Endocrine Disruptors in Food: Impact on Gut Microbiota and Metabolic Diseases

The results presented in this article constitute part of Yolanda Gálvez-Ontiveros doctoral thesis, performed in the Nutrition and Food Sciences Doctorate Program of the University of Granada.Endocrine disruptors (EDCs) have been associated with the increased incidence of metabolic disorders. In this work, we conducted a systematic review of the literature in order to identify the current knowledge of the interactions between EDCs in food, the gut microbiota, and metabolic disorders in order to shed light on this complex triad. Exposure to EDCs induces a series of changes including microbial dysbiosis and the induction of xenobiotic pathways and associated genes, enzymes, and metabolites involved in EDC metabolism. The products and by-products released following the microbial metabolism of EDCs can be taken up by the host; therefore, changes in the composition of the microbiota and in the production of microbial metabolites could have a major impact on host metabolism and the development of diseases. The remediation of EDC-induced changes in the gut microbiota might represent an alternative course for the treatment and prevention of metabolic diseases.This work was carried out within the frame of GP/EFSA/ENCO/380 2018/03/G04: OBEMIRISK: Knowledge platform for assessing the risk of Bisphenols on gut microbiota and its role in obesogenic phenotype: looking for biomarkers. This research was also funded by Plan Estatal de I+D+I 2013-2016, Proyecto cofinanciado FEDER-ISCIII PI17/01758, Proyecto cofinanciado FEDER-Consejería de Salud y Familias, Junta de Andalucía PE-0250-2019 and by Fundación Mapfre MAPFRE2018

Expression of LPP3 in Bergmann glia is required for proper cerebellar sphingosine-1-phosphate metabolism/signaling and development

Bioactive lipids serve as intracellular and extracellular mediators in cell signaling in normal and pathological conditions. Here we describe that an important regulator of some of these lipids, the lipid phosphate phosphatase-3 (LPP3), is abundantly expressed in specific plasma membrane domains of Bergmann glia (BG), a specialized type of astrocyte with key roles in cerebellum development and physiology. Mice selectively lacking expression of LPP3/Ppap2b in the nervous system are viable and fertile but exhibit defects in postnatal cerebellum development and modifications in the cytoarchitecture and arrangement of BG with a mild non-progressive motor coordination defect. Lipid and gene profiling studies in combination with pharmacological treatments suggest that most of these effects are associated with alterations in sphingosine-1- phosphate (S1P) metabolism and signaling. Altogether our data indicate that LPP3 participates in several aspects of neuron-glia communication required for proper cerebellum developmen

Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury

Heart and kidney have a closely interrelated pathophysiology. Acute kidney injury (AKI) is associated with significantly increased rates of cardiovascular events, a relationship defined as cardiorenal syndrome type 3 (CRS3). The underlying mechanisms that trigger heart disease remain, however, unknown, particularly concerning the clinical impact of AKI on cardiac outcomes and overall mortality. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are independently involved in the pathogenesis of both heart and kidney failure, and recent studies have proposed TWEAK as a possible therapeutic target; however, its specific role in cardiac damage associated with CRS3 remains to be clarified. Firstly, we demonstrated in a retrospective longitudinal clinical study that soluble TWEAK plasma levels were a predictive biomarker of mortality in patients with AKI. Furthermore, the exogenous application of TWEAK to native ventricular cardiomyocytes induced relevant calcium (Ca2+) handling alterations. Next, we investigated the role of the TWEAK–Fn14 axis in cardiomyocyte function following renal ischaemia–reperfusion (I/R) injury in mice. We observed that TWEAK–Fn14 signalling was activated in the hearts of AKI mice. Mice also showed significantly altered intra-cardiomyocyte Ca2+ handling and arrhythmogenic Ca2+ events through an impairment in sarcoplasmic reticulum Ca2+-adenosine triphosphatase 2a pump (SERCA2a) and ryanodine receptor (RyR2) function. Administration of anti-TWEAK antibody after reperfusion significantly improved alterations in Ca2+ cycling and arrhythmogenic events and prevented SERCA2a and RyR2 modifications. In conclusion, this study establishes the relevance of the TWEAK–Fn14 pathway in cardiac dysfunction linked to CRS3, both as a predictor of mortality in patients with AKI and as a Ca2+ mishandling inducer in cardiomyocytes, and highlights the cardioprotective benefits of TWEAK targeting in CRS3This work was mainly supported by projects from the Instituto de Salud Carlos III (ISCIII) (PI20/00763, PI20/01482, CPII20/00022, FI18/00261, FI21/00212, CD19/00029, IFEQ21/00012, PI19/00588, PI22/00469) and co-funded by the European Union, Ministerio de Universidades (FPU20/03005), Ministerio de Ciencia e Innovaci on (RYR2019-026916-I), the Education and Research Council of Madrid (PEJ-2021- AI/SAL-21426), Biomedicine Network Comunidad de Madrid (P2022/BMD-7223 CIFRA_COR-CM), Spanish Network in Inflammasoma and Pyroptosis in Chronic Disease and Cancer (RED2022-134511-T), and the Spanish Society of Nephrology SEN/SENEFRO Foundatio

Prenatal Administration of Oleic Acid or Linolenic Acid Reduces Neuromorphological and Cognitive Alterations in Ts65dn Down Syndrome Mice

Background: The cognitive impairments that characterize Down syndrome (DS) have been attributed to brain hypocellularity due to neurogenesis impairment during fetal stages. Thus, enhancing prenatal neurogenesis in DS could prevent or reduce some of the neuromorphological and cognitive defects found in postnatal stages. Objectives: As fatty acids play a fundamental role in morphogenesis and brain development during fetal stages, in this study, we aimed to enhance neurogenesis and the cognitive abilities of the Ts65Dn (TS) mouse model of DS by administering oleic or linolenic acid. Methods: In total, 85 pregnant TS females were subcutaneously treated from Embryonic Day (ED) 10 until Postnatal Day (PD) 2 with oleic acid (400 mg/kg), linolenic acid (500 mg/kg), or vehicle. All analyses were performed on their TS and Control (CO) male and female progeny. At PD2, we evaluated the short-term effects of the treatments on neurogenesis, cellularity, and brain weight, in 40 TS and CO pups. A total of 69 TS and CO mice were used to test the long-term effects of the prenatal treatments on cognition from PD30 to PD45, and on neurogenesis, cellularity, and synaptic markers, at PD45. Data were compared by ANOVAs. Results: Prenatal administration of oleic or linolenic acid increased the brain weight (+36.7% and +45%, P < 0.01), the density of BrdU (bromodeoxyuridine)- (+80% and +115%; P < 0.01), and DAPI (4',6-diamidino-2-phenylindole)-positive cells (+64% and +22%, P < 0.05) of PD2 TS mice with respect to the vehicle-treated TS mice. Between PD30 and PD45, TS mice prenatally treated with oleic or linolenic acid showed better cognitive abilities (+28% and +25%, P < 0.01) and a higher density of the postsynaptic marker PSD95 (postsynaptic density protein 95) (+65% and +44%, P < 0.05) than the vehicle-treated TS animals. Conclusion: The beneficial cognitive and neuromorphological effects induced by oleic or linolenic acid in TS mice suggest that they could be promising pharmacotherapies for DS-associated cognitive deficits.This study was supported by “Fondazione Generali e Assicurazioni Generali”, Italy; Fundación Tatiana Pérez de Guzmán el Bueno, IDIVAL (NVAL 19/23), and the Spanish Ministry of Economy and Competitiveness (PSI-2016- 76194-R, AEI/FEDER, EU)

Novel Pixelwise Co-Registered Hematoxylin-Eosin and Multiphoton Microscopy Image Dataset for Human Colon Lesion Diagnosis

Colorectal cancer presents one of the most elevated incidences of cancer worldwide. Colonoscopy relies on histopathology analysis of hematoxylin-eosin (H&E) images of the removed tissue. Novel techniques such as multi-photon microscopy (MPM) show promising results for performing real-time optical biopsies. However, clinicians are not used to this imaging modality and correlation between MPM and H&E information is not clear. The objective of this paper is to describe and make publicly available an extensive dataset of fully co-registered H&E and MPM images that allows the research community to analyze the relationship between MPM and H&E histopathological images and the effect of the semantic gap that prevents clinicians from correctly diagnosing MPM images. The dataset provides a fully scanned tissue images at 10x optical resolution (0.5 µm/px) from 50 samples of lesions obtained by colonoscopies and colectomies. Diagnostics capabilities of TPF and H&E images were compared. Additionally, TPF tiles were virtually stained into H&E images by means of a deep-learning model. A panel of 5 expert pathologists evaluated the different modalities into three classes (healthy, adenoma/hyperplastic, and adenocarcinoma). Results showed that the performance of the pathologists over MPM images was 65% of the H&E performance while the virtual staining method achieved 90%. MPM imaging can provide appropriate information for diagnosing colorectal cancer without the need for H&E staining. However, the existing semantic gap among modalities needs to be corrected.This work was supported by the PICCOLO project. This project has received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement No. 732111. The sole responsibility of this publication lies with the authors. The European Union is not responsible for any use that may be made of the information contained therein. This research has also been supported by the project ONKOTOOLS (KK2020/00069) funded by the Basque Government Industry Department under the ELKARTEK program

Long-term anticoagulation in secondary ischemic stroke prevention: The prospective multicenter RESTAIC registry

Background and Objective: Oral anticoagulation (OAC) for secondary stroke prevention is recommended in atrial fibrillation (AF) and other sources of cardioembolic stroke. Our objectives were to explore the differences in ischemic and hemorrhagic events when using OAC for secondary stroke prevention according to the type of anticoagulant treatment and to analyze the number and reasons for OAC switches during long-term follow-up. Methods: Ischemic stroke (IS) patients who were discharged on OAC for secondary stroke prevention from January 2014 to October 2017 were recruited in a prospective, multicenter, hospital-based registry. Follow-up at 3 months was scheduled at the outpatient clinic with subsequent annual phone interviews for 3 years. Patients were classified into three study groups according to OAC at discharge: Vitamin K antagonist (VKA), Factor Xa inhibitor (FXa), or direct thrombin inhibitor (DTI). We compared stroke recurrences, intracranial hemorrhage, major bleeding, and all-cause mortality during the follow-up. We recorded any switches in OAC and the main reasons for the change. Results: A total of 241 patients were included. An anticoagulant was indicated in the presence of a source of cardioembolic stroke in 240 patients (99.6%) and lupus plus antiphospholipid syndrome in one patient. Up to 86 patients (35.6%) were on OAC before the index stroke; in 71 (82.5%) of them, this was VKA. At hospital discharge, 105 were treated with FXa (43.8%), 96 with VKA (39.6%), and 40 with DTI (16.6%). The cumulative incidences at 3 years were 17% for stroke recurrence, 1.6% for intracranial hemorrhage, 4.9% for major hemorrhage, and 22.8% for all-cause mortality, with no differences among the OAC groups in any outcomes. During the follow-up, 40 OAC switches were recorded (63% of them to FXa), mostly due to stroke recurrence. Conclusion: Long-term OAC in secondary stroke prevention is associated with a lower frequency of bleeding complications than stroke recurrences. No differences between anticoagulant drugs were found in any of the analyzed outcomes. The main cause for OAC switch during follow-up was stroke recurrence.This study was supported by grants from the Foundation for Biomedical Research of La Paz University Hospital (PI 1131

Texture-Based Analysis of 18F-Labeled Amyloid PET Brain Images

Amyloid positron emission tomography (PET) brain imaging with radiotracers like [18F]florbetapir (FBP) or [18F]flutemetamol (FMM) is frequently used for the diagnosis of Alzheimer’s disease. Quantitative analysis is usually performed with standardized uptake value ratios (SUVR), which are calculated by normalizing to a reference region. However, the reference region could present high variability in longitudinal studies. Texture features based on the grey-level co-occurrence matrix, also called Haralick features (HF), are evaluated in this study to discriminate between amyloid-positive and negative cases. A retrospective study cohort of 66 patients with amyloid PET images (30 [18F]FBP and 36 [18F]FMM) was selected and SUVRs and 6 HFs were extracted from 13 cortical volumes of interest. Mann–Whitney U-tests were performed to analyze differences of the features between amyloid positive and negative cases. Receiver operating characteristic (ROC) curves were computed and their area under the curve (AUC) was calculated to study the discriminatory capability of the features. SUVR proved to be the most significant feature among all tests with AUCs between 0.692 and 0.989. All HFs except correlation also showed good performance. AUCs of up to 0.949 were obtained with the HFs. These results suggest the potential use of texture features for the classification of amyloid PET image

Clostridioides difficile-associated diarrhea in surgical service patients in Mexico

Introduction: Clostridium difficile is the first cause of healthcare-associated diarrhea in developed countries. In recent years the incidence of C. difficile infection (CDI) has increased worldwide. There is not much information on the topic in Mexico, and little is known about the risk factors for the infection in patients that are hospitalized in surgical services. Materials and methods: A case-control study was conducted that compared the epidemiologic findings and risk factors between surgical patients with PCR-confirmed CDI, surgical patients with diarrhea and a negative PCR test, and surgical patients with no diarrhea. The statistical analysis was carried out using the SPSS version 22.0 program. Results: The majority of the surgical patients with CDI belonged to the areas of neurosurgery, cardiac surgery, orthopedics, and general surgery. A total of 53% of the CDI cases were associated with the hypervirulent CD NAP1/027 strain. The presence of mucus in stools (OR: 1.5, p = 0.001), fever (OR: 1.4, p = 0.011), leukocytes in stools (OR: 3.2, p < 0.001), hospitalization within the past twelve weeks (OR: 2.0, p < 0.001), antibiotic use (OR: 1.3, p = 0.023), and ceftriaxone use (OR: 1.4, p = 0.01) were independent risk factors for the development of CDI

Diarrea asociada a Clostridioides difficile en pacientes de servicios quirúrgicos en México

Introducción: Clostridioides difficile (CD) es la primera causa de diarrea asociada al cuidadode salud en los países desarrollados. En los últimos a˜nos, la incidencia de la infección asociadaa CD (ICD) ha aumentado en el ámbito mundial. En México, la información al respecto es escasay se conoce poco sobre los factores de riesgo para esta enfermedad en pacientes hospitalizadosen servicios quirúrgicosMaterial y métodos: Estudio de casos y controles. Se compararon hallazgos epidemiológicos yfactores de riesgo entre pacientes quirúrgicos con ICD confirmada por PCR contra pacientes qui-rúrgicos con diarrea PCR negativa y contra pacientes quirúrgicos sin diarrea. Se realizó análisisestadístico mediante el paquete estadístico SPSS versión 22.0.Resultados: La mayoría de los pacientes quirúrgicos con ICD correspondían a las áreas de neu-rocirugía, cardiocirugía, ortopedia y cirugía general. El 53% de los casos de ICD se asociaron a lacepa hipervirulenta de CD NAP1/027. La presencia de moco en heces (RM 1.5, p = 0.001), fiebre(RM 1.4, p = 0.011), leucocitos en heces (RM 3.2, p = < 0.001), hospitalización en las últimas12 semanas (RM 2.0, p = < 0.001), uso de antibióticos (RM 1.3, p = 0.023) y uso de ceftriaxona(RM 1.4, p = 0.01) constituyeron factores de riesgo independientes para el desarrollo de ICD. Conclusiones: La diarrea por CD en servicios quirúrgicos es frecuente en nuestra institución(Hospital Civil de Guadalajara Fray Antonio Alcalde)

Novel Pixelwise Co-Registered Hematoxylin-Eosin and Multiphoton Microscopy Image Dataset for Human Colon Lesion Diagnosis

Colorectal cancer presents one of the most elevated incidences of cancer worldwide. Colonoscopy relies on histopathology analysis of hematoxylin-eosin (H&E) images of the removed tissue. Novel techniques such as multi-photon microscopy (MPM) show promising results for performing real-time optical biopsies. However, clinicians are not used to this imaging modality and correlation between MPM and H&E information is not clear. The objective of this paper is to describe and make publicly available an extensive dataset of fully co-registered H&E and MPM images that allows the research community to analyze the relationship between MPM and H&E histopathological images and the effect of the semantic gap that prevents clinicians from correctly diagnosing MPM images. The dataset provides a fully scanned tissue images at 10x optical resolution (0.5 m/px) from 50 samples of lesions obtained by colonoscopies and colectomies. Diagnostics capabilities of TPF and H&E images were compared. Additionally, TPF tiles were virtually stained into H&E images by means of a deep-learning model. A panel of 5 expert pathologists evaluated the different modalities into three classes (healthy, adenoma/hyperplastic, and adenocarcinoma). Results showed that the performance of the pathologists over MPM images was 65% of the H&E performance while the virtual staining method achieved 90%. MPM imaging can provide appropriate information for diagnosing colorectal cancer without the need for H&E staining. However, the existing semantic gap among modalities needs to be corrected.This work was supported by the PICCOLO project. This project has received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement No. 732111. The sole re- sponsibility of this publication lies with the authors. The European Union is not responsible for any use that may be made of the information contained therei