Chronic ethanol induces a pro-inflammatory switch in interleukin-1ß regulation of GABAergic signaling in the medial prefrontal cortex of male mice.

Neuroimmune pathways regulate brain function to influence complex behavior and play a role in several neuropsychiatric diseases, including alcohol use disorder (AUD). In particular, the interleukin-1 (IL-1) system has emerged as a key regulator of the brain's response to ethanol (alcohol). Here we investigated the mechanisms underlying ethanol-induced neuroadaptation of IL-1ß signaling at GABAergic synapses in the prelimbic region of the medial prefrontal cortex (mPFC), an area responsible for integrating contextual information to mediate conflicting motivational drives. We exposed C57BL/6J male mice to the chronic intermittent ethanol vapor-2 bottle choice paradigm (CIE-2BC) to induce ethanol dependence, and conducted ex vivo electrophysiology and molecular analyses. We found that the IL-1 system regulates basal mPFC function through its actions at inhibitory synapses on prelimbic layer 2/3 pyramidal neurons. IL-1ß can selectively recruit either neuroprotective (PI3K/Akt) or pro-inflammatory (MyD88/p38 MAPK) mechanisms to produce opposing synaptic effects. In ethanol naïve conditions, there was a strong PI3K/Akt bias leading to a disinhibition of pyramidal neurons. Ethanol dependence produced opposite IL-1 effects - enhanced local inhibition via a switch in IL-1ß signaling to the canonical pro-inflammatory MyD88 pathway. Ethanol dependence also increased cellular IL-1ß in the mPFC, while decreasing expression of downstream effectors (Akt, p38 MAPK). Thus, IL-1ß may represent a key neural substrate in ethanol-induced cortical dysfunction. As the IL-1 receptor antagonist (kineret) is already FDA-approved for other diseases, this work underscores the high therapeutic potential of IL-1 signaling/neuroimmune-based treatments for AUD.

The relative role of executive control and personality traits in grit.

Although grit is predictive of wellbeing, educational achievement, and success in life, it has been conceptualized as largely distinct from cognitive ability. The present study investigated the link between grit and executive functions since regulation abilities might underlie the expression of grit. A hundred thirty-four people were administered personality questionnaires (grit, impulsiveness, and mindfulness) and four experimental tasks tapping into Miyake's and Braver's models of executive functioning (including measures of flexibility, inhibition, working memory, and control mode dimensions). Multivariate analyses showed that two composite scores (trait and executive functioning) were reliably predictive of grit, although it was the trait composite (characterized by low impulsivity and high mindfulness) that explained more variance. Importantly, gritty participants did not demonstrate enhanced executive functioning. Instead, they exhibited a different pattern of performance that might be reflecting a cautious profile of control, characterized by paying attention to all available information, less reliance on previous contextual cues but sensitive to conflicting information of the current context. These findings converge with Duckworth's idea that high grit people do not necessarily have a greater cognitive capacity. Rather, they use it in a different way.

Characterization of hypersensitivity reactions to polysulfone hemodialysis membranes.

BACKGROUND: In recent years, cases have been reported in which unexpected systemic hypersensitivity reactions occurred in patients dialyzed with polysulfone- or polyethersulfone-biocompatible membranes in the absence of other risk factors. The pathomechanisms involved in these reactions are largely unknown. OBJECTIVE: To characterize hypersensitivity reactions to polysulfone hemodialysis using clinical and laboratory data and to identify biomarkers suitable for endotype identification and diagnosis. METHODS: We prospectively collected data from 29 patients with suspected hypersensitivity reactions to polysulfone hemodialysis membranes. Clinical laboratory parameters such as tryptase, blood cell counts, and complement levels were recorded. Acute samples were obtained from 18 cases for the ex vivo assessment of basophil activation by flow cytometry analysis of CD63, CD203, and FcεRI cell membrane expression. Serum cytokines and anaphylatoxin concentrations were evaluated in 16 cases by Luminex and cytometric bead array analysis. RESULTS: Tryptase was elevated during the acute reaction in 4 cases. Evidence of basophil activation was obtained in 10 patients. Complement activation was found in only 2 cases. However, C5a serum levels tended to increase during the acute reaction in those patients with hypoxemia. Significantly higher serum levels of interleukin-6 were observed during the acute reactions to polysulfone hemodialysis (P = .0103). CONCLUSION: Based on biomarker analysis, various endotypes were identified, including type I-like (with the involvement of mast cells or basophils), complement, and cytokine (interleukin-6) release-related reactions, with some patients showing mixed reactions. Further research is needed to unravel the exact mechanisms involved in the activation of these cellular and molecular pathways.

CCN2 (Cellular Communication Network Factor 2) Deletion Alters Vascular Integrity and Function Predisposing to Aneurysm Formation.

BACKGROUND: CCN2 (cellular communication network factor 2) is a matricellular protein involved in cell communication and microenvironmental signaling responses. CCN2 is known to be overexpressed in several cardiovascular diseases, but its role is not completely understood. METHODS: Here, CCN2 involvement in aortic wall homeostasis and response to vascular injury was investigated in inducible <i>Ccn2</i>-deficient mice, with induction of vascular damage by infusion of Ang II (angiotensin II; 15 days), which is known to upregulate CCN2 expression in the aorta. RESULTS: Ang II infusion in CCN2-silenced mice lead to 60% mortality within 10 days due to rapid development and rupture of aortic aneurysms, as evidenced by magnetic resonance imaging, echography, and histological examination. <i>Ccn2</i> deletion decreased systolic blood pressure and caused aortic structural and functional changes, including elastin layer disruption, smooth muscle cell alterations, augmented distensibility, and increased metalloproteinase activity, which were aggravated by Ang II administration. Gene ontology analysis of RNA sequencing data identified aldosterone biosynthesis as one of the most enriched terms in CCN2-deficient aortas. Consistently, treatment with the mineralocorticoid receptor antagonist spironolactone before and during Ang II infusion reduced aneurysm formation and mortality, underscoring the importance of the aldosterone pathway in Ang II-induced aorta pathology. CONCLUSIONS: CCN2 is critically involved in the functional and structural homeostasis of the aorta and in maintenance of its integrity under Ang II-induced stress, at least, in part, by disruption of the aldosterone pathway. Thus, this study opens new avenues to future studies in disorders associated to vascular pathologies.

Baseline capacities and motivation in executive control training of healthy older adults.

OBJECTIVES: Normal aging involves progressive prefrontal declines and impairments in executive control. This study aimed to examine the efficacy of an executive-control training focusing on working memory and inhibition, in healthy older adults, and to explore the role of individual differences in baseline capacities and motivation in explaining training gains. METHODS: Forty-four healthy older adults were randomly assigned to an experimental (training executive control) or active control group (training processing speed). Participants completed six online training sessions distributed across two weeks. Transfer effects to working memory (Operation Span test), response inhibition (Stop-Signal test), processing speed (Pattern Comparison) and reasoning (Raven's Advanced Progressive Matrices and Cattell Culture Fair test) were evaluated. Furthermore, we explored individual differences in baseline capacities and assessed motivation during and after the intervention. RESULTS: The experimental group, but not the active control, showed significant transfer to response inhibition. Moreover, a general compensation effect was found: older adults with lower baseline capacities achieved higher levels of training improvement. Motivation was not related to training performance. CONCLUSION: Our results encourage the use of executive control training to improve cognitive functions, reveal the importance of individual differences in training-related gains, and provide further support for cognitive plasticity during healthy aging.

Electrophysiological Prints of Grit.

While scientific interest in understanding the grit trait has grown exponentially in recent years, one important gap in the grit literature relates to its biological and neural substrate. In the present study, we adopted a hypotheses-driven approach in a large sample of young adults (N = 120) with diverse educational backgrounds and work experiences in order to investigate the electrophysiological correlates of grit both during rest and while performing a learning task. Additionally, we selected a measure of impulsiveness to better understand the neural similarities and differences between grit and related self-control constructs. Based on previous work that implicated the prefrontal cortex in grit, we hypothesized that high grit participants would have lower frontal theta/beta ratio (a broadly used index that reflects prefrontally-mediated top-down processes, which might indicate better control over subcortical information). Furthermore, we expected the perseverance of effort facet of grit to be linked to higher complexity during task engagement because previous research has shown complexity indexes (entropy and fractal dimension) to be linked to effort while performing cognitive tasks. Our results revealed that although there were no differences at rest as a function of grit, the participants with high grit and high consistency of interest scores exhibited lower frontal theta/beta ratios during the learning task. This pattern suggests that individual differences in grit might be more evident when top-down control processes are at work. Furthermore, there was a positive association between perseverance of effort and entropy at task, which might indicate more effort and engagement in the task. Finally, no association was found between the neural indexes (frontal theta/beta ratio, entropy, or fractal dimension) and impulsiveness, neither impulsiveness mediated between grit and brain measures. Finally, when controlling for impulsiveness and demographic variables (gender, age, education, and work experience) the effects at the facet level remained statistically significant. While there is still a long way to fully understand the neural mechanisms of grit, the present work constitutes a step toward unveiling the electrophysiological prints of grit.

The Influence of Cross-Linguistic Similarity and Language Background on Writing to Dictation.

This study used a word dictation task to examine the influence of a variety of factors on word writing production: cognate status (cognate vs. non-cognate words), orthographic (OS) and phonological similarity (PS) within the set of cognate words, and language learning background [late bilinguals (LBs) with academic literacy and formal instruction in English and Spanish, and heritage speakers (HSs) with academic literacy and formal instruction only in English]. Both accuracy and reaction times for the first key pressed by participants (indicating lexical access), and the time required to type the rest of the word after the first keypress (indicating sublexical processing) was assessed. The results revealed an effect of PS on the dictation task particularly for the first keypress. That is, cognates with high PS were processed faster than cognates with low PS. In contrast to reading studies in which PS only revealed a significant effect when the OS between languages was high (O+P+ vs. O+P-), in the dictation to writing task, the phonology had a more general effect across all conditions, regardless of the level of OS. On the other hand, OS tended to be more influential for typing the rest of the word. This pattern is interpreted as indicating the importance of phonology (and PS in cognates) for initial lexical retrieval when the input is aural. In addition, the role of OS and PS during co-activation was different between groups probably due to the participants' linguistic learning environment. Concretely, HSs were found to show relatively lower OS effects, which is attributed to the greater emphasis on spoken language in their Spanish language learning experiences, compared to the formal education received by the LBs. Thus, the study demonstrates that PS can influence lexical processing of cognates, as long as the task demands specifically require phonological processing, and that variations in language learning experiences also modulate lexical processing in bilinguals.

The Effect of Nutritional Interventions on Long-Term Patient Survival in Advanced Chronic Kidney Disease.

Patients with end-stage kidney disease (ESKD) are at high risk of malnutrition and subsequent related mortality when starting dialysis. However, there have been few clinical studies on the effect of nutritional interventions on long-term patient survival. A 2-year longitudinal study was conducted from January 2012 to December 2016. A total of 186 patients with non-dialysis ESKD started the nutritional education program (NEP), and 169 completed it. A total of 128 patients participated in a NEP over 6 months (personalized diet, education and oral supplementation, if needed). The control group (n = 45) underwent no specific nutritional intervention. The hospitalization rate was significantly lower for the patients with NEP (13.7%) compared with the control patients (26.7%) (p = 0.004). The mortality odds ratio for the patients who did not receive NEP was 2.883 (95% CI 0.993-8.3365, p = 0.051). The multivariate analysis showed an independent association between mortality and age (OR, 1.103; 95% CI 1.041-1.169; p = 0.001) and between mortality and the female sex (OR, 3.332; 95% CI 1.054-10.535; p = 0.040) but not between mortality and those with NEP (p = 0.051). Individualized nutrition education has long-term positive effects on nutritional status, reduces hospital admissions and increases survival among patients with advanced CKD who are starting dialysis programs.

Is peritoneal dialysis suitable technique CKD patients over 65 years? A prospective multicenter study.

BACKGROUND: Chronic kidney disease (CKD) is increasing in patients older than 65 years and is related to morbidity, frailty, and dependence. Peritoneal dialysis (PD) has classically been associated with young patients with an active life. HYPOTHESIS: PD should be offered to patients over 65 years. We search for any unfavorable results that may advice not to recommend PD therapy for this group. OBJECTIVE: To describe PD treatment and outcomes in patients > 65 years, to compare their results with patients < 65 years and to identify areas with room for improvement in a real-life study. STUDY: Prospective, observational, and multicenter study performed in incident PD patients, from January 2003 until January 2018. RESULTS: We included 2,435 PD patients, 31.9% were older than 65 years; there was a difference of 25 years between both groups. Median follow up was 2.1 years. Older than 65 years group had more comorbidity: Diabetes (29.5% vs 17.2%; p < 0.001), previous CV events 34.5% vs 14.0%; p < 0.001), Charlson index (3.8 vs 3.0; p < 0.001). We did not find differences in efficacy and PD adequacy objectives fulfillment, anaemia management or blood pressure during follow-up. Peritonitis rate was higher in older 65 years group (0.65 vs 0.45 episodes/patient/year; p < 0.001), but there was not differences in germs, admission rate and follow up. Mortality was higher in older 65 years group (28.4% vs 9.4%) as expected. PD permanence probability was similar (2.1 years). The main cause of PD withdrawal was transplant in group < 65 years (48.3%) and transfer to HD in group > 65 years. The main reason was caregiver or patient fatigue (20.2%), and not technique failure (7.3%). Multivariate Cox regression analysis showed a relation (HR [95%CI]) between mortality and age > 65 years 2.4 [1.9-3.0]; DM 1.6 [1.3-2.1]; CV events 2.1 [1.7-2.7]. Multivariate Cox regression analysis identify a relation between technique failure and age > 65 years 1.5 [1.3-1.9]; DM 1.6 [1.3-1.9] and previous transplant 1.5 [1.2-2.0]. CONCLUSION: Patients older than 65 years fulfilled PD adequacy criteria during the follow up. We believe PD is a valid option for patients older 65 years. It is necessary to try to prevent infections and patient/caregiver fatigue, to avoid HD transfer for reasons not related to technique failure.

Dual mechanisms of cognitive control in mindful individuals.

Not much research has adopted a multicomponent approach to examine the relationship between mindfulness and cognitive control. Studies addressing this issue have produced mixed results that may be due to the incorporation of different questionnaires to assess mindfulness and to the assessment of different stages and types of mindfulness itself. In the present study, we aimed to investigate to which extent dispositional mindfulness relates to a dynamic use of control modes as understood from the dual mechanisms of control theory. Further, we aimed to test this hypothesis by including two different frequently used mindfulness questionnaires in order to explore their confluence. Hundred thirty young adults completed two well-established assessment tools of mindfulness (Mindful Attention Awareness Scale and Five Facets Mindfulness Questionnaire) and two well-validated experimental tasks measuring proactive/reactive control modes (AX-Continuous Performance Task and Cued Task-Switching Paradigm). The data analyses were performed considering the continuous values in multiple regression analyses, as it is thought to better capture individual differences. The results replicate the previous findings suggesting that mindful individuals tend to use proactive and reactive control in a balanced manner in comparison to low mindfulness individuals, who tend to rely more on proactive control. Moreover, mindful individuals showed greater flexibility when the two processing modes were available. Hence, the major effects were found by using the two questionnaires. Altogether our findings indicate that mindful individuals, who have been characterized by an enhanced focus on the present moment without judgment, are less attached to the previous contextual information, which allows them to exhibit a more flexible performance.

Cathodal transcranial direct current stimulation over the right dorsolateral prefrontal cortex cancels out the cost of selective retrieval on subsequent analogical reasoning.

Analogical reasoning involves mapping the relation between two concepts within a specific field into a new domain to selectively retrieve a possible solution. Neuroimaging studies have shown that both selective retrieval and reasoning by analogy are related to activity in prefrontal regions such as the dorsolateral prefrontal cortex (DLPFC). In the present study, we investigate the role of the right DLPFC in modulating memory accessibility and its impact on analogical reasoning by using transcranial direct current stimulation (tDCS). Participants performed a four-term reasoning task after performing repeated selective retrieval of previously presented items, some of which could be used as solutions in the analogical test. During selective retrieval, half of the participants received cathodal tDCS over the right DLPFC and the other half received sham stimulation. The results reveal that whereas the sham group showed the expected cost in performance that is associated with selective retrieval, the cathodal group did not exhibit such an impairment in reasoning. No general effects of tDCS on analogical performance were observed. Altogether, our results support the involvement of the right DLPFC as a core component of a control network that selectively contributes to the retrieval component of analogical reasoning, but with little role in mapping relations between different domains.

Structural alignment and its prosocial effects in first and second languages.

The present study examined structural alignment (prepositional object dative and double object dative) and its prosocial effects in Spanish-English bilinguals (English L2) and native English speakers (English L1). A scripted picture description paradigm in which a confederate and participant alternately described pictures was used. L1 and L2 speakers of English displayed comparable levels of structural alignment. In a second phase of the experiment we show that after being exposed to structural alignment by the confederate, L1 but not L2 participants displayed an increase in prosocial behavior as reflected by the time they were willing to help with an extra task. Possible explanations and implications are then discussed.

Event versus activity-based cues and motivation in school-related prospective memory tasks.

Prospective memory (PM), the ability to remember an intention in the future, is essential to children's everyday lives. We explored age differences (6- to 7- vs. 10- to 11-year-olds) in PM depending on the nature of the task and the children's motivation. Children performed event-based PM tasks (in which the cue was presented during the ongoing activity) and activity-based PM tasks (in which the cue consisted of finishing the ongoing activity). Additionally, the children were assigned to either a reward condition or a no-reward condition. The results showed better performance in event than in activity based tasks, with older children outperforming younger children in both. There was a marginal effect of reward for PM accuracy. These patterns suggest that the cue detection process and children's motivation play a role in PM performance during development.

Inhibitory control during selective retrieval may hinder subsequent analogical thinking.

Analogical reasoning is a complex cognitive activity that involves access and retrieval of pre-existing knowledge in order to find a suitable solution. Prior work has shown that analogical transfer and reasoning can be influenced by unconscious activation of relevant information. Based on this idea, we report two experiments that examine whether reduced access to relevant information in memory may further disrupt analogical reasoning unwittingly. In both experiments, we use an adaptation of the retrieval practice paradigm [1] to modulate memory accessibility of potential solutions to a subsequent set of analogy problems of the type 'A is to B as C is to ?'. Experiment 1 showed a retrieval-induced impairment in analogical problem solving. Experiment 2 replicated this finding and demonstrated that it cannot be due to the deliberative episodic retrieval of the solutions to the analogies. These findings, predictable from an inhibitory framework of memory control, provide a new focus for theories of analogical transfer and highlight the importance of unconscious memory processes that may modulate problem solving.

Interacciones farmacológicas de los captores del fósforo / Pharmacological interactions of phosphate binders

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EEG Multiscale Complexity in Schizophrenia During Picture Naming.

Introduction: Patients with schizophrenia show cognitive deficits that are evident both behaviourally and with EEG recordings. Recent studies have suggested that non-linear analyses of EEG might more adequately reflect the complex, irregular, non-stationary behavior of neural processes than more traditional ERP measures. Non-linear analyses have been mainly applied to EEGs from patients at rest, whereas differences in complexity might be more evident during task performance. Objective: We aimed to investigate changes in non-linear brain dynamics of patients with schizophrenia during cognitive processing. Method: 18 patients and 17 matched healthy controls were asked to name pictures. EEG data were collected at rest and while they were performing a naming task. EEGs were analyzed with the classical Lempel-Ziv Complexity (LZC) and with the Multiscale LZC. Electrodes were grouped in seven regions of interest (ROI). Results: As expected, controls had fewer naming errors than patients. Regarding EEG complexity, the interaction between Group, Task and ROI indicated that patients showed higher complexity values in right frontal regions only at rest, where no differences in complexity between patients and controls were found during the naming task. EEG complexity increased from rest to task in controls in left temporal-parietal regions, while no changes from rest to task were observed in patients. Finally, differences in complexity between patients and controls depended on the frequency bands: higher values of complexity in patients at rest were only observed in fast bands, indicating greater heterogeneity in patients in local dynamics of neuronal assemblies. Conclusion: Consistent with previous studies, schizophrenic patients showed higher complexity than controls in frontal regions at rest. Interestingly, we found different modulations of brain complexity during a simple cognitive task between patients and controls. These data can be interpreted as indicating schizophrenia-related failures to adapt brain functioning to the task, which is reflected in poorer behavioral performance. HIGHLIGHTS:     - We measured classical and multiscale Lempel-Ziv Complexity (LZCN and MLZC) of the EEG signal of patients with schizophrenia and controls at rest and while performing a cognitive task.    - We found that patients and controls showed a different pattern of brain complexity depending on their cognitive state (at rest or under cognitive challenge).    - Our results illustrate the value of the MLZC in the characterization of the pattern of brain complexity in schizophrenia on function of frequency bands.    - Nonlinear methodologies of EEG analysis can help to characterize brain dysfunction in schizophrenia.

Role of TLR4 in the Modulation of Central Amygdala GABA Transmission by CRF Following Restraint Stress.

AIMS: Stress induces neuroimmune responses via Toll-like receptor 4 (TLR4) activation. Here, we investigated the role of TLR4 in the effects of the stress peptide corticotropin-releasing factor (CRF) on GABAergic transmission in the central nucleus of the amygdala (CeA) following restraint stress. METHODS: Tlr4 knock out (KO) and wild-type rats were exposed to no stress (naïve), a single restraint stress (1 h) or repeated restraint stress (1 h per day for 3 consecutive days). After 1 h recovery from the final stress session, whole-cell patch-clamp electrophysiology was used to investigate the effects of CRF (200 nM) on CeA GABAA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs). RESULTS: TLR4 does not regulate baseline GABAergic transmission in the CeA of naive and stress-treated animals. However, CRF significantly increased the mean sIPSC frequencies (indicating enhanced GABA release) across all genotypes and stress treatments, except for the Tlr4 KO rats that experienced repeated restraint stress. CONCLUSIONS: Overall, our results suggest a limited role for TLR4 in CRF's modulation of CeA GABAergic synapses in naïve and single stress rats, though TLR4-deficient rats that experienced repeated psychological stress exhibit a blunted CRF cellular response. SHORT SUMMARY: TLR4 has a limited role in CRF's activation of the CeA under basal conditions, but interacts with the CRF system to regulate GABAergic synapse function in animals that experience repeated psychological stress.

The Cost of Prospective Memory in Children: The Role of Cue Focality.

Prospective memory (PM) is an essential ability in daily life, since it involves remembering to perform an intention. While PM largely develops during childhood and adolescence, its underlying mechanisms are still poorly understood. In general, age differences in PM have been found with tasks in which the prospective cues are not part of the ongoing activity (non-focal PM tasks). In the present study, we evaluated the cognitive cost produced by a PM task over the ongoing activity by comparing the performance of a single-task condition with that of an ongoing activity condition involving a prospective intention. Specifically, to determine the impact of cue focality on performance as a function of age, we tested two groups of children (6 and 11 years old) in three experimental conditions: single, focal and non-focal prospective cues. In the single-task condition, children were only asked to perform the ongoing task (to categorize images as animal or non-animal). In the focal condition, in addition to performing the ongoing activity, participants were asked to press different keys whenever the image appearing on the screen was a kite or a ball. In the non-focal condition, children were to press the keys if the color of the frame of the screen changed to magenta or gray. Although reaction times were greater for the non-focal conditions in both age groups, the results showed worse performance on the ongoing activity for both the focal and the non-focal conditions (relative to the single-task condition) in the younger children. This difference was less pronounced in older children so that response times for focal and non-focal cues differed from the single condition, but the difference in performance between focal and single task conditions was not reliable. These findings, which are partly in line with the dual process framework (McDaniel et al., 2015), suggest that while non-focal prospective cues compromise attentional control in younger and older children, focal cues seem to rely on less effortful processes in older children.

Experience with code-switching modulates the use of grammatical gender during sentence processing.

Using code-switching as a tool to illustrate how language experience modulates comprehension, the visual world paradigm was employed to examine the extent to which gender-marked Spanish determiners facilitate upcoming target nouns in a group of Spanish-English bilingual code-switchers. The first experiment tested target Spanish nouns embedded in a carrier phrase (Experiment 1b) and included a control Spanish monolingual group (Experiment 1a). The second set of experiments included critical trials in which participants heard code-switches from Spanish determiners into English nouns (e.g., la house) either in a fixed carrier phrase (Experiment 2a) or in variable and complex sentences (Experiment 2b). Across the experiments, bilinguals revealed an asymmetric gender effect in processing, showing facilitation only for feminine target items. These results reflect the asymmetric use of gender in the production of code-switched speech. The extension of the asymmetric effect into Spanish (Experiment 1b) underscores the permeability between language modes in bilingual code-switchers.