Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation

The TUBA1A gene encodes tubulin alpha-1A, a protein that is highly expressed in the fetal brain. Alpha- and beta-tubulin subunits form dimers, which then co-assemble into microtubule polymers: dynamic, scaffold-like structures that perform key functions during neurogenesis, neuronal migration, and cortical organisation. Mutations in TUBA1A have been reported to cause a range of brain malformations. We describe four unrelated patients with the same de novo missense mutation in TUBA1A, c.5G>A, p.(Arg2His), as found by next generation sequencing. Detailed comparison revealed similar brain phenotypes with mild variability. Shared features included developmental delay, microcephaly, hypoplasia of the cerebellar vermis, dysplasia or thinning of the corpus callosum, small pons, and dysmorphic basal ganglia. Two of the patients had bilateral perisylvian polymicrogyria. We examined the effects of the p.(Arg2His) mutation by computer-based protein structure modelling and heterologous expression in HEK-293 cells. The results suggest the mutation subtly impairs microtubule function, potentially by affecting inter-dimer interaction. Based on its sequence context, c.5G>A is likely to be a common recurrent mutation. We propose that the subtle functional effects of p.(Arg2His) may allow for other factors (such as genetic background or environmental conditions) to influence phenotypic outcome, thus explaining the mild variability in clinical manifestations

Uropathogenic Escherichia coli Modulates Immune Responses and Its Curli Fimbriae Interact with the Antimicrobial Peptide LL-37

Bacterial growth in multicellular communities, or biofilms, offers many potential advantages over single-cell growth, including resistance to antimicrobial factors. Here we describe the interaction between the biofilm-promoting components curli fimbriae and cellulose of uropathogenic E. coli and the endogenous antimicrobial defense in the urinary tract. We also demonstrate the impact of this interplay on the pathogenesis of urinary tract infections. Our results suggest that curli and cellulose exhibit differential and complementary functions. Both of these biofilm components were expressed by a high proportion of clinical E. coli isolates. Curli promoted adherence to epithelial cells and resistance against the human antimicrobial peptide LL-37, but also increased the induction of the proinflammatory cytokine IL-8. Cellulose production, on the other hand, reduced immune induction and hence delayed bacterial elimination from the kidneys. Interestingly, LL-37 inhibited curli formation by preventing the polymerization of the major curli subunit, CsgA. Thus, even relatively low concentrations of LL-37 inhibited curli-mediated biofilm formation in vitro. Taken together, our data demonstrate that biofilm components are involved in the pathogenesis of urinary tract infections by E. coli and can be a target of local immune defense mechanisms

De novo mutations in GRIN1 cause extensive bilateral polymicrogyria

Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria

Moving to music:Effects of heard and imagined musical cues on movement-related brain activity

Music is commonly used to facilitate or support movement, and increasingly used in movement rehabilitation. Additionally, there is some evidence to suggest that music imagery, which is reported to lead to brain signatures similar to music perception, may also assist movement. However, it is not yet known whether either imagined or musical cueing changes the way in which the motor system of the human brain is activated during simple movements. Here, functional Magnetic Resonance Imaging (fMRI) was used to compare neural activity during wrist flexions performed to either heard or imagined music with self-pacing of the same movement without any cueing. Focusing specifically on the motor network of the brain, analyses were performed within a mask of BA4, BA6, the basal ganglia (putamen, caudate and pallidum), the motor nuclei of the thalamus and the whole cerebellum. Results revealed that moving to music compared with self-paced movement resulted in significantly increased activation in left cerebellum VI. Moving to imagined music led to significantly more activation in pre-supplementary motor area (pre-SMA) and right globus pallidus, relative to self-paced movement. When the music and imagery cueing conditions were contrasted directly, movements in the music condition showed significantly more activity in left hemisphere cerebellum VII and right hemisphere and vermis of cerebellum IX, while the imagery condition revealed more significant activity in pre-SMA. These results suggest that cueing movement with actual or imagined music impacts upon engagement of motor network regions during the movement, and suggest that heard and imagined cues can modulate movement in subtly different ways. These results may have implications for the applicability of auditory cueing in movement rehabilitation for different patient populations

Neuroimaging: what neuroradiological features distinguish abusive from non-abusive head trauma? A systematic review

Objectives To identify the evidence base behind the neuroradiological features that differentiate abusive head trauma (AHT) from non-abusive head trauma (nAHT). Design Systematic review. Setting Literature search of 14 databases, websites, textbooks, conference abstracts and references (1970–February 2010). Studies had two independent reviews (three if disputed) and critical appraisal. Patients Primary comparative studies of children <11 years old hospitalised with AHT and nAHT diagnosed on CT or MRI. Main outcome measures Neuroradiological features that differentiated AHT from nAHT. Results 21 studies of children predominantly <3 years old were analysed. Subdural haemorrhages (SDH) were significantly associated with AHT (OR 8.2, 95% CI 6.1 to 11). Subarachnoid haemorrhages were seen equally in AHT and nAHT and extradural haemorrhages (EDH) were significantly associated with nAHT (OR for AHT 0.1, 95% CI 0.07 to 0.18). Multiple (OR 6, 95% CI 2.5 to 14.4), interhemispheric (OR 7.9, 95% CI 4.7 to 13), convexity (OR 4.9, 95% CI 1.3 to 19.4) and posterior fossa haemorrhages (OR 2.5, 95% CI 1 to 6) were associated with AHT. Hypoxic-ischaemic injury (HII) (OR 3.7, 95% CI 1.4 to 10) and cerebral oedema (OR 2.2, 95% CI 1.0 to 4.5) were significantly associated with AHT, while focal parenchymal injury was not a discriminatory feature. SDH of low attenuation were more common in AHT than in nAHT. Conclusion Multiple SDH over the convexity, interhemispheric haemorrhages, posterior fossa SDH, HII and cerebral oedema are significantly associated with AHT and should be considered together with clinical features when identifying the condition