BAFF Index and CXCL13 levels in the cerebrospinal fluid associate respectively with intrathecal IgG synthesis and cortical atrophy in multiple sclerosis at clinical onset

Abstract Background B lymphocytes are thought to play a relevant role in multiple sclerosis (MS) pathology. The in vivo analysis of intrathecally produced B cell-related cytokines may help to clarify the mechanisms of B cell recruitment and immunoglobulin production within the central nervous system (CNS) in MS. Methods Paired cerebrospinal fluid (CSF) and serum specimens from 40 clinically isolated syndrome suggestive of MS or early-onset relapsing-remitting MS patients (CIS/eRRMS) and 17 healthy controls (HC) were analyzed for the intrathecal synthesis of IgG (quantitative formulae and IgG oligoclonal bands, IgGOB), CXCL13, BAFF, and IL-21. 3D-FLAIR, 3D-DIR, and 3D-T1 MRI sequences were applied to evaluate white matter (WM) and gray matter (GM) lesions and global cortical thickness (gCTh). Results Compared to HC, CIS/eRRMS having IgGOB (IgGOB+, 26 patients) had higher intrathecal IgG indexes ( p \u2009<\u20090.01), lower values of BAFF Index (11.9\u2009\ub1\u20096.1 vs 17.5\u2009\ub1\u20095.2, p \u2009<\u20090.01), and higher CSF CXCL13 levels (27.7\u2009\ub1\u200933.5 vs 0.9\u2009\ub1\u20091.5, p \u2009<\u20090.005). In these patients, BAFF Index but not CSF CXCL13 levels inversely correlated with the intrathecal IgG synthesis ( r \u2009>\u20090.5 and p \u2009<\u20090.05 for all correlations). CSF leukocyte counts were significantly higher in IgGOB+ compared to IgGOB\u2212 ( p \u2009<\u20090.05) and HC ( p \u2009<\u20090.01), and correlated to CSF CXCL13 concentrations ( r 0.77, p \u2009<\u20090.001). The gCTh was significantly lower in patients with higher CSF CXCL13 levels (2.41\u2009\ub1\u20090.1 vs 2.49\u2009\ub1\u20090.1\ua0mm, p \u2009<\u20090.05), while no difference in MRI parameters of WM and GM pathology was observed between IgGOB+ and IgGOB\u2212. Conclusions The intrathecal IgG synthesis inversely correlated with BAFF Index and showed no correlation with CSF CXCL13. These findings seem to indicate that intrathecally synthesized IgG are produced by long-term PCs that have entered the CNS from the peripheral blood, rather than produced by PCs developed in the meningeal follicle-like structures (FLS). In this study, CXCL13 identifies a subgroup of MS patients characterized by ..

The Timing and Effort of Lexical Access in Natural and Degraded Speech

Understanding speech is effortless in ideal situations, and although adverse conditions, such as caused by hearing impairment, often render it an effortful task, they do not necessarily suspend speech comprehension. A prime example of this is speech perception by cochlear implant users, whose hearing prostheses transmit speech as a significantly degraded signal. It is yet unknown how mechanisms of speech processing deal with such degraded signals, and whether they are affected by effortful processing of speech. This paper compares the automatic process of lexical competition between natural and degraded speech, and combines gaze fixations, which capture the course of lexical disambiguation, with pupillometry, which quantifies the mental effort involved in processing speech. Listeners' ocular responses were recorded during disambiguation of lexical embeddings with matching and mismatching durational cues. Durational cues were selected due to their substantial role in listeners' quick limitation of the number of lexical candidates for lexical access in natural speech. Results showed that lexical competition increased mental effort in processing natural stimuli in particular in presence of mismatching cues. Signal degradation reduced listeners' ability to quickly integrate durational cues in lexical selection, and delayed and prolonged lexical competition. The effort of processing degraded speech was increased overall, and because it had its sources at the pre-lexical level this effect can be attributed to listening to degraded speech rather than to lexical disambiguation. In sum, the course of lexical competition was largely comparable for natural and degraded speech, but showed crucial shifts in timing, and different sources of increased mental effort. We argue that well-timed progress of information from sensory to pre-lexical and lexical stages of processing, which is the result of perceptual adaptation during speech development, is the reason why in ideal situations speech is perceived as an undemanding task. Degradation of the signal or the receiver channel can quickly bring this well-adjusted timing out of balance and lead to increase in mental effort. Incomplete and effortful processing at the early pre-lexical stages has its consequences on lexical processing as it adds uncertainty to the forming and revising of lexical hypotheses

Do Musicians and Non-musicians Differ in Speech-on-Speech Processing?

Earlier studies have shown that musically trained individuals may have a benefit in adverse listening situations when compared to non-musicians, especially in speech-on-speech perception. However, the literature provides mostly conflicting results. In the current study, by employing different measures of spoken language processing, we aimed to test whether we could capture potential differences between musicians and non-musicians in speech-on-speech processing. We used an offline measure of speech perception (sentence recall task), which reveals a post-task response, and online measures of real time spoken language processing: gaze-tracking and pupillometry. We used stimuli of comparable complexity across both paradigms and tested the same groups of participants. In the sentence recall task, musicians recalled more words correctly than non-musicians. In the eye-tracking experiment, both groups showed reduced fixations to the target and competitor words' images as the level of speech maskers increased. The time course of gaze fixations to the competitor did not differ between groups in the speech-in-quiet condition, while the time course dynamics did differ between groups as the two-talker masker was added to the target signal. As the level of two-talker masker increased, musicians showed reduced lexical competition as indicated by the gaze fixations to the competitor. The pupil dilation data showed differences mainly in one target-to-masker ratio. This does not allow to draw conclusions regarding potential differences in the use of cognitive resources between groups. Overall, the eye-tracking measure enabled us to observe that musicians may be using a different strategy than non-musicians to attain spoken word recognition as the noise level increased. However, further investigation with more fine-grained alignment between the processes captured by online and offline measures is necessary to establish whether musicians differ due to better cognitive control or sound processing

Development of Quantum Dot (QD) Based Color Converters for Multicolor Display.

Many displays involve the use of color conversion layers. QDs are attractive candidates as color converters because of their easy processability, tuneable optical properties, high photoluminescence quantum yield, and good stability. Here, we show that emissive QDs with narrow emission range can be made in-situ in a polymer matrix, with properties useful for color conversion. This was achieved by blending the blue-emitting pyridine based polymer with a cadmium selenide precursor and baking their films at different temperatures. To achieve efficient color conversion, blend ratio and baking temperature/time were varied. We found that thermal decomposition of the precursor leads to highly emissive QDs whose final size and emission can be controlled using baking temperature/time. The formation of the QDs inside the polymer matrix was confirmed through morphological studies using atomic force microscopy (AFM) and transmission electron microscopy (TEM). Hence, our approach provides a cost-effective route to making highly emissive color converters for multi-color displays

The Association between serum cytokines and damage to large and small nerve fibers in diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a frequent complication of type 2 diabetes mellitus (DM) and may involve small and large peripheral nerve fibers. Recent evidence suggests a role of cytokines in DPN. The paper is aimed at exploring whether the serum concentration of cytokines is associated with small and large nerve fiber function and with neuropathic pain (NP). We recruited a group of 32 type 2 DM patients who underwent serum cytokines (TNF-α, IL-2, IL-4, IL-6, and IL-10) dosage as well as electrodiagnostic and quantitative sensory testing (QST) assessment to explore damage to large and small nerve fibers. Raised serum levels of IL-6 and IL-10 correlated with markers of large nerve fiber sensory and motor axonal damage. Raised IL-10 serum level was associated with signs of motor nerve demyelination. No differences were found in pain characteristics and electrodiagnostic and QST markers of small nerve fiber function in relation to cytokines serum levels. IL-6 and IL-10 serum levels were associated with large nerve fiber damage but not to small fibers function or NP. IL-6 and IL-10 cytokines might play a role in the pathogenesis of nerve fiber damage or represent a compensatory or neuroprotective mechanism

Olfactory neuroepithelium alterations and cognitive correlates in schizophrenia

BACKGROUND: Few studies have investigated alterations of olfactory neuroepithelium (ONE) as a biomarker of schizophrenia, and none its association with cognitive functioning. METHOD: Fresh ONE cells from twelve patients with schizophrenia and thirteen healthy controls were collected by nasal brushing, cultured in proper media and passed twelve times. Markers of cell proliferation (BrdU incorporation, Cyclin-D1 and p21 protein level) were quantified.Cognitive function was measured using Brief Neuropsychological Examination-2. PRIMARY OUTCOME: proliferation of ONE cells from schizophrenic patients at passage 3. Secondary outcome: association between alteration of cell proliferation and cognitive function. RESULTS: Fresh ONE cells from patients showed a faster cell proliferation than those from healthy controls at passage 3. An opposite trend was observed at passage 9, ONE cells of patients with schizophrenia showing slower cell proliferation as compared to healthy controls. In schizophrenia, overall cognitive function (Spearman's rho -0.657, p\u202f<\u202f0.01), verbal memory - immediate recall, with interference at 10\u202fs and 30\u202fs (Spearman's rho from -0.676 to 0.697, all p\u202f<\u202f0.01) were inversely associated with cell proliferation at passage 3. CONCLUSION: Fresh ONE cells collected by nasal brushing might eventually represent a tool for diagnosing schizophrenia based upon markers of cell proliferation, which can be easily implemented as single-layer culture. Cell proliferation at passage 3 can be regarded as a promising proxy of cognitive functioning in schizophrenia. Future studies should replicate these findings, and may assess whether ONE alterations are there before onset of psychosis, serving as an early sign in patients with at risk mental state

S-Glutathionylation at Cys328 and Cys542 Impairs STAT3 Phosphorylation.

STAT3 is a latent transcription factor that promotes cell survival and proliferation and is often constitutively active in cancers. Although many reports provide evidence that STAT3 is a direct target of oxidative stress, its redox regulation is poorly understood. Under oxidative conditions STAT3 activity can be modulated by S-glutathionylation, a reversible redox modification of cysteine residues. This suggests the possible cross-talk between phosphorylation and glutathionylation and points out that STAT3 is susceptible to redox regulation. Recently, we reported that decreasing the GSH content in different cell lines induces inhibition of STAT3 activity through the reversible oxidation of thiol groups. In the present work, we demonstrate that GSH/diamide treatment induces S-glutathionylation of STAT3 in the recombinant purified form. This effect was completely reversed by treatment with the reducing agent dithiothreitol, indicating that S-glutathionylation of STAT3 was related to formation of protein-mixed disulfides. Moreover, addition of the bulky negatively charged GSH moiety impairs JAK2-mediated STAT3 phosphorylation, very likely interfering with tyrosine accessibility and thus affecting protein structure and function. Mass mapping analysis identifies two glutathionylated cysteine residues, Cys328 and Cys542, within the DNA-binding domain and the linker domain, respectively. Site direct mutagenesis and in vitro kinase assay confirm the importance of both cysteine residues in the complex redox regulatory mechanism of STAT3. Cells expressing mutant were resistant in this regard. The data presented herein confirmed the occurrence of a redox-dependent regulation of STAT3, identified the more redox-sensitive cysteines within STAT3 structure, and may have important implications for development of new drugs

Changes of consultation-liaison psychiatry practice in Italian general hospitals: A comparative 20-year multicenter study

Introduction: Conducted under the auspices of the Italian Society of Consultation Liaison Psychiatry (SIPC) the aim of this study was to describe the characteristics of Consultation Liaison Psychiatry (CLP) activity in Italy (SIPC-2—2018) over the past 20 years by comparing with data from the first Italian nation-wide study (SIPC-1—1998). Methods: We collected data on CLP visits of 3,943 patients from 10 Italian hospitals over a period of 1 year. Data were compared with those from the SIPC-1 1998 study (4,183 participants). Patients were assessed with the same ad hoc 60-item Patient Registration Form recording information from five different areas: Sociodemographic, hospitalization-related, consultation-related, interventions and outcome. Results: Compared with participants from the previous study, SIPC-2-2018 participants were significantly older (d = 0.54) and hospitalized for a longer duration (d = 0.20). The current study detected an increase in the proportion of referrals from surgical wards and for individuals affected by onco-hematologic diseases. Depressive disorders still represented the most frequent psychiatric diagnosis, followed by adjustment and stress disorders and delirium/dementia. Also, CLP psychiatrists prescribed more often antidepressants (Φ = 0.13), antipsychotics (Φ = 0.09), mood stabilizers (Φ = 0.24), and less often benzodiazepines (Φ = 0.07). Conclusion: CLP workload has increased considerably in the past 20 years in Italy, with changes in patient demographic and clinical characteristics. A trend toward increase in medication-based patient management was observed. These findings suggest that the psychiatric needs of patients admitted to the general hospital are more frequently addressed by referring physicians, although Italian CLP services still deserve better organization and autonomy

A crossmodal crossover: opposite effects of visual and auditory perceptual load on steady-state evoked potentials to irrelevant visual stimuli

Mechanisms of attention are required to prioritise goal-relevant sensory events under conditions of stimulus competition. According to the perceptual load model of attention, the extent to which task-irrelevant inputs are processed is determined by the relative demands of discriminating the target: the more perceptually demanding the target task, the less unattended stimuli will be processed. Although much evidence supports the perceptual load model for competing stimuli within a single sensory modality, the effects of perceptual load in one modality on distractor processing in another is less clear. Here we used steady-state evoked potentials (SSEPs) to measure neural responses to irrelevant visual checkerboard stimuli while participants performed either a visual or auditory task that varied in perceptual load. Consistent with perceptual load theory, increasing visual task load suppressed SSEPs to the ignored visual checkerboards. In contrast, increasing auditory task load enhanced SSEPs to the ignored visual checkerboards. This enhanced neural response to irrelevant visual stimuli under auditory load suggests that exhausting capacity within one modality selectively compromises inhibitory processes required for filtering stimuli in another

Cognitive ability across the life course and cortisol levels in older age

Elevated cortisol levels have been hypothesised to contribute to cognitive ageing, but study findings are inconsistent. In the present study, we examined the association between salivary cortisol in older age and cognitive ability across the life course. We used data from 370 members of the 36-Day Sample of the Scottish Mental Survey 1947, who underwent cognitive testing at age 11, and were then followed up at around age 78, completing further cognitive tests and providing diurnal salivary cortisol samples. We hypothesised that higher cortisol levels would be associated with lower cognitive ability in older age and greater cognitive decline from childhood to older age, but also lower childhood cognitive ability. Few of the tested associations were significant, and of those that were, most suggested a positive relationship between cortisol and cognitive ability. Only one cognitive measure showed any sign of cortisol-related impairment. However, after correcting for multiple comparisons, no results remained significant. These findings suggest that cortisol may not play an important role in cognitive ageing across the life course