Molecular basis and cellular mechanisms of eosinophilic esophagitis for the clinical practice

Introduction: Eosinophilic esophagitis (EoE) is a chronic, allergen-driven inflammatory esophageal disease characterized by predominantly eosinophilic inflammation leading to esophageal dysfunction. Recent efforts to understand EoE have increased our knowledge of the disease.

Areas covered: Multiple cells, molecules, and genes interplay with early life environmental factors in the pathophysiology of EoE to converge in the esophageal epithelium at the center of disease pathogenesis. Epithelial cells constitute a mayor cytokine source for TSLP and Calpain-14; an impaired epithelial barrier function allowing penetration of food and microbiota-derived antigens is involved in triggering and maintaining inflammation. Eosinophil and mast cell-derived products, including TGFβ, together with IL-1β and TNFα, promote epithelial mesenchymal transition in EoE, contributing to tissue remodeling by synthetizing and depositing extracellular matrix in subepithelial layers. This article aims to provide a state-of-the-art update on the pathophysiology of EoE applied to clinical practice, and latest research and developments with potential interest to improve the diagnosis and treatment of patients with EoE are revised.

Expert commentary: Preliminary approaches have provided promising results toward incorporating minimally invasive methods for patient diagnosis and monitoring in clinical practice. Early diagnosis and optimized therapies will allow for personalized medicine in EoE.     

A soluble mouse brain splice variant of type 2alpha corticotropin-releasing factor (CRF) receptor binds ligands and modulates their activity

Peptides of the corticotropin-releasing factor (CRF) family signal through the activation of two receptors, CRF receptor type 1 (CRFR1) and type 2 (CRFR2), both of which exist as multiple splice variants. We have identified a cDNA from mouse brain encoding a splice variant, soluble CRFR2alpha (sCRFR2alpha), in which exon 6 is deleted from the gene encoding CRFR2alpha. Translation of this isoform produces a predicted 143-aa soluble protein. The translated protein includes a majority of the first extracellular domain of the CRFR2alpha followed by a unique 38-aa hydrophilic C terminus resulting from a frame shift produced by deletion of exon 6. By using RT-PCR and Southern hybridization, the relative mRNA expression levels of full-length (seven transmembrane domains) CRFR2alpha and the soluble form (sCRFR2alpha) in the mouse brain were measured with a single reaction. The results demonstrate high levels of expression of sCRFR2alpha in the olfactory bulb, cortex, and midbrain regions. A rabbit antiserum raised against a synthetic peptide fragment encoding the unique C terminus revealed specific sCRFR2alpha immunoreactivity in mouse brain slices by immunohistochemistry and in extracts of brain regions by RIA. Interestingly, the sCRFR2alpha immunoreactivity distribution closely approximated that of CRFR1 expression in rodent brain. A protein corresponding to sCRFR2alpha, expressed and purified from either mammalian or bacterial cell systems, binds several CRF family ligands with low nanomolar affinities. Furthermore, the purified sCRFR2alpha protein inhibits cellular responses to CRF and urocortin 1. These data support a potential role of the sCRFR2alpha protein as a possible biological modulator of CRF family ligands.     

The unconditioned stimulus pre‐exposure effect in preweanling rats in taste aversion learning: Role of the training context and injection cues

The unconditioned stimulus pre‐exposure effect (US‐PE) refers to the interference paradigm in which acquisition of the conditioned response is retarded due to prior experience with the US. Most studies analyzing the psychological mechanisms underlying this effect have been conducted with adult rats. The most widely accepted hypothesis explains this effect as a contextual blocking effect. Contextual cues associated with the US block the conditioned stimulus (CS)‐US association during conditioning. The modulatory role of a context devoid of distinctive olfactory attributes is not observable until approximately PD23 in rats, including modulation of interference paradigms such as latent inhibition or extinction. In this study, we analyzed US‐PE in preweanling rats along with the role of the training context in this effect in terms of conditioned taste aversion preparation. Pre‐exposure to LiCl before conditioning retarded the acquisition of taste aversion. The US‐PE was observed in preweanling rats when, during pre‐exposure, subjects were exposed to the conditioning context, and this effect was not attenuated either by the administration of the US in a familiar environment (Experiment 1a), or by the presence of an alternative, more salient context during pre‐exposure (Experiment 1b). Additionally, the US‐PE was still observed when the route by which the US was administered was changed between the pre‐exposure and conditioning phases (Experiment 2a) as well as when the injection cues were removed during conditioning (Experiment 2b). These experiments show a strong US‐PE in preweanling rats and fail to support the contextual blocking hypothesis, at least in this stage of ontogeny. © 2012 Wiley Periodicals, Inc. Dev Psychobiol 55: 193–204, 2013     

Deregulated cellular circuits driving immunoglobulins and complement consumption associate with the severity of COVID-19 patients

SARS-CoV-2 infection causes an abrupt response by the host immune system, which is largely responsible for the outcome of COVID-19. We investigated whether the specific immune responses in the peripheral blood of 276 patients were associated with the severity and progression of COVID-19. At admission, dramatic lymphopenia of T, B, and NK cells is associated with severity. Conversely, the proportion of B cells, plasmablasts, circulating follicular helper T cells (cTfh) and CD56^–CD16⁺ NK-cells increased. Regarding humoral immunity, levels of IgM, IgA, and IgG were unaffected, but when degrees of severity were considered, IgG was lower in severe patients. Compared to healthy donors, complement C3 and C4 protein levels were higher in mild and moderate, but not in severe patients, while the activation peptide of C5 (C5a) increased from the admission in every patient, regardless of their severity. Moreover, total IgG, the IgG1 and IgG3 isotypes, and C4 decreased from day 0 to day 10 in patients who were hospitalized for more than two weeks, but not in patients who were discharged earlier. Our study provides important clues to understand the immune response observed in COVID-19 patients, associating severity with an imbalanced humoral response, and identifying new targets for therapeutic intervention.     

Reciprocal translocations in myelodysplastic syndromes and chronic myelomonocytic leukemias: Review of 5,654 patients with an evaluable karyotype

The infrequency of translocations in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemias (CMML) makes their identification and reporting interesting for the recognition of the recurrent ones and the genes involved in these neoplasias. The aims of this study were to identify new translocations associated with MDS and CMML and to establish their frequency in a cohort of 8,016 patients from the Spanish Group of MDS database. The karyotype was evaluable in 5,654 (70%) patients. Among those, 2,014 (36%) had chromosomal abnormalities, including 213 (10%) translocations identified in 195 patients. The translocations were balanced in 183 (86%) cases and unbalanced in 30 (14%) cases. All chromosomes were found to be involved in translocations, with the single exception of the Y chromosome. The chromosomes most frequently involved were in decreasing frequency: 3, 1, 7, 2, 11, 5, 12, 6, and 17. Translocations were found in karyotypes as the unique chromosomal abnormality (33%), associated with another chromosomal abnormality (11%), as a part of a complex karyotype (17%), and as a part of a monosomal karyotype (38%). There were 155 translocations not previously described in MDS or CMML and nine of them appeared to be recurrent. © 2013 Wiley Periodicals, Inc.     

Analysis of the smear layer generated by different activation systems: an in vitro study

Clinical Oral Investigations - To evaluate via scanning electron microscopy the amount of smear layer generated during the use of sonic and ultrasonic activation systems with standardized...     

Microbiome composition comparison in oral and atherosclerotic plaque from patients with and without periodontitis

Odontology - There is no conclusive evidence regarding a causal relationship between periodontitis and atherosclerosis. In this study, we examined the microbiome in the oral cavity and atheromatous...