Similar white matter but opposite grey matter changes in schizophrenia and high-functioning autism.

OBJECTIVE: High-functioning autism (HFA) and schizophrenia (SZ) are two of the main neurodevelopmental disorders, sharing several clinical dimensions and risk factors. Their exact relationship is poorly understood, and few studies have directly compared both disorders. Our aim was thus to directly compare neuroanatomy of HFA and SZ using a multimodal MRI design. METHODS: We scanned 79 male adult subjects with 3T MRI (23 with HFA, 24 with SZ and 32 healthy controls, with similar non-verbal IQ). We compared them using both diffusion-based whole-brain tractography and T1 voxel-based morphometry. RESULTS: HFA and SZ groups exhibited similar white matter alterations in the left fronto-occipital inferior fasciculus with a decrease in generalized fractional anisotropy compared with controls. In grey matter, the HFA group demonstrated bilateral prefrontal and anterior cingulate increases in contrast with prefrontal and left temporal reductions in SZ. CONCLUSION: HFA and SZ may share common white matter deficits in long-range connections involved in social functions, but opposite grey matter abnormalities in frontal regions that subserve complex cognitive functions. Our results are consistent with the fronto-occipital underconnectivity theory of HFA and the altered connectivity hypothesis of SZ and suggest the existence of both associated and diametrical liabilities to these two conditions.

Automatic fiber bundle segmentation in massive tractography datasets using a multi-subject bundle atlas.

This paper presents a method for automatic segmentation of white matter fiber bundles from massive dMRI tractography datasets. The method is based on a multi-subject bundle atlas derived from a two-level intra-subject and inter-subject clustering strategy. This atlas is a model of the brain white matter organization, computed for a group of subjects, made up of a set of generic fiber bundles that can be detected in most of the population. Each atlas bundle corresponds to several inter-subject clusters manually labeled to account for subdivisions of the underlying pathways often presenting large variability across subjects. An atlas bundle is represented by the multi-subject list of the centroids of all intra-subject clusters in order to get a good sampling of the shape and localization variability. The atlas, composed of 36 known deep white matter bundles and 47 superficial white matter bundles in each hemisphere, was inferred from a first database of 12 brains. It was successfully used to segment the deep white matter bundles in a second database of 20 brains and most of the superficial white matter bundles in 10 subjects of the same database.

Robust clustering of massive tractography datasets.

This paper presents a clustering method that detects the fiber bundles embedded in any MR-diffusion based tractography dataset. Our method can be seen as a compressing operation, capturing the most meaningful information enclosed in the fiber dataset. For the sake of efficiency, part of the analysis is based on clustering the white matter (WM) voxels rather than the fibers. The resulting regions of interest are used to define subset of fibers that are subdivided further into consistent bundles using a clustering of the fiber extremities. The dataset is reduced from more than one million fiber tracts to about two thousand fiber bundles. Validations are provided using simulated data and a physical phantom. We see our approach as a crucial preprocessing step before further analysis of huge fiber datasets. An important application will be the inference of detailed models of the subdivisions of white matter pathways and the mapping of the main U-fiber bundles.

Enhanced Automatic Segmentation for Superficial White Matter Fiber Bundles for Probabilistic Tractography Datasets.

This paper presents an enhanced algorithm for automatic segmentation of superficial white matter (SWM) bundles from probabilistic dMRI tractography datasets, based on a multi-subject bundle atlas. Previous segmentation methods use the maximum Euclidean distance between corresponding points of the subject fibers and the atlas centroids. However, this scheme might include noisy fibers. Here, we propose a three step approach to discard noisy fibers improving the identification of fibers. The first step applies a fiber clustering and the segmentation is performed between the centroids of the clusters and the atlas centroids. This step removes outliers and enables a better identification of fibers with similar shapes. The second step applies a fiber filter based on two different fiber similarities. One is the Symmetrized Segment-Path Distance (SSPD) over 2D ISOMAP and the other is an adapted version of SSPD for 3D space. The last step eliminates noisy fibers by removing those that connect regions that are far from the main atlas bundle connections. We perform an experimental evaluation using ten subjects of the Human Connectome (HCP) database. The evaluation only considers the bundles connecting precentral and postcentral gyri, with a total of seven bundles per hemisphere. For comparison, the bundles of the ten subjects were manually segmented. Bundles segmented with our method were evaluated in terms of similarity to manually segmented bundles and the final number of fibers. The results show that our approach obtains bundles with a higher similarity score than the state-of-the-art method and maintains a similar number of fibers.Clinical relevance-Many brain pathologies or disorders can occur in specific regions of the SWM automatic segmentation of reliable SWM bundles would help applications to clinical research.

Impact of serpentinized peridotite mine waste on the composition and quality of sediments in the Ría de Ortigueira (Galicia, NW Spain).

The Ría de Ortigueira is an environmentally well conserved; however, the sediments show high concentrations of toxic elements. In some zones, the concentrations of Ni (60-1080 mg kg-1) and Cr (9-567 mg kg-1) were extremely high, while the concentrations of other toxic elements were within normal ranges. PCA revealed that metal enrichment was due to dumping of waste sludge from a peridotite mine. The study of marine currents showed that the exit of the contaminated waste towards the external zone is restricted by the low energy of the residual currents, and the sludge therefore remains trapped in the internal zones. The potential ecological risk was moderate for all areas of the ría, reaching high values close to the mouth of the river Landoi. Finally, geochemical fractioning showed that most of the metals are associated with Fe oxyhydroxides which can become unstable and release adsorbed or coprecipitated metals, especially Ni.

The effect of the number of fibers in tractography reconstruction of white matter bundles.

The study of white matter (WM) through diffusion Magnetic Resonance Imaging (dMRI) is crucial to obtain a better understanding of human brain connections and functions, at a macroscopic level. A large number of works have focused on long range brain connections, while recently, several studies have also analyzed superficial WM connectivity. In recent years, with the massive use of HCP database, and its processing with known softwares like DSI Studio and MRtrix, it is necessary to evaluate the influence of tractography parameters on the reconstruction of fiber bundles and further analyses. We study the effect of the number of fibers, for whole brain tractography, on the reconstruction of deep and superficial WM bundles based on their segmentation using multi-subject bundle atlases. For DSI Studio (deterministic algorithm), a value of 1M fibers could reconstruct most of deep white matter (DWM) bundles, while a value of 1.5M was required for superficial white matter (SWM) bundles. In the case of MRtrix (probabilistic algorithm), a value of 3M fibers was found to be suitable for the study of both kinds of fibers. Furthermore, we found the tracking of SWM bundles to be more sensitive to several parameters than DWM, for DSI Studio.

Saccharomyces cerevisiae RNA polymerase I terminates transcription at the Reb1 terminator in vivo.

We have mapped transcription termination sites for RNA polymerase I in the yeast Saccharomyces cerevisiae. S1 nuclease mapping shows that the primary terminator is the Reb1p terminator located at +93 downstream of the 3' end of 25S rRNA. Reverse transcription coupled with quantitative PCR shows that approximately 90% of all transcripts terminate at this site. Transcripts which read through the +93 site quantitatively terminate at a fail-safe terminator located further downstream at +250. Inactivation of Rnt1p (an RNase III involved in processing the 3' end of 25S rRNA) greatly stabilizes transcripts extending to both sites and increases readthrough at the +93 site. In vivo assay of mutants of the Reb1p terminator shows that this site operates in vivo by the same mechanism as has previously been delineated through in vitro studies.

HRTEM Microstructural Characterization of ß-WO3 Thin Films Deposited by Reactive RF Magnetron Sputtering.

Though tungsten trioxide (WO3) in bulk, nanosphere, and thin film samples has been extensively studied, few studies have been dedicated to the crystallographic structure of WO3 thin films. In this work, the evolution from amorphous WO3 thin films to crystalline WO3 thin films is discussed. WO3 thin films were fabricated on silicon substrates (Si/SiO2) by RF reactive magnetron sputtering. Once a thin film was deposited, two successive annealing treatments were made: an initial annealing at 400 °C for 6 h was followed by a second annealing at 350 °C for 1 h. Film characterization was carried out by X-ray diffraction (XRD), high-resolution electron transmission microscopy (HRTEM), scanning electron microscopy (SEM), and atomic force microscopy (AFM) techniques. The ß-WO3 final phase grew in form of columnar crystals and its growth plane was determined by HRTEM.

Whole genome sequencing of Shigella sonnei through PulseNet Latin America and Caribbean: advancing global surveillance of foodborne illnesses.

OBJECTIVES: Shigella sonnei is a globally important diarrhoeal pathogen tracked through the surveillance network PulseNet Latin America and Caribbean (PNLA&C), which participates in PulseNet International. PNLA&C laboratories use common molecular techniques to track pathogens causing foodborne illness. We aimed to demonstrate the possibility and advantages of transitioning to whole genome sequencing (WGS) for surveillance within existing networks across a continent where S. sonnei is endemic. METHODS: We applied WGS to representative archive isolates of S. sonnei (n = 323) from laboratories in nine PNLA&C countries to generate a regional phylogenomic reference for S. sonnei and put this in the global context. We used this reference to contextualise 16 S. sonnei from three Argentinian outbreaks, using locally generated sequence data. Assembled genome sequences were used to predict antimicrobial resistance (AMR) phenotypes and identify AMR determinants. RESULTS: S. sonnei isolates clustered in five Latin American sublineages in the global phylogeny, with many (46%, 149 of 323) belonging to previously undescribed sublineages. Predicted multidrug resistance was common (77%, 249 of 323), and clinically relevant differences in AMR were found among sublineages. The regional overview showed that Argentinian outbreak isolates belonged to distinct sublineages and had different epidemiologic origins. CONCLUSIONS: Latin America contains novel genetic diversity of S. sonnei that is relevant on a global scale and commonly exhibits multidrug resistance. Retrospective passive surveillance with WGS has utility for informing treatment, identifying regionally epidemic sublineages and providing a framework for interpretation of prospective, locally sequenced outbreaks.

Creation of a whole brain short association bundle atlas using a hybrid approach.

The Human brain connection map is far from being complete. In particular the study of the superficial white matter (SWM) is an unachieved task. Its description is essential for the understanding of human brain function and the study of pathogenesis triggered by abnormal connectivity. In this work we expanded a previously developed method for the automatic creation of a whole brain SWM bundle atlas. The method is based on a hybrid approach. First a cortical parcellation is used to extract fibers connecting two regions. Then an intra-and inter-subject hierarchical clustering are applied to find well-defined SWM bundles reproducible across subjects. In addition to the fronto-parietal and insula regions of the left hemisphere, the analysis was extended to the temporal and occipital lobes, including all their internal regions, for both hemispheres. Validation steps are performed in order to test the robustness of the method and the reproducibility of the obtained bundles. First the method was applied to two independent groups of subjects, in order to discard bundles without match across the two independent atlases. Then, the resulting intersection atlas was projected on a third independent group of subjects in order to filter out bundles without reproducible and reliable projection. The final multi-subject U-fiber atlas is composed of 100 bundles in total, 50 per hemisphere, from which 35 are common to both hemispheres. The atlas can be used in clinical studies for segmentation of the SWM bundles in new subjects, and measure DW values or complement functional data.

Short association bundle atlas based on inter-subject clustering from HARDI data.

This paper is focused on the study of short brain association fibers. We present an automatic method to identify short bundles of the superficial white matter based on inter-subject hierarchical clustering. Our method finds clusters of similar fibers, belonging to the different subjects, according to a distance measure between fibers. First, the algorithm obtains representative bundles and subsequently we perform an automatic labeling based on the anatomy, of the most stable connections. The analysis was applied to two independent groups of 37 subjects. Results between the two groups were compared, in order to keep reproducible connections for the atlas creation. The method was applied using linear and non-linear registration, where the non-linear registration showed significantly better results. A final atlas with 35 bundles in the left hemisphere and 27 in the right hemisphere from the whole brain was obtained. Finally results were validated using the atlas to segment 26 new subjects from another HARDI database.

Spatial normalization of brain images and beyond.

The deformable atlas paradigm has been at the core of computational anatomy during the last two decades. Spatial normalization is the variant endowing the atlas with a coordinate system used for voxel-based aggregation of images across subjects and studies. This framework has largely contributed to the success of brain mapping. Brain spatial normalization, however, is still ill-posed because of the complexity of the human brain architecture and the lack of architectural landmarks in standard morphological MRI. Multi-atlas strategies have been developed during the last decade to overcome some difficulties in the context of segmentation. A new generation of registration algorithms embedding architectural features inferred for instance from diffusion or functional MRI is on the verge to improve the architectural value of spatial normalization. A better understanding of the architectural meaning of the cortical folding pattern will lead to use some sulci as complementary constraints. Improving the architectural compliance of spatial normalization may impose to relax the diffeomorphic constraint usually underlying atlas warping. A two-level strategy could be designed: in each region, a dictionary of templates of incompatible folding patterns would be collected and matched in a way or another using rare architectural information, while individual subjects would be aligned using diffeomorphisms to the closest template. Manifold learning could help to aggregate subjects according to their morphology. Connectivity-based strategies could emerge as an alternative to deformation-based alignment leading to match the connectomes of the subjects rather than images.

Automatic segmentation of short association bundles using a new multi-subject atlas of the left hemisphere fronto-parietal brain connections.

Human brain connection map is far from being complete. In particular the study of the superficial white matter (SWM) is an unachieved task. Its description is essential for the understanding of human brain function and the study of the pathogenesis associated to it. In this work we developed a method for the automatic creation of a SWM bundle multi-subject atlas. The atlas generation method is based on a cortical parcellation for the extraction of fibers connecting two different gyri. Then, an intra-subject fiber clustering is applied, in order to divide each bundle into sub-bundles with similar shape. After that, a two-step inter-subject fiber clustering is used in order to find the correspondence between the sub-bundles across the subjects, fuse similar clusters and discard the outliers. The method was applied to 40 subjects of a high quality HARDI database, focused on the left hemisphere fronto-parietal and insula brain regions. We obtained an atlas composed of 44 bundles connecting 22 pair of ROIs. Then the atlas was used to automatically segment 39 new subjects from the database.

Protamine inhibits angiogenesis and growth of C6 rat glioma; a synergistic effect when combined with carmustine.

Protamine inhibits angiogenesis and blocks endothelial, fibroblast and platelet growth factors. Human and experimental gliomas spread and grow in response to both paracrine and autocrine release of these factors. Our objective was to study the effect of protamine administration on cell proliferation, angiogenesis and tumoral growth of C6 glioma. Additionally, we compared the antitumoral effect of protamine with that of another inhibitor of angiogenesis, suramin, and investigated a potential synergistic antitumoral action of low doses of protamine combined with the antineoplastic carmustine. C6 glioma cells were implanted subcutaneously in Wistar rats. A highly malignant glioma developed in 80% of animals; when the tumour reached a diameter of 1.5 cm, either protamine, suramin, carmustine or protamine plus carmustine were administered in various doses. Tumour parameters were measured and compared between groups. In a dose-dependent manner, protamine reduced tumour volume (P < 0.001), mitotic index (P < 0.05), vascular density (P < 0.05) and cell viability (P < 0.005) of C6 glioma. An ultrastructural study demonstrated membranous inclusions in the cytoplasm of 28% of tumoral and endothelial cells of tumours from animals treated with protamine. The inhibition of tumoral growth produced by moderate doses of protamine was similar to that produced by toxic doses of suramin. The combination of protamine and carmustine had a synergistic curtailing effect on tumoral growth (P < 0.001). Our results indicate that protamine is an effective agent against glioblastoma; in non-toxic doses it could potentiate the antineoplastic effect of nitrosoureas for the treatment of glial tumours.

The ribosomal gene spacer as a tool for the taxonomy of Leishmania.

A recombinant DNA ribosomal gene spacer of Leishmania braziliensis Y was used as probe to test different Leishmania species. Based on the similarity of their restriction patterns, three groups were distinguished with respect to international Leishmania references: first a group with a similar restriction pattern to L. braziliensis Y and the reference organism L. mexicana garnhami JAP78; a second group with restriction patterns similar to the reference organism L. mexicana mexicana M379; and finally a group where all the restriction patterns were related to the reference organism L. braziliensis braziliensis M2903. These results support the existence of L. garnhami as an independent Leishmania species; they confirm previous studies on L. mexicana and L. braziliensis and open the way for the more exact diagnosis of New World Leishmaniasis.

Repetitive sequences in the ribosomal intergenic spacer of Trypanosoma cruzi.

A fragment of Trypanosoma cruzi ribosomal intergenic spacer (IGS) located at 6.7 kb from the 3' end of the 24S rRNA gene was analyzed. This IGS fragment is characterized by the presence of three types of repetitive elements (designated Spacer Repetitive Elements, SRE), short direct repeats (5-6 bp) and chi-like recombinational sequences. SRE elements are composed of relatively short repeats (43-145 bp) which show variabilities consisting of nucleotide changes, insertions and deletions. SRE-1 element (145 bp) has a short oligo(dA) tail at the end of the repeat and can be found flanked by other SRE elements. SRE elements are species-specific, suggesting that probes based on them may be diagnostic for Trypanosoma cruzi.

Identification of new world Leishmania using ribosomal gene spacer probes.

DNA probes from the nontranscribed ribosomal spacer (NTS), of Leishmania garnhami and Leishmania braziliensis were constructed and tested for sensitivity and specificity against different Leishmania isolates. The L. garnhami probes were species-specific under hybridization conditions of high stringency, but displayed specificity for the mexicana complex under conditions of intermediate stringency. The L. braziliensis probes showed 'complex' specificity. RFLP for the nontranscribed spacer within the braziliensis complex revealed very homogeneous patterns even for organisms currently accepted as different species. A PCR assay for the detection of Leishmania from the braziliensis complex is presented.

Paradoxical effect of aspirin on the growth of C6 rat glioma and on time of development of ENU-induced tumors of the nervous system.

PURPOSE: Administration of acetylsalicylic acid (ASA), an inhibitor of the synthesis of prostaglandins and thrombzoxanes, decreases the incidence of colorectal cancer and other neoplasms and inhibits in vitro some tumor growth. We studied the effect of various doses of ASA on the growth of C6 glioma implanted in rats as well as the effect of chronic administration of ASA on time of development and incidence of tumors of the central nervous system (CNS) induced by prenatal exposure to ethylnitrosourea (ENU). METHODS: In a controlled study, various doses of ASA, 12.5, 25, 50, 100, 200, 300, and 400 mg/kg per day, were administered to Wistar rats in whom a subcutaneous C6 glioma had been transplanted. Changes in tumor size, histologic characteristics, mitotic index, cell proliferation, and vascular density were studied. In a parallel experiment, we administered ASA (70 mg/kg per day) to rats who were prenatally exposed to ENU; treatment started on day 50 of age, and continued until the end of the experiment at day 400. The time of tumor development as well as incidence, localization, and histological diagnosis were compared with matched controls. RESULTS: A paradoxical effect of ASA administration was observed on the dynamics of cell proliferation of C6 glioma. When high ASA doses were administered (200 or 400 mg/kg per day), tumor volume, cell proliferation, vascular density, and mitotic index increased. In contrast, when low doses were administered (12.5 or 25 mg/kg per day) the tumor size diminished. In the second experiment, localization and incidence of CNS tumors induced by ENU were similar in animals treated with ASA and in controls; however, in rats treated with ASA the time of tumor development was shortened. CONCLUSIONS: The growth-promoting effects of high doses of ASA found in the present study in both transplanted and chemically-induced brain tumors, might be due to the blockage of autocrine inhibitory factors dependent on the cyclooxygenase pathway or by increased vascular permeability and blood supply to the tumor due to inhibition of platelet aggregation. In contrast, the inhibition of tumor growth obtained with low ASA doses in transplanted glioma might be due to different mechanisms such as the induction of apoptosis.

Interstitial quinacrine for elimination of abnormal tissue; therapy of experimental glioma.

BACKGROUND: When quinacrine is injected interstitially, an intense migration of leukocytes and accumulation of various lymphokines is obtained locally, and the reaction is followed by cicatricial fibrosis. This property has been used in humans to induce tubal fibrosis in women and pleurodesis in patients with pleural effusion. METHODS: In a controlled study, a single dose of 150 mg of quinacrine was injected interstitially into a C6 glioma implanted in the subcutaneous tissue of Wistar rats. Changes in size, histologic variations, and microscopic characteristics of leukocyte subpopulations infiltrating the tumor were studied by immunohistochemistry. Tumor necrosis factor and interleukin-1 beta were measured at different times in tumor homogenates. RESULTS: The day after the injection of quinacrine, infiltration of leukocytes and macrophages was observed, accompanied by an accumulation of proinflammatory endogenous cytokines. Tumoral necrosis soon ensued; complete tumor disappearance was obtained in 72% of the animals. Cicatrization proceeded without injury of perilesional structures. In all controls injected with the vehicle, a large tumor developed (P <.0001). CONCLUSIONS: Quinacrine, when administered interstitially in a single dose, elicits an intense local recruitment and proliferation of activated immune cells that, at the dose used in this study, induces tissue necrosis within a radius of 1 cm around the site of quinacrine injection, leaving the surrounding tissue unharmed.