The photopic negative response in autism spectrum disorder

Background: Visual function can be atypical in autism spectrum disorder and structural imaging of the ganglion cell layers has been reported to differ in these individuals. Therefore, we sought to investigate if the photopic negative response of the full field electroretinograms, a measure of ganglion cell function, could help explain the visual perceptual differences in autism spectrum disorder and support the structural changes observed. / Methods: Participants (n = 55 autism spectrum disorder, aged 5.4–26.7 years) and control (n = 87, aged 5.4–27.3 years) were recruited for the study. Full-field light-adapted electroretinograms using a Troland protocol with 10 flash strengths from −0.367 to 1.204 log photopic cd.s.m−2 were recorded in each eye. The photopic negative response amplitudes at Tmin and at t = 72 ms were compared between groups along with the a- and b-wave values. / Results: There were no significant interactions between groups for the Photopic Negative Response measures of amplitude or time (p > 0.30). There was a group interaction between groups and flash strengths for the b-wave amplitude as previously reported (p < 0.001). / Conclusion: The photopic negative response results suggest that there are no significant differences in the summed retinal ganglion cell responses produced by a full-field stimulus

Spatial variability and changes of metabolite concentrations in the cortico-spinal tract in multiple sclerosis using coronal CSI

We characterized metabolic changes along the cortico-spinal tract (CST) in multiple sclerosis (MS) patients using a novel application of chemical shift imaging (CSI) and considering the spatial variation of metabolite levels. Thirteen relapsing-remitting (RR) and 13 primary-progressive (PP) MS patients and 16 controls underwent (1)H-MR CSI, which was applied to coronal-oblique scans to sample the entire CST. The concentrations of the main metabolites, i.e., N-acetyl-aspartate, myo-Inositol (Ins), choline containing compounds (Cho) and creatine and phosphocreatine (Cr), were calculated within voxels placed in regions where the CST is located, from cerebral peduncle to corona radiata. Differences in metabolite concentrations between groups and associations between metabolite concentrations and disability were investigated, allowing for the spatial variability of metabolite concentrations in the statistical model. RRMS patients showed higher CST Cho concentration than controls, and higher CST Ins concentration than PPMS, suggesting greater inflammation and glial proliferation in the RR than in the PP course. In RRMS, a significant, albeit modest, association between greater Ins concentration and greater disability suggested that gliosis may be relevant to disability. In PPMS, lower CST Cho and Cr concentrations correlated with greater disability, suggesting that in the progressive stage of the disease, inflammation declines and energy metabolism reduces. Attention to the spatial variation of metabolite concentrations made it possible to detect in patients a greater increase in Cr concentration towards the superior voxels as compared to controls and a stronger association between Cho and disability, suggesting that this step improves our ability to identify clinically relevant metabolic changes

A novel approach with "skeletonised MTR" measures tract-specific microstructural changes in early primary-progressive MS

We combined tract‐based spatial statistics (TBSS) and magnetization transfer (MT) imaging to assess white matter (WM) tract‐specific short‐term changes in early primary‐progressive multiple sclerosis (PPMS) and their relationships with clinical progression. Twenty‐one PPMS patients within 5 years from onset underwent MT and diffusion tensor imaging (DTI) at baseline and after 12 months. Patients' disability was assessed. DTI data were processed to compute fractional anisotropy (FA) and to generate a common WM “skeleton,” which represents the tracts that are “common” to all subjects using TBSS. The MT ratio (MTR) was computed from MT data and co‐registered with the DTI. The skeletonization procedure derived for FA was applied to each subject's MTR image to obtain a “skeletonised” MTR map for every subject. Permutation tests were used to assess (i) changes in FA, principal diffusivities, and MTR over the follow‐up, and (ii) associations between changes in imaging parameters and changes in disability. Patients showed significant decreases in MTR over one year in the corpus callosum (CC), bilateral corticospinal tract (CST), thalamic radiations, and superior and inferior longitudinal fasciculi. These changes were located both within lesions and the normal‐appearing WM. No significant longitudinal change in skeletonised FA was found, but radial diffusivity (RD) significantly increased in several regions, including the CST bilaterally and the right inferior longitudinal fasciculus. MTR decreases, RD increases, and axial diffusivity decreases in the CC and CST correlated with a deterioration in the upper limb function. We detected tract‐specific multimodal imaging changes that reflect the accrual of microstructural damage and possibly contribute to clinical impairment in PPMS. We propose a novel methodology that can be extended to other diseases to map cross‐subject and tract‐specific changes in MTR

Who Watches the Watchmen? An Appraisal of Benchmarks for Multiple Sequence Alignment

Multiple sequence alignment (MSA) is a fundamental and ubiquitous technique in bioinformatics used to infer related residues among biological sequences. Thus alignment accuracy is crucial to a vast range of analyses, often in ways difficult to assess in those analyses. To compare the performance of different aligners and help detect systematic errors in alignments, a number of benchmarking strategies have been pursued. Here we present an overview of the main strategies--based on simulation, consistency, protein structure, and phylogeny--and discuss their different advantages and associated risks. We outline a set of desirable characteristics for effective benchmarking, and evaluate each strategy in light of them. We conclude that there is currently no universally applicable means of benchmarking MSA, and that developers and users of alignment tools should base their choice of benchmark depending on the context of application--with a keen awareness of the assumptions underlying each benchmarking strategy.Comment: Revie

Early pericalcarine atrophy in acute optic neuritis is associated with conversion to multiple sclerosis

Background: Previous work showed that pericalcarine cortical volume loss is evident early after presentation with acute clinically isolated optic neuritis (ON). The aims of this study were: (1) to determine whether pericalcarine atrophy in patients with ON is associated with conversion to multiple sclerosis (MS); (2) to investigate whether regional atrophy preferentially affects pericalcarine cortex; and (3) to investigate potential causes of early pericalcarine atrophy using MRI. / Methods: 28 patients with acute ON and 10 controls underwent structural MRI (brain and optic nerves) and were followed-up over 12 months. Associations between the development of MS, optic nerve, optic radiation and pericalcarine cortical damage measures were investigated using multiple linear regression models. Regional cortical volumetric differences between patients and controls were calculated using t tests. / Results: The development of MS at 12 months was associated with greater whole brain and optic radiation lesion loads, shorter acute optic nerve lesions and smaller pericalcarine cortical volume at baseline. Regional atrophy was not evident in other sampled cortical regions. Pericalcarine atrophy was not directly associated with whole brain lesion load, optic radiation measures or optic nerve lesion length. However, the association between pericalcarine atrophy and MS was not independent of these parameters. / Conclusions: Reduced pericalcarine cortical volumes in patients with early clinically isolated ON were associated with the development of MS but volumes of other cortical regions were not. Hence pericalcarine cortical regions appear particularly susceptible to early damage. These findings could be explained by a combination of pathological effects to visual grey and white matter in patients with ON

The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis.

The recently completed European trial of interferon beta-1b (IFN beta -1b) in patients with secondary progressive multiple sclerosis (SP multiple sclerosis) has given an opportunity to assess the impact of treatment on cerebral atrophy using serial MRI. Unenhanced T-1-weighted brain imaging was acquired in a subgroup of 95 patients from five of the European centres; imaging was performed at 6-month intervals from month 0 to month 36. A blinded observer measured cerebral volume on four contiguous 5 mm cerebral hemisphere slices at each time point, using an algorithm with a high level of reproducibility and automation. There was a significant and progressive reduction in cerebral volume in both placebo and treated groups, with a mean reduction of 3.9 and 2.9%, respectively, by month 36 (P = 0.34 between groups). Exploratory subgroup analyses indicated that patients without gadolinium (Gd) enhancement at the baseline had a greater reduction of cerebral volume in the placebo group (mean reduction at month 36: placebo 5.1%, IFN beta -1b 1.8%, P < 0.05) whereas those with Gd-enhancing lesions showed a trend to greater reduction of cerebral volume if the patient was on IFN<beta>-1b (placebo 2.6%, IFN beta -1b, 3.7%; P > 0.05). These results are consistent with ongoing tissue loss in both arms of this study of secondary progressive multiple sclerosis. This finding is concordant with previous observations that disease progression, although delayed, is not halted by IFN beta. The different pattern seen in patients with and without baseline gadolinium enhancement suggests that part of the cerebral volume reduction observed in IFN beta -treated patients may be due to the anti-inflammatory/antioedematous effect of the drug. Longer periods of observation and larger groups of patients may be needed to detect the effects of treatment on cerebral atrophy in this population of patients with advanced disease

Intestinal transplantation in composite visceral grafts or alone

Under FK 506-based immunosuppression, the entire cadaver small bowel except for a few proximal and distal centimeters was translated to 17 randomly matched patients, of whom two had antigraft cytotoxic antibodies (positive cross-match). Eight patients received the intestine only, eight had intestine in continuity with the liver, and one received a full multivisceral graft that included the liver, stomach, and pancreas. One liver-intestine recipient died after an intestinal anastomotic leak, sepsis, and graft- versus-host disease. The other 16 patients are alive after 1 to 23 months, in one case after chronic rejection, graft removal, and retransplantation. Twelve of the patients have been liberated from total parenteral nutrition, including all whose transplantation was 2 months or longer ago. The grafts have supported good nutrition, and in children, have allowed growth and weight gain. Management of these patients has been difficult and often complicated, but the end result has been satisfactory in most cases, justifying further clinical trials. The convalescence of the eight patients receiving intestine only has been faster and more trouble free than after liver-intestine or multivisceral transplantation, with no greater difficulty in the control of rejection

Intestinal transplantation in composite visceral grafts or alone

Under FK 506-based immunosuppression, the entire cadaver small bowel except for a few proximal and distal centimeters was translated to 17 randomly matched patients, of whom two had antigraft cytotoxic antibodies (positive cross-match). Eight patients received the intestine only, eight had intestine in continuity with the liver, and one received a full multivisceral graft that included the liver, stomach, and pancreas. One liver-intestine recipient died after an intestinal anastomotic leak, sepsis, and graft- versus-host disease. The other 16 patients are alive after 1 to 23 months, in one case after chronic rejection, graft removal, and retransplantation. Twelve of the patients have been liberated from total parenteral nutrition, including all whose transplantation was 2 months or longer ago. The grafts have supported good nutrition, and in children, have allowed growth and weight gain. Management of these patients has been difficult and often complicated, but the end result has been satisfactory in most cases, justifying further clinical trials. The convalescence of the eight patients receiving intestine only has been faster and more trouble free than after liver-intestine or multivisceral transplantation, with no greater difficulty in the control of rejection

Interstitial-mediated dislocation climb and the weakening of particle-reinforced alloys under irradiation

Dislocations can climb out of their glide plane by absorbing (or emitting) point defects [vacancies and self-interstitial atoms (SIAs)]. In contrast with conservative glide motion, climb relies on the point defects' thermal diffusion and hence operates on much longer timescales, leading to some forms of creep. While equilibrium point defect concentrations allow dislocations to climb to relieve nonglide stresses, point defect supersaturations also lead to osmotic forces, driving dislocation motion even in the absence of external stresses. Self-interstitial atoms typically have significantly higher formation energies than vacancies, so their contribution to climb is usually ignored. However, under irradiation conditions, both types of defect are athermally created in equal numbers. In this paper, we use simple thermodynamic arguments to show that the contribution of interstitials cannot be neglected in irradiated materials and that the osmotic force they induce on dislocations is many orders of magnitude larger than that caused by vacancies. This explains why the prismatic dislocation loops observed by in situ transmission electron microscope irradiations are more often of interstitial rather than vacancy character. Using discrete dislocation dynamics simulations, we investigate the effect on dislocation-obstacle interactions and find reductions in the depinning time of many orders of magnitude. This has important consequences for the strength of particle-reinforced alloys under irradiation