Encoding dysfunctions in a dynamic-static paradigm for visuospatial working memory in first-episode psychosis patients: a 2-year follow-up study.

Aim: To investigate static and dynamic visuospatial working memory (VSWM) processes in first-episode psychosis (FEP) patients and explore the validity of such measures as specific trait markers of schizophrenia. Methods: Twenty FEP patients and 20 age-, sex-, laterality- and education-matched controls carried out a dynamic and static VSWM paradigm. At 2-year follow up 13 patients met Diagnostic and Statistical Manual (of Mental Health Disorders) - Fourth Edition (DSM-IV) criteria for schizophrenia, 1 for bipolar disorder, 1 for brief psychotic episode and 5 for schizotypal personality disorder. Results: Compared with controls, the 20 FEP patients showed severe impairment in the dynamic VSWM condition but much less impairment in the static condition. No specific bias in stimulus selection was detected in the two tasks. Two-year follow-up evaluations suggested poorer baseline scores on the dynamic task clearly differentiated the 13 FEP patients who developed schizophrenia from the seven who did not. Conclusions: Results suggest deficits in VSWM in FEP patients. Specific exploratory analyses further suggest that deficit in monitoring-manipulation VSWM processes, especially involved in our dynamic VSWM task, can be a reliable marker of schizophrenia.

A new electrophysiological index for working memory load in humans.

Working memory, the ability to store and simultaneously manipulate information, is affected in several neuropsychiatric disorders which lead to severe cognitive and functional deficits. An electrophysiological marker for this process could help identify early cerebral function abnormalities. In subjects performing working memory-specific n-back tasks, event-related potential analysis revealed a positive-negative waveform (PNwm) component modulated in amplitude by working memory load. It occurs in the expected time range for this process, 140-280 ms after stimulus onset, superimposed on the classical P200 and N200 components. Independent Component Analysis extracted two functional components with latencies and topographical scalp distributions similar to the PNwm. Our results imply that the PNwm represents a new electrophysiological index for working memory load in humans.

Natalizumab treatment alters the expression of T-cell trafficking marker LFA-1 α-chain (CD11a) in MS patients.

OBJECTIVE: To determine the long-term effect of natalizumab (NTZ) treatment on the expression of integrins and chemokine receptors involved in the migration of T cells towards the central nervous system (CNS). METHODS: We drew the blood of 23 patients just before starting NTZ therapy and every 12 months thereafter, for up to 48 months of treatment. We assessed the ex-vivo expression of phenotype markers (CCR7 and CD45RA), CNS-addressing integrins (CD11a, CD49d and CD29) and chemokine receptors (CXCR3 and CCR6) in CD4+ or CD8+ T-cell subsets by flow cytometry. RESULTS: As compared to the pre-NTZ values, there was a marked increase in central memory (CCR7+/CD45RA-) CD4+ T cells and in effector memory (CCR7-/CD45RA-) CD8+ T cells at 12 and 24 months. In addition to an expected downregulation of both VLA-4 subunits (CD49d/CD29), we also found decreased T-cell expression of CXCR3 at 12 months, and of CD11a (LFA-1 αL subunit) at 12 months, but mostly at 24 months of NTZ treatment. CONCLUSION: Our data show a nadir of CD11a expression at 2 years of NTZ treatment, at the peak of incidence of progressive multifocal leukoencephalopathy (PML), indirectly suggesting that a lack of these molecules may play a role in the onset of PML in NTZ-treated patients.

Constitutive activation of Wnt signaling favors generation of memory CD8 T cells.

T cell factor-1 (TCF-1) and lymphoid enhancer-binding factor 1, the effector transcription factors of the canonical Wnt pathway, are known to be critical for normal thymocyte development. However, it is largely unknown if it has a role in regulating mature T cell activation and T cell-mediated immune responses. In this study, we demonstrate that, like IL-7Ralpha and CD62L, TCF-1 and lymphoid enhancer-binding factor 1 exhibit dynamic expression changes during T cell responses, being highly expressed in naive T cells, downregulated in effector T cells, and upregulated again in memory T cells. Enforced expression of a p45 TCF-1 isoform limited the expansion of Ag-specific CD8 T cells in response to Listeria monocytogenes infection. However, when the p45 transgene was coupled with ectopic expression of stabilized beta-catenin, more Ag-specific memory CD8 T cells were generated, with enhanced ability to produce IL-2. Moreover, these memory CD8 T cells expanded to a larger number of secondary effectors and cleared bacteria faster when the immunized mice were rechallenged with virulent L. monocytogenes. Furthermore, in response to vaccinia virus or lymphocytic choriomeningitis virus infection, more Ag-specific memory CD8 T cells were generated in the presence of p45 and stabilized beta-catenin transgenes. Although activated Wnt signaling also resulted in larger numbers of Ag-specific memory CD4 T cells, their functional attributes and expansion after the secondary infection were not improved. Thus, constitutive activation of the canonical Wnt pathway favors memory CD8 T cell formation during initial immunization, resulting in enhanced immunity upon second encounter with the same pathogen.

Flippase (FLP) recombinase-mediated marker recycling in the dermatophyte Arthroderma vanbreuseghemii.

Biological processes can be elucidated by investigating complex networks of relevant factors and genes. However, this is not possible in species for which dominant selectable markers for genetic studies are unavailable. To overcome the limitation in selectable markers for the dermatophyte Arthroderma vanbreuseghemii (anamorph: Trichophyton mentagrophytes), we adapted the flippase (FLP) recombinase-recombination target (FRT) site-specific recombination system from the yeast Saccharomyces cerevisiae as a selectable marker recycling system for this fungus. Taking into account practical applicability, we designed FLP/FRT modules carrying two FRT sequences as well as the flp gene adapted to the pathogenic yeast Candida albicans (caflp) or a synthetic codon-optimized flp (avflp) gene with neomycin resistance (nptII) cassette for one-step marker excision. Both flp genes were under control of the Trichophyton rubrum copper-repressible promoter (PCTR4). Molecular analyses of resultant transformants showed that only the avflp-harbouring module was functional in A. vanbreuseghemii. Applying this system, we successfully produced the Ku80 recessive mutant strain devoid of any selectable markers. This strain was subsequently used as the recipient for sequential multiple disruptions of secreted metalloprotease (fungalysin) (MEP) or serine protease (SUB) genes, producing mutant strains with double MEP or triple SUB gene deletions. These results confirmed the feasibility of this system for broad-scale genetic manipulation of dermatophytes, advancing our understanding of functions and networks of individual genes in these fungi.

B and T lymphocyte attenuator regulates CD8+ T cell-intrinsic homeostasis and memory cell generation.

B and T lymphocyte attenuator (BTLA) is a negative regulator of T cell activation, but its function in vivo is not well characterized. Here we show that mice deficient in full-length BTLA or its ligand, herpesvirus entry mediator, had increased number of memory CD8(+) T cells. The memory CD8(+) T cell phenotype resulted from a T cell-intrinsic perturbation of the CD8(+) T cell pool. Naive BTLA-deficient CD8(+) T cells were more efficient than wild-type cells at generating memory in a competitive antigen-specific system. This effect was independent of the initial expansion of the responding antigen-specific T cell population. In addition, BTLA negatively regulated antigen-independent homeostatic expansion of CD4(+) and CD8(+) T cells. These results emphasize two central functions of BTLA in limiting T cell activity in vivo.

La lithiase rénale: un marqueur du risque cardiovasculaire [Kidney stone as a cardiovascular risk marker].

Si le passage d'un calcul rénal est souvent considéré comme un événement médical mineur, quoique très douloureux, de plus en plus d'études indiquent qu'il doit être pris au sérieux puisqu'il peut indiquer un risque cardiovasculaire augmenté. Nous revoyons ici les études qui associent risque cardiovasculaire et calcul rénal et les liens physiopathologiques qui les unissent. Nous montrons que la lithiase est un événement intervenant tôt dans la vie d'un individu à risque de développer des complications cardiovasculaires. Ainsi, la lithiase ne doit pas être banalisée, mais doit être considérée comme une première alerte devant inciter le médecin traitant à recenser précocement les facteurs de risque cardiovasculaires et à mettre en place une stratégie de prévention. Cette approche pourrait permettre de diminuer l'incidence d'événements cardiovasculaires chez les patients formeurs de lithiases. Most of the time, kidney stones are considered as minor, but painful events. However, several studies have recently shown an association between kidney stone and an increased cardio-vascular risk. We review here these studies and explore the underlying pathophysiological hypotheses. At the end, we propose that lithiasis should be considered as a red flag intervening early during life-time and allowing a check of cardiovascular risk factors and early preventive intervention. Such approach may be successful in reducing the incidence of cardio-vascular events in stone formers.

Ghosts in contemporary African diasporic literature : re-visioning history, memory and identity

Starting from the observation that ghosts are strikingly recurrent and prominent figures in late-twentieth African diasporic literature, this dissertation proposes to account for this presence by exploring its various functions. It argues that, beyond the poetic function the ghost performs as metaphor, it also does cultural, theoretical and political work that is significant to the African diaspora in its dealings with issues of history, memory and identity. Toni Morrison's Beloved (1987) serves as a guide for introducing the many forms, qualities and significations of the ghost, which are then explored and analyzed in four chapters that look at Fred D'Aguiar's Feeding the Ghosts (1998), Gloria Naylor's Mama Day (1988), Paule Marshall's Praisesong for the Widow (1983) and a selection of novels, short stories and poetry by Michelle Cliff. Moving thematically through these texts, the discussion shifts from history through memory to identity as it examines how the ghost trope allows the writers to revisit sites of trauma; revise historical narratives that are constituted and perpetuated by exclusions and invisibilities; creatively and critically repossess a past marked by violence, dislocation and alienation and reclaim the diasporic culture it contributed to shaping; destabilize and deconstruct the hegemonic, normative categories and boundaries that delimit race or sexuality and envision other, less limited and limiting definitions of identity. These diverse and interrelated concerns are identified and theorized as participating in a project of "re-vision," a critical project that constitutes an epistemological as much as a political gesture. The author-based structure allows for a detailed analysis of the texts and highlights the distinctive shapes the ghost takes and the particular concerns it serves to address in each writer's literary and political project. However, using the ghost as a guide into these texts, taken collectively, also throws into relief new connections between them and sheds light on the complex ways in which the interplay of history, memory and identity positions them as products of and contributions to an African diasporic (literary) culture. If it insists on the cultural specificity of African diasporic ghosts, tracing its origins to African cultures and spiritualities, the argument also follows gothic studies' common view that ghosts in literary and cultural productions-like other related figures of the living dead-respond to particular conditions and anxieties. Considering the historical and political context in which the texts under study were produced, the dissertation makes connections between the ghosts in them and African diasporic people's disillusionment with the broken promises of the civil rights movement in the United States and of postcolonial independence in the Caribbean. It reads the texts' theoretical concerns and narrative qualities alongside the contestation of traditional historiography by black and postcolonial studies as well as the broader challenge to conventional notions such as truth, reality, meaning, power or identity by poststructuralism, postcolonialism or queer theory. Drawing on these various theoretical approaches and critical tools to elucidate the ghost's deconstructive power for African diasporic writers' concerns, this work ultimately offers a contribution to "speciality studies," which is currently emerging as a new field of scholarship in cultural theory.

Visual binding abilities in the initial and advanced stages of schizophrenia

OBJECTIVE: The study tests the hypothesis that intramodal visual binding is disturbed in schizophrenia and should be detectable in all illness stages as a stable trait marker. METHOD: Three groups of patients (rehospitalized chronic schizophrenic, first admitted schizophrenic and schizotypal patients believed to be suffering from a pre-schizophrenic prodrome) and a group of normal control subjects were tested on three tasks targeting visual 'binding' abilities (Muller-Lyer's illusion and two figure detection tasks) in addition to control parameters such as reaction time, visual selective attention, Raven's test and two conventional cortical tasks of spatial working memory (SWM) and a global local test. RESULTS: Chronic patients had a decreased performance on the binding tests. Unexpectedly, the prodromal group exhibited an enhanced Gestalt extraction on these tests compared both to schizophrenic patients and to healthy subjects. Furthermore, chronic schizophrenia was associated with a poor performance on cortical tests of SWM, global local and on Raven. This association appears to be mediated by or linked to the chronicity of the illness. CONCLUSION: The study confirms a variety of neurocognitive deficits in schizophrenia which, however, in this sample seem to be linked to chronicity of illness. However, certain aspects of visual processing concerned with Gestalt extraction deserve attention as potential vulnerability- or prodrome- indicators. The initial hypothesis of the study is rejected.

Cerebrospinal fluid antimicroglial antibodies in Alzheimer disease: a putative marker of an ongoing inflammatory process.

Immunocompetent microglia play an important role in the pathogenesis of Alzheimer's disease (AD). Antimicroglial antibodies in the cerebrospinal fluid (CSF) in clinically diagnosed AD patients have been previously recorded. Here, we report the results of the analysis of the CSF from 38 autopsy cases: 7 with definite AD; 14 with mild and 10 with moderate Alzheimer's type pathology; and 7 controls. Antimicroglial antibodies were identified in 70% of patients with definite AD, in 80% of patients with moderate and in 28% of patients with mild Alzheimer's type pathology. CSF antimicroglial antibodies were not observed in any of the control cases. The results show that CSF antimicroglial antibodies are present in the majority of patients with definite AD and also in cases with moderate Alzheimer's type changes. They may also indicate dysregulation of microglial function. Together with previous observations, these findings indicate that compromised immune defense mechanisms play an important role in the pathogenesis of AD.

Memory and effector CD8 T-cell responses after nanoparticle vaccination of melanoma patients.

Induction of cytotoxic CD8 T-cell responses is enhanced by the exclusive presentation of antigen through dendritic cells, and by innate stimuli, such as toll-like receptor ligands. On the basis of these 2 principles, we designed a vaccine against melanoma. Specifically, we linked the melanoma-specific Melan-A/Mart-1 peptide to virus-like nanoparticles loaded with A-type CpG, a ligand for toll-like receptor 9. Melan-A/Mart-1 peptide was cross-presented, as shown in vitro with human dendritic cells and in HLA-A2 transgenic mice. A phase I/II study in stage II-IV melanoma patients showed that the vaccine was well tolerated, and that 14/22 patients generated ex vivo detectable T-cell responses, with in part multifunctional T cells capable to degranulate and produce IFN-γ, TNF-α, and IL-2. No significant influence of the route of immunization (subcutaneous versus intradermal) nor dosing regimen (weekly versus daily clusters) could be observed. It is interesting to note that, relatively large fractions of responding specific T cells exhibited a central memory phenotype, more than what is achieved by other nonlive vaccines. We conclude that vaccination with CpG loaded virus-like nanoparticles is associated with a human CD8 T-cell response with properties of a potential long-term immune protection from the disease.

Cognitive and emotional effects of carotid stenosis.

PRINCIPLES: Patients with carotid artery stenosis (CAS) are at risk of ipsilateral stroke and chronic compromise of cerebral blood flow. It is under debate whether the hypo-perfusion or embolism in CAS is directly related to cognitive impairment. Alternatively, CAS may be a marker for underlying risk factors, which themselves influence cognition. We aimed to determine cognitive performance level and the emotional state of patients with CAS. We hypo-thesised that patients with high grade stenosis, bilateral stenosis, symptomatic patients and/or those with relevant risk factors would suffer impairment of their cognitive performance and emotional state. METHODS: A total of 68 patients with CAS of ≥70% were included in a prospective exploratory study design. All patients underwent structured assessment of executive functions, language, verbal and visual memory, motor speed, anxiety and depression. RESULTS: Significantly more patients with CAS showed cognitive impairments (executive functions, word production, verbal and visual memory, motor speed) and anxiety than expected in a normative sample. Bilateral and symptomatic stenosis was associated with slower processing speed. Cognitive performance and anxiety level were not influenced by the side and the degree of stenosis or the presence of collaterals. Factors associated with less co-gnitive impairment included higher education level, female gender, ambidexterity and treated hypercholesterolemia. CONCLUSIONS: Cognitive impairment and increased level of anxiety are frequent in patients with carotid stenosis. The lack of a correlation between cognitive functioning and degree of stenosis or the presence of collaterals, challenges the view that CAS per se leads to cognitive impairment.

Characterization of Melan-A reactive memory CD8+ T cells in a healthy donor.

Melan-A specific CD8+ T cells are thought to play an important role against the development of melanoma. Their in vivo expansion is often observed with advanced disease. In recent years, low levels of Melan-A reactive CD8+ T cells have also been found in HLA-A2 healthy donors, but these cells harbor naive characteristics and are thought to be mostly cross-reactive for the Melan-A antigen. Here, we report on a large population of CD8+ T cells reactive for the Melan-A antigen, identified in one donor with no evidence of melanoma. Interestingly, this population is oligoclonal and displays a clear memory phenotype. However, a detailed study of these cells indicated that they are unlikely to be directly specific for melanoma, so that their in vivo expansion may have been driven by an exogenous antigen. Screening of a Melan-A cross-reactive peptide library suggested that these cells may be specific for an epitope derived from a Mycobacterium protein, which would provide a further example of CD8+ T cell cross-reactivity between a pathogen antigen and a tumor antigen. Finally, we discuss potential perspectives regarding the role of such cells in heterologous immunity, by influencing the balance between protective immunity and pathology, e.g. in the case of melanoma development.

Selective bystander proliferation of memory CD4+ and CD8+ T cells upon NK T or T cell activation.

Ag-experienced or memory T cells have increased reactivity to recall Ag, and can be distinguished from naive T cells by altered expression of surface markers such as CD44. Memory T cells have a high turnover rate, and CD8(+) memory T cells proliferate upon viral infection, in the presence of IFN-alphabeta and/or IL-15. In this study, we extend these findings by showing that activated NKT cells and superantigen-activated T cells induce extensive bystander proliferation of both CD8(+) and CD4(+) memory T cells. Moreover, proliferation of memory T cells can be induced by an IFN-alphabeta-independent, but IFN-gamma- or IL-12-dependent pathway. In these conditions of bystander activation, proliferating memory (CD44(high)) T cells do not derive from activation of naive (CD44(low)) T cells, but rather from bona fide memory CD44(high) T cells. Together, these data demonstrate that distinct pathways can induce bystander proliferation of memory T cells.