Correlations between peripheral levels of inflammatory mediators and frontolimbic structures in bipolar disorder: an exploratory analysis.

BACKGROUND: Altered peripheral immune/inflammatory system and brain volumetric changes have been implicated in the pathophysiology of bipolar disorder (BD). This study aimed to evaluate how peripheral levels of cytokines are related to volumetric brain changes in euthymic patients with BD. METHODS: Euthymic patients with BD (n = 21) and healthy controls (n = 22) were enrolled in this exploratory study. Blood samples were collected on the same day of clinical assessment and neuroimaging. Cytokines were measured through cytometric bead array method. Neuroimaging data were acquired using a sagittal three-dimensional magnetic resonance imaging T1-weighted fast field echo sequence and was processed using FreeSurfer. RESULTS: Compared to controls, BD patients had significantly lower volumes in the cingulate, medial-orbitofrontal (MOF) and parahippocampal regions. We found a negative correlation between right MOF volume and interferon-gamma levels (ß = -0.431, P = .049) and a positive correlation between interleukin-10 levels and left posterior cingulate volume (ß = 0.457, P = .048). CONCLUSION: Our results support the involvement of inflammatory pathways in structural brain changes in BD.

Epidemiology and Etiopathogeny of COVID-19.

Despite the recent announcement of the new pathogenic coronavirus to man, SARS-CoV2, a large number of publications are presented to the scientific community. An organized and systematic review of the epidemiological, etiological, and pathogenic factors of COVID-19 is presented. This is a systematic review using the databases MEDLINE, EMBASE, Web of Science, SCIELO; the descriptors coronavirus, SARS-CoV-2, etiology, epidemiology, pathophysiology, pathogenesis, COVID-19, with publications from December 2019 to January 2021, resulting in more than 800 publications and 210 selected. The data suggest that COVID-19 is associated with SAR-CoV-2 infection, with the transmission of contagion by fomites, salivary droplets, and other forms, such as vertical and fecal-oral. The bat and other vertebrates appear to be reservoirs and part of the transmission chain. The virus uses cell receptors to infect human cells, especially ACE2, like other coronaviruses. Heat shock proteins have different roles in the infection, sometimes facilitating it, sometimes participating in more severe conditions, when not serving as a therapeutic target. The available data allow us to conclude that COVID-19 is a pandemic viral disease, behaving as a challenge for public health worldwide, determining aggressive conditions with a high mortality rate in patients with risk factors, without treatment, but with the recent availability of the first vaccines.

Covid-19: the renin-angiotensin system imbalance hypothesis.

The emergency of SARS-CoV-2 in China started a novel challenge to the scientific community. As the virus turns pandemic, scientists try to map the cellular mechanisms and pathways of SARS-CoV-2 related to the pathogenesis of Coronavirus Disease 2019 (Covid-19). After transmembrane angiotensin-converting enzyme 2 (ACE2) has been found to be SARS-CoV-2 receptor, we hypothesized an immune-hematological mechanism for Covid-19 based on renin-angiotensin system (RAS) imbalance to explain clinical, laboratory and imaging findings on disease course. We believe that exaggerated activation of ACE/Angiotensin II (Ang II)/Angiotensin Type 1 (AT1) receptor RAS axis in line with reduction of ACE2/Angiotensin-(1-7)/Mas receptor may exert a pivotal role in the pathogenesis of Covid-19. In this perspective, we discuss potential mechanisms and evidence on this hypothesis.

A Decentralized Low-Chattering Sliding Mode Formation Flight Controller for a Swarm of UAVs.

In this paper, a nonlinear robust formation flight controller for a swarm of unmanned aerial vehicles (UAVs) is presented. It is based on the virtual leader approach and is capable of achieving and maintaining a formation with time-varying shape. By using a decentralized architecture, the local controller in each UAV uses information only from the UAV itself, its neighbors, and from the virtual leader. Also, a synchronization control objective provides a mechanism to weight between the fleet achieving the desired formation shape, that is, achieving the desired relative position between the UAVs, and each UAV achieving its desired absolute position. The use of a combination of a sliding mode controller and a low pass filter reduces the usual chattering effect, providing a smooth control signal while maintaining robustness. Simulation results show the effectiveness of the proposed decentralized controller.

Photochemical and photocatalytic degradation of 1-propanol using UV/H2 O2 : Identification of malonate as byproduct.

1-propanol is a primary alcohol extensively used in the pharmaceutical, chemical, and food industries. It has been also found as a contaminant in the atmosphere and is considered a model compound to mimic the behavior and fate of aliphatic alcohols exposed to environmental conditions. In order to understand that role of relevant variables, this paper presents results obtained with a simple experimental set-up to investigate the reactivity of 1-propanol under mild oxidizing conditions. Coupling this system with CE-C4 D allowed the quantification of the carboxylic acids formed. For the described experiments, aqueous solutions of 1-propanol were placed inside a photoreactor and oxidized upon the addition of TiO2 and/or H2 O2 . According to the described results, the addition of H2 O2 (0.1% w/w) was the most significant variable, roughly tripled the amount of carboxylic acids generated and led to the conversion of up to 70% of the initially available 1-propanol (1 mmol/L). More importantly, the reaction yielded the formation (within 10 min) of propionate (50 µmol/L), acetate (400 µmol/L), formate (50 µmol/L), and malonate (200 µmol/L). The latter is critically important because it represents the first example of the photochemical oxidation of both terminal carbons of the C3 -chain of 1-propanol under mild conditions, and opens new avenues for the production of this important chemical building block.

Analysis of inorganic cations and amino acids in high salinity samples by capillary electrophoresis and conductivity detection: Implications for in-situ exploration of ocean worlds.

With growing interest in exploring ocean worlds, such as Europa and Enceladus, there is a fundamental need to develop liquid-based analytical techniques capable of handling high salinity samples while performing both bulk and trace species measurements. In this context, CE with capacitively coupled contactless conductivity detection (CE-C4 D) has tremendous potential. One of its advantages is that this combination allows the detection of a wide number of charged species (both organic and inorganic) without the need of derivatization. Amino acids are an example of organic targets that are powerful biosignatures in the search for life beyond Earth. Simultaneous information on the inorganic cations in a sample helps with assessing the habitability of an extraterrestrial environment, as well as providing sample context for any measurements of trace amino acids. In this work, we present a series of flight-compatible methods capable of simultaneously measuring inorganic cations and amino acids in samples of varying salinity by CE-C4 D. Regardless of the sample total salinity, 5.0 M acetic acid was selected as the optimum BGE. The methods were evaluated by analyzing natural samples of low and high salinity from Hot Creek Gorge, Mono Lake, and Santa Monica beach. Prospects for mission implementation are also discussed.

Kidney-brain axis inflammatory cross-talk: from bench to bedside.

Epidemiologic data suggest that individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing neuropsychiatric disorders, cognitive impairment, and dementia. This risk is generally explained by the high prevalence of both symptomatic and subclinical ischemic cerebrovascular lesions. However, other potential mechanisms, including cytokine/chemokine release, production of reactive oxygen species (ROS), circulating and local formation of trophic factors and of renin-angiotensin system (RAS) molecules, could also be involved, especially in the absence of obvious cerebrovascular disease. In this review, we discuss experimental and clinical evidence for the role of these mechanisms in kidney-brain cross-talk. In addition, we hypothesize potential pathways for the interactions between kidney and brain and their pathophysiological role in neuropsychiatric and cognitive changes found in patients with CKD. Understanding the pathophysiologic interactions between renal impairment and brain function is important in order to minimize the risk for future cognitive impairment and to develop new strategies for innovative pharmacological treatment.

Home-based tDCS for apathy in Alzheimer's disease: a protocol for a randomized double-blinded controlled pilot study.

BACKGROUND: Apathy is among the most common behavioral symptoms in dementia and is consistently associated with negative outcomes in Alzheimer's disease (AD). Despite its prevalence and clinical relevance, available pharmacological and non-pharmacological strategies to treat apathy in AD have been marked, respectively, by potentially severe side effects and/or limited efficacy. Transcranial direct current stimulation (tDCS) is a relatively novel non-pharmacological method of neuromodulation with promising results. Compared to previous tDCS formats, recent technological advances have increased the portability of tDCS, which creates the potential for caregiver-administered, home use. Our study aims to evaluate the feasibility, safety, and efficacy of home-based tDCS for the treatment of apathy in AD. METHODS/DESIGN: This is an experimenter- and participant-blinded, randomized, sham-controlled, parallel-group (1:1 for two groups) pilot clinical trial, involving 40 subjects with AD. After a brief training, caregivers will administer tDCS for participants at home under remote televideo supervision by research staff to ensure the use of proper technique. Participants will be assessed at baseline, during treatment (week 2, week 4, and week 6), and 6 weeks post-treatment. Dependent measures will cover cognitive performance, apathy, and other behavioral symptoms. Data about side effects and acceptability will also be collected. DISCUSSION: Our study will address apathy, an overlooked clinical problem in AD. Our findings will advance the field of non-pharmacological strategies for neuropsychiatric symptoms, presenting a great potential for clinical translation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04855643.

Non-Invasive Neuromodulation Methods to Alleviate Symptoms of Huntington's Disease: A Systematic Review of the Literature.

Huntington's disease (HD) is a progressive and debilitating neurodegenerative disease. There is growing evidence for non-invasive neuromodulation tools as therapeutic strategies in neurodegenerative diseases. This systematic review aims to investigate the effectiveness of noninvasive neuromodulation in HD-associated motor, cognitive, and behavioral symptoms. A comprehensive literature search was conducted in Ovid MEDLINE, Cochrane Central Register of Clinical Trials, Embase, and PsycINFO from inception to 13 July 2021. Case reports, case series, and clinical trials were included while screening/diagnostic tests involving non-invasive neuromodulation, review papers, experimental studies on animal models, other systematic reviews, and meta-analyses were excluded. We have identified 19 studies in the literature investigating the use of ECT, TMS, and tDCS in the treatment of HD. Quality assessments were performed using Joanna Briggs Institute's (JBI's) critical appraisal tools. Eighteen studies showed improvement of HD symptoms, but the results were very heterogeneous considering different intervention techniques and protocols, and domains of symptoms. The most noticeable improvement involved depression and psychosis after ECT protocols. The impact on cognitive and motor symptoms is more controversial. Further investigations are required to determine the therapeutic role of distinct neuromodulation techniques for HD-related symptoms.

Advancing school dropout early warning systems: the IAFREE relational model for identifying at-risk students.

Introduction: There is a global effort to address the school dropout phenomenon. The urgency to act on it comes from the harmful evidence that school dropout has on societal and individual levels. Early Warning Systems (EWS) for school dropout at-risk student identification have been developed to anticipate and help schools have a better chance of acting on it. However, several studies point to a doubt that Correct EWS may come too late because they use only publicly available and general student and school information. We hypothesize that having a tool to assess more subjective and inter-relational factors would help anticipate where and when to act to prevent school dropout. This study aimed to develop a multidimensional measure for assessing relational factors for predicting school dropout (SD) risk in the Brazilian context. Methods: We performed several procedures, including (a) the specialized literature review, (b) the item development of the Relational Factors for the Risk of School Dropout Scale (IAFREE in Portuguese), (c) the content validity analysis, (d) a pilot study, and (e) the administration of the IAFREE to a large Brazilian sample of high school and middle school students (N = 15,924). Results: After the theoretical steps, we found content validity for five relational dimensions for SD (Student-School, Student-School Professionals, Student-Family, Student-Community, and Student-Student) that include 12 facets of risk factors. At the empirical stage, confirmatory analysis corroborated the proposed theoretical model with 12 first-order risk factors and 5 s-order dimensions (36 items). Further, through the Item Response Theory analysis, we assessed the individual item parameters of the items, providing a brief measure without losing psychometric quality (IAFREE-12). Discussion: We discuss how this model may fill gaps in Correct EWS models and how to advance it. The IAFREE is a good measure for scholars investigating the risk of SD. These results are important for implementing an early warning system for SD that looks into the complexity of the school dropout phenomenon.

Weight-drop model as a valuable tool to study potential neurobiological processes underlying behavioral and cognitive changes secondary to mild traumatic brain injury.

The pathophysiology of post-traumatic brain injury (TBI) behavioral and cognitive changes is not fully understood, especially in its mild presentation. We designed a weight drop TBI model in mice to investigate the role of neuroinflammation in behavioral and cognitive sequelae following mild TBI. C57BL/6 mice displayed depressive-like behavior at 72 h after mild TBI compared with controls, as indicated by a decrease in the latency to first immobility and climbing time in the forced swim test. Additionally, anxiety-like behavior and hippocampal-associated spatial learning and memory impairment were found in the elevated plus maze and in the Barnes maze, respectively. Levels of a set of inflammatory mediators and neurotrophic factors were analyzed at 6 h, 24 h, 72 h, and 30 days after injury in ipsilateral and contralateral hemispheres of the prefrontal cortex and hippocampus. Principal components analysis revealed two principal components (PC), which represented 59.1% of data variability. PC1 (cytokines and chemokines) expression varied between both hemispheres, while PC2 (neurotrophic factors) expression varied only across the investigated brain areas. Our model reproduces mild TBI-associated clinical signs and pathological features and might be a valuable tool to broaden the knowledge regarding mild TBI pathophysiology as well as to test potential therapeutic targets.

Potential Role of Adult Hippocampal Neurogenesis in Traumatic Brain Injury.

Traumatic brain injury (TBI) is a serious cause of disability and death among young and adult individuals, displaying complex pathophysiology including cellular and molecular mechanisms that are not fully elucidated. Many experimental and clinical studies investigated the potential relationship between TBI and the process by which neurons are formed in the brain, known as neurogenesis. Currently, there are no available treatments for TBI's long-term consequences being the search for novel therapeutic targets, a goal of highest scientific and clinical priority. Some studies evaluated the benefits of treatments aimed at improving neurogenesis in TBI. In this scenario, herein, we reviewed current pre-clinical studies that evaluated different approaches to improving neurogenesis after TBI while achieving better cognitive outcomes, which may consist in interesting approaches for future treatments.

A variable gain physiological controller for a rotary left ventricular assist device.

This paper deals with designing a physiological adaptive control law for a turbodynamic ventricular assist device (TVAD) using a lumped parameter time-varying model that describes the cardiovascular system. The TVAD is a rotary blood pump driven by an electrical motor. The system simulation also includes the adaptive feedback controller, which provides a physiologically correct cardiac output under different preload and afterload conditions. The cardiac output is estimated at each heartbeat, and the control objective is achieved by dynamically changing the motor speed controller's reference based on the systolic pressure error. TVADs provide support for blood circulation in patients with heart failure. To improve the performance of these devices, several control strategies have been developed over the years, with an emphasis on the physiological strategies that adapt their parameters to improve the patient's condition. In this paper, a new strategy is proposed using a variable gain physiological controller to keep the cardiac output in a reference value under changes in both preload and afterload. Computational models are used to evaluate the performance of this control technique, which has shown better results of adaptability than constant speed controllers and constant gain controllers.

Simulating cardiac disorders with a lumped parameter synergistic model.

A lumped parameter synergistic model of the human cardiovascular system (CVS) is proposed to integrate the heart's electrical activity with its mechanical activity. This model can represent the physiological condition of a patient in an effective way, whether it is considered normal or with some cardiac disorders. The electrical activity is coupled to the CVS model through electrocardiogram (ECG) signals in the suggested model. The variations in ECG morphology are detected by appropriate algorithms and changes parameters of the CVS model, such as systemic resistance and end-systolic pressure-volume relationship.Clinical relevance- It provides interpretation and analysis of physiological data of the cardiovascular system, both of electrical and mechanical cardiac behavior, evaluated together.

An Inverse Problem Approach for Parameter Estimation of Cardiovascular System Models.

Left ventricular assist devices (LVADs) are mechanical pumps that help patients with chronic heart failure waiting for a heart transplant. Mathematical models of these devices can be used along cardiovascular system (CVS) models to evaluate the assistance performance under different operating modes. The estimation of the CVS model parameters for a particular patient and numerical simulations allow the implementation of adequate LVAD operation mode. This work presents a method to estimate the parameters of a CVS model using only one hemodynamic variable: the systemic arterial pressure (Ps). Synthetic signals of Ps are used to solve this ill-posed inverse problem partially, and the results show the high accuracy of the proposed method, which achieves 0.5%.Clinical relevance- The measurements of hemodynamic variables using noninvasive techniques avoid many clinical problems arising from invasive measures such as infections.

Circulating Angiotensin-(1-7) Is Reduced in Alzheimer's Disease Patients and Correlates With White Matter Abnormalities: Results From a Pilot Study.

INTRODUCTION: Alzheimer's disease (AD) is the leading cause of dementia worldwide. Despite the extensive research, its pathophysiology remains largely unelucidated. Currently, more attention is being given to the disease's vascular and inflammatory aspects. In this context, the renin-angiotensin system (RAS) emerges as a credible player in AD pathogenesis. The RAS has multiple physiological functions, conducted by its two opposing axes: the classical, led by Angiotensin II (Ang II), and the alternative, driven by Angiotensin-(1-7) [Ang-(1-7)]. These peptides were shown to interact with AD pathology in animal studies, but evidence from humans is scarce. Only 20 studies dosed RAS molecules in AD patients' bloodstream, none of which assessed both axes simultaneously. Therefore, we conducted a cross-sectional, case-control exploratory study to compare plasma levels of Ang II and Ang-(1-7) in AD patients vs. age-matched controls. Within each group, we searched for correlations between RAS biomarkers and measures from magnetic resonance imaging (MRI). METHODS: We evaluated patients with AD (n = 14) and aged-matched controls (n = 14). Plasma Ang II and Ang-(1-7) were dosed using ELISA. Brain MRI was performed in a 3 Tesla scan, and a three-dimensional T1-weighted volumetric sequence was obtained. Images were then processed by FreeSurfer to calculate: (1) white matter hypointensities (WMH) volume; (2) volumes of hippocampus, medial temporal cortex, and precuneus. Statistical analyses used non-parametrical tests (Mann-Whitney and Spearman). RESULTS: Ang-(1-7) levels in plasma were significantly lower in the AD patients than in controls [median (25th-75th percentiles)]: AD [101.5 (62.43-126.4)] vs. controls [209.3 (72-419.1)], p = 0.014. There was no significant difference in circulating Ang II. In the AD patients, but not in controls, there was a positive and significant correlation between Ang-(1-7) values and WMH volumes (Spearman's rho = 0.56, p = 0.038). Ang-(1-7) did not correlate with cortical volumes in AD or in controls. Ang II did not correlate with any MRI variable in none of the groups. CONCLUSION: If confirmed, our results strengthen the hypothesis that RAS alternative axis is downregulated in AD, and points to a possible interaction between Ang-(1-7) and cerebrovascular lesions in AD.

Epstein-Barr Virus-Associated Carcinoma of the Larynx: A Systematic Review with Meta-Analysis.

Over the past few decades, several publications have investigated the role of Epstein-Barr virus (EBV) in head and neck squamous cell carcinomas, and an increasing number of them have shown its presence in laryngeal tumors. The purpose of this meta-analysis was to evaluate the association of EBV with laryngeal carcinoma. The search was carried out in two databases, Scopus and PubMed, using the following terms: "Epstein-Barr virus" and "laryngeal carcinoma". A total of 187 records were found, of which 31 were selected for meeting the inclusion and exclusion criteria. The meta-analysis yielded an overall pooled prevalence of 43.72% (95% confidence interval (CI): 34.35-53.08). Studies carried out in Europe and Eurasia had slightly higher pooled prevalence than other subgroups, while the prevalence of studies performed in developed countries was higher than in developing countries (46.37% vs. 34.02%). Furthermore, laryngeal carcinoma occurred almost three times as often among EBV-infected individuals compared to those without EBV infection (odds ratio = 2.86 (95% CI: 1.18-6.90); Begg's test, p = 0.843 and Egger's test, p = 0.866). Our findings support the idea that EBV is related to laryngeal carcinoma. However, further studies are needed before recognizing a definitive etiological role of EBV in the development and/or progression of laryngeal carcinomas.

Comments on "On decentralized adaptive full-order sliding mode control of multiple UAVs".

In this note is shown that the controller proposed in the paper [ISA Trans 71 (2017) 196-205] has the conceptual flaw of not being decentralized as claimed. A corrected control law is then proposed, maintaining most of the characteristics of the original controller while using only the available information for each agent. The stability of this proposed corrected controller is shown using Lyapunov function technique.

Eotaxin-1/CCL11 correlates with left superior temporal gyrus in bipolar disorder: A preliminary report suggesting accelerated brain aging.

BACKGROUND: Neuropsychiatric disorders have been linked to immune mechanisms. Altered peripheral levels of eotaxin-1/CCL11; a cytokine implicated in allergic reactions and aging process; have been reported in bipolar disorder (BD). Several brain areas, especially the temporal lobe, seem to display volume loss and accelerated aging in BD. This study aimed at exploring potential associations between eotaxins and brain volumes in patients with BD compared to controls. METHODS: Twenty-two euthymic patients with BD and 22 controls were enrolled in this study. Serum levels of eotaxin-1/CCL11, eotaxin-2/CCL24 and eotaxin-3/CCL26 were determined alongside brain volumes. RESULTS: There were no differences in the levels of eotaxins between patients and controls. A negative correlation was found between eotaxin-1/CCL11 levels and left-hemisphere's superior-temporal volume only in BD patients, which persisted with covariate adjusted model. CONCLUSION: This study corroborates the emerging evidence of association between inflammation and brain volumes in BD. Our preliminary results also support the hypothesis of a possible role of eotaxin-1/CCL11 in accelerated brain aging in BD.

Effect of immune activation on the kynurenine pathway and depression symptoms - A systematic review and meta-analysis.

Dysregulated kynurenine (KYN) pathway has been implicated in the pathophysiology of depression. In this systematic review, we examined the relationship between kynurenine pathway metabolites (KYN, kynurenic acid KYNA, tryptophan TRP, quinolinic acid QUIN, KYN/TRP ratio) and depression symptoms in the context of pro-inflammatory activation and immune response. Out of 5,082 articles, fifteen studies were suitable; ten studies (N = 315 medically ill patients treated with interferon-alpha IFN-α) reported baseline and post-intervention plasma KYN, TRP and KYN/TRP ratios which were included in quantitative meta-analysis. Data from five studies were summarized (IFN-α, interferon-beta IFN-ß, and lipopolysaccharide LPS). We found that IFN-α treatment in patients with chronic illnesses was associated with decreased TRP, increased levels of KYN and KYN/TRP ratio and depression scores from baseline to follow-up at both 4 and 24 weeks. Our findings suggest that increased risk of depression observed after immune-activating agents in patients with chronic medical illnesses is likely mediated by the kynurenine pathway. Further prospective studies are required to investigate the exact pathophysiology of the KYN pathway in depression.