Global IL4Rα blockade exacerbates heart failure after an ischemic event in mice and humans.

Ischemic heart failure continues to be a highly prevalent disease among westernized countries and there is great interest in understanding the mechanisms preventing or exacerbating disease progression. The literature suggests an important role for the activation of interleukin-13 or interleukin-4 signaling in improving ischemic heart failure outcomes after myocardial infarction in mice. Dupilumab, a neutralizing antibody that inhibits the shared IL13/IL4 receptor subunit IL4Rα, is widely used for conditions such as ectopic dermatitis in humans. If global depletion of IL4Rα influences ischemic heart failure, either in mice or in humans taking dupilumab, is unknown. Here, we investigated the pathophysiological effects of global IL4Rα genetic deletion in adult mice after surgically induced myocardial infarction (MI). We also determined heart failure risk in patients with ischemic heart disease and concomitant usage of dupilumab using the collaborative patient data network TriNetX. Global deletion of IL4Rα results in exacerbated cardiac dysfunction associated with reduced capillary size after myocardial infarction in mice. In agreement with our findings in mice, dupilumab treatment significantly increased the risk of heart failure development in patients with preexisting diagnosis of ischemic heart disease. Our results indicate that systemic IL4Rα signaling is protective against heart failure development in adult mice and human patients specifically following an ischemic event. Thus, the compelling evidence presented hereby advocates for the development of a randomized clinical trial specifically investigating heart failure development after myocardial ischemia in patients taking dupilumab for another underlying condition.NEW & NOTEWORTHY A body of literature suggests a protective role for IL4Rα signaling postmyocardial infarction in mice. Here, our observational study demonstrates that humans taking the IL4Rα neutralizing antibody, dupilumab, have increased incidence of heart failure following an ischemic event. Similarly, global IL4Rα deletion in mice exacerbates heart failure postinfarct. To our knowledge, this is the first study reporting an adverse association in humans of dupilumab use with heart failure following a cardiac ischemic event.

Subcortical Aphasia: An Update.

PURPOSE OF REVIEW: This review aims to rediscuss the leading theories concerning the role of basal ganglia and the thalamus in the genesis of aphasic symptoms in the absence of gross anatomical lesions in cortical language areas as assessed by conventional neuroimaging studies. RECENT FINDINGS: New concepts in language processing and modern neuroimaging techniques have enabled some progress in resolving the impasse between the current dominant theories: (a) direct and specific linguistic processing and (b) subcortical structures as processing relays in domain-general functions. Of particular interest are studies of connectivity based on functional magnetic resonance imaging (MRI) and tractography that highlight the impact of white matter pathway lesions on aphasia development and recovery. Connectivity studies have put into evidence the central role of the arcuate fasciculus (AF), inferior frontal occipital fasciculus (IFOF), and uncinate fasciculus (UF) in the genesis of aphasia. Regarding the thalamus, its involvement in lexical-semantic processing through modulation of the frontal cortex is becoming increasingly apparent.

Locomotion and morphological adaptations in the glass lizard Ophiodes cf. fragilis (Raddi, 1820) (Squamata: Anguidae).

There are few studies related to the biological and ecological aspects of the glass snake, a limbless lizard and with a wide geographic distribution. The aim of this study was to analyze the locomotion mode of specimens of Ophiodes cf. fragilis in different substrates and to investigate the morphological adaptations associated with this type of behavior. We observed that the analyzed specimens presented slide-push locomotion modes and lateral undulation in different substrates, using their hind limbs to aid locomotion in three of the four substrates analyzed. The bones of the hind limbs (proximal - femur - and distal - tibia and fibula) were present and highly reduced and the femur is connected to a thin pelvic girdle. Our data support that hind limbs observed in species of this genus are reduced rather than vestigial. The costocutaneous musculature was macroscopically absent. This is the first study of locomotor behavior and morphology associated with locomotion in Ophiodes, providing important information for studies on morphological evolution in the genus.

Knockdown of the inducible nitric oxide synthase (NOS2) splicing variant S3 promotes autophagic cell death from nitrosative stress in SW480 human colon cancer cells.

Low levels of nitric oxide (NO) produced by constitutively expressed inducible NO synthase (NOS2) in tumor cells may be an important factor in their development. NOS2 expression is associated with high mortality rates for various cancers. Alternative splicing of NOS2 down-regulates its enzymatic activity, resulting in decreased intracellular NO concentrations. Specific probes to detect alternative splicing of NOS2 were used in two isogenic human colon cancer cell lines derived either from the primary tumor (SW480) or from a lymph node metastasis (SW620). Splicing variant of NOS2 S3, lacking exons 9, 10, and 11, was overexpressed in SW480 cells. NOS2 S3 was silenced in SW480 cells. Flow-cytometry analysis was used to estimate the intracellular NO levels and to analyze the cell cycle of the studied cell lines. Western blot analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were used to determine apoptosis and autophagy markers. SW480 and SW620 cells expressed NOS2 S3. Overexpression of the NOS2 S3 in SW480 cells downregulated intracellular NO levels. SW480 cells with knocked down NOS2 S3 (referred to as S3C9 cells) had higher intracellular levels of NO compared to the wild-type SW480 cells under serum restriction. Higher NO levels resulted in the loss of viability of S3C9 cells, which was associated with autophagy. Induction of autophagy by elevated intracellular NO levels in S3C9 cells under serum restriction, suggests that autophagy operates as a cytotoxic response to nitrosative stress. The expression of NOS2 S3 plays an important role in regulating intracellular NO production and maintaining viability in SW480 cells under serum restriction. These findings may prove significant in the design of NOS2/NO-based therapies for colon cancer.

IL4Rα signaling promotes neonatal cardiac regeneration and cardiomyocyte cell cycle activity.

Neonatal heart regeneration depends on proliferation of pre-existing cardiomyocytes, yet the mechanisms driving regeneration and cardiomyocyte proliferation are not comprehensively understood. We recently reported that the anti-inflammatory cytokine, interleukin 13 (IL13), promotes neonatal cardiac regeneration; however, the signaling pathway and cell types mediating this regenerative response remain unknown. Here, we hypothesized that expression of the type II heterodimer receptor for IL13, comprised of IL4Rα and IL13Rα1, expressed directly on cardiomyocytes mediates cardiomyocyte cell cycle and heart regeneration in neonatal mice. Our data demonstrate that indeed global deletion of one critical subunit of the type II receptor, IL4Rα (IL4Rα-/-), decreases cardiomyocyte proliferation during early postnatal development and significantly impairs cardiac regeneration following injury in neonatal mice. While multiple myocardial cell types express IL4Rα, we demonstrate that IL4Rα deletion specifically in cardiomyocytes mediates cell cycle activity and neonatal cardiac regeneration. This demonstrates for the first time a functional role for IL4Rα signaling directly on cardiomyocytes in vivo. Reciprocally, we examined the therapeutic benefit of activating the IL4Rα receptor in non-regenerative hearts via IL13 administration. Following myocardial infarction, administration of IL13 reduced scar size and promoted cardiomyocyte DNA synthesis and karyokinesis, but not complete cytokinesis, in 6-day old non-regenerative mice. Our data demonstrate a novel role for IL4Rα signaling directly on cardiomyocytes during heart regeneration and suggest the potential for type II receptor activation as one potential therapeutic target for promoting myocardial repair.

Subcortical Aphasia.

PURPOSE OF REVIEW: Subcortical structures have long been thought to play a role in language processing. Increasingly spirited debates on language studies, arising from as early as the nineteenth century, grew remarkably sophisticated as the years pass. In the context of non-thalamic aphasia, a few theoretical frameworks have been laid out. The disconnection hypothesis postulates that basal ganglia insults result in aphasia due to a rupture of connectivity between Broca and Wernicke's areas. A second viewpoint conjectures that the basal ganglia would more directly partake in language processing, and a third stream proclaims that aphasia would stem from cortical deafferentation. On the other hand, thalamic aphasia is more predominantly deemed as a resultant of diaschisis. This article reviews the above topics with recent findings on deep brain stimulation, neurophysiology, and aphasiology. RECENT FINDINGS: The more recent approach conceptualizes non-thalamic aphasias as the offspring of unpredictable cortical hypoperfusion. Regarding the thalamus, there is mounting evidence now pointing to leading contributions of the pulvinar/lateral posterior nucleus and the anterior/ventral anterior thalamus to language disturbances. While the former appears to relate to lexical-semantic indiscrimination, the latter seems to bring about a severe breakdown in word selection and/or spontaneous top-down lexical-semantic operations. The characterization of subcortical aphasias and the role of the basal ganglia and thalamus in language processing continues to pose a challenge. Neuroimaging studies have pointed a path forward, and we believe that more recent methods such as tractography and connectivity studies will significantly expand our knowledge in this particular area of aphasiology.

Helicobacter pylori infection modulates the expression of miRNAs associated with DNA mismatch repair pathway.

Genetic and epigenetic inactivation of DNA mismatch repair (MMR) genes might lead to modifications in cancer-related gene expression and cancer development. Recently, it has been shown that the infection by Helicobacter pylori, the major causative agent of gastric cancer, induces DNA damage and inhibits MMR DNA repair. Also, it has been reported that microRNAs (miRs) have an important role in regulating genomic stability and MMR DNA repair. Thus, the aim of this study was to identify miRs regulating MMR pathway in H. pylori-associated gastric carcinogenesis. To address this question, a gastric epithelial cell line and AGS cancer gastric cells were infected with several H. pylori strains. MMR gene expression and miRs correlating with H. pylori strain infection were evaluated. The results showed that H. pylori infection significantly down-regulated the expression of all selected MMR genes. Also, H. pylori infection modulated the expression of several miRs (including miR-150-5p, miR-155-5p, and miR-3163), after 4, 8, and 12 h of infection. Computational prediction of candidate miRs and their predicted MMR targeting sites were obtained from TargetScan, mirDB, and MetaCore. The generated data indicated that the selected miRs (miR-150-5p, miR-155-5p, and miR-3163) could possibly target and modulate MMR genes (POLD3, MSH2, and MSH3, respectively). The target validation was performed using mimics and luciferase gene reporter assays. Briefly, this study shows that H. pylori impairs MMR DNA repair pathway and identifies miRs that regulate MMR gene expression in gastric cancer. © 2016 Wiley Periodicals, Inc.

Physical Exercise As Stabilizer For Alzheimer'S Disease Cognitive Decline: Current Status.

INTRODUCTION: Mental health decline is one of the main responsible factors for augments in health care costs, and diagnosis of Alzheimer's disease (AD). Some studies stated physical exercise is useful for reduction in cognitive decline and AD. Moreover, a recent review argued that evidence are scarce due to few studies published and lack of configuration information of exercise protocol, such as intensity and duration of exercise, number of sessions and other relevant data, to allow appropriate assessment. MATERIALS AND METHODS: Here, we discussed the possible confounders or factors responsible for these differences and possible neurophysiological mechanisms. RESULTS: Most studies revealed a possible positive association between physical exercise and cognitive assessments. There are inconsistencies in studies design responsible for varying use of cognitive assessments and different assessments of fitness. However, these studies do not fail to provide evidence about the benefits of exercise, but fail to make it possible because of the lack of dose-response information in AD patients. Physical exercise of moderate intensity should be considered as standard recommendation to reduce cognitive decline, probably due to the improvement in neurodegenerative mechanisms, and the increase in neuroplastic and neuroprotective neurotrophic factors. CONCLUSION: Therefore, it is suggested that physical exercise is an important neuroprotective modulator, bringing significant control of the disease and amplifying brain functions.

Somatostatin and the pathophysiology of Alzheimer's disease.

Among the central features of Alzheimer's disease (AD) progression are altered levels of the neuropeptide somatostatin (SST), and the colocalisation of SST-positive interneurons (SST-INs) with amyloid-ß plaques, leading to cell death. In this theoretical review, I propose a molecular model for the pathogenesis of AD based on SST-IN hypofunction and hyperactivity. Namely, hypofunctional and hyperactive SST-INs struggle to control hyperactivity in medial regions in early stages, leading to axonal Aß production through excessive presynaptic GABAB inhibition, GABAB1a/APP complex downregulation and internalisation. Concomitantly, excessive SST-14 release accumulates near SST-INs in the form of amyloids, which bind to Aß to form toxic mixed oligomers. This leads to differential SST-IN death through excitotoxicity, further disinhibition, SST deficits, and increased Aß release, fibrillation and plaque formation. Aß plaques, hyperactive networks and SST-IN distributions thereby tightly overlap in the brain. Conversely, chronic stimulation of postsynaptic SST2/4 on gulutamatergic neurons by hyperactive SST-INs promotes intense Mitogen-Activated Protein Kinase (MAPK) p38 activity, leading to somatodendritic p-tau staining and apoptosis/neurodegeneration - in agreement with a near complete overlap between p38 and neurofibrillary tangles. This model is suitable to explain some of the principal risk factors and markers of AD progression, including mitochondrial dysfunction, APOE4 genotype, sex-dependent vulnerability, overactive glial cells, dystrophic neurites, synaptic/spine losses, inter alia. Finally, the model can also shed light on qualitative aspects of AD neuropsychology, especially within the domains of spatial and declarative (episodic, semantic) memory, under an overlying pattern of contextual indiscrimination, ensemble instability, interference and generalisation.

Effects of the Use of Beta-Blockers on Chronic Obstructive Pulmonary Disease Associated with Cardiovascular Comorbities: Systematic Review and Meta-analysis.

Cardiovascular comorbidity is common in individuals with chronic obstructive pulmonary disease (COPD). This factor interferes with pharmacological treatment. The use of ß-blockers has been proposed for their known cardioprotective effects. However, due to their adverse reactions, and the risk of causing bronchospasm, there is reluctance to use them. To summarize existing evidence on the effects of ß-blocker use in COPD associated with cardiovascular comorbidities in relation to disease severity, exacerbation, and mortality outcomes. EMBASE, Medline, Lilacs, Cochrane Library, and Science Direct databases were used. Observational studies that evaluated the effects of ß-blockers on individuals with COPD and cardiovascular comorbidities, and related disease severity, exacerbations, or mortality outcomes were included. Studies that did not present important information about the sample and pharmacological treatment were excluded. Twenty studies were included. Relevance to patient care and clinical practice: The use of ß-blockers in individuals with COPD and cardiovascular disease caused positive effects on mortality and exacerbations outcomes, compared with the results of individuals who did not use them. The severity of the disease caused a slight change in forced expiratory volume in 1 second. The odds ratio for mortality was 0.50 (95% confidence interval [CI], 0.39 to 0.63; p<0.00001), and for exacerbations, 0.76 (95% CI, 0.62 to 0.92; p=0.005), being favorable to the group that used ß-blockers. Further studies are needed to study the effect of using a specific ß-blocker in COPD associated with a specific cardiovascular comorbidity.

IL-13 promotes functional recovery after myocardial infarction via direct signaling to macrophages.

There is great interest in identifying signaling pathways that promote cardiac repair after myocardial infarction (MI). Prior studies suggest a beneficial role for IL-13 signaling in neonatal heart regeneration; however, the cell types mediating cardiac regeneration and the extent of IL-13 signaling in the adult heart after injury are unknown. We identified an abundant source of IL-13 and the related cytokine, IL-4, in neonatal cardiac type 2 innate lymphoid cells, but this phenomenon declined precipitously in adult hearts. Moreover, IL-13 receptor deletion in macrophages impaired cardiac function and resulted in larger scars early after neonatal MI. By using a combination of recombinant IL-13 administration and cell-specific IL-13 receptor genetic deletion models, we found that IL-13 signaling specifically to macrophages mediated cardiac functional recovery after MI in adult mice. Single transcriptomics revealed a subpopulation of cardiac macrophages in response to IL-13 administration. These IL-13-induced macrophages were highly efferocytotic and were identified by high IL-1R2 expression. Collectively, we elucidated a strongly proreparative role for IL-13 signaling directly to macrophages following cardiac injury. While this pathway is active in proregenerative neonatal stages, reactivation of macrophage IL-13 signaling is required to promote cardiac functional recovery in adults.

The Development of Biocomposite Filaments for 3D Printing by Utilizing a Polylactic Acid (PLA) Polymer Matrix Reinforced with Cocoa Husk Cellulose Fibers.

Vegetable fibers are increasingly used in biocomposites, but there is a need for further development in utilizing by-products like cocoa husks. Three-dimensional printing, through Fused Filament Fabrication (FFF), is advancing rapidly and may be of great interest for applying biocomposite materials. This study focuses on developing innovative and fully biodegradable filaments for the FFF process. PLA filaments were prepared using cellulose fibers derived from cocoa husks (5% mass ratio). One set of filaments incorporated fibers from untreated husks (UCFFs), while another set utilized fibers from chemically treated husks (TCFFs). The fabricated materials were analyzed using scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and Fourier transform infrared (FTIR) techniques, and they were also tested for tensile strength. ANOVA reveals that both UCFFs and TCFFs significantly predict tensile strength, with the UCFFs demonstrating an impressive R2 value of 0.9981. The optimal tensile strength for the filament test specimens was 16.05 MPa for TCFF8 and 13.58 MPa for UCFF8, utilizing the same printing parameters: 70% infill and a layer thickness of 0.10 mm. Additionally, there was an 18% improvement in the tensile strength of the printed specimens using the filaments filled with chemically treated cocoa husk fibers compared to the filaments with untreated fibers.

Effectiveness of an affect-adjusted, supervised, multimodal, online and home-based exercise group protocol for major depression: A randomized controlled trial.

This randomized controlled trial investigated the effectiveness of an affect-adjusted, supervised, multimodal, online, and home-based exercise group protocol as an adjunct therapy to antidepressants on depressive symptoms, cardiorespiratory fitness, and side effects related to antidepressants in adults with major depression (MDD, diagnosed by a clinician). Depressive symptom scales were administered by a psychiatrist and self-reported. A health-related measure (i.e., cardiorespiratory fitness), was also administered. The exercise intervention was adjusted by perceived effort and affect (pleasure and enjoyment) toward exercise and lasted 12 weeks. In total, 59 adults with MDD were divided into two groups: the exercise-group (EG; exercise + pharmacotherapy) with 26-patients (76.9 % females, mean age 28.5 years) and the control-group (CG, pharmacotherapy) with 33-patients (78.7 % females, mean age 25.6 years). The EG had a lower dropout rate (15.3 %) than CG and an increase in cardiorespiratory fitness (CRF), which was not observed in the CG. Both groups showed a decrease in self-reported depressive symptoms. However, the EG had significantly lower depressive symptom scores at t1 and t2. The EG also had higher remission rates (t1, EG: = 42.3 % and CG = 27.2 %) and remission rates (t2, EG: = 72.7 % and CG = 48.1 %) than CG, which were maintained during the four month follow-up. Side effects from anti-depressant medication were larger in the EG compared to CG. Complementing usual care for MDD with exercise resulted in better clinical outcomes and supports the use of this type of exercise protocol in the clinical management of depression.

Myofibroblast Ccn3 is regulated by Yap and Wwtr1 and contributes to adverse cardiac outcomes.

Introduction: While Yap and Wwtr1 regulate resident cardiac fibroblast to myofibroblast differentiation following cardiac injury, their role specifically in activated myofibroblasts remains unexplored. Methods: We assessed the pathophysiological and cellular consequence of genetic depletion of Yap alone (Yap fl/fl ;Postn MCM ) or Yap and Wwtr1 (Yap fl/fl ;Wwtr1 fl/+ ;Postn MCM ) in adult mouse myofibroblasts following myocardial infarction and identify and validate novel downstream factors specifically in cardiac myofibroblasts that mediate pathological remodeling. Results: Following myocardial infarction, depletion of Yap in myofibroblasts had minimal effect on heart function while depletion of Yap/Wwtr1 resulted in smaller scars, reduced interstitial fibrosis, and improved ejection fraction and fractional shortening. Single cell RNA sequencing of interstitial cardiac cells 7 days post infarction showed suppression of pro-fibrotic genes in fibroblasts derived from Yap fl/fl ,Wwtr1 fl/+ ;Postn MCM hearts. In vivo myofibroblast depletion of Yap/Wwtr1 as well in vitro knockdown of Yap/Wwtr1 dramatically decreased RNA and protein expression of the matricellular factor Ccn3. Administration of recombinant CCN3 to adult mice following myocardial infarction remarkably aggravated cardiac function and scarring. CCN3 administration drove myocardial gene expression of pro-fibrotic genes in infarcted left ventricles implicating CCN3 as a novel driver of cardiac fibrotic processes following myocardial infarction. Discussion: Yap/Wwtr1 depletion in myofibroblasts attenuates fibrosis and significantly improves cardiac outcomes after myocardial infarction and we identify Ccn3 as a factor downstream of Yap/Wwtr1 that contributes to adverse cardiac remodeling post MI. Myofibroblast expression of Yap, Wwtr1, and Ccn3 could be further explored as potential therapeutic targets for modulating adverse cardiac remodeling post injury.

The utilisation of primary health care system concepts positively impacts the assistance of patients with rare diseases despite limited knowledge and experience by health care professionals: A qualitative synopsis of the evidence including approximately 78 000 individuals.

Background: Individuals with rare diseases (RD) have been historically understudied. Previous publications reported that existing primary health care (PHC) workforces and associated infrastructure had been shown to improve their access and health-related outcomes in low- and middle-income countries (LMICs). As current evidence about the impact of PHC on patients diagnosed with RD is yet highly dispersed, this scoping review aimed to collate available evidence of the impact of PHC on patients with RD and summarize published information from multiple stakeholders about the perceived usefulness and barriers to effective use of the PHC system. Methods: We searched Embase, Health System Evidence, PubMed, LILACS / BVS, and The Cochrane Library, from inception to September 1, 2022, for publications providing clear expert- or experience-based insights or data from patients living with RD at the PHC level of care. We included publications highlighting barriers to integrated care of patients with RD, reported by multiple social actors involved in caring for patients with RD. Two investigators screened publications, extracted data, and clustered information among records deemed eligible for inclusion. Data synthesis was performed using narrative and thematic-based analysis. Major findings identified and coded through a semantic-driven analysis were processed in vosViewer software and reported using descriptive statistics. Findings: Eighty publications were included in this review. Quali-quantitative analyses evidenced that the PHC level is essential for approaching patients with RD, mainly due to its longitudinal, multidisciplinary, and coordinated care delivery. In addition, several publications highlighted that the medical curriculum is inappropriate for preparing health care providers to deal with patients presenting unusual signs and symptoms and being diagnosed with RD. PHC teams are essential in orienting patients and families on emergency events. Technology-related concepts were reported in 19 publications, emphasizing their effectiveness on early diagnosis, optimal treatment definition, improvement of quality of life, and long-lasting follow-up. Conclusions: We provided valuable information on the effectiveness of the PHC in fostering a creative, integrative, and supportive environment for patients living with RD. Our results can be helpful to several stakeholders in deciding what actions are still pending to achieve a solid and positive experience for patients with RD in the PHC. Registration: PROSPERO (CRD42022332347).

The neural hierarchy of consciousness: A theoretical model and review on neurophysiology and NCCs.

The chief undertaking in the studies of consciousness is that of unravelling the neural correlates of consciousness. To this day, this crusade remains at an impasse, with a clash of two main theoretical stances: the Global Neuronal Workspace and the Recurrent Processing. Yet, cellular and neurophysiological studies of consciousness have been mostly dissociated from the two. Herein, a theoretical review will be put forth with the aim to change that. In its first half, I will cover the hard available evidence on the neurophysiology of consciousness, and in its second half, I will weave a theoretical model that reconciles the all-or-none cortical ignition (P3b) and graded recurrent processing (VAN) theories on the basis of neurophysiological evidence. As should be made clear, this Neural Hierarchy model substantiates and expands on a novel take on conscious awareness: the levels of processing approach, partitioning the conscious architecture into lower- and higher-order, graded and nonlinear.

Semantic processing and neurobiology in Alzheimer's disease and Mild Cognitive Impairment.

In the present theoretical review we will perform a critical surveillance of linguistic and semantic processing in Mild Cognitive Impairment and Alzheimer's disease, explicitly favouring a neurobiological prism. We conjecture that most linguistic alterations arise from semantic indiscrimination through inhibitory hypofunction. Specifically, a conjoint cluster of cholinergic dysfunction, Aß load and somatostatin-positive cell loss renders the semantic network disinhibited and overly noisy: fine discriminatory processes in temporal and medial-frontal regions cannot differentiate semantic representations from baseline unconscious activity, which leads to failures in faithful retrieval (preferentially idiosyncratic lexical-semantic links, e.g., proper names), verbal fluency anomalies, semantic interference, dampened N400 effects, and various semiological deviances.

Prevalence and Impact of Comorbidities in Individuals with Chronic Obstructive Pulmonary Disease: A Systematic Review.

This study aimed to describe the prevalence of comorbidities associated with chronic obstructive pulmonary disease (COPD) and their relation with relevant outcomes. A systematic review based on the PRISMA methodology was performed from January 2020 until July 2021. The MEDLINE, Lilacs, and Scielo databases were searched to identify studies related to COPD and its comorbidities. Observational studies on the prevalence of comorbidities in COPD patients and costs with health estimates, reduced quality of life, and mortality were included. Studies that were restricted to one or more COPD pain assessments and only specific comorbidities such as osteoporosis, bronchitis, and asthma were excluded. The initial search identified 1,409 studies and after applying the inclusion and exclusion criteria, 20 studies were finally selected for analysis (comprising data from 447,459 COPD subjects). The most frequent COPD comorbidities were: hypertension (range, 17%-64.7%), coronary artery disease (19.9%-47.8%), diabetes (10.2%-45%), osteoarthritis (18%-43.8%), psychiatric conditions (12.1%-33%), and asthma (14.7%-32.5%). Several comorbidities had an impact on the frequency and severity of COPD exacerbations, quality of life, and mortality risk, in particular malignancies, coronary artery disease, chronic heart failure, and cardiac arrhythmias. Comorbidities, especially cardiovascular diseases and diabetes, are frequent in COPD patients, and some of them are associated with higher mortality.

Temporal variation of phytoplankton from the tropical reservoir Valle de Bravo, Mexico.

Valle de Bravo reservoir is used for aquatic, fishing and as a source of drinking water to Mexico City. Annual data on composition, abundances, species richness and diversity of the phytoplankton surface community and some physical-chemical parameters variations were discussed. Results showed a spatial homogeneity for environmental descriptors and phytoplankton samples but a temporal significant difference between months. Pulses of high algal densities corresponded to late stratification (October, 103 x 10(3) cell ml(-1)), early stratification (April, 107 x 10(3) cell ml(-1)) and plenty stratification (June, 69 x 10(3) cell ml(-1)). Taxa that reached higher densities were: Microcystis spp., Snowella septentrionalis, Anabaena spp., Aphanizomenon yezoense and Fragilaria crotonensis. Contribution of each taxon to the total phytoplankton density showed that majorities were rare (41%) or dominants (40%). Frequent alternation between pulses and low densities and diversity of phytoplankton as well as a relative high number of taxa found (68), could be explained by daily strong winds, unstable epilimnion thickness and incorporation and extraction of substantial volumes of water occurred in the reservoir. Dominances of cyanobacteria and some chlorococcal species and a high temporal fluctuated Shannon-Wiener diversity index (0.45- 2.35 bits) pointing to eutrophic and perturbed conditions.

Neurophysiological basis of the N400 deflection, from Mismatch Negativity to Semantic Prediction Potentials and late positive components.

The first theoretical model on the neurophysiological basis of the N400: the deflection reflects layer I dendritic plateaus on a preparatory state of synaptic integration that precedes layer V somatic burst firing for conscious identification of the higher-order features of the stimulus (a late positive shift). Plateaus ensue from apical disinhibition by vasoactive intestinal polypeptide-positive interneurons (VIPs) through suppression of Martinotti cells, opening the gates for glutamatergic feedback to trigger dendritic regenerative potentials. Cholinergic transients contribute to these dynamics directly, holding a central role in the N400 deflection. The stereotypical timing of the (frontal) glutamatergic feedback and the accompanying cholinergic transients account for the enigmatic "invariability" of the peak latency in the face of a gamut of different stimuli and paradigms. The theoretical postulations presented here may bring about unprecedented level of detail for the N400 deflection to be used in the study of schizophrenia, Alzheimer's disease and other higher-order pathologies. The substrates of a late positive component, the Mismatch Negativity and the Semantic Prediction Potentials are also surveyed.