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Homeobox A1 (HOXA1) has been proposed as a candidate gene for autism spectrum disorder (ASD) as it regulates embryological patterning of hind-brain structures implicated in autism neurobiology. In line with this notion, a nonsynonymous single nucleotide polymorphism within a highly conserved domain of HOXA1A218G (rs10951154)has been linked to both ASD risk, and cross-sectional differences in superior posterior lobar cerebellar anatomy in late adulthood. Despite evidence for early onset and developmentally dynamic cerebellar involvement in ASD, little is known of the relationship between A218G genotype and maturation of the cerebellum over early development. We addressed this issue using 296 longitudinally acquired structural magnetic resonance imaging brain scans from 116 healthy individuals between 5 and 23 years of age. Mixed models were used to compare the relationship between age and semi-automated measures of cerebellar volume in A-homozygotes (AA) and carriers of the G allele (Gcar). Total cerebellar volume increased between ages of 5 and 23 years in both groups. However, this was accelerated in the Gcar relative to the AA group (Genotype-by-age interaction term, P?=?0.03), and driven by genotype-dependent differences in the rate of bilateral superior posterior lobar volume change with age (P?=?0.002). Resultantly, although superior posterior lobar volume did not differ significantly between genotype groups at age 5 (P?=?0.9), by age 23 it was 12% greater in Gcar than AA (P?=?0.002). Our results suggest that common genetic variation within this putative ASD risk gene has the capacity to modify the development of cerebellar systems implicated in ASD neurobiology.

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.

Children who are adept at any one of the three academic 'R's (reading, writing and arithmetic) tend to be good at the others, and grow into adults who are similarly skilled at diverse intellectually demanding activities. Determining the neuroanatomical correlates of this relatively stable individual trait of general intelligence has proved difficult, particularly in the rapidly developing brains of children and adolescents. Here we demonstrate that the trajectory of change in the thickness of the cerebral cortex, rather than cortical thickness itself, is most closely related to level of intelligence. Using a longitudinal design, we find a marked developmental shift from a predominantly negative correlation between intelligence and cortical thickness in early childhood to a positive correlation in late childhood and beyond. Additionally, level of intelligence is associated with the trajectory of cortical development, primarily in frontal regions implicated in the maturation of intelligent activity. More intelligent children demonstrate a particularly plastic cortex, with an initial accelerated and prolonged phase of cortical increase, which yields to equally vigorous cortical thinning by early adolescence. This study indicates that the neuroanatomical expression of intelligence in children is dynamic.

Antibiotic prophylaxis is indicated for patients undergoing amputation for severe ischaemia or gangrene. However, the adequacy of tissue levels of antibiotics in ischaemic tissue is not known. In this study the serum and tissue antibiotic levels were measured after intravenous administration of metronidazole (15 mg/kg body weight) and cephradine (20 mg/kg body weight). In 11 patients, venous samples were taken at time 0 (induction of anaesthesia) 10, 30 and 60 min. Samples of 2 g each of fat and muscle were collected from the amputation site and three distal sites. Metronidazole and cephradine levels were measured and the degree of limb ischaemia estimated preoperatively by an isotope limb blood flow method. Our results indicate that both metronidazole and cephradine penetrate ischaemic tissues to levels equivalent of a Mean Inhibitory Concentration (MIC) 50 for most organisms encountered in vascular surgery, and that the degree of ischaemia does not alter this.