Neuroanatomic, epigenetic and genetic differences in monozygotic twins discordant for attention deficit hyperactivity disorder.

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.

Successful pharmacotherapy for the treatment of severe feeding aversion with mechanistic insights from cross-species neuronal remodeling.

Pediatric feeding disorders affect up to 5% of children, causing severe food intake problems that can result in serious medical and developmental outcomes. Behavioral intervention (BI) is effective in extinguishing feeding aversions, and also expert-dependent, time/labor-intensive and not well understood at a neurobiological level. Here we first conducted a double-blind, placebo-controlled trial comparing BI with BI plus d-cycloserine (DCS). DCS is a partial N-methyl-d-aspartate (NMDA) receptor agonist shown to augment extinction therapies in multiple anxiety disorders. We examined whether DCS enhanced extinction of feeding aversion in 15 children with avoidant/restrictive food intake disorder (ages 20-58 months). After five treatment days, BI improved feeding by 37%. By contrast, BI+DCS improved feeding by 76%. To gain insight into possible mechanisms of successful intervention, we next tested the neurobiological consequences of DCS in a murine model of feeding aversion and avoidance. In mice with conditioned food aversion, DCS enhanced avoidance extinction across a broad dose range. Confocal fluorescence microscopy and three-dimensional neuronal reconstruction indicated that DCS enlarged dendritic spine heads-the primary sites of excitatory plasticity in the brain-within the orbitofrontal prefrontal cortex, a sensory-cognition integration hub. DCS also increased phosphorylation of the plasticity-associated extracellular signal-regulated kinase 1/2. In summary, DCS successfully augments the extinction of food aversion in children and mice, an effect that may involve plasticity in the orbitofrontal cortex. These results warrant a larger-scale efficacy study of DCS for the treatment of pediatric feeding disorders and further investigations of neural mechanisms.

Google Haul Out: Earth Observation Imagery and Digital Aerial Surveys in Coastal Wildlife Management and Abundance Estimation.

As the sampling frequency and resolution of Earth observation imagery increase, there are growing opportunities for novel applications in population monitoring. New methods are required to apply established analytical approaches to data collected from new observation platforms (e.g., satellites and unmanned aerial vehicles). Here, we present a method that estimates regional seasonal abundances for an understudied and growing population of gray seals (Halichoerus grypus) in southeastern Massachusetts, using opportunistic observations in Google Earth imagery. Abundance estimates are derived from digital aerial survey counts by adapting established correction-based analyses with telemetry behavioral observation to quantify survey biases. The result is a first regional understanding of gray seal abundance in the northeast US through opportunistic Earth observation imagery and repurposed animal telemetry data. As species observation data from Earth observation imagery become more ubiquitous, such methods provide a robust, adaptable, and cost-effective solution to monitoring animal colonies and understanding species abundances.

Defining the neuroanatomic basis of motor coordination in children and its relationship with symptoms of attention-deficit/hyperactivity disorder.

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.

The management of testicular masses and acute scrotal pain.

Within military primary care patients may present with testicular masses or acute scrotal pain. The aim of this article is to examine, by means of case studies, the differential diagnosis, treatment and clinical considerations in managing patients in the military environment.

Subcortical and cortical morphological anomalies as an endophenotype in obsessive-compulsive disorder.

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.

Neandertal roots: Cranial and chronological evidence from Sima de los Huesos.

Seventeen Middle Pleistocene crania from the Sima de los Huesos site (Atapuerca, Spain) are analyzed, including seven new specimens. This sample makes it possible to thoroughly characterize a Middle Pleistocene hominin paleodeme and to address hypotheses about the origin and evolution of the Neandertals. Using a variety of techniques, the hominin-bearing layer could be reassigned to a period around 430,000 years ago. The sample shows a consistent morphological pattern with derived Neandertal features present in the face and anterior vault, many of which are related to the masticatory apparatus. This suggests that facial modification was the first step in the evolution of the Neandertal lineage, pointing to a mosaic pattern of evolution, with different anatomical and functional modules evolving at different rates.

Suprarenal clamping is a safe method of aortic control when infrarenal clamping is not desirable.

We evaluated the safety of suprarenal aortic clamping in patients with abdominal aortic aneurysm (AAA) treated by open aortic replacement by retrospectively reviewing all patients who underwent elective AAA replacement at a university hospital from 1993 until 2003. We reviewed 249 patient charts and divided them into three groups according to the clamp location during aortic replacement: group 1, infrarenal clamp group (n = 185); group 2, suprarenal clamp group (n = 52); and group 3, supraceliac clamp group (n = 12). Groups 1 and 2 were compared with respect to risk factors, intraoperative events, and postoperative events. Statistical analysis was done using Wilcoxon's rank-sum test, chi-squared test, and Fisher's exact test. Risk factors were comparable in groups 1 and 2 except for weight, which was higher in group 1. Intraoperative urine output, hypotensive episodes, and use of renal protective drugs were comparable in the two groups. Operation time, blood loss, and use of IV fluids were all significantly higher in group 2, while total aortic clamp time was higher in group 1. Postoperative events were comparable except for postoperative peak creatinine, intensive care unit length of stay, and postoperative length of stay, which were higher in group 2; however, discharge creatinine was comparable without a significant difference. Suprarenal clamping is a safe method of aortic control during open AAA replacement surgery. The selection of clamping site should be individualized according to the intraoperative anatomy. Supraceliac clamping is not necessarily the preferable method of aortic control when the infrarenal location is not suitable for clamping.

Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation.

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.

Association of the dopamine receptor D4 (DRD4) gene 7-repeat allele with children with attention-deficit/hyperactivity disorder (ADHD): an update.

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.

The resident view of professionalism behavior frequency in outstanding and "not outstanding" faculty.

BACKGROUND: Professionalism assessment has become necessary for all postgraduate training programs because it is now required for accreditation. To validate the novel items we generated to assess professionalism, we tested whether residents' ratings of faculty they judged as outstanding in professionalism would be distinguishable from those they judged as not outstanding. METHODS: Educators from core clinical disciplines generated 20 items assessing professionalism behaviors on a 7-point frequency scale anchored by "always" and "never." Thirty-five surgical and pediatric residents completed the form twice, anonymously rating 1 faculty member they judged as outstanding and another they judged as not outstanding. RESULTS: The residents produced 69 faculty ratings with means that differed significantly on all items between the outstanding and not-outstanding faculty. The form was highly unidimensional, with the primary factor's eigenvalue being 11.5 and Cronbach's alpha being 0.97. Groups differed most on items, ie, "listens well," "inspires trust," "answers questions directly," and "demonstrates respect for all." CONCLUSION: The behaviors that best distinguished clinical faculty judged by residents as outstanding professionals were listening, trustworthiness, answering directly, and respect.

Detection of plasmid DNA vectors following gene transfer to the murine airways.

Non-viral gene therapy is being considered as a treatment for cystic fibrosis. In clinical studies and in studies using the mouse airways as a model, current formulations result in only transient transgene expression. A number of reasons for this have been proposed including the loss of plasmid DNA from cells. The aim of these studies was to investigate why transgene expression from non-viral vectors is transient in the mouse lung. Plasmid DNA encoding the luciferase reporter gene was complexed with the cationic lipid GL67 and delivered to the mouse airways. The persistence of plasmid DNA in the mouse lungs was investigated using quantitative PCR and Southern hybridization. Results showed that intact plasmid DNA persisted in the mouse lung in the absence of any detectable luciferase activity. The de novo methylation of plasmid DNA in vivo was investigated as a potential cause of this transient gene expression but results suggested that plasmid DNA does not become de novo methylated in the mouse lung. Therefore processes other than the loss of plasmid DNA from the lung or the de novo methylation of plasmid DNA vectors must be responsible for the transient transgene expression.

Environment, agriculture, and settlement patterns in a marginal Polynesian landscape.

Beginning ca. A.D. 1400, Polynesian farmers established permanent settlements along the arid southern flank of Haleakala Volcano, Maui, Hawaiian Islands; peak population density (43-57 persons per km(2)) was achieved by A.D. 1700-1800, and it was followed by the devastating effects of European contact. This settlement, based on dryland agriculture with sweet potato as a main crop, is represented by >3,000 archaeological features investigated to date. Geological and environmental factors are the most important influence on Polynesian farming and settlement practices in an agriculturally marginal landscape. Interactions between lava flows, whose ages range from 3,000 to 226,000 years, and differences in rainfall create an environmental mosaic that constrained precontact Polynesian farming practices to a zone defined by aridity at low elevation and depleted soil nutrients at high elevation. Within this productive zone, however, large-scale agriculture was concentrated on older, tephra-blanketed lava flows; younger flows were reserved for residential sites, small ritual gardens, and agricultural temples.

Structural study of new hydrocarbon nano-crystals by energy-filtered electron diffraction.

A new brittle hydrocarbon has been successfully synthesized in polycrystalline form, and its crystal structure solved by quantitative electron diffraction. By 3D tilting of the nano-crystals, the lattice type and unit cell parameters were determined. (Triclinic, [Formula: see text] A, [Formula: see text] A, [Formula: see text] A, [Formula: see text] degrees, [Formula: see text] degrees, and [Formula: see text] degrees.) Spot diffraction patterns were obtained at -165 degrees C using the Koehler selected-area mode on a LEO 912 TEM fitted with an omega in-column elastic energy filter. The direct methods algorithm was then applied to merged intensities and a trial structure obtained assuming single scattering. This was further refined to obtain good agreement with a small residual of about 10% using multiple scattering calculations. A diagram of the proposed structure is given.

Surgical thrombectomy: current role in thromboembolic occlusions.

Thromboembolic disease occurs in a heterogeneous group of patients with significant co-morbidities and variable presentations, resulting in high morbidity and mortality rates. To decrease these complications, multiple different endovascular modalities have been developed and used to treat this challenging problem. Physicians are now left with a broad array of endovascular and surgical options. Unfortunately, there are little data that accurately compare these modalities. Therefore, an individual approach to each patient with acute ischemia from thromboembolic disease must be employed. In order to tailor the treatment to the needs of each patient, the physician must be familiar with the techniques, complications, technology, and relative strengths and weaknesses of each treatment modality. This article will first outline the main technical considerations for performing surgical thromboembolectomy. The complications of operative thromboembolectomy will then be discussed followed by the data comparing operative and nonoperative therapy. Finally, clinical scenarios that are best treated by surgical intervention will be described.

Double-blind, placebo-controlled study of single-dose amphetamine formulations in ADHD.

OBJECTIVE: To compare the efficacy and time course of single morning doses of Adderall, extended-release, and immediate-release dextroamphetamine sulfate. METHOD: Thirty-five children with attention-deficit/hyperactivity disorder, combined type, were given Adderall, immediate-release dextroamphetamine, dextroamphetamine Spansules, and placebo in a randomized, double-blind, crossover study. Behavior ratings, locomotor activity measurements, and academic measures were obtained over a period of 8 weeks. RESULTS: All three drugs exhibited robust efficacy versus placebo on nearly all measures. The effects of dextroamphetamine Spansules were less robust in the morning, particularly compared with Adderall, but they lasted 3 to 6 hours longer, depending on the measure. Although parent behavior ratings and locomotor activity showed improvements up to 12 hours after single doses of all three drugs, the number of math problems attempted and completed correctly 4 hours after dosing were only robustly increased by Spansules. CONCLUSIONS: Both immediate-release amphetamines demonstrated earlier onset of effects, but dextroamphetamine Spansules showed more sustained effects that were present on a wider range of measures.

Mesenteric revascularization in a contaminated abdomen: a case report.

The management of acute mesenteric ischemia in the contaminated abdomen may require the use of an autogenous graft to achieve mesenteric revascularization. The authors present a case of an ischemic small bowel perforation in a 62-year-old-woman whose preoperative angiogram demonstrated occlusion of the celiac, superior mesenteric, and inferior mesenteric arteries. Vein mapping of the right greater saphenous vein demonstrated a dual saphenous system whose individual diameters were more than 4 millimeters. Exploratory laparotomy revealed a diffusely ischemic small bowel and liver, as well as abdominal sepsis from the perforated small bowel. Revascularization was accomplished by using saphenous vein in a nonreversed orientation as a bifurcated conduit from the supraceliac aorta to the hepatic and superior mesenteric arteries. Following revascularization, the liver and small bowel immediately regained a normal perfused appearance and the perforated segment of small bowel was resected and reanastomosed. She returned for a follow-up clinic visit 5 months later and was found to have an asymptomatic 6 cm aneurysm involving the proximal mesenteric vein bypass. The aneurysmal aspect of the vein bypass was replaced with a polytetrafluoroethylene interposition graft originating from the supraceliac aorta. On follow-up 3 months later, her aortomesenteric bypass is patent without aneurysmal recurrence, and she is clinically asymptomatic from any symptoms of mesenteric ischemia.