Genetic nurse counsellors can be an acceptable and cost-effective alternative to clinical geneticists for breast cancer risk genetic counselling. Evidence from two parallel randomised controlled equivalence trials

This study compared genetic nurse counsellors with standard services for breast cancer genetic risk counselling services in two regional genetics centres, in Grampian region, North East Scotland and in Cardiff, Wales. Women referred for genetic counselling were randomised to an initial genetic counselling appointment with either a genetic nurse counsellor (intervention) or a clinical geneticist (current service, control). Participants completed postal questionnaires before, immediately after the counselling episode and 6 months later to assess anxiety, general health status, perceived risk and satisfaction. A parallel economic evaluation explored factors influencing cost-effectiveness. The two concurrent randomised controlled equivalence trials were conducted and analysed separately. In the Grampian trial, 289 patients (193 intervention, 96 control) and in the Wales trial 297 patients (197 intervention and 100 control) returned a baseline questionnaire and attended their appointment. Analysis suggested at least likely equivalence in anxiety (the primary outcome) between the two arms of the trials. The cost per counselling episode was £11.54 less for nurse-based care in the Grampian trial and £12.50 more for nurse-based care in Cardiff. The costs were sensitive to the grade of doctor (notionally) replaced and the extent of consultant supervision required by the nurse. In conclusion, care based on genetic nurse counsellors was not significantly different from conventional cancer genetic services in both trial locations

Seasonal melting and the formation of sedimentary rocks on Mars, with predictions for the Gale Crater mound

A model for the formation and distribution of sedimentary rocks on Mars is proposed. The rate-limiting step is supply of liquid water from seasonal melting of snow or ice. The model is run for a O(10^2) mbar pure CO2 atmosphere, dusty snow, and solar luminosity reduced by 23%. For these conditions snow only melts near the equator, and only when obliquity >40 degrees, eccentricity >0.12, and perihelion occurs near equinox. These requirements for melting are satisfied by 0.01-20% of the probability distribution of Mars' past spin-orbit parameters. Total melt production is sufficient to account for aqueous alteration of the sedimentary rocks. The pattern of seasonal snowmelt is integrated over all spin-orbit parameters and compared to the observed distribution of sedimentary rocks. The global distribution of snowmelt has maxima in Valles Marineris, Meridiani Planum and Gale Crater. These correspond to maxima in the sedimentary-rock distribution. Higher pressures and especially higher temperatures lead to melting over a broader range of spin-orbit parameters. The pattern of sedimentary rocks on Mars is most consistent with a Mars paleoclimate that only rarely produced enough meltwater to precipitate aqueous cements and indurate sediment. The results suggest intermittency of snowmelt and long globally-dry intervals, unfavorable for past life on Mars. This model makes testable predictions for the Mars Science Laboratory rover at Gale Crater. Gale Crater is predicted to be a hemispheric maximum for snowmelt on Mars.Comment: Submitted to Icarus. Minor changes from submitted versio

Brain Changes in Long-Term Zen Meditators Using Proton Magnetic Resonance Spectroscopy and Diffusion Tensor Imaging: A Controlled Study

Introduction: This work aimed to determine whether 1H magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) are correlated with years of meditation and psychological variables in long-term Zen meditators compared to healthy non-meditator controls. Materials and Methods: Design. Controlled, cross-sectional study. Sample. Meditators were recruited from a Zen Buddhist monastery. The control group was recruited from hospital staff. Meditators were administered questionnaires on anxiety, depression, cognitive impairment and mindfulness. 1H-MRS (1.5 T) of the brain was carried out by exploring four areas: both thalami, both hippocampi, the posterior superior parietal lobule (PSPL) and posterior cingulate gyrus. Predefined areas of the brain were measured for diffusivity (ADC) and fractional anisotropy (FA) by MR-DTI. Results: Myo-inositol (mI) was increased in the posterior cingulate gyrus and Glutamate (Glu), N-acetyl-aspartate (NAA) and N-acetyl-aspartate/Creatine (NAA/Cr) was reduced in the left thalamus in meditators. We found a significant positive correlation between mI in the posterior cingulate and years of meditation (r = 0.518; p = .019). We also found significant negative correlations between Glu (r =20.452; p = .045), NAA (r =20.617; p = .003) and NAA/Cr (r =20.448; P = .047) in the left thalamus and years of meditation. Meditators showed a lower Apparent Diffusion Coefficient (ADC) in the left posterior parietal white matter than did controls, and the ADC was negatively correlated with years of meditation (r =20.4850, p = .0066). Conclusions: The results are consistent with the view that mI, Glu and NAA are the most important altered metabolites. This study provides evidence of subtle abnormalities in neuronal function in regions of the white matter in meditators

A Population Genetic Approach to Mapping Neurological Disorder Genes Using Deep Resequencing

Deep resequencing of functional regions in human genomes is key to identifying potentially causal rare variants for complex disorders. Here, we present the results from a large-sample resequencing (n = 285 patients) study of candidate genes coupled with population genetics and statistical methods to identify rare variants associated with Autism Spectrum Disorder and Schizophrenia. Three genes, MAP1A, GRIN2B, and CACNA1F, were consistently identified by different methods as having significant excess of rare missense mutations in either one or both disease cohorts. In a broader context, we also found that the overall site frequency spectrum of variation in these cases is best explained by population models of both selection and complex demography rather than neutral models or models accounting for complex demography alone. Mutations in the three disease-associated genes explained much of the difference in the overall site frequency spectrum among the cases versus controls. This study demonstrates that genes associated with complex disorders can be mapped using resequencing and analytical methods with sample sizes far smaller than those required by genome-wide association studies. Additionally, our findings support the hypothesis that rare mutations account for a proportion of the phenotypic variance of these complex disorders

NMDA receptors are selectively partitioned into complexes and supercomplexes during synapse maturation

How neuronal proteomes self-organize is poorly understood because of their inherent molecular and cellular complexity. Here, focusing on mammalian synapses we use blue-native PAGE and ‘gene-tagging’ of GluN1 to report the first biochemical purification of endogenous NMDA receptors (NMDARs) directly from adult mouse brain. We show that NMDARs partition between two discrete populations of receptor complexes and B1.5MDa supercomplexes. We tested the assembly mechanism with six mouse mutants, which indicates a tripartite requirement of GluN2B, PSD93 and PSD95 gate the incorporation of receptors into B1.5MDa supercomplexes, independent of either canonical PDZ-ligands or GluN2A. Supporting the essential role of GluN2B, quantitative gene-tagging revealed a fourfold molar excess of GluN2B over GluN2A in adult forebrain. NMDAR supercomplexes are assembled late in postnatal development and triggered by synapse maturation involving epigenetic and activity-dependent mechanisms. Finally, screening the quaternary organization of 60 native proteins identified numerous discrete supercomplexes that populate the mammalian synapse

L: Structural and functional abnormalities of retinal ganglion cells measured in vivo at the onset of optic nerve head surface change in experimental glaucoma. Invest Ophthalmol Vis Sci 2012

PURPOSE. To compare peripapillary retinal nerve fiber layer thickness (RNFLT), RNFL retardance, and retinal function at the onset of optic nerve head (ONH) surface topography change in experimental glaucoma (EG). METHODS. Thirty-three rhesus macaques had three or more weekly baseline measurements in both eyes of ONH surface topography, peripapillary RNFLT, RNFL retardance, and multifocal electroretinography (mfERG). Laser photocoagulation was then applied to the trabecular meshwork of one eye to induce chronic elevation of IOP and weekly recordings continued alternating between ONH surface topography and RNFLT during one week and RNFL retardance and mfERG the next week. Data were pooled for the group at the onset of ONH surface topography change in each EG eye, which was defined as the first date when either the mean position of the disc (MPD) fell below the 95% confidence limit of each eye's individual baseline range and/or when the topographic change analysis (TCA) map was subjectively judged as having demonstrated change, whichever came first. Analysis of variance with post hoc tests corrected for multiple comparisons were used to assess parameter changes. RESULTS. At onset of ONH surface topography change, there was no significant difference for RNFLT versus baseline or fellow control eyes. RNFL retardance and mfERG were significantly reduced in the recordings just prior (median of 9 days) to ONH onset (P < 0.01) and had progressed significantly (P < 0.001) an average of 17 days later (median of 7 days after ONH onset). RNFLT did not exhibit significant thinning until 15 days after onset of ONH surface topography change (P < 0.001). CONCLUSIONS. These results support the hypothesis that during the course of glaucomatous neurodegeneration, axonal cytoskeletal and retinal ganglion cell functional abnormalities exist before thinning of peripapillary RNFL axon bundles begins. (Invest Ophthalmol Vis Sci

Local ganglion cell contributions to the macaque electroretinogram revealed by experimental nerve fiber layer bundle defect. Invest Ophthalmol Vis Sci.

PURPOSE. To assess the structural and functional consequences of local ganglion cell (GC) loss in an experimental model of a retinal nerve fiber layer (NFL) bundle defect. To evaluate and compare three commonly used multifocal electroretinogram (mfERG) stimuli, as well as the standard transient patternreversal ERG (pERG) and the photopic full-field ERG, for detection of local GC damage. METHODS. Intraretinal axotomy was achieved by multiple treatments with a diode laser adapted to a slit lamp biomicroscope. Retinal laser burns were applied along an arc, subtending approximately 60°, about one disc diameter superotemporal to the optic nerve. Functional measures were acquired before laser application and at numerous time points thereafter. These included mfERGs for three different stimuli: a standard fast m-sequence flicker, a global-field flash paradigm (MOFO), and a slowed m-sequence (with seven dark frames inserted to each m-step [7F]). pERGs were measured for a 24°ϫ 32°checker-board stimulus (0.56 cyc/deg, 90% contrast, 75 cd/m 2 , 5 reversals/s). Photopic full-field ERGs were measured for red flashes (0.42 log photopic cd-s/m 2 ) on a blue rod-saturating background (30 scotopic cd/m 2 ). Retinal photography, fluorescein angiography and postmortem histologic evaluation of the optic nerve, NFL, and retinal tissues were performed. RESULTS. After six laser sessions, the NFL bundle defect appeared to be complete and contiguous and was visible both proximal to and distal to the site of the photoablation by clinical examination of the fundus and stereoscopic photographs. Histologic evaluation demonstrated localized loss of GC axons, confirmed at the level of the retrobulbar optic nerve. Retinal cross sections in the temporal retina (distal to the axotomy) showed loss of GC soma and NFL degeneration, whereas all other layers appeared intact. mfERGs showed loss of high-frequency components (HFCs) for responses located within the arcuate region corresponding to the NFL defect. Local GC damage was most easily detected using the slowed 7F m-sequence stimulus. This stimulus elicited relatively large HFCs that were significantly reduced from local responses after axotomy and that were tetrodotoxin (TTX)-sensitive in a control experiment. Low-frequency component loss with the 7F stimulus did not reach statistical significance. The photopic full-field ERG was not significantly affected. pERG amplitudes declined significantly from baseline but remained within normal limits. CONCLUSIONS. Focal loss of GC function in the macaque retina is most easily detected using the slowed-sequence mfERG. Local 7F HFCs depend on intact GC function. (Invest Ophthalmol Vis Sci. 2003;44:4567-4579

A Comparison of Optic Nerve Head Morphology Viewed by Spectral Domain Optical Coherence Tomography and by Serial Histology

A comparison between SD-OCT imaging and serial histology in the same normal optic nerve head identifies potential deep targets for longitudinal glaucoma imaging