Facultad de Medicina

Chronic rhinosinusitis (CRS) is a clinical syndrome defined by typical sinonasal symptoms persisting for at least 12weeks. CRS is divided into two distinct phenotypes, CRS with nasal polyps (CRSwNP) and without (CRSsNP). The aim of the review is to provide an update on the current knowledge in CRS endotypes. The prevailing hypothesis regarding the pathogenesis of CRS suggests that dysfunctional interactions between the host and environmental stressors at the mucosal surface drive the diverse inflammatory mechanisms. Genetic and epigenetic variations in the mucosal immune system are believed to play a significant role in the pathomechanisms of CRS. Various environmental agents (such as microbes and irritants) have been implicated in CRS. In a healthy state, the sinonasal mucosa acts as a barrier, modulating environmental stimulation and mounting appropriate immune responses against pathogens with minimal tissue damage. Different endotypes may exist based on the specific mechanistic pathways driving the chronic tissue inflammation of CRS. There is a need to understand endotypes in order to better predict, diagnose, and treat CRS. This literature review provides an update on the role of the endotypes in CRS and the limitations of endotyping CRS in clinical practice. Understanding of the pathogenesis and optimal management of CRS has progressed significantly in the last decades; however, there still are several unmet needs in endotype research.

En el libro se ofrecen pautas claras, actuales y prácticas sobre aquellos conceptos fundamentales en la prevención y tratamiento de las adicciones digitales, como la conceptualización como adicciones comportamentales, las principales tipologías de uso, las consecuencias psicológicas, los instrumentos estandarizados para la evaluación, así como multitud de recursos adicionales donde los especialistas podrán encontrar decálogos de reconocidas organizaciones internacionales sobre el manejo de una temática que ha generado un gran debate social.

Background: The pathological mechanism of the gastrointestinal forms of food aller-gies is less understood in comparison to other clinical phenotypes, such as asthmaand anaphylaxis Importantly, high-IgE levels are a poor prognostic factor in gastroin-testinal allergies.Methods: This study investigated how high-IgE levels influence the development ofintestinal inflammation and the metabolome in allergic enteritis (AE), using IgE knock-in (IgEki) mice expressing high levels of IgE. In addition, correlation of the altered me-tabolome with gut microbiome was analysed.Results: Ovalbumin-sensitized and egg-white diet-fed (OVA/EW) BALB/c WT micedeveloped moderate AE, whereas OVA/EW IgEki mice induced more aggravated in-testinal inflammation with enhanced eosinophil accumulation. Untargeted metabo-lomics detected the increased levels of N-tau-methylhistamine and 2,3-butanediol,and reduced levels of butyric acid in faeces and/or sera of OVA/EW IgEki mice, whichwas accompanied with reduced Clostridium and increased Lactobacillus at the genus level. Non-sensitized and egg-white diet-fed (NC/EW) WT mice did not exhibit anysigns of AE, whereas NC/EW IgEki mice developed marginal degrees of AE. Comparedto NC/EW WT mice, enhanced levels of lysophospholipids, sphinganine and sphin-gosine were detected in serum and faecal samples of NC/EW IgEki mice. In addi-tion, several associations of altered metabolome with gut microbiome—for exampleAkkermansia with lysophosphatidylserine—were detected.Conclusions: Our results suggest that high-IgE levels alter intestinal and systemic levelsof endogenous and microbiota-associated metabolites in experimental AE. This studycontributes to deepening the knowledge of molecular mechanisms for the developmentof AE and provides clues to advance diagnostic and therapeutic strategies of allergicdiseases

Background: Background MR-guided focused ultrasound (FUS) thermoablation is an established therapy for movement disorders. FUS candidates must meet a predefined threshold of skull density ratio (SDR), a parameter that accounts for the efficiency in reaching ablative temperatures. Randomized sham-controlled trials to provide definitive therapeutic evidence employ pure randomization of subjects into active treatment or control arms. The latter design has several general limitations. Objective: Objective To demonstrate that SDR values are not associated with clinically and demographically relevant variables in patients with Parkinson’s disease (PD). This in turn would allow using SDR as an arm-allocation parameter, separating patients who will receive active FUS treatment and best medical management treatment (BMT). Methods: Methods We studied a cohort of 215 PD patients who were candidates for FUS subthalamotomy to determine if the SDR was correlated with demographic or clinical variables that could introduce bias for group allocation in a controlled trial. Results: Results SDR was unassociated with age, gender, and clinical motor features nor with levodopa daily dose in our cohort of PD patients. A negative association with age was found for the female subgroup. Conclusions: Conclusions Our results show that in a PD population considered for FUS subthalamotomy treatment, the SDR may be a valid group-allocation parameter. This could be considered as the basis for a controlled study comparing FUS subthalamotomy vs BMT.

The human gut microbiome establishes and matures during infancy, and dysregulation at this stage may lead to pathologies later in life. We conducted a multi-omics study comprising three generations of family members to investigate the early development of the gut microbiota. Fecal samples from 200 individuals, including infants (0-12 months old; 55% females, 45% males) and their respective mothers and grandmothers, were analyzed using two independent metabolomics platforms and metagenomics. For metabolomics, gas chromatography and capillary electrophoresis coupled to mass spectrometry were applied. For metagenomics, both 16S rRNA gene and shotgun sequencing were performed. Here we show that infants greatly vary from their elders in fecal microbiota populations, function, and metabolome. Infants have a less diverse microbiota than adults and present differences in several metabolite classes, such as short- and branched-chain fatty acids, which are associated with shifts in bacterial populations. These findings provide innovative biochemical insights into the shaping of the gut microbiome within the same generational line that could be beneficial in improving childhood health outcomes.

Purpose of Review Allergic diseases have become a burden in industrialized societies. Among children, food allergy (FA) constitutes a major impairment of quality of life. FA is partly due to a lack or loss of tolerance to food antigens at the level of the intestinal mucosa, where the microbiota plays a crucial role. Early changes in the composition of the gut microbiota may influence the development of the immune system and can be related to the risk of allergic diseases, including FA. This review will focus on the role of sphingolipids and the major bacteria involved in their metabolism, in the development of food antigen sensitization and FA. Recent Findings Numerous studies have identified different patterns of microbial composition between individuals with and without FA, pointing to an interaction between gut microbiota, enterocytes, and immune cells. When this interaction is lost and an imbalance in the composition of the intestinal microbiota occurs, the integrity of the epithelial barrier may be altered, leading to intestinal permeability and sensitization to food antigens and the development of FA. Gram- negative bacteria, especially those of the Proteobacteria phylum, have been associated with the development of FA. Investigating the interactions between the intestinal microbiota and the immune system, their influence on intestinal barrier function, and their production of metabolites and signaling molecules may contribute to understanding the pathogenesis of FA. Summary Sphingolipids, a class of bioactive amphipathic lipids found in cell membranes, have emerged as critical regulators of inflammation. In this review, we will attempt to summarize the existing knowledge on the role of these molecules and the major bacteria involved in their metabolism in the mechanisms underlying sensitization to food antigens and the development of FA.

The prevalence and severity of allergic diseases have increased over the last 30 years. Understanding the mechanisms responsible for these diseases is a major challenge in current allergology, as it is crucial for the transition towards precision medicine, which encompasses predictive, preventive, and personalized strategies. The urge to identify predictive biomarkers of allergy at early stages of life is crucial, especially in the context of major allergic diseases such as food allergy and atopic dermatitis. Identifying these biomarkers could enhance our understanding of the immature immune responses, improve allergy handling at early ages and pave the way for preventive and therapeutic approaches. This minireview aims to explore the relevance of three biomarker categories (proteome, microbiome, and metabolome) in early life. First, levels of some proteins emerge as potential indicators of mucosal health and metabolic status in certain allergic diseases. Second, bacterial taxonomy provides insight into the composition of the microbiota through high-throughput sequencing methods. Finally, metabolites, representing the end products of bacterial and host metabolic activity, serve as early indicators of changes in microbiota and host metabolism. This information could help to develop an extensive identification of biomarkers in AD and FA and their potential in translational personalized medicine in early life.

The diagnosis of mast cell activation syndrome (MCAS) is defined by 3 criteria: (1) typical clinical signs and symptoms of acute, recurrent (episodic), and systemic mast cell activation (MCA); (2) increase in tryptase level to >20% + 2 ng/mL within 1-4 hours after onset of the acute crisis; and (3) response of MCA symptoms to antimediator therapy. Classification of MCAS requires highly sensitive and specific methodological approaches for the assessment of clonal bone marrow mast cells at low frequencies. The Spanish Network on Mastocytosis score has been used successfully as a predictive model for selecting MCAS candidates for bone marrow studies based on a high probability of an underlying clonal mast cell disorder. In this article, we propose a diagnostic algorithm and focus on the practical evaluation and management of patients with suspected MCAS.

Allergic asthma is a prominent disease especially during childhood. Indoor allergens, in general, and particularly house dust mites (HDM) are the most prevalent sensitizers associated with allergic asthma. Available data show that 65–130 million people are mite-sensitized world-wide and as many as 50% of these are asthmatic. In fact, sensitization to HDM in the first years of life can produce devastating effects on pulmonary function leading to asthmatic syndromes that can be fatal. To date, there has been considerable research into the pathological pathways and structural changes associated with allergic asthma. However, limitations related to the disease heterogeneity and a lack of knowledge into its pathophysiology have impeded the generation of valuable data needed to appropriately phenotype patients and, subsequently, treat this disease. Here, we report a systematic and integral analysis of the disease, from airway remodelling to the immune response taking place throughout the disease stages. We present an overview of metabolomics, the management of complex multifactorial diseases through the analysis of all possible metabolites in a biological sample, obtaining a global interpretation of biological systems. Special interest is placed on the challenges to obtain biological samples and the methodological aspects to acquire relevant information, focusing on the identification of novel biomarkers associated with specific phenotypes of allergic asthma. We also present an overview of the metabolites cited in the literature, which have been related to inflammation and immune response in asthma and other allergy-related diseases.

Nowadays, the treatment of musculoskeletal diseases represents a major challenge in the developed world. Diseases such as osteoporosis, osteoarthritis and arthritis have a high incidence and prevalence as a consequence of population aging, and they are also associated with a socioeconomic burden. Many efforts have been made to find a treatment for these diseases with various levels of success, but new approaches are still needed to deal with these pathologies. In this context, one peptide derived for the C-terminal extreme of the Parathormone related Peptide (PTHrP) called Osteostatin can be useful to treat musculoskeletal diseases. This pentapeptide (TRSAW) has demonstrated both in different in vitro and in vivo models, its role as a molecule with anti-resorptive, anabolic, anti-inflammatory, and anti-antioxidant properties. Our aim with this work is to review the Osteostatin main features, the knowledge of its mechanisms of action as well as its possible use for the treatment of osteoporosis, bone regeneration and fractures and against arthritis given its anti-inflammatory properties.