Accumulation of Alpha-Synuclein and Increase in the Inflammatory Response in the substantia nigra, Jejunum, and Colon in a Model of O3 Pollution in Rats.

This work aimed to study the effect of repeated exposure to low doses of ozone on alpha-synuclein and the inflammatory response in the substantia nigra, jejunum, and colon. Seventy-two male Wistar rats were divided into six groups. Each group received one of the following treatments: The control group was exposed to air. The ozone groups were exposed for 7, 15, 30, 60, and 90 days for 0.25 ppm for four hours daily. Afterward, they were anesthetized, and their tissues were extracted and processed using Western blotting, immunohistochemistry, and qPCR. The results indicated a significant increase in alpha-synuclein in the substantia nigra and jejunum from 7 to 60 days of exposure and an increase in NFκB from 7 to 90 days in the substantia nigra, while in the jejunum, a significant increase was observed at 7 and 15 days and a decrease at 60 and 90 days for the colon. Interleukin IL-17 showed an increase at 90 days in the substantia nigra in the jejunum and increases at 30 days and in the colon at 15 and 90 days. Exposure to ozone increases the presence of alpha-synuclein and induces the loss of regulation of the inflammatory response, which contributes significantly to degenerative processes.

Changes in SOD and NF-κB Levels in Substantia Nigra and the Intestine through Oxidative Stress Effects in a Wistar Rat Model of Ozone Pollution.

This work aimed to elucidate how O3 pollution causes a loss of regulation in the immune response in both the brain and the intestine. In this work, we studied the effect of exposing rats to low doses of O3 based on the association between the antioxidant response of superoxide dismutase (SOD) levels and the nuclear factor kappa light chains of activated B cells (NFκB) as markers of inflammation. Method: Seventy-two Wistar rats were used, divided into six groups that received the following treatments: Control and 7, 15, 30, 60, and 90 days of O3. After treatment, tissues were extracted and processed using Western blotting, biochemical, and immunohistochemical techniques. The results indicated an increase in 4-hydroxynonenal (4HNE) and Cu/Zn-SOD and a decrease in Mn-SOD, and SOD activity in the substantia nigra, jejunum, and colon decreased. Furthermore, the translocation of NFκB to the nucleus increased in the different organs studied. In conclusion, repeated exposure to O3 alters the regulation of the antioxidant and inflammatory response in the substantia nigra and the intestine. This indicates that these factors are critical in the loss of regulation in the inflammatory response; they respond to ozone pollution, which can occur in chronic degenerative diseases.

Chronic hyperkalemia, diagnosis and management. Colombian consensus.

OBJECTIVE: Generate recommendations for the diagnosis, management, and follow-up of chronic hyperkalemia. METHOD: This consensus was made by nephrologists and cardiologists following the GRADE methodology. RESULTS: Chronic hyperkalemia can be defined as a biochemical condition with or without clinical manifestations characterized by a recurrent elevation of serum potassium levels that may require pharmacological and or non-pharmacological intervention. It can be classified as mild (K+ 5.0 to < 5.5 mEq/L), moderate (K+ 5.5 to 6.0 mEq/L) or severe (K+ > 6.0 mEq/L). Its incidence and prevalence have yet to be determined. Risk factors: chronic kidney disease, chronic heart failure, diabetes mellitus, age ≥ 65 years, hypertension, and drugs that inhibit the renin angiotensin aldosterone system (RAASi), among others. There is no consensus for the management of chronic hyperkalemia. The suggested pattern for patients is to identify and eliminate or control risk factors, provide advice on potassium intake and, for whom it is indicated, optimize RAASi therapy, administer oral potassium binders and correct metabolic acidosis. CONCLUSIONS: The recommendation is to pay attention to the diagnosis, management, and follow-up of chronic hyperkalemia, especially in patients with risk factors.

OBJETIVO: Generar recomendaciones para el diagnóstico, el manejo y el seguimiento de la hiperkalemia crónica. MÉTODO: Este consenso fue realizado por nefrólogos y cardiólogos siguiendo la metodología GRADE. RESULTADOS: La hiperkalemia crónica puede definirse como una condición bioquímica, con o sin manifestaciones clínicas, caracterizada por una elevación recurrente de las concentraciones séricas de potasio que puede requerir una intervención farmacológica, no farmacológica o ambas. Puede clasificarse en leve (K+ 5,0 a < 5,5 mEq/l), moderada (K+ 5,5 a 6,0 mEq/l) o grave (K+ > 6,0 mEq/l). Su incidencia y prevalencia no han sido claramente determinadas. Se consideran factores de riesgo la enfermedad renal crónica, la insuficiencia cardiaca crónica, la diabetes mellitus, la edad ≥ 65 años, la hipertensión arterial y el tratamiento con inhibidores del sistema renina-angiotensina-aldosterona (iSRAA), entre otros. No hay consenso sobre el manejo de la hiperkalemia crónica. Se sugiere identificar y eliminar o controlar los factores de riesgo, brindar asesoramiento sobre la ingesta de potasio y, para quien esté indicado, optimizar la terapia con iSRAA, administrar aglutinantes orales del potasio y corregir la acidosis metabólica. CONCLUSIONES: Se recomienda prestar atención al diagnóstico, el manejo y el seguimiento de la hiperkalemia crónica, en especial en los pacientes con factores de riesgo.

Immune Checkpoint Inhibitors in Advanced Cutaneous Squamous Cell Carcinoma: Real-World Experience from a Canadian Comprehensive Cancer Centre.

Immune checkpoint inhibitors (ICI) cemiplimab and pembrolizumab have revolutionized the treatment of advanced cutaneous squamous cell carcinoma (cSCC). We aimed to evaluate the effectiveness and safety of ICI in a real-world cSCC population, including patients with conditions that would exclude clinical trial participation. In this single-center, retrospective cohort study, we included all non-trial patients with advanced cSCC treated with ICI between 2017 and 2022. We evaluated investigator-assessed best overall response (BOR) and immune-related adverse events (irAEs). We correlated survival outcomes with age, performance status, immune status and irAEs. Of the 36 patients identified, the best overall response (BOR) to ICI was a partial response (PR) in 41.7%, a complete response (CR) in 27.8%, and stable disease in (SD) 13.9%. The progression-free survival (PFS) rate for 1 year was 58.1%; the median PFS was 21.3 months (95% CI 6.4-NE). The 1-year overall survival (OS) was 76.7%, and the median OS was 38.6 months (95% CI 25.4-NE). Immune-compromised patients, ECOG performance 2-3, and age ≥ 75 years were not significantly associated with PFS or OS. IrAE grades 3-4 were seen in 13.9% of patients. In our Canadian experience with real-world patients, ICI was an effective and safe treatment for advanced cSCC patients. Patients achieved great benefits with ICI regardless of age, immune status or ECOG performance status. We acknowledge the small sample size and retrospective methodology as the main limitations of our study.

Ozone Environmental Pollution: Relationship between the Intestine and Neurodegenerative Diseases.

Repeated exposure to environmental ozone causes a chronic state of oxidative stress. This state is present in chronic degenerative diseases and induces a loss of control of the inflammatory response. Redox system dysfunction and failures in control of inflammatory responses are involved in a vicious circle that maintains and increases the degenerative process. The intestine also responds to secondary reactive species formed by exposure to ozone doses, generating noxious stimuli that increase degenerative damage. This review aims to elucidate how environmental pollution, mainly by ozone, induces a state of chronic oxidative stress with the loss of regulation of the inflammatory response, both in the intestine and in the brain, where the functionality of both structures is altered and plays a determining role in some neurodegenerative and chronic degenerative diseases. For this purpose, we searched for information on sites such as the Cochrane Library Database, PubMed, Scopus, and Medscape. Reviewing the data published, we can conclude that environmental pollutants are a severe health problem. Ozone pollution has different pathways of action, both molecular and systemic, and participates in neurodegenerative diseases such as Parkinson's and Alzheimer's disease as well in bowel diseases as Inflammatory Bowel Disease, Crohn's Disease, and Irritable Bowel Syndrome.

Effect of the Addition of Different Natural Waxes on the Mechanical and Rheological Behavior of PLA-A Comparative Study.

In this study, poly(lactic acid) (PLA) blended with different natural waxes (beeswax, candelilla, carnauba, and cocoa) was investigated. Different wax amounts, 3, 5, 10, and 15 wt%, were incorporated into the PLA using a Brabender internal mixer. The blends were characterized by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), rotational rheometer (RR), dynamic mechanical analysis (DMA), and contact angle to observe the effect of the different waxes on the PLA physicochemical, rheological, mechanical behavior, and wetting properties. The complex viscosity of the blends was studied by employing a RR. The effect of the addition of the waxes on the mechanical properties of PLA was evaluated by DMA in the tension modality. A slight decrease in the thermal stability of PLA was observed with the addition of the waxes. However, in the case of the mechanical properties, the cocoa wax showed a considerable effect, especially in the elongation at break of PLA. Likewise, waxes had an essential impact on the water affinity of PLA. Specifically, with the addition of cocoa, the PLA became more hydrophilic, while the rest of the waxes increased the hydrophobic character.

Prediction of Behavioral Improvement Through Resting-State Electroencephalography and Clinical Severity in a Randomized Controlled Trial Testing Bumetanide in Autism Spectrum Disorder.

BACKGROUND: Mechanism-based treatments such as bumetanide are being repurposed for autism spectrum disorder. We recently reported beneficial effects on repetitive behavioral symptoms that might be related to regulating excitation-inhibition (E/I) balance in the brain. Here, we tested the neurophysiological effects of bumetanide and the relationship to clinical outcome variability and investigated the potential for machine learning-based predictions of meaningful clinical improvement. METHODS: Using modified linear mixed models applied to intention-to-treat population, we analyzed E/I-sensitive electroencephalography (EEG) measures before and after 91 days of treatment in the double-blind, randomized, placebo-controlled Bumetanide in Autism Medication and Biomarker study. Resting-state EEG of 82 subjects out of 92 participants (7-15 years) were available. Alpha frequency band absolute and relative power, central frequency, long-range temporal correlations, and functional E/I ratio treatment effects were related to the Repetitive Behavior Scale-Revised (RBS-R) and the Social Responsiveness Scale 2 as clinical outcomes. RESULTS: We observed superior bumetanide effects on EEG, reflected in increased absolute and relative alpha power and functional E/I ratio and in decreased central frequency. Associations between EEG and clinical outcome change were restricted to subgroups with medium to high RBS-R improvement. Using machine learning, medium and high RBS-R improvement could be predicted by baseline RBS-R score and EEG measures with 80% and 92% accuracy, respectively. CONCLUSIONS: Bumetanide exerts neurophysiological effects related to clinical changes in more responsive subsets, in whom prediction of improvement was feasible through EEG and clinical measures.

Resisting an invasion: A review of the triatomine vector (Kissing bug) defense strategies against a Trypanosoma sp infection.

Triatomines are an important group of insects in the Americas. They serve as transmission vectors for Trypanosoma cruzi, the etiologic agent responsible for the deadly Chagas disease in humans. The digenetic parasite has a complex life cycle, alternating between mammalian and insect hosts, facing different environments. In the insect vector, the metacyclic trypomastigote (non-replicative) and epimastigote (replicative) stages face a set of insect-mediated environmental changes, such as intestinal pH, body temperature, nutrient availability, and vector immune response. These insects have the ability to differentiate between self and non-self-particles using their innate immune system. This immune system comprises physical barriers, cellular responses (phagocytosis, nodules and encapsulation), humoral factors, including effector mechanisms (antimicrobial peptides and prophenoloxidase cascade) and the intestinal microbiota. Here, we consolidate and synthesize the available literature to describe the defense mechanisms deployed by the triatomine vector against the parasite, as documented in recent years, the possible mechanisms developed by the parasite to protect against the insect's specific microenvironment and innate immune responses, and future perspectives on the Triatomine-Trypanosome interaction.

Hiperkalemia crónica, diagnóstico y manejo. Consenso colombiano / Chronic hyperkalemia, diagnosis and management. Colombian consensus

Resumen Objetivo: Generar recomendaciones para el diagnóstico, el manejo y el seguimiento de la hiperkalemia crónica. Método: Este consenso fue realizado por nefrólogos y cardiólogos siguiendo la metodología GRADE. Resultados: La hiperkalemia crónica puede definirse como una condición bioquímica, con o sin manifestaciones clínicas, caracterizada por una elevación recurrente de las concentraciones séricas de potasio que puede requerir una intervención farmacológica, no farmacológica o ambas. Puede clasificarse en leve (K+ 5,0 a < 5,5 mEq/l), moderada (K+ 5,5 a 6,0 mEq/l) o grave (K+ > 6,0 mEq/l). Su incidencia y prevalencia no han sido claramente determinadas. Se consideran factores de riesgo la enfermedad renal crónica, la insuficiencia cardiaca crónica, la diabetes mellitus, la edad ≥ 65 años, la hipertensión arterial y el tratamiento con inhibidores del sistema renina-angiotensina-aldosterona (iSRAA), entre otros. No hay consenso sobre el manejo de la hiperkalemia crónica. Se sugiere identificar y eliminar o controlar los factores de riesgo, brindar asesoramiento sobre la ingesta de potasio y, para quien esté indicado, optimizar la terapia con iSRAA, administrar aglutinantes orales del potasio y corregir la acidosis metabólica. Conclusiones: Se recomienda prestar atención al diagnóstico, el manejo y el seguimiento de la hiperkalemia crónica, en especial en los pacientes con factores de riesgo.

Abstract Objective: Generate recommendations for the diagnosis, management, and follow-up of chronic hyperkalemia. Method: This consensus was made by nephrologists and cardiologists following the GRADE methodology. Results: Chronic hyperkalemia can be defined as a biochemical condition with or without clinical manifestations characterized by a recurrent elevation of serum potassium levels that may require pharmacological and or non-pharmacological intervention. It can be classified as mild (K+ 5.0 to < 5.5 mEq/L), moderate (K+ 5.5 to 6.0 mEq/L) or severe (K+ > 6.0 mEq/L). Its incidence and prevalence have yet to be determined. Risk factors: chronic kidney disease, chronic heart failure, diabetes mellitus, age ≥ 65 years, hypertension, and drugs that inhibit the renin angiotensin aldosterone system (RAASi), among others. There is no consensus for the management of chronic hyperkalemia. The suggested pattern for patients is to identify and eliminate or control risk factors, provide advice on potassium intake and, for whom it is indicated, optimize RAASi therapy, administer oral potassium binders and correct metabolic acidosis. Conclusions: The recommendation is to pay attention to the diagnosis, management, and follow-up of chronic hyperkalemia, especially in patients with risk factors.

Characteristics and Outcomes of Heart Failure Patients from a Middle-Income Country: The RECOLFACA Registry.

Background: There is a lack of epidemiological data around heart failure (HF) in Latin America; the potential impact description of this disease in middle-income countries is relevant. Objective: This study aimed to describe the characteristics and healthcare resource utilization patterns of HF patients at baseline and six-month follow-up. Methods: This retrospective observational study used data from the RECOLFACA (Registro Colombiano de Falla Cardíaca) registry, which includes data obtained from the examination of clinical records from 2,528 patients in 60 Colombian healthcare institutions. Baseline and six-month follow-up data were evaluated from patients with previous hospital admissions due to HF during the 12 months prior to enrollment. Results: This study analyzed 2,045 patients (42.8% female) with a mean age of 67.71 ± 13.64 years. The most common etiologies were ischemic (44.4%) and hypertensive heart disease (38.5%). At baseline, 53.4% of patients were classified with NYHA class II, and 73.6% had a reduced left ventricle ejection fraction (LVEF). A year prior to entering the registry, patients were hospitalized an average of 1.4 ± 1.1 times due to HF. Prescription of evidence-based treatment at baseline included sacubitril/valsartan (10%), ACEI (33%), ARB (41%), beta-blocker (79%), diuretics (68%), and MRA (56%). The average quality of life score measured using the EQ-5D-3L questionnaire was 78.7 ± 20.8 at baseline and 82.3 ± 20.1 at the six-month follow-up. The mortality rate was 6.7%. Conclusions: The use of information from the RECOLFACA registry allowed characterization as well as analyses of healthcare resource utilization of patients with heart failure in Colombia. The results of this study show that multiple evidence-based treatments for HF are being widely used in Colombia, but there seems to be room for improvement regarding some interventions for the treatment of patients with HF.

Improved Manual Annotation of EEG Signals through Convolutional Neural Network Guidance.

The development of validated algorithms for automated handling of artifacts is essential for reliable and fast processing of EEG signals. Recently, there have been methodological advances in designing machine-learning algorithms to improve artifact detection of trained professionals who usually meticulously inspect and manually annotate EEG signals. However, validation of these methods is hindered by the lack of a gold standard as data are mostly private and data annotation is time consuming and error prone. In the effort to circumvent these issues, we propose an iterative learning model to speed up and reduce errors of manual annotation of EEG. We use a convolutional neural network (CNN) to train on expert-annotated eyes-open and eyes-closed resting-state EEG data from typically developing children (n = 30) and children with neurodevelopmental disorders (n = 141). To overcome the circular reasoning of aiming to develop a new algorithm and benchmarking to a manually-annotated gold standard, we instead aim to improve the gold standard by revising the portion of the data that was incorrectly learned by the network. When blindly presented with the selected signals for re-assessment (23% of the data), the two independent expert-annotators changed the annotation in 25% of the cases. Subsequently, the network was trained on the expert-revised gold standard, which resulted in improved separation between artifacts and nonartifacts as well as an increase in balanced accuracy from 74% to 80% and precision from 59% to 76%. These results show that CNNs are promising to enhance manual annotation of EEG artifacts and can be improved further with better gold-standard data.

Ozone Pollution, Oxidative Stress, Regulatory T Cells and Antioxidants.

Ozone pollution, is a serious health problem worldwide. Repeated exposure to low ozone doses causes a loss of regulation of the oxidation-reduction systems, and also induces a chronic state of oxidative stress. This fact is of special importance for the regulation of different systems including the immune system and the inflammatory response. In addition, the oxidation-reduction balance modulates the homeostasis of these and other complex systems such as metabolism, survival capacity, cell renewal, and brain repair, etc. Likewise, it has been widely demonstrated that in chronic degenerative diseases, an alteration in the oxide-reduction balance is present, and this alteration causes a chronic loss in the regulation of the immune response and the inflammatory process. This is because reactive oxygen species disrupt different signaling pathways. Such pathways are related to the role of regulatory T cells (Treg) in inflammation. This causes an increase in chronic deterioration in the degenerative disease over time. The objective of this review was to study the relationship between environmental ozone pollution, the chronic state of oxidative stress and its effect on Treg cells, which causes the loss of regulation in the inflammatory response as well as the role played by antioxidant systems in various pathologies.

Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study.

Neuronal excitation-inhibition (E/I) imbalances are considered an important pathophysiological mechanism in neurodevelopmental disorders. Preclinical studies on tuberous sclerosis complex (TSC), suggest that altered chloride homeostasis may impair GABAergic inhibition and thereby E/I-balance regulation. Correction of chloride homeostasis may thus constitute a treatment target to alleviate behavioral symptoms. Recently, we showed that bumetanide-a chloride-regulating agent-improved behavioral symptoms in the open-label study Bumetanide to Ameliorate Tuberous Sclerosis Complex Hyperexcitable Behaviors trial (BATSCH trial; Eudra-CT: 2016-002408-13). Here, we present resting-state EEG as secondary analysis of BATSCH to investigate associations between EEG measures sensitive to network-level changes in E/I balance and clinical response to bumetanide. EEGs of 10 participants with TSC (aged 8-21 years) were available. Spectral power, long-range temporal correlations (LRTC), and functional E/I ratio (fE/I) in the alpha-frequency band were compared before and after 91 days of treatment. Pre-treatment measures were compared against 29 typically developing children (TDC). EEG measures were correlated with the Aberrant Behavioral Checklist-Irritability subscale (ABC-I), the Social Responsiveness Scale-2 (SRS-2), and the Repetitive Behavior Scale-Revised (RBS-R). At baseline, TSC showed lower alpha-band absolute power and fE/I than TDC. Absolute power increased through bumetanide treatment, which showed a moderate, albeit non-significant, correlation with improvement in RBS-R. Interestingly, correlations between baseline EEG measures and clinical outcomes suggest that most responsiveness might be expected in children with network characteristics around the E/I balance point. In sum, E/I imbalances pointing toward an inhibition-dominated network are present in TSC. We established neurophysiological effects of bumetanide although with an inconclusive relationship with clinical improvement. Nonetheless, our results further indicate that baseline network characteristics might influence treatment response. These findings highlight the possible utility of E/I-sensitive EEG measures to accompany new treatment interventions for TSC. Clinical Trial Registration: EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016.

Growing solitary fibrous tumor of the prostate during COVID-19 pandemic.

Solitary fibrous tumor (SFT) is an uncommon neoplasm tipically located on the pleura (Chick et al., 2013 Mar). Althought prostatic cancer tend to be adenocarcinoma, prostatic solitary fibrous tumor might be a rare cause of prostatic growth. They usually are asymptomatic although they can produce lower urinary tract symptoms (LUTS). Diagnosis is anatomopathological although Magnetic Resonance (MRI) can be useful to evaluate local and metastatic involvement (Liu et al., 2019). An adequate treatment is the most important prognostic factor and it involves complete surgical resection. We report an 85-year-old male that had an enormous SFT with LUTS treated with surgery which was delayed because of COVID-19 pandemic.

Chronic exposure to ozone induces cardiac antioxidant response and overexpression of either mitochondrial fision protein DRP1 and hipertrophyc-related proteins.

Pollution is considered a risk factor for cardiovascular disease; however, the mechanisms to explain this relationship are not well understood; ozone is one of the most abundant and studied air contaminants. Our study aimed to evaluate the effect of chronic exposition of rats to controlled low doses of ozone on oxidative stress, apoptosis, mitochondrial dynamics, and cardiac hypertrophy. Male Wistar rats were daily exposed to low ozone doses during 7, 15, 30, and 60 days, 4 h/day. Hearts were dissected, and homogenates were prepared. Oxidative stress was evaluated by TBARS and protein nitrosylation in addition to Superoxide dismutase 1 (SOD1) and Catalase levels; the apoptosis related-proteins caspase 3, caspase 9, Bax, Bcl-2, and the mitochondrial dynamic-associated proteins Fis1, Drp1, OPA1, and Mfn1 were quantified by western blot among the cardiac hypertrophy indicator alpha-actin (cardiac actin). There were no changes in the oxidative stress markers, however SOD1 expression increases. Caspase 3 expression decreased, whereas caspase 9 increased without changes in Bax or Bcl-2. Mitochondrial fission may be favored according to the increased expression of Drp1 but not changes in fusion-related proteins OPA1 and Mfn1. Finally, the molecular marker for cardiac hypertrophy was overexpressed after 30 and 60 days of ozone exposition. The chronic exposition to ozone induces a deleterious effect on cardiac mitochondria. Antioxidant defenses also show changes in relation to exposure time, as well as an apparent pro-hypertrophic effect associated with altered mitochondrial dynamics.

Robin's Viewer: Using deep-learning predictions to assist EEG annotation.

Machine learning techniques such as deep learning have been increasingly used to assist EEG annotation, by automating artifact recognition, sleep staging, and seizure detection. In lack of automation, the annotation process is prone to bias, even for trained annotators. On the other hand, completely automated processes do not offer the users the opportunity to inspect the models' output and re-evaluate potential false predictions. As a first step toward addressing these challenges, we developed Robin's Viewer (RV), a Python-based EEG viewer for annotating time-series EEG data. The key feature distinguishing RV from existing EEG viewers is the visualization of output predictions of deep-learning models trained to recognize patterns in EEG data. RV was developed on top of the plotting library Plotly, the app-building framework Dash, and the popular M/EEG analysis toolbox MNE. It is an open-source, platform-independent, interactive web application, which supports common EEG-file formats to facilitate easy integration with other EEG toolboxes. RV includes common features of other EEG viewers, e.g., a view-slider, tools for marking bad channels and transient artifacts, and customizable preprocessing. Altogether, RV is an EEG viewer that combines the predictive power of deep-learning models and the knowledge of scientists and clinicians to optimize EEG annotation. With the training of new deep-learning models, RV could be developed to detect clinical patterns other than artifacts, for example sleep stages and EEG abnormalities.