RESUMEN

BACKGROUND: C9orf72 gene repeat expansion (C9RE) is the most frequent gene variant associated with amyotrophic lateral sclerosis (ALS). We aimed to study the phenotype of motor neurone disease (MND) patients with C9RE in a Portuguese cohort. METHODS: Demographical and clinical data of MND patients with (C9RE+) and without C9RE were compared. ALS al Rating Scale-Revised (ALSFRS-R) and Edinburgh Cognitive and Behavioural ALS Screen (ECAS) were used to evaluate functional and cognitive performance, respectively. Survival analysis was performed using Kaplan Meier log-rank test and Cox proportional hazards model. RESULTS: We included 761 patients of whom 61 (8.0 %) were C9RE+. C9RE+ patients had a higher frequency of ALS (95.1 vs 78.4 %, p = 0.002), and lower frequency of progressive muscular atrophy (3.3 vs 16.7 %, p = 0.006). C9RE+ was associated with earlier age of onset (58.1 vs 62.6 years, p = 0.003) and more frequent MND family history (65.5 vs 11.4 %, p < 0.001). Gender, ethnicity, onset site, diagnostic delay, disease progression rate until diagnosis (ΔF), ALSFRS-R and time until non-invasive ventilation did not differ between groups. Cognitive/behavioural symptoms and ECAS did not differ between groups, except a worse visuospatial score in C9RE+ group (p = 0.035). Death rate was 1.8 and 1.6 times higher in C9RE+ patients with MND and ALS, respectively. Significant survival prognostic factors in C9RE+ group were diagnosis delay (HR = 0.96, 95 %CI 0.92-0.99, p = 0.008) and ΔF (HR = 1.93, 95 %CI 1.26-2.96, p = 0.002). CONCLUSION: Our study corroborates most previous cohorts' findings, but harbours some singularities regarding onset site, phenotype, and cognitive profile, that contribute to a better understanding of C9RE epidemiology.

Asunto(s)

Proteína C9orf72 , Expansión de las Repeticiones de ADN , Enfermedad de la Neurona Motora , Fenotipo , Humanos , Masculino , Portugal/epidemiología , Femenino , Persona de Mediana Edad , Proteína C9orf72/genética , Enfermedad de la Neurona Motora/genética , Enfermedad de la Neurona Motora/epidemiología , Anciano , Expansión de las Repeticiones de ADN/genética , Estudios de Cohortes , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/diagnóstico

RESUMEN

Trained Immunity is defined as a biological process normally induced by exogenous or endogenous insults that triggers epigenetic and metabolic reprogramming events associated with long-term adaptation of innate immune cells. This trained phenotype confers enhanced responsiveness to subsequent triggers, resulting in an innate immune "memory" effect. Trained Immunity, in the past decade, has revealed important benefits for host defense and homeostasis, but can also induce potentially harmful outcomes associated with chronic inflammatory disorders or autoimmune diseases. Interestingly, evidence suggest that the "trainers" prompting trained immunity are frequently glycans structures. In fact, the exposure of different types of glycans at the surface of pathogens is a key driver of the training phenotype, leading to the reprogramming of innate immune cells through the recognition of those glycan-triggers by a variety of glycan-binding proteins (GBPs) expressed by the immune cells. ß-glucan or mannose-enriched structures in Candida albicans are some of the examples that highlight the potential of glycans in trained immunity, both in homeostasis and in disease. In this review, we will discuss the relevance of glycans exposed by pathogens in establishing key immunological hubs with glycan-recognizing receptors expressed in immune cells, highlighting how this glycan-GBP network can impact trained immunity. Finally, we discuss the power of glycans and GBPs as potential targets in trained immunity, envisioning potential therapeutic applications.

Asunto(s)

Homeostasis , Inmunidad Innata , Polisacáridos , Humanos , Polisacáridos/química , Polisacáridos/inmunología , Animales , Memoria Inmunológica , Candida albicans/inmunología , Candida albicans/fisiología , Inmunidad Entrenada

RESUMEN

Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut. There is growing evidence in Crohn's disease (CD) of the existence of a preclinical period characterized by immunological changes preceding symptom onset that starts years before diagnosis. Gaining insight into this preclinical phase will allow disease prediction and prevention. Analysis of preclinical serum samples, up to 6 years before IBD diagnosis (from the PREDICTS cohort), revealed the identification of a unique glycosylation signature on circulating antibodies (IgGs) characterized by lower galactosylation levels of the IgG fragment crystallizable (Fc) domain that remained stable until disease diagnosis. This specific IgG2 Fc glycan trait correlated with increased levels of antimicrobial antibodies, specifically anti-Saccharomyces cerevisiae (ASCA), pinpointing a glycome-ASCA hub detected in serum that predates by years the development of CD. Mechanistically, we demonstrated that this agalactosylated glycoform of ASCA IgG, detected in the preclinical phase, elicits a proinflammatory immune pathway through the activation and reprogramming of innate immune cells, such as dendritic cells and natural killer cells, via an FcγR-dependent mechanism, triggering NF-κB and CARD9 signaling and leading to inflammasome activation. This proinflammatory role of ASCA was demonstrated to be dependent on mannose glycan recognition and galactosylation levels in the IgG Fc domain. The pathogenic properties of (anti-mannose) ASCA IgG were validated in vivo. Adoptive transfer of antibodies to mannan (ASCA) to recipient wild-type mice resulted in increased susceptibility to intestinal inflammation that was recovered in recipient FcγR-deficient mice. Here we identify a glycosylation signature in circulating IgGs that precedes CD onset and pinpoint a specific glycome-ASCA pathway as a central player in the initiation of inflammation many years before CD diagnosis. This pathogenic glyco-hub may constitute a promising new serum biomarker for CD prediction and a potential target for disease prevention.

Asunto(s)

Enfermedad de Crohn , Inmunoglobulina G , Manosa , Polisacáridos , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Animales , Humanos , Glicosilación , Manosa/metabolismo , Manosa/inmunología , Ratones , Polisacáridos/inmunología , Polisacáridos/metabolismo , Femenino , Saccharomyces cerevisiae/inmunología , Masculino , Adulto , Anticuerpos Antifúngicos/sangre , Anticuerpos Antifúngicos/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Biomarcadores/sangre , Persona de Mediana Edad , Fragmentos Fc de Inmunoglobulinas/inmunología , Glicoproteínas

RESUMEN

Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition affecting the gastrointestinal tract (GIT). Glucagon-like peptide-2 (GLP-2) analogs possess high potential in the treatment of IBD by enhancing intestinal repair and attenuating inflammation. Due to the enzymatic degradation and poor intestinal absorption, GLP-2 analogs are administered parenterally, which leads to poor patient compliance. This work aims to develop IBD-targeted nanoparticles (NPs) for the oral delivery of the GLP-2 analog, Teduglutide (TED). Leveraging the overproduction of Reactive Oxygen Species (ROS) in the IBD environment, ROS-sensitive NPs are developed to target the intestinal epithelium, bypassing the mucus barrier. PEGylation of NPs facilitates mucus transposition, but subsequent PEG removal is crucial for cellular internalization. This de-PEGylation is possible by including a ROS-sensitive thioketal linker within the system. ROS-sensitive NPs are established, with the ability to fully de-PEGylate via ROS-mediated cleavage. Encapsulation of TED into NPs resulted in the absence of absorption in 3D in vitro models, potentially promoting a localized action, and avoiding adverse effects due to systemic absorption. Upon oral administration to colitis-induced mice, ROS-sensitive NPs are located in the colon, displaying healing capacity and reducing inflammation. Cleavable PEGylated NPs demonstrate effective potential in managing IBD symptoms and modulating the disease's progression.

RESUMEN

The saphenous vein graft (SVG) remains the most used conduit as a second graft in Coronary Artery Bypass Grafting (CABG).1 Traditionally, surgeons harvest SVG with an open approach, making a long incision along the medial part of the leg or thigh. This procedure can potentially result in important complications, such as delayed wound healing, postoperative pain and infection.2 Thus, less invasive techniques for vessel harvesting have grown in popularity. Endoscopic vein harvesting (EVH) is a minimally invasive harvesting procedure, which only requires a short incision, leading to less wound complications and a faster return to normal daily activities. This article intends to describe how we do EVH technique in our centre, from the preparation of the patient to the postoperative period and share some tips and tricks from our experience.

Asunto(s)

Puente de Arteria Coronaria , Endoscopía , Vena Safena , Recolección de Tejidos y Órganos , Humanos , Recolección de Tejidos y Órganos/métodos , Vena Safena/trasplante , Puente de Arteria Coronaria/métodos , Endoscopía/métodos

RESUMEN

BACKGROUND: Rare bone diseases (RBD) cause physical and sensory disability that affects quality of life. Mobility challenges are common for people with RBDs, and travelling to gait analysis labs can be very complex. Smartphone sensors could provide remote monitoring. RESEARCH QUESTION: This study aimed to search for and identify variables that can be used to discriminate between people with RBD and healthy people by using built-in smartphone sensors in a real-world setting. METHODS: In total, 18 participants (healthy: n=9; RBD: n=9), controlled by age and sex, were included in this cross-sectional study. A freely available App (Phyphox) was used to gather data from built-in smartphone sensors (accelerometer & gyroscope) at 60 Hz during a 15-min walk on a level surface without turns or stops. Temporal gait parameters like cadence, mean stride time and, coefficient variance (CoVSt) and nonlinear analyses, as the largest Lyapunov exponent (LLE) & sample entropy (SE) in the three accelerometer axes were used to distinguish between the groups and describe gait patterns. RESULTS: The LLE (p=0.04) and the SE of the z-axis (p=0.01), which are correlated with balance control during walking and regularity of the gait, are sufficiently sensitive to distinguish between RBD and controls. SIGNIFICANCE: The use of smartphone sensors to monitor gait in people with RBD allows for the identification of subtle changes in gait patterns, which can be used to inform assessment and management strategies in larger cohorts.

Asunto(s)

Acelerometría , Análisis de la Marcha , Teléfono Inteligente , Humanos , Femenino , Masculino , Estudios Transversales , Persona de Mediana Edad , Acelerometría/instrumentación , Anciano , Enfermedades Raras , Enfermedades Óseas/fisiopatología , Marcha/fisiología , Estudios de Casos y Controles , Aplicaciones Móviles , Adulto

RESUMEN

The consumption of non-sugar sweeteners (NSS) has increased during pregnancy. The European Food Safety Agency suggested that steviol glycosides, such as Rebaudioside A (RebA), the major sweetener component of stevia, are safe for humans up to a dose of 4 mg/kg body weight/day. However, the World Health Organization recommended in 2023 the restraint of using NSS, including stevia, at any life stage, highlighting the need to study NSS safety in early periods of development. We aimed to study the mitochondrial and cardiometabolic effects of long-term RebA consumption during the reproductive stage of the life cycle. Female rats were exposed to RebA (4 mg steviol equivalents/kg body weight/day) in the drinking water from 4 weeks before mating until weaning. Morphometry, food and water consumption, glucose and lipid homeostasis, heart structure, function, and mitochondrial function were assessed. RebA showed an atrophic effect in the heart, decreasing cardiomyocyte cross-sectional area and myocardial fibrosis without repercussions on cardiac function. Mitochondrial and myofilamentary functions were not altered. Glucose tolerance and insulin sensitivity were not affected, but fasting glycemia and total plasma cholesterol decreased. This work suggests that this RebA dose is safe for female consumption during the reproductive stage, from a cardiometabolic perspective. However, studies on the effects of RebA exposure on the offspring are mandatory.

RESUMEN

BACKGROUND: Achondroplasia is a rare genetic skeletal condition characterized by disproportionate short stature. There is limited evidence on postural control in adults with achondroplasia and how lower limb lengthening (intervention) interacts with body dynamics. This study investigated sway variability during quiet standing in adults with achondroplasia with natural growth (N) and with lower limb lengthening (LL). METHODS: Sixteen adults performed bilateral/unilateral standing tasks. Linear (total excursion, amplitude, and ellipse area) and nonlinear (sample entropy and correlation dimension) center of pressure sway metrics were analyzed in the anteroposterior/mediolateral directions. Relationships between posture metrics, strength, and physical activity were explored. Between-groups statistics were calculated. RESULTS: The LL group exhibited amplified linear sway, indicating larger postural deviations, and reduced sample entropy and correlation dimension, indicative of more rigid and repeated corrections. The N group exhibited more unpredictable and adaptive movement corrections. Numerous correlations emerged between strength and posture measures, with relationships altered by intervention. CONCLUSIONS: Adults with achondroplasia display distinct balance strategies influenced by intervention. The results indicate that LL is associated with altered variability and adaptability compared to natural development. Relationships with muscle strength spotlight a key role of muscle capacity in postural control modulation after growth alterations in this population.

RESUMEN

Aquaporin-3 (AQP3) is a membrane channel with dual aquaglyceroporin/peroxiporin activity, facilitating the diffusion of water, glycerol and H2O2 across cell membranes. AQP3 shows aberrant expression in melanoma and its role in cell adhesion, migration and proliferation is well described. Gold compounds were shown to modulate AQP3 activity with reduced associated toxicity, making them promising molecules for cancer therapy. In this study, we validated the phenotype resulting from AQP3-silencing of two melanoma cell lines, MNT-1 and A375, which resulted in decreased H2O2 permeability. Subsequently, the AQP3 inhibitory effect of a new series of organogold compounds derived from Auphen, a potent AQP3 inhibitor, was first evaluated in red blood cells (RBCs) that highly express AQP3, and then in HEK-293T cells with AQP3 overexpression to ascertain the compounds' specificity. The first screening in RBCs unveiled two organogold compounds as promising blockers of AQP3 permeability. Moderate reduction of glycerol permeability but drastic inhibition of H2O2 permeability was detected for some of the gold derivatives in both AQP3-overexpressing cells and human melanoma cell lines. Additionally, all compounds were effective in impairing cell adhesion, proliferation and migration, although in a cell type-dependent manner. In conclusion, our data show that AQP3 peroxiporin activity is crucial for melanoma progression and highlight organogold compounds as promising AQP3 inhibitors with implications in melanoma cell adhesion, proliferation and migration, unveiling their potential as anticancer drugs against AQP3-overexpressing tumours. KEY POINTS: AQP3 affects cellular redox balance. Gold compounds inhibit AQP3 permeability in melanoma cells. AQP3 is involved in cell adhesion, proliferation and migration of melanoma. Blockage of AQP3 peroxiporin activity impairs melanoma cell migration. Gold compounds are potential anticancer drug leads for AQP3-overexpressing cancers.

Asunto(s)

Acuaporina 3 , Adhesión Celular , Movimiento Celular , Proliferación Celular , Melanoma , Acuaporina 3/metabolismo , Acuaporina 3/genética , Humanos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/metabolismo , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Células HEK293 , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/farmacología

RESUMEN

The pursuit for the fountain of youth has long been a fascination amongst scientists and humanity. Ageing is broadly characterized by a cellular decline with increased susceptibility to age-related diseases, being intimately associated with epigenetic modifications. Recently, reprogramming-induced rejuvenation strategies have begun to greatly alter longevity research not only to tackle age-related defects but also to possibly reverse the cellular ageing process. Hence, in this review, we highlight the major epigenetic changes during ageing and the state-of-art of the current emerging epigenetic reprogramming strategies leveraging on transcription factors. Notably, partial reprogramming enables the resetting of the ageing clock without erasing cellular identity. Promising chemical-based rejuvenation strategies harnessing small molecules, including DNA methyltransferase and histone deacetylase inhibitors are also discussed. Moreover, in parallel to longevity interventions, the foundations of epigenetic clocks for accurate ageing assessment and evaluation of reprogramming approaches are briefly presented. Going further, with such scientific breakthroughs, we are witnessing a rise in the longevity biotech industry aiming to extend the health span and ideally achieve human rejuvenation one day. In this context, we overview the main scenarios proposed for the future of the socio-economic and ethical challenges associated with such an emerging field. Ultimately, this review aims to inspire future research on interventions that promote healthy ageing for all.

Asunto(s)

Metilación de ADN , Longevidad , Humanos , Adolescente , Longevidad/genética , Envejecimiento/genética , Senescencia Celular/genética , Epigénesis Genética , Reprogramación Celular/genética

Asunto(s)

Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Estudios de Casos y Controles , Inhibidores de la Bomba de Protones/efectos adversos , Progresión de la Enfermedad

RESUMEN

OBJECTIVES: We investigated the impact of school reopening on SARS-CoV-2 transmission in Italy, Germany, and Portugal in autumn 2022 when the Omicron variant was prevalent. METHODS: A prospective international study was conducted using the case reproduction number (Rc) calculated with the time parametrization of Omicron. For Germany and Italy, staggered difference-in-differences analysis was employed to explore the causal relationship between school reopening and Rc changes, accounting for varying reopening dates. In Portugal, interrupted time series analysis was used due to simultaneous school reopenings. Multivariable models were adopted to adjust for confounders. RESULTS: In Italy and Germany, post-reopening Rc estimates were significantly lower compared to those from regions/states that had not yet reopened at the same time points, both in the student population (overall average treatment effect for the treated subpopulation [O-ATT]: -0.80 [95% CI: -0.94;-0.66] for Italy; O-ATT-0.30 [95% CI: -0.36;-0.23] for Germany) and the adult population (O-ATT: -0.04 [95% CI: -0.07;-0.01] for Italy; O-ATT: -0.07 [95% CI: -0.11;-0.03] for Germany). In Portugal, there was a significant decreasing trend in Rc following school reopenings compared to the pre-reopening period (sustained effect: -0.03 [95% CI: -0.04; -0.03] in students; -0.02 [95% CI: -0.03; -0.02] in adults). CONCLUSIONS: We found no evidence of a causal relationship between school reopenings in autumn 2022 and Omicron SARS-CoV-2 transmission.

Asunto(s)

COVID-19 , Adulto , Humanos , Portugal/epidemiología , COVID-19/epidemiología , Estudios Prospectivos , SARS-CoV-2 , Alemania/epidemiología , Italia/epidemiología , Instituciones Académicas

RESUMEN

The estimation of biological sex is a critical step in the assessment of the biological profile of an anonymous skeletonized individual. In certain recovery circumstances, the most dimorphic skeletal areas, such as the pelvis, are absent or fragmented; in that case, other bones of the skeleton, including the clavicle and scapula, can be used to predict sex. The purpose of this research is to generate new models for the estimation of sex with clavicular and scapular measurements using a study-sample of 129 individuals with clavicle (65 males and 64 females) and 112 individuals with scapula (50 males and 62 females) from the Lisbon Identified Skeletal Collection (Portugal). A decision tree classifier (C4.5) and logistic regression (LR) were employed to create univariable and multivariable sex prediction models. Accuracy under cross-validation of the classification models is high (up to 93.8%), with minimal bias (<5%), particularly in the multivariable models. The proposed LR models facilitate the probabilistic estimation of biological sex, accounting for the significant overlap in the expression of sexual dimorphism.

Asunto(s)

Clavícula , Determinación del Sexo por el Esqueleto , Masculino , Femenino , Humanos , Portugal , Clavícula/anatomía & histología , Antropología Forense , Etnicidad , Escápula/anatomía & histología , Análisis Discriminante

RESUMEN

OBJECTIVE: To investigate mirror activity in amyotrophic lateral sclerosis (ALS) patients, using a simple paradigm of signal quantification. METHODS: Patients were asked to perform a brief isometric maximum contraction of the abductor digiti minimi (ADM) or tibialis anterior (TA) on one side, while relaxing the contralateral side of the body. Both sides were investigated. Signals were stored and analyzed offline, for quantification of electromyographic signal. Clinical signs of upper motor neuron (UMN) dysfunction, transcranial magnetic stimulation (TMS) for the upper (UL) and lower limbs (LL), the ADM ipsilateral cortical silent period (iSP) and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) cognitive scale were also investigated. RESULTS: 42 ALS patients were included. In the 4 investigated muscles the amount of mirror activity was significantly higher than in the matched healthy group. The amount of mirror activity was similar between sides, but significantly higher in UL and LL with abnormal TMS results for ADM (p = 0.005) and TA (p = 0.002), as well as in UL with abnormal iSP values (p = 0.009). No association was found between mirror activity and clinical signs of UMN involvement. CONCLUSIONS: Mirror activity is a common phenomenon in ALS. Mirror activity intensity corresponds to the severity of UMN dysfunction, as measured by TMS, and probably derives from the abnormal transcallosal inhibition as mirrored by iSP abnormality. SIGNIFICANCE: Mirror activity is increased in ALS and is associated with abnormal transcallosal inhibition and UMN dysfunction.

Asunto(s)

Esclerosis Amiotrófica Lateral , Trastornos del Movimiento , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico , Músculo Esquelético , Neurofisiología , Estimulación Magnética Transcraneal/métodos

RESUMEN

INTRODUCTION/BACKGROUND: Idiopathic Inflammatory Myopathies (IIM) continue to be a major clinical challenge worldwide. The exact aetiopathogenesis of this chronic and disabling disease remains elusive, preventing the development of novel and effective therapeutic strategies and leading to a high incidence of damage. The complexity of treating these diseases is even greater due to the numerous comorbidities that affect these patients. METHODS: Retrospective review of the cohort of patients diagnosed with IIM and followed in a dedicated unit of a tertiary hospital between 1971 and December 2022, with particular attention to damage and comorbidities. Damage was assessed using the Myositis Damage Index. Comorbidities were recorded and analysed as a whole and also assessed using the Charlson Comorbidity Index. Health Assessment Questionnaire (HAQ) Disability Index (DI) was performed by phone call in December 2022, to all patients actively followed-up in the Unit. RESULTS: Analysis of 149 patients with a mean follow-up of 9 years (range 0-51) revealed >90% with damage and comorbidities. Most comorbidities were a consequence of the damage and were particularly related to prolonged steroid therapy. Cardiovascular damage, which occurred either as cardiovascular risk factors or as end-organ sequelae (cardiovascular disease and chronic kidney disease), was the main cause and a major contributor to death. Depression was also high on the list of associated comorbidities. Median HAQ was 2.09 representing high negative impact in quality of life. CONCLUSIONS: Although survival rates have increased in recent decades, patients with IIM carry a high burden of disease with poor quality of life, mainly caused by damage and comorbidities. While comorbidities accumulation is the major factor for poor quality of life, damage severity is the main predictor for mortality. Improved therapeutic strategies are needed to reduce the need for steroids and to introduce routine screening and management of comorbidities as an essential partner of immunosuppressive therapy, leading to comprehensive care of myositis patients and effective improvement of their quality of life.

Asunto(s)

Miositis , Calidad de Vida , Humanos , Miositis/patología , Estudios de Cohortes , Comorbilidad , Costo de Enfermedad

RESUMEN

The immune system is coordinated by an intricate network of stimulatory and inhibitory circuits that regulate host responses against endogenous and exogenous insults. Disruption of these safeguard and homeostatic mechanisms can lead to unpredictable inflammatory and autoimmune responses, whereas deficiency of immune stimulatory pathways may orchestrate immunosuppressive programs that contribute to perpetuate chronic infections, but also influence cancer development and progression. Glycans have emerged as essential components of homeostatic circuits, acting as fine-tuners of immunological responses and potential molecular targets for manipulation of immune tolerance and activation in a wide range of pathologic settings. Cell surface glycans, present in cells, tissues and the extracellular matrix, have been proposed to serve as "self-associated molecular patterns" that store structurally relevant biological data. The responsibility of deciphering this information relies on different families of glycan-binding proteins (including galectins, siglecs and C-type lectins) which, upon recognition of specific carbohydrate structures, can recalibrate the magnitude, nature and fate of immune responses. This process is tightly regulated by the diversity of glycan structures and the establishment of multivalent interactions on cell surface receptors and the extracellular matrix. Here we review the spatiotemporal regulation of selected glycan-modifying processes including mannosylation, complex N-glycan branching, core 2 O-glycan elongation, LacNAc extension, as well as terminal sialylation and fucosylation. Moreover, we illustrate examples that highlight the contribution of these processes to the control of immune responses and their integration with canonical tolerogenic pathways. Finally, we discuss the power of glycans and glycan-binding proteins as a source of immunomodulatory signals that could be leveraged for the treatment of autoimmune inflammation and chronic infection.

Asunto(s)

Autoinmunidad , Proteínas Portadoras , Polisacáridos/metabolismo , Galectinas , Inmunidad

RESUMEN

Pregnant women with cardiovascular risk (CVR) factors are highly prone to develop cardiovascular disease later in life. Thus, recent guidelines suggest extending the follow-up period to 1 yr after delivery. We aimed to evaluate cardiovascular remodeling during pregnancy and determine which CVR factors and potential biomarkers predict postpartum cardiac and vascular reverse remodeling (RR). Our study included a prospective cohort of 76 healthy and 54 obese and/or hypertensive and/or with gestational diabetes pregnant women who underwent transthoracic echocardiography, pulse-wave velocity (PWV), and blood collection at the 1st trimester (1T) and 3rd trimester (3T) of pregnancy as well as at the 1st/6th/12th mo after delivery. Generalized linear mixed-effects models was used to evaluate the extent of RR and its potential predictors. Pregnant women develop cardiac hypertrophy, as confirmed by a significant increase in left ventricular mass (LVM). Moreover, ventricular filling pressure (E/e') and atrial volume increased significantly during gestation. Significant regression of left ventricular (LV) volume, LVM, and filling pressures was observed as soon as 1 mo postpartum. The LV global longitudinal strain worsened slightly and recovered at 6 mo postpartum. PWV decreased significantly from 1T to 3T and normalized at 1 mo postpartum. We found that arterial hypertension, smoking habits, and obesity were independent predictors of increased LVM during pregnancy and postpartum. High C-reactive protein (CRP) and low ST2/IL33-receptor levels are potential circulatory biomarkers of worse LVM regression. Arterial hypertension, age, and gestational diabetes positively correlated with PWV. Altogether, our findings pinpoint arterial hypertension as a critical risk factor for worse RR and CRP, and ST2/IL33 receptors as potential biomarkers of postpartum hypertrophy reversal.NEW & NOTEWORTHY This study describes the impact of cardiovascular risk factors (CVR) in pregnancy-induced remodeling and postpartum reverse remodeling (up to 1 yr) by applying advanced statistic methods (multivariate generalized linear mixed-effects models) to a prospective cohort of pregnant women. Aiming to extrapolate to pathological conditions, this invaluable "human model" allowed us to demonstrate that arterial hypertension is a critical CVR for worse RR and that ST2/IL33-receptors and CRP are potential biomarkers of postpartum hypertrophy reversal.

Asunto(s)

Enfermedades Cardiovasculares , Diabetes Gestacional , Hipertensión , Embarazo , Femenino , Humanos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Estudios Prospectivos , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Factores de Riesgo , Periodo Posparto , Obesidad/complicaciones , Obesidad/diagnóstico , Cardiomegalia , Biomarcadores , Factores de Riesgo de Enfermedad Cardiaca

RESUMEN

Idiopathic inflammatory myopathies (IIM) are a group of chronic autoimmune diseases mainly affecting proximal muscles. Absence of meaningful prognostic factors in IIM has hindered new therapies development. Glycans are essential molecules that regulate immunological tolerance and consequently the onset of autoreactive immune response. We showed that muscle biopsies from patients with IIM revealed a deficiency in the glycosylation pathway resulting in loss of branched N-glycans. At diagnosis, this glycosignature predicted disease relapse and treatment refractoriness. Peripheral CD4+ T cells from active-disease patients shown a deficiency in branched N-glycans, linked to increased IL-6 production. Glycan supplementation, restoring homeostatic glycosylation profile, led to a decrease in IL-6 levels. This study highlights the biological and clinical importance of glycosylation in IIM immunopathogenesis, providing a potential mechanism for IL-6 production. This pinpoints muscle glycome as promising biomarker for personalized follow-up and a potential target for new therapies in a patients' subgroup with an ominous evolution.

RESUMEN

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterised by the progressive loss of motor neurons in the brain and spinal cord. The fact that ALS's disease course is highly heterogeneous, and its determinants not fully known, combined with ALS's relatively low prevalence, renders the successful application of artificial intelligence (AI) techniques particularly arduous. OBJECTIVE: This systematic review aims at identifying areas of agreement and unanswered questions regarding two notable applications of AI in ALS, namely the automatic, data-driven stratification of patients according to their phenotype, and the prediction of ALS progression. Differently from previous works, this review is focused on the methodological landscape of AI in ALS. METHODS: We conducted a systematic search of the Scopus and PubMed databases, looking for studies on data-driven stratification methods based on unsupervised techniques resulting in (A) automatic group discovery or (B) a transformation of the feature space allowing patient subgroups to be identified; and for studies on internally or externally validated methods for the prediction of ALS progression. We described the selected studies according to the following characteristics, when applicable: variables used, methodology, splitting criteria and number of groups, prediction outcomes, validation schemes, and metrics. RESULTS: Of the starting 1604 unique reports (2837 combined hits between Scopus and PubMed), 239 were selected for thorough screening, leading to the inclusion of 15 studies on patient stratification, 28 on prediction of ALS progression, and 6 on both stratification and prediction. In terms of variables used, most stratification and prediction studies included demographics and features derived from the ALSFRS or ALSFRS-R scores, which were also the main prediction targets. The most represented stratification methods were K-means, and hierarchical and expectation-maximisation clustering; while random forests, logistic regression, the Cox proportional hazard model, and various flavours of deep learning were the most widely used prediction methods. Predictive model validation was, albeit unexpectedly, quite rarely performed in absolute terms (leading to the exclusion of 78 eligible studies), with the overwhelming majority of included studies resorting to internal validation only. CONCLUSION: This systematic review highlighted a general agreement in terms of input variable selection for both stratification and prediction of ALS progression, and in terms of prediction targets. A striking lack of validated models emerged, as well as a general difficulty in reproducing many published studies, mainly due to the absence of the corresponding parameter lists. While deep learning seems promising for prediction applications, its superiority with respect to traditional methods has not been established; there is, instead, ample room for its application in the subfield of patient stratification. Finally, an open question remains on the role of new environmental and behavioural variables collected via novel, real-time sensors.

Asunto(s)

Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico , Inteligencia Artificial , Encéfalo , Análisis por Conglomerados , Bases de Datos Factuales

RESUMEN

BACKGROUND: Collection of real-world evidence (RWE) is important in achondroplasia. Development of a prospective, shared, international resource that follows the principles of findability, accessibility, interoperability, and reuse of digital assets, and that captures long-term, high-quality data, would improve understanding of the natural history of achondroplasia, quality of life, and related outcomes. METHODS: The Europe, Middle East, and Africa (EMEA) Achondroplasia Steering Committee comprises a multidisciplinary team of 17 clinical experts and 3 advocacy organization representatives. The committee undertook an exercise to identify essential data elements for a standardized prospective registry to study the natural history of achondroplasia and related outcomes. RESULTS: A range of RWE on achondroplasia is being collected at EMEA centres. Whereas commonalities exist, the data elements, methods used to collect and store them, and frequency of collection vary. The topics considered most important for collection were auxological measures, sleep studies, quality of life, and neurological manifestations. Data considered essential for a prospective registry were grouped into six categories: demographics; diagnosis and patient measurements; medical issues; investigations and surgical events; medications; and outcomes possibly associated with achondroplasia treatments. CONCLUSIONS: Long-term, high-quality data are needed for this rare, multifaceted condition. Establishing registries that collect predefined data elements across age spans will provide contemporaneous prospective and longitudinal information and will be useful to improve clinical decision-making and management. It should be feasible to collect a minimum dataset with the flexibility to include country-specific criteria and pool data across countries to examine clinical outcomes associated with achondroplasia and different therapeutic approaches.

Asunto(s)

Acondroplasia , Calidad de Vida , Humanos , Europa (Continente) , Sistema de Registros , Acondroplasia/epidemiología