Imaging EEG synchronization in schizophrenia patients with S-estimator

Recently a new measure of the cooperative behavior of simultaneous time series was introduced (Carmeli et al. NeuroImage 2005). This measure called S-estimator is defined from the embedding dimension in a state space. S-estimator quantifies the amount of synchronization within a data set by comparing the actual dimensionality of the set with the expected full dimensionality of the asynchronous set. It has the advantage of being a multivariate measure over traditionally used in systems neuroscience bivariate measures of synchronization. Multivariate measures of synchronization are of particular interest for applications in the field of modern multichannel EEG research, since they easily allow mapping of local and/or regional synchronization and are compatible with other imaging techniques. We applied Sestimator to the analysis of EEG synchronization in schizophrenia patients vs. matched controls. The whole-head mapping with S-estimator revealed a specific pattern of local synchronization in schizophrenia patients. The differences in the landscape of synchronization included decreased local synchronization in the territories over occipital and midline areas and increased synchronization over temporal areas. In frontal areas, the S-estimator revealed a tendency for an asymmetry: decreased S-values over the left hemisphere were adjacent to increased values over the right hemisphere. Separate calculations showed reproducibility of this pattern across the main EEG frequency bands. The maintenance of the same synchronization landscape across EEG frequencies probably implies the structural changes in the cortical circuitry of schizophrenia patients. These changes are regionally specific and suggest that schizophrenia is a misconnectivity rather than hypo- or hyper-connectivity disorder.

Repeat Dispensing

Repeat Dispensing

Genetic variability in Brazilian populations of Biomphalaria straminea complex detected by simple sequence repeat anchored polymerase chain reaction amplification

Biomphalaria glabrata, B. tenagophila and B. straminea are intermediate hosts of Schistosoma mansoni, in Brazil. The latter is of epidemiological importance in the northwest of Brazil and, due to morphological similarities, has been grouped with B. intermedia and B. kuhniana in a complex named B. straminea. In the current work, we have standardized the simple sequence repeat anchored polymerase chain reaction (SSR-PCR) technique, using the primers (CA)8RY and K7, to study the genetic variability of these species. The similarity level was calculated using the Dice coefficient and genetic distance using the Nei and Li coefficient. The trees were obtained by the UPGMA and neighbor-joining methods. We have observed that the most related individuals belong to the same species and locality and that individuals from different localities, but of the same species, present clear heterogeneity. The trees generated using both methods showed similar topologies. The SSR-PCR technique was shown to be very efficient in intrapopulational and intraspecific studies of the B. straminea complex snails.

Sequencing of simple sequence repeat anchored polymerase chain reaction amplification products of Biomphalaria glabrata

Simple sequence repeat anchored polymerase chain reaction amplification (SSR-PCR) is a genetic typing technique based on primers anchored at the 5' or 3' ends of microsatellites, at high primer annealing temperatures. This technique has already been used in studies of genetic variability of several organisms, using different primer designs. In order to conduct a detailed study of the SSR-PCR genomic targets, we cloned and sequenced 20 unique amplification products of two commonly used primers, CAA(CT)6 and (CA)8RY, using Biomphalaria glabrata genomic DNA as template. The sequences obtained were novel B. glabrata genomic sequences. It was observed that 15 clones contained microsatellites between priming sites. Out of 40 clones, seven contained complex sequence repetitions. One of the repeats that appeared in six of the amplified fragments generated a single band in Southern analysis, indicating that the sequence was not widespread in the genome. Most of the annealing sites for the CAA(CT)6 primer contained only the six repeats found within the primer sequence. In conclusion, SSR-PCR is a useful genotyping technique. However, the premise of the SSR-PCR technique, verified with the CAA(CT)6 primer, could not be supported since the amplification products did not result necessarily from microsatellite loci amplification.

Bowel cancer screening: the repeat test (English and 10 translations)

Format: 6 page A5 leaflet Target group: Participants in the Northern Ireland Bowel cancer screening programme who require a second test. Description: This leaflet provides step by step instructions on using the Faecal Immunochemical Test (FIT) for bowel cancer screening.

Colposcopic evaluation after a repeat atypical squamous cells of undetermined significance (ASCUS) smear.

OBJECTIVES: Management of patients with atypical squamous cells of undetermined significance (ASCUS) remains controversial. We chose to repeat the Pap smear after four months. If ASCUS persisted in this second test, the patient was advised to undergo colposcopy. Our objective is to determine the clinical significance and the prediction of neoplasia among these patients through a colposcopic examination. METHODS: Of 29,827 patients who had a Pap smear, ASCUS were detected in 1387 (5%) and persisted in the repeat smear of 225 (16%). Colposcopy and an additional Pap smear were performed on 186 patients. RESULTS: Out of 186 colposcopic evaluations, 91 (49%) were normal and the patients had a negative Pap smear. Colposcopy was abnormal in 95/186 patients (51%) (Table 1). Histology of the directed biopsies revealed 38 (21%) low-grade squamous intraepithelial lesions (LSIL) and 17 (9%) high-grade squamous intraepithelial lesions (HSIL). Forty patients (21%) with normal biopsies had ASCUS for the third time in the Pap smear. CONCLUSIONS: Colposcopic evaluation after a repeated Pap smear with ASCUS is an appropriate cost-effective management. Finding 30% of LSIL or HSIL justifies this additional investigation.

Surgical outcomes following repeat non-penetrating glaucoma filtration surgery at a tertiary referral centre

Purpose:To determine the surgical outcomes of patients undergoing repeat deep sclerectomies with collagen implant (DSCI) at a tertiary referral centre. Methods:The medical notes of 208 patients undergoing multiple DSCI were reviewed. Those undergoing repeat DSCI were identified and post operative data for each DSCI were analysed. Group A: the first DSCI; group B: second DSCI; group C: third DSCI. Results:Mean age was 66.8 ±13.0 years. At 12 months, percentage of mean IOP reduction in groups were 18%, 24% and 17% respectively. Mean interval to starting glaucoma medications, re-operation, mitomycin injection and goniopuncture all decreased as the number of operations increased. There was a significant reduction in complete success rates between groups A and B and groups B and C. Few minor complications were observed in all 3 groups. Conclusions:Despite the possibility of bleb independent outflow pathways in patients undergoing non-penetrating surgery, there are significantly reduced success rates in eyes undergoing repeat DSCI. This has important implications for the choice of subsequent operations in patients who have failed non-penetrating filtration surgery.

The serine repeat antigen (SERA) gene family phylogeny in Plasmodium: the impact of GC content and reconciliation of gene and species trees.

Plasmodium falciparum is the parasite responsible for the most acute form of malaria in humans. Recently, the serine repeat antigen (SERA) in P. falciparum has attracted attention as a potential vaccine and drug target, and it has been shown to be a member of a large gene family. To clarify the relationships among the numerous P. falciparum SERAs and to identify orthologs to SERA5 and SERA6 in Plasmodium species affecting rodents, gene trees were inferred from nucleotide and amino acid sequence data for 33 putative SERA homologs in seven different species. (A distance method for nucleotide sequences that is specifically designed to accommodate differing GC content yielded results that were largely compatible with the amino acid tree. Standard-distance and maximum-likelihood methods for nucleotide sequences, on the other hand, yielded gene trees that differed in important respects.) To infer the pattern of duplication, speciation, and gene loss events in the SERA gene family history, the resulting gene trees were then "reconciled" with two competing Plasmodium species tree topologies that have been identified by previous phylogenetic studies. Parsimony of reconciliation was used as a criterion for selecting a gene tree/species tree pair and provided (1) support for one of the two species trees and for the core topology of the amino acid-derived gene tree, (2) a basis for critiquing fine detail in a poorly resolved region of the gene tree, (3) a set of predicted "missing genes" in some species, (4) clarification of the relationship among the P. falciparum SERA, and (5) some information about SERA5 and SERA6 orthologs in the rodent malaria parasites. Parsimony of reconciliation and a second criterion--implied mutational pattern at two key active sites in the SERA proteins-were also seen to be useful supplements to standard "bootstrap" analysis for inferred topologies.

Synchronization of EEG: bivariate and multivariate measures.

Synchronization behavior of electroencephalographic (EEG) signals is important for decoding information processing in the human brain. Modern multichannel EEG allows a transition from traditional measurements of synchronization in pairs of EEG signals to whole-brain synchronization maps. The latter can be based on bivariate measures (BM) via averaging over pair-wise values or, alternatively, on multivariate measures (MM), which directly ascribe a single value to the synchronization in a group. In order to compare BM versus MM, we applied nine different estimators to simulated multivariate time series with known parameters and to real EEGs.We found widespread correlations between BM and MM, which were almost frequency-independent for all the measures except coherence. The analysis of the behavior of synchronization measures in simulated settings with variable coupling strength, connection probability, and parameter mismatch showed that some of them, including S-estimator, S-Renyi, omega, and coherence, aremore sensitive to linear interdependences,while others, like mutual information and phase locking value, are more responsive to nonlinear effects. Onemust consider these properties together with the fact thatMM are computationally less expensive and, therefore, more efficient for the large-scale data sets than BM while choosing a synchronization measure for EEG analysis.

Bowel cancer screening: the repeat test (English and 10 translations)

This leaflet provides step by step instructions on using the Faecal Immunochemical Test (FIT) for bowel cancer screening.The translations are of the 2010 versions when screening was for 60��-69 year olds but this has been extended to 60��-74 year olds.

Abnormal EEG Synchronization Correlates with Demyelination in Alzheimer's Disease

Introduction : The pathological processes caused by Alzheimer's disease (AD) supposedly disrupt communication between and within the distributed cortical networks due to the dysfunction/loss of synapses and myelination breakdown. Indeed, recently (Knyazeva et al. 2008), we have revealed the whole-head topography of EEG synchronization specific to AD. Here we analyze whether and how these abnormalities of synchronization are related to the demyelination of cortico-cortical fibers. Methods : Fifteen newly diagnosed AD patients (CDR 0.5-1) and 15 controls matched for age, participated in the study. Their multichannel (128) EEGs were recorded during 3-5 min at rest. They were submitted to the multivariate phase synchronization (MPS) analysis for mapping regional synchronization. To obtain individual whole-head maps, the MPS was computed for each sensor considering its 2nd nearest topographical neighbors. Separate calculations were performed for the delta, theta, alpha-1/−2, and beta-1/−2 EEG bands. The same subjects were scanned on a 3 Tesla Philips scanner. The protocol included a high-resolution T1-weighted sequence and a Magnetization Transfer Imaging (MTI) acquisition. For each subject, we defined a 3mm thick layer of white matter exactly below the cortical gray matter. The magnetization transfer ratio (MTR) - an estimator of myelination - was calculated for this layer in 39 Brodmann-defined ROIs per hemisphere. To assess the between-group differences, we used a permutation version of Hotelling's T2 test or two-sample T-test (Pcorrected <0.05). For correlation analysis, Spearman Rank Correlation was calculated. Results : In AD patients, we have found an abnormal landscape of synchronization characterized by a decrease in MPS over the fronto-temporal region of the left hemisphere and an increase over the temporo-parieto-occipital regions bilaterally. Also, we have shown a widespread decrease in regional MTR in the AD patients for all the areas excluding motor, premotor, and primary sensory ones. Assuming that AD-related changes in synchronization are associated with demyelination, we hypothesized a correlation between the regional MTR values and MPS values in the hypo- and hyper-synchronized clusters. We found that MPS in the left fronto-temporal hypo-synchronized cluster directly correlates with myelination in BA42-46 of the left hemisphere: the lower the myelination in individual patients, the lower the EEG synchronization. By contrast, in the posterior hyper-synchronized cluster, MPS inversely correlated with myelination, i.e., the lower the myelination, the higher the synchronization. This posterior hyper-synchronization, more characteristic for early-onset AD, probably, results from the initial effect of the disease on cortical inhibition, reducing cortical capacity for decoupling irrelevant connections. Remarkably, it showed different topography of correlations in early- vs. late-onset patients. In the early-onset patients, hyper-synchronization was mainly related to demyelination in posterior BAs, the effect being significant in all the EEG frequency bands. In the late-onset patients, widely distributed correlations were significant for the EEG delta band, suggesting an interaction between the cerebral manifestations of AD and the age of its onset, i.e., topographically selective impairment of cortical inhibition in early-onset AD vs. its wide-spread weakening in old age. Conclusions : Overall, our results document that the degradation of white matter is a significant factor of AD pathogenesis leading to functional dysconnection, the latter being reflected in EEG synchronization abnormalities.

Skin hyperemia induced by local heating : why is it blunted on repeat stimulations ?

Background: In human skin, local heating produces local vasodilatation, a response termed thermal hyperemia. Thermal hyperemia is largely mediated by nitric oxide (NO). It is blunted on repeat stimulations applied to the same skin spot, a phenomenon termed desensitization. As this phenomenon could reflect a desensitization in the vasodilator effects of NO, we investigated whether a prior exposure to exogenous NO would result in an attenuated vasodilatory response to a subsequent thermal challenge. Methods: Thirteen healthy young men were studied. Skin blood flow (SkBF) was mesured on forearm skin with laser Doppler imaging. Exposure to exogenous NO was carried out by iontophoresis of sodium nitroprusside (SNP), a donor of NO. A local thermal stimulus (temperature step from 34 to 41°C maintained for 30 minutes) was applied with temperature-controlled chambers. We tested the influence of a previous transient exposure to exogenous NO on : 1) thermal hyperemia and 2) the response to a second identical exposure to exogeneous NO. Results: Thermal hyperemia (plateau SkBF at 30 minutes minus SkBF at 34°C) obtained on a site preexposed to exogenous NO two hours before was lower than obtained on a site preexposed to iontophoretic current only (mean±SD 395±139 perfusion units [PU] vs 540±79 PU ; p<0.01). When repeated on the same skin site two hours after the first one, exposure to exogenous NO led to a blunted vasodilatory response (298±121 PU vs 394±92 PU), although this difference was not statistically significant (p≈0.09). Conclusion: In forearm human skin, prior exposure to exogenous NO partially inhibits thermal hyperemia. These data support that desensitization of thermal hyperemia depends on a downregulation of the NO-cGMP pathway, possibly downstream from the endogenous production of NO.

Prospective universal application of mycobacterial interspersed repetitive-unit-variable-number tandem-repeat genotyping to characterize Mycobacterium tuberculosis isolates for fast identification of clustered and orphan cases.

The use of molecular tools for genotyping Mycobacterium tuberculosis isolates in epidemiological surveys in order to identify clustered and orphan strains requires faster response times than those offered by the reference method, IS6110 restriction fragment length polymorphism (RFLP) genotyping. A method based on PCR, the mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) genotyping technique, is an option for fast fingerprinting of M. tuberculosis, although precise evaluations of correlation between MIRU-VNTR and RFLP findings in population-based studies in different contexts are required before the methods are switched. In this study, we evaluated MIRU-VNTR genotyping (with a set of 15 loci [MIRU-15]) in parallel to RFLP genotyping in a 39-month universal population-based study in a challenging setting with a high proportion of immigrants. For 81.9% (281/343) of the M. tuberculosis isolates, both RFLP and MIRU-VNTR types were obtained. The percentages of clustered cases were 39.9% (112/281) and 43.1% (121/281) for RFLP and MIRU-15 analyses, and the numbers of clusters identified were 42 and 45, respectively. For 85.4% of the cases, the RFLP and MIRU-15 results were concordant, identifying the same cases as clustered and orphan (kappa, 0.7). However, for the remaining 14.6% of the cases, discrepancies were observed: 16 of the cases clustered by RFLP analysis were identified as orphan by MIRU-15 analysis, and 25 cases identified as orphan by RFLP analysis were clustered by MIRU-15 analysis. When discrepant cases showing subtle genotypic differences were tolerated, the discrepancies fell from 14.6% to 8.6%. Epidemiological links were found for 83.8% of the cases clustered by both RFLP and MIRU-15 analyses, whereas for the cases clustered by RFLP or MIRU-VNTR analysis alone, links were identified for only 30.8% or 38.9% of the cases, respectively. The latter group of cases mainly comprised isolates that could also have been clustered, if subtle genotypic differences had been tolerated. MIRU-15 genotyping seems to be a good alternative to RFLP genotyping for real-time interventional schemes. The correlation between MIRU-15 and IS6110 RFLP findings was reasonable, although some uncertainties as to the assignation of clusters by MIRU-15 analysis were identified.

Spoligotyping and variable number tandem repeat analysis of Mycobacterium bovis isolates from cattle in Brazil

We performed spoligotyping and 12-mycobacterial interspersed repetitive unit-variable number tandem repeats (MIRU-VNTRs) typing to characterise Mycobacterium bovis isolates collected from tissue samples of bovines with lesions suggestive for tuberculosis during slaughter inspection procedures in abattoirs in Brazil. High-quality genotypes were obtained with both procedures for 61 isolates that were obtained from 185 bovine tissue samples and all of these isolates were identified as M. bovis by conventional identification procedures. On the basis of the spoligotyping, 53 isolates were grouped into nine clusters and the remaining eight isolates were unique types, resulting in 17 spoligotypes. The majority of the Brazilian M. bovis isolates displayed spoligotype patterns that have been previously observed in strains isolated from cattle in other countries. MIRU-VNTR typing produced 16 distinct genotypes, with 53 isolates forming eight of the groups, and individual isolates with unique VNTR profiles forming the remaining eight groups. The allelic diversity of each VNTR locus was calculated and only two of the 12-MIRU-VNTR loci presented scores with either a moderate (0.4, MIRU16) or high (0.6, MIRU26) discriminatory index (h). Both typing methods produced similar discriminatory indexes (spoligotyping h = 0.85; MIRU-VNTR h = 0.86) and the combination of the two methods increased the h value to 0.94, resulting in 29 distinct patterns. These results confirm that spoligotyping and VNTR analysis are valuable tools for studying the molecular epidemiology of M. bovis infections in Brazil.

Glutathione Precursor, N-Acetyl-Cysteine, Modulates EEG Synchronization in Schizophrenia Patients

Background: Glutathione (GSH) dysregulation at the gene, protein and functional levels observed in schizophrenia patients, and schizophrenia-like anomalies in GSH deficit experimental models, suggest that genetic glutathione synthesis impairments represent one major risk factor for the disease (Do et al., 2009). In a randomized, double blind, placebo controlled, add-on clinical trial of 140 patients, the GSH precursor N-Acetyl-Cysteine (NAC, 2g/day, 6 months) significantly improved the negative symptoms and reduced sideeffects due to antipsychotics (Berk et al., 2008). In a subset of patients (n=7), NAC (2g/day, 2 months, cross-over design) also improved auditory evoked potentials, the NMDA-dependent mismatch negativity (Lavoie et al, 2008). Methods: To determine whether increased GSH levels would modulate the topography of functional brain connectivity, we applied a multivariate phase synchronization (MPS) estimator (Knyazeva et al, 2008) to dense-array EEGs recorded during rest with eyes closed at the protocol onset, the point of crossover, and at its end. Results: The whole-head imaging revealed a specific synchronization landscape in NAC compared to placebo condition. In particular, NAC increased MPS over frontal and left temporal regions in a frequency-specific manner. The topography and direction of MPS changes were similar and robust in all 7 patients. Moreover, these changes correlated with the changes in the Liddle's score of disorganization, thus linking EEG synchronization to the improvement of the clinical picture. Conclusions: The data suggest an important pathway towards new therapeutic strategies that target GSH dysregulation in schizophrenia. They also show the utility of MPS mapping as a marker of treatment efficacy.