Glycome dynamics in T and B cell development: basic immunological mechanisms and clinical applications

Glycans cover the surfaces of all mammalian cells through a process called glycosylation. Nearly all proteins and receptors that integrate the intricate series of co-stimulatory/inhibitory pathways of the immune system are glycosylated. Growing evidence indicates that the development of the immune system at the origins of T and B cell development is tightly regulated by glycosylation. In this opinion, we hypothesize that the glycome composition of developing T and B cells is developmentally regulated. We discuss how glycans play fundamental roles in lymphocyte development and how glycans early define T and B cell functionality in multiple aspects of adaptive immunity. These advances can provide opportunities for the discovery of novel disease factors and more effective candidate treatments for various conditions.This work was funded by the EU (ERC, GlycanSwitch, Grant Agreement N° 101071386). Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council Executive Agency. Funded by the European Union (GlycanTrigger, Grant Agreement N°: 101093997. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or European Health and Digital Executive Agency. Neither the European Union nor the granting authority can be held responsible for them. M.M.V. and E.L-G. received funding from the Portuguese Foundation for Science and Technology (FCT) of the Portuguese Ministry of Science, Technology and Higher Education (M.M.V.: PD/BD/135452/2017, COVID/BD/152488/2022; E.L-G.: UI/BD/152866/2022)

Chiropractic Manipulation: Reasons for Concern?

Chiropractic's popularity is rising among the general population. Moreover, few studies have been conducted to properly evaluate its safety. We report three cases of serious neurological adverse events in patients treated with chiropractic manipulation. The first case is a 41 years old woman who developed a vertebro-basilar stroke 48 h after cervical manipulation. The second case represents a 68 years old woman who presented a neuropraxic injury of both radial nerves after three sessions of spinal manipulation. The last case is a 34 years old man who developed a cervical epidural haematoma after a chiropractic treatment for neck pain. In all three cases there were criteria to consider a causality relation between the neurological adverse events and the chiropractic manipulation. The described serious adverse events promptly recommend the implementation of a risk alert system

Safety and Family-Centered Care during Restriction of Hospital Visits due to COVID-19: The Experience of Family Members

Background: Person and Family Centered Care (PFCC) has demonstrated important contributions to health care outcomes. However, in response to the need for safety due to the pandemic COVID-19, measures were taken to restrict hospital visits. So, the aim of this study was to understand the healthcare experience of family members of patients hospitalized during the pandemic period regarding safety and person- and family-centered care. Methods: Qualitative interpretative study, conducted through semi-structured interviews with six family members of people hospitalized during the pandemic period. Content analysis was performed using Atlas.ti software version 22 (Berlin, Germany) and Bardin’s methodology. Results and Conclusions: Restrictions on hospital visits due to the pandemic of COVID-19 have led to a distancing of families from the hospital setting and influenced healthcare practice, making it difficult to involve families in the care process. In some cases, healthcare professionals made efforts to provide PFCC, attempting to minimize the impact of the visitation restriction. However, there were reported experiences of care delivery that did not consider social and psychological factors and did not place the person and family at the center of the care process, relying instead on the biomedical model. These practices left out important factors for the provision of safe care. It is crucial, even in pandemic settings, that healthcare professionals provide person- and family-centered care to the extent possible, promoting the safety of care. The family should be involved in the care of the person in the inpatient setting.info:eu-repo/semantics/publishedVersio

Loss and Recovery of Mgat3 and GnT-III Mediated E-cadherin N-glycosylation Is a Mechanism Involved in Epithelial-Mesenchymal-Epithelial Transitions

BACKGROUND: N-acetylglucosaminyltransferase-III (GnT-III) is a glycosyltransferase encoded by Mgat3 that catalyzes the addition of β1,4-bisecting-N-acetylglucosamine on N-glycans. GnT-III has been pointed as a metastases suppressor having varying effects on cell adhesion and migration. We have previously described the existence of a functional feedback loop between E-cadherin expression and GnT-III-mediated glycosylation. The effects of GnT-III-mediated glycosylation on E-cadherin expression and cellular phenotype lead us to evaluate Mgat3 and GnT-III-glycosylation role during Epithelial-Mesenchymal-Transition (EMT) and the reverted process, Mesenchymal-Epithelial-Transition (MET). METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the expression profile and genetic mechanism controlling Mgat3 expression as well as GnT-III-mediated glycosylation, in general and specifically on E-cadherin, during EMT/MET. We found that during EMT, Mgat3 expression was dramatically decreased and later recovered when cells returned to an epithelial-like phenotype. We further identified that Mgat3 promoter methylation/demethylation is involved in this expression regulation. The impact of Mgat3 expression variation, along EMT/MET, leads to a variation in the expression levels of the enzymatic product of GnT-III (bisecting GlcNAc structures), and more importantly, to the specific modification of E-cadherin glycosylation with bisecting GlcNAc structures. CONCLUSIONS/SIGNIFICANCE: Altogether, this work identifies for the first time Mgat3 glycogene expression and GnT-III-mediated glycosylation, specifically on E-cadherin, as a novel and major component of the EMT/MET mechanism signature, supporting its role during EMT/MET

The resolution of acute inflammation induced by cyclic AMP is dependent on annexin A1

Annexin A1 (AnxA1) is a glucocorticoid-regulated protein known for its anti-inflammatory and pro-resolving effects. We have shown previously that the cAMP-enhancing compounds rolipram (ROL; a PDE4 inhibitor) and Bt2cAMP (a cAMP mimetic) drive caspase-dependent resolution of neutrophilic inflammation. In this follow-up study, we investigated whether AnxA1 could be involved in the pro-resolving properties of these compounds using a model of LPS-induced inflammation in BALB/c mice. The treatment with ROL or Bt2cAMP at the peak of inflammation shortened resolution intervals, improved resolution indices, and increased AnxA1 expression. In vitro studies showed that ROL and Bt2cAMP induced AnxA1 expression and phosphorylation, and this effect was prevented by PKA inhibitors, suggesting the involvement of PKA in ROL-induced AnxA1 expression. Akin to these in vitro findings, H89 prevented ROL- and Bt2cAMP-induced resolution of inflammation, and it was associated with decreased levels of intact AnxA1. Moreover, two different strategies to block the AnxA1 pathway (by using N-t-Boc-Met-Leu-Phe, a nonselective AnxA1 receptor antagonist, or by using an anti-AnxA1 neutralizing antiserum) prevented ROL- and Bt2cAMP-induced resolution and neutrophil apoptosis. Likewise, the ability of ROL or Bt2cAMP to induce neutrophil apoptosis was impaired in AnxA-knock-out mice. Finally, in in vitro settings, ROL and Bt2cAMP overrode the survival-inducing effect of LPS in human neutrophils in an AnxA1-dependent manner. Our results show that AnxA1 is at least one of the endogenous determinants mediating the pro-resolving properties of cAMP-elevating agents and cAMP-mimetic drug

Mannosylated glycans impair normal T-cell development by reprogramming commitment and repertoire diversity

T-cell development ensures the formation of diverse repertoires of T-cell receptors (TCRs) that recognize a variety of antigens. Glycosylation is a major posttranslational modification present in virtually all cells, including T-lymphocytes, that regulates activity/functions. Although these structures are known to be involved in TCR-selection in DP thymocytes, it is unclear how glycans regulate other thymic development processes and how they influence susceptibility to disease. Here, we discovered stage-specific glycome compositions during T-cell development in human and murine thymocytes, as well as dynamic alterations. After restricting the N-glycosylation profile of thymocytes to high-mannose structures, using specific glycoengineered mice (Rag1CreMgat1fl/fl), we showed remarkable defects in key developmental checkpoints, including ß-selection, regulatory T-cell generation and γδT-cell development, associated with increased susceptibility to colon and kidney inflammation and infection. We further demonstrated that a single N-glycan antenna (modeled in Rag1CreMgat2fl/fl mice) is the sine-qua-non condition to ensure normal development. In conclusion, we revealed that mannosylated thymocytes lead to a dysregulation in T-cell development that is associated with inflammation susceptibility.Funded by the “2022 Lupus Research Alliance (LRA) Lupus Innovation Award”. Institutional funding from the Portuguese Foundation for Science and Technology (FCT): projects NORTE-01-0145-FEDER-000029, POCI-01/0145-FEDER-016601, POCI-01-0145-FEDER-028772, and PTDC/MEC-REU/28772/2017 (SSP). This study was co-funded by the European Union (ERC Synergy, GlycanSwitch, 101071386). Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council Executive Agency. The study was also co-funded by the European Union, GlycanTrigger project, Grant Agreement No: 101093997. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or European Health and Digital Executive Agency. Neither the European Union nor the granting authority can be held responsible for them. A grant was received from the Portuguese group of study in autoimmune diseases (NEDAI) to SSP. MMV (PD/BD/135452/2017; COVID/BD/152488/2022) received funding from the FCT

Social and ethical criteria for prioritizing patients: a survey of students and health professionals in Portugal

O estudo quali-quantitativo explora o dilema ético da microalocação dos recursos da saúde. Objetiva identificar e comparar a opinião de dois grupos da sociedade portuguesa - estudantes e profissionais de saúde sobre a importância das características pessoais dos pacientes no momento de os priorizar e se as escolhas se explicam por referenciais bioéticos de caráter utilitaristas ou deontológicos. Os dados foram recolhidos através de um questionário aplicado a uma amostra de 180 estudantes universitários e 60 profissionais de saúde. Os respondentes perante hipotéticos cená- rios de emergência clínica tiveram de escolher de entre dois pacientes (distinguidos por idade, sexo, responsabilidade social, situação económica e laboral, comportamentos lesivos da saúde e registo criminal) quem tratar e justificar a escolha. Foram usados testes estatísticos de associação para comparar as respostas dos dois grupos e análise de conteúdo para categorizar as justificações. Os resultados sugerem a existência de diferenças nas escolhas dos dois grupos, com os profissionais de saúde a revelarem aceitar menos a utilização de critérios sociais em contexto de escassez e coexistência de critérios utilitaristas e deontológicos, com predomínio da eficiência por parte dos profissionais de saúde e da equidade por parte dos estudantesThis qualitative/quantitative study examines the ethical dilemma of microallocation of health resources. It seeks to identify and compare the opinion of two groups in Portuguese society – students and health professionals – on the importance of personal characteristics of patients at the moment of prioritizing them and if the choices can be explained by bioethical references of a utilitarian or deontological nature. Data were collected by means of a questionnaire administered to a sample of 180 students and 60 health professionals. Faced with hypothetical emergency scenarios, the respondents had to choose between two patients (distinguished by: age, gender, social responsibility, economic and employment situation, harmful health behaviors and criminal record), duly selecting who to treat and then justifying their choice. The results suggest the existence of differences in choices between the two groups, with health professionals revealing they are less prepared to accept the use of social criteria in a context of scarce resources and co-existence of utilitarian and deontological criteria, with a predominance of efficiency on the part of health professionals and equity on the part of students.info:eu-repo/semantics/publishedVersio

Allopurinol Reduces the Lethality Associated with Acute Renal Failure Induced by Crotalus durissus terrificus Snake Venom: Comparison with Probenecid

In Brazil, among registered snake bites, those by the genus Crotalus originate the highest mortality rate. The rattlesnake Crotalus durissus terrificus is the most frequently implicated in these accidents. The kidney is a particularly vulnerable organ to the venom of this rattlesnake. In fact, the most serious complication of Crotalus snake bite is the renal dysfunction, and among the fatal cases of Crotalus bites in Brazil 5% are patients treated with antivenom. The hyperuricemia has been observed in human accidents with snake venoms, but this parameter has not received any special attention as a relevant factor in the etiology of renal dysfunction caused by these venoms. This study examined the effects of treatments with low-cost and low-risk uricostatic (allopurinol) and uricosuric (probenecid) drugs on the envenomation by C. d. terrificus, showing that allopurinol and probenecid mitigated certain nephrotoxic effects, as well as the survival of envenomed mice was improved through the effects of allopurinol on reduction of oxidative stress and intracellular formation of uric acid. This new knowledge provides consistent evidences linking uric acid with the renal dysfunction induced by rattlesnake bites and that the allopurinol deserves to be clinically evaluated as an approach complementary to anti-snake venom serotherapy

LL-LACTOGAL - Descriptive Analysis - Presentation of First Results

Musculoskeletal disorders are a major cause of sickness and absenteeism. However the relationship between musculoskeletal disease and work is not always clear. This paper aims to present some preliminary results, on a descriptive analysis of the methodology developed and applied in the project LL-LACTOGAL. It is expected to give a contribution to the clarification of this relationship. The project is in development in a specific production sector of a food industry unit. The approach spans seven different methods. A description of the overall sample and some preliminary results are presented. The preliminary results give an overall picture of musculoskeletal disease signals in the plant