up mean age of n = 15) prompted reexamination of this gene. The DRD4 7-repeat allele was significantly more frequent in ADHD cases than controls (OR = 1.2; P = 0.028). Further, within the ADHD group, the 7-repeat allele was associated with better cognitive performance (measured by the WISC-III) (P = 0.013-0.07) as well as a trend for association with better long-term outcome. This provides further evidence of the role of the DRD4 7-repeat allele in the etiology of ADHD and suggests that this allele may be associated with a more benign form of the disorder., ((c) 2006 Wiley-Liss, Inc.)

Context: Data from a previous prospective study of lobar volumes in children with attention-deficit/hyperactivity disorder (ADHD) are reexamined using a measure of cortical thickness., Objective: To determine whether regional differences in cortical thickness or cortical changes across time characterize ADHD and predict or reflect its clinical outcome., Design, Setting, and Participants: Longitudinal study of 163 children with ADHD (mean age at entry, 8.9 years) and 166 controls recruited mainly from a local community in Maryland. Participants were assessed with magnetic resonance imaging. Ninety-seven patients with ADHD (60%) had 2 or more images and baseline and follow-up clinical evaluations (mean follow-up, 5.7 years)., Main Outcome Measures: Cortical thickness across the cerebrum. Patients with ADHD were divided into better and worse outcome groups on the basis of a mean split in scores on the Children's Global Assessment Scale and persistence/remission of DSM-IV-defined ADHD., Results: Children with ADHD had global thinning of the cortex (mean reduction, -0.09 mm; P=.02), most prominently in the medial and superior prefrontal and precentral regions. Children with worse clinical outcome had a thinner left medial prefrontal cortex at baseline than the better outcome group (-0.38 mm; P=.003) and controls (-0.25 mm; P=.002). Cortical thickness developmental trajectories did not differ significantly between the ADHD and control groups throughout except in the right parietal cortex, where trajectories converged. This normalization of cortical thickness occurred only in the better outcome group., Conclusions: Children with ADHD show relative cortical thinning in regions important for attentional control. Children with a worse outcome have "fixed" thinning of the left medial prefrontal cortex, which may compromise the anterior attentional network and encumber clinical improvement. Right parietal cortex thickness normalization in patients with a better outcome may represent compensatory cortical change.

Introduction: Long-term outcomes in children with atypical psychosis have been poorly studied. Four to 6 weeks of inpatient observation and up to 11 years (mean, 4.0 +/- 1.3 years) of follow- up have afforded us some experience with this probably heterogeneous group of transiently psychotic patients commonly mislabeled as schizophrenic. Despite severe preadmission morbidity, some patients have successfully remained neuroleptic-free since discharge. Predictors of good versus poor outcome were sought., Methods: Of roughly 150 patients admitted with the presumptive diagnosis of schizophrenia, 32 patients were discharged meeting criteria for psychosis not otherwise specified (NOS), otherwise labeled by the NIMH team as "multidimensionally impaired" (MDI). Admission and biannual follow-up data included a semistructured clinical interview with the Schedule for Affective Disorders and Schizophrenia for School Age Children (K-SADS), IQ testing, clinical rating scales (e.g., Clinical Global Impression Scale (CGI), Children's Global Assessment Scale (C-GAS), Brief Psychiatric Rating Scale (BPRS), Scales for the Assessment Negative and Positive Symptoms (SANS and SAPS), and Bunney-Hamburg (B-H)). At follow-up (as of February 2005) 38% of patients (12 of 32) met criteria for bipolar 1 disorder, 12% (4 of 23) for major depressive disorder (MDD), and 3% (1 of 32) for schizoaffective disorder. The remaining 47% of patients (15 of 32) were divided into two groups on the basis of whether they were in remission and neuroleptic-free ("good outcome," n = 5) or still severely impaired and/or psychotic regardless of pharmacotherapy ("poor outcome," n = 10) at follow-up., Results: Good-outcome patients had a significantly higher baseline level of functioning (on admission and on medications). This was demonstrated by better scores on CGI (3.5 +/- 0.6 versus 4.8 +/- 0.8; p = 0.03) and C-GAS (66.3 +/- 6.3 versus 38.6 +/- 11.5; p = 0.01). Groups were otherwise comparable in demographic data (gender, race, socioeconomic status, age at onset), months of neuroleptic exposure, severity of psychotic symptoms, and level of premorbid functioning., Conclusion: C-GAS (which correctly classified 85.7% of good-outcome subjects) and CGI at baseline appear to predict outcome. On other variables, MDI subgroups were remarkably similar.

Context: Various anatomic brain abnormalities have been reported for attention-deficit/hyperactivity disorder (ADHD), with varying methods, small samples, cross-sectional designs, and without accounting for stimulant drug exposure., Objective: To compare regional brain volumes at initial scan and their change over time in medicated and previously unmedicated male and female patients with ADHD and healthy controls., Design, Setting, and Participants: Case-control study conducted from 1991-2001 at the National Institute of Mental Health, Bethesda, Md, of 152 children and adolescents with ADHD (age range, 5-18 years) and 139 age- and sex-matched controls (age range, 4.5-19 years) recruited from the local community, who contributed 544 anatomic magnetic resonance images., Main Outcome Measures: Using completely automated methods, initial volumes and prospective age-related changes of total cerebrum, cerebellum, gray and white matter for the 4 major lobes, and caudate nucleus of the brain were compared in patients and controls., Results: On initial scan, patients with ADHD had significantly smaller brain volumes in all regions, even after adjustment for significant covariates. This global difference was reflected in smaller total cerebral volumes (-3.2%, adjusted F(1,280) = 8.30, P =.004) and in significantly smaller cerebellar volumes (-3.5%, adjusted F(1,280) = 12.29, P =.001). Compared with controls, previously unmedicated children with ADHD demonstrated significantly smaller total cerebral volumes (overall F(2,288) = 6.65; all pairwise comparisons Bonferroni corrected, -5.8%; P =.002) and cerebellar volumes (-6.2%, F( 2,288) = 8.97, P<.001). Unmedicated children with ADHD also exhibited strikingly smaller total white matter volumes (F(2,288) = 11.65) compared with controls (-10.7%, P<.001) and with medicated children with ADHD (-8.9%, P<.001). Volumetric abnormalities persisted with age in total and regional cerebral measures (P =.002) and in the cerebellum (P =.003). Caudate nucleus volumes were initially abnormal for patients with ADHD (P =.05), but diagnostic differences disappeared as caudate volumes decreased for patients and controls during adolescence. Results were comparable for male and female patients on all measures. Frontal and temporal gray matter, caudate, and cerebellar volumes correlated significantly with parent- and clinician-rated severity measures within the ADHD sample (Pearson coefficients between -0.16 and -0.26; all P values were <.05)., Conclusions: Developmental trajectories for all structures, except caudate, remain roughly parallel for patients and controls during childhood and adolescence, suggesting that genetic and/or early environmental influences on brain development in ADHD are fixed, nonprogressive, and unrelated to stimulant treatment.

Background: Anatomic studies of boys with attention-deficit/hyperactivity disorder (ADHD) have detected decreased volumes in total and frontal brain, basal ganglia, and cerebellar vermis. We tested these findings in a sample of girls with ADHD., Methods: Anatomic brain magnetic resonance images from 50 girls with ADHD, of severity comparable with that in previously studied boys, and 50 healthy female control subjects, aged 5 to 15 years, were obtained with a 1.5-T scanner with contiguous 2-mm coronal slices and 1.5-mm axial slices. We measured volumes of total cerebrum, frontal lobes, caudate nucleus, globus pallidus, cerebellum, and cerebellar vermis. Behavioral measures included structured psychiatric interviews, parent and teacher ratings, and the Wechsler vocabulary and block design subtests., Results: Total brain volume was smaller in girls with ADHD than in control subjects (effect size, 0.40; P =.05). As in our previous study in boys with ADHD, girls with ADHD had significantly smaller volumes in the posterior-inferior cerebellar vermis (lobules VIII-X; effect size, 0.54; P =.04), even when adjusted for total cerebral volume and vocabulary score. Patients and controls did not differ in asymmetry in any region. Morphometric differences correlated significantly with several ratings of ADHD severity and were not predicted by past or present stimulant drug exposure., Conclusions: These results confirm previous findings for boys in the posterior-inferior lobules of the cerebellar vermis. The influence of the cerebellar vermis on prefrontal and striatal circuitry should be explored.

Although the etiology of attention-deficit/hyperactivity disorder (ADHD) is likely multifactorial, family, adoption, and twin studies suggest that genetic factors contribute significantly. Polymorphisms of the dopamine 4 receptor (DRD4) affect receptor binding, and one allele with seven tandem repeats in exon 3 (DRD4*7R) has been associated with ADHD. We examined this putative association in 41 children with severe ADHD and 56 healthy controls who were group matched for ethnicity and sex. The frequency of the DRD4*7R allele did not vary by diagnosis (0.220 vs 0.205 in patients and controls, respectively). Behavioral and brain anatomic MRI measures, previously found to discriminate patients from controls, did not differ significantly between subjects having and those lacking a DRD4*7R allele. These data do not support the reported association between DRD4*7R and the behavioral or brain morphometric phenotype associated with ADHD.

Porcelain restorations are widely used in restorative dentistry with general success. On occasion however, fracture of the porcelain occurs. Sometimes a repair may be attempted using resin composite and one of the many bonding systems available. This in vitro investigation sought to determine and compare the shear bond strengths between a visible light-cured resin composite (Prisma TPH) and dental porcelain (Matchmaker Porcelain) for three different bonding systems (Scotchbond Multipurpose Plus (SMP); One-Step (OS); DenTASTIC (D)) with a view to conducting a larger study to assist in material selection. All measurements were performed one week following the preparation and storage of specimens in distilled water, at 37 degrees C, using a Universal Testing Machine at a crosshead speed of 0.5 mm/min. Although the mean shear bond strengths differed significantly (P < 0.05) (OS > SMP) and the Weibull modulus value of SMP was significantly (P < 0.05) lower than both OS and D the almost exclusive cohesive mode of failure observed, within the porcelain itself, suggested that the test was more a reflection of the quality of the underlying porcelain than the union under investigation. It was thus concluded that the shear bond strength test employed here, and in other studies did not truly reflect the shear bond strength at the porcelain/composite interface and that a more meaningful test should be developed. The observed cohesive failure may account for repeated clinical failures of porcelain repairs where bonding to an inherently flawed porcelain structure inevitably results in further failure.

Evidence of immune system abnormalities in adult schizophrenia has prompted examination of the human leukocyte antigen (HLA) system. Childhood onset schizophrenia offers a unique opportunity to test neurodevelopmental hypotheses of schizophrenia, including those which implicate components of the immune system. In the present study, class I and II HLA antigens were typed using sequence-specific primers and the polymerase chain reaction in 28 childhood onset schizophrenics and 51 ethnically matched healthy subjects. Groups were compared for frequencies of HLA antigens reported to be associated with schizophrenia and/or autoimmune disorders. We hypothesized that antigen frequencies would differ between schizophrenic and healthy children, suggesting that some dimension of the neurodevelopmental disturbance experienced by these children may be mediated by subtle abnormalities of immune function. There were no significant differences between schizophrenic and healthy subjects in the frequency of any antigen tested. These findings do not support HLA-associated pathology in childhood onset schizophrenia.

We have altered the spontaneous contractile activity of neonatal cardiac myocytes in culture to investigate the re-lationship between mechanical forces, myofibril assembly, and the localization and translation of (alpha)-myosin heavy chain mRNA. Immunofluorescence and in situ hybridization techniques revealed that contracting myocytes display well aligned myofibrils and a diffuse distribution of (alpha)-myosin heavy chain mRNA. Inhibition of contractile activity with the calcium channel blocker verapamil (10 microM) resulted in myofibril disassembly and a perinuclear mRNA distribution within six hours. There was a significant decrease (P<0. 05) of mRNA levels, 5 to 15 micron away from the nucleus following 6 hours of verapamil treatment compared with control cells. Inhibition of protein synthesis with cycloheximide (10 microM) also resulted in perinuclear mRNA localization despite having little effect on contractile activity or myofibril assembly. To determine if the 3' untranslated region of (alpha)-myosin heavy chain mRNA was sufficient for localizing the entire message, a chimeric construct composed of beta-galactosidase coding region followed by (alpha)-myosin heavy chain 3' untranslated region sequences was made as a reporter plasmid and transfected into cultured myocytes. A perinuclear accumulation of ss-galactosidase was exhibited in many of the contractile arrested cells (48.3+/-2.4%, n=7). In contrast, significantly fewer (P<0.05) contracting control (29.1+/-3.3%, n=7) and strongly contracting, isoproterenol-treated cells (27.2+/-6.1%, n=3) exhibited a perinuclear localization of protein. The distribution of the reporter protein was not affected by the contractile state in cells transfected with a constitutively translated 3'UTR. We propose that mechanical activity of neonatal cardiac myocytes regulates the intracellular localization of alpha-myosin heavy chain mRNA via the 3' untranslated region mediated by an initial block in translation.

The pathology of thrombophlebitis primarily results from the obliteration of venous valves in the lower extremities. The objective of this study was to develop a prosthetic venous valve that could be implanted in the human femoral system to ameliorate the deleterious effects of thrombophlebitis. Prosthetic venous valves were produced from two materials: Pellethane valves were fabricated from a dip-casting process; umbilical vein valves were produced by a fixation process. The valves were evaluated as implants within the external jugular veins of 10 research dogs. Each animal was implanted with one Pellethane valve in one external jugular vein and one umbilical vein venous valve in the contralateral jugular vein. Each valve was positioned over a stainless-steel cylinder that had been implanted into the jugular veins in such a manner that there existed no blood-cylinder interaction. Patency of the valves was determined by X-ray venography at 24, 48, and 72 h and at 5 and 8 days postoperatively. All of the umbilical vein venous valves were occluded by the end of 48 h, whereas two of the Pellethane venous valves remained patent for at least 5 days but were occluded at 8 days. The results of this study suggest the possibility of success of Pellethane valve implants in the venous circulation and indicate future directions for study.