Schmidt´s syndrome found by tan: a case report.

Addison´s disease can form part of type 2 autoimmune polyglandular syndrome. The article reports the case of a 41-year-old female patient with hypothyroidism and vitiligo, who came to the emergency department complaining of asthenia that had worsened in recent months, as well as anorexia, nausea, and weight loss (6 kg in a year). Cutaneous hyperpigmentation was the main finding on physical examination, together with vitiligo lesions on the face, hands, and armpits. Further study revealed a low serum cortisol level, normal urine-free cortisol, and an elevated adrenocorticotropic hormone (ACTH). Antiperoxidase antibodies and 17-alpha-hidroxylase antibodies were both positive. Treatment was started with prednisolone and fludrocortisone, and a good clinical response was obtained. This case report aims to draw attention to the high level of clinical suspicion required to diagnose Addison´s disease and the need to screen actively for other potentially associated autoimmune diseases that may be associated.

Lipidomic scanning of self-lipids identifies headless antigens for natural killer T cells.

To broadly measure the spectrum of cellular self-antigens for natural killer T cells (NKT), we developed a sensitive lipidomics system to analyze lipids trapped between CD1d and NKT T cell receptors (TCRs). We captured diverse antigen complexes formed in cells from natural endogenous lipids, with or without inducing endoplasmic reticulum (ER) stress. After separating protein complexes with no, low, or high CD1d-TCR interaction, we eluted lipids to establish the spectrum of self-lipids that facilitate this interaction. Although this unbiased approach identified fifteen molecules, they clustered into only two related groups: previously known phospholipid antigens and unexpected neutral lipid antigens. Mass spectrometry studies identified the neutral lipids as ceramides, deoxyceramides, and diacylglycerols, which can be considered headless lipids because they lack polar headgroups that usually form the TCR epitope. The crystal structure of the TCR-ceramide-CD1d complex showed how the missing headgroup allowed the TCR to predominantly contact CD1d, supporting a model of CD1d autoreactivity. Ceramide and related headless antigens mediated physiological TCR binding affinity, weak NKT cell responses, and tetramer binding to polyclonal human and mouse NKT cells. Ceramide and sphingomyelin are oppositely regulated components of the "sphingomyelin cycle" that are altered during apoptosis, transformation, and ER stress. Thus, the unique molecular link of ceramide to NKT cell response, along with the recent identification of sphingomyelin blockers of NKT cell activation, provide two mutually reinforcing links for NKT cell response to sterile cellular stress conditions.

Refractory Fetal and Neonatal Supraventricular Tachycardia Associated With Mitral Valve Mass.

Primary cardiac tumors in children are rare and mostly benign but can cause significant cardiovascular complications, including arrhythmias. We present a rare case of fetal and neonatal refractory supraventricular tachycardia linked to a probable mitral valve hemangioma, resulting in severe neonatal and maternal morbidity. Despite challenges, pharmacological therapy ultimately successfully managed the condition, highlighting the importance of individualized treatment in such complex cases.

Modeling 3D Tumor Invasiveness to Modulate Macrophage Phenotype in a Human-Based Hydrogel Platform.

The immune system is a pivotal player in determining tumor fate, contributing to the immunosuppressive microenvironment that supports tumor progression. Considering the emergence of biomaterials as promising platforms to mimic the tumor microenvironment, human platelet lysate (PLMA)-based hydrogel beads are proposed as 3D platforms to recapitulate the tumor milieu and recreate the synergistic tumor-macrophage communication. Having characterized the biomaterial-mediated pro-regenerative macrophage phenotype, an osteosarcoma spheroid encapsulated into a PLMA hydrogel bead is explored to study macrophage immunomodulation through paracrine signaling. The culture of PLMA-Tumor beads on the top of a 2D monolayer of macrophages reveals that tumor cells triggered morphologic and metabolic adaptations in macrophages. The cytokine profile, coupled with the upregulation of gene and protein anti-inflammatory biomarkers clearly indicates macrophage polarization toward an M2-like phenotype. Moreover, the increased gene expression of chemokines identified as pro-tumoral environmental regulators suggest a tumor-associated macrophage phenotype, exclusively stimulated by tumor cells. This pro-tumoral microenvironment is also found to enhance tumor invasiveness ability and proliferation. Besides providing a robust in vitro immunomodulatory tumor model that faithfully recreates the tumor-macrophage interplay, this human-based platform has the potential to provide fundamental insights into immunosuppressive signaling and predict immune-targeted response.

Modeling hypothalamic pathophysiology in vitro for metabolic, circadian, and sleep disorders.

The hypothalamus, a small and intricate brain structure, orchestrates numerous neuroendocrine functions through specialized neurons and nuclei. Disruption of this complex circuitry can result in various diseases, including metabolic, circadian, and sleep disorders. Advances in in vitro models and their integration with new technologies have significantly benefited research on hypothalamic function and pathophysiology. We explore existing in vitro hypothalamic models and address their challenges and limitations as well as translational findings. We also highlight how collaborative efforts among multidisciplinary teams are essential to develop relevant and translational experimental models capable of replicating intricate neural circuits and neuroendocrine pathways, thereby advancing our understanding of therapeutic targets and drug discovery in hypothalamus-related disorders.

Orogenital and anal infection by Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, and other sexually transmitted infections in men who have sex with men in Lisbon.

BACKGROUND: Men who have sex with men (MSM) are at risk for sexually transmitted infections (STIs), but more data on extragenital carriage are needed. AIM: We assessed the genital and extragenital prevalence of bacterial and other STIs in MSM in a Lisbon sexual health clinic. METHODS: We screened oral, anal, and urine samples of MSM visiting the GAT-CheckpointLX clinic June 2017-December 2021 for Chlamydia trachomatis (including lymphogranuloma venereum, LGV), Neisseria gonorrhoeae, Mycoplasma genitalium, Trichomonas vaginalis, Mycoplasma hominis, Ureaplasma urealyticum, and U. parvum. Ano-oro-genital lesions were tested for LGV, Treponema pallidum, and Herpes Simplex Virus. Blood was tested for HIV and T. pallidum antibodies. RESULTS: N. gonorrhoeae was found in 16.6% of the MSM followed by C. trachomatis (13.2%), M. genitalium (10.3%) and T. vaginalis (0.2%). The most frequent occurrence was anorectal (C. trachomatis, M. genitalium) and oral (N. gonorrhoeae). We found high carriage of U. urealyticum (36.1%) and M. hominis (22.1%). LGV was detected in 21.8% of chlamydia-positive anorectal swabs. Syphilis was detected in 22.6% of tested MSM, while 13.8% had HIV. Gonorrhoea and chlamydia were significantly more prevalent in MSM with concomitant HIV or syphilis. CONCLUSION: The substantial extragenital prevalence of bacterial STIs in MSM, and HIV and syphilis coinfections, suggest screening has value in identifying hidden carriage and in contributing for providing better care.

Impaired neuron differentiation in GBA-associated Parkinson's disease is linked to cell cycle defects in organoids.

The mechanisms underlying Parkinson's disease (PD) etiology are only partially understood despite intensive research conducted in the field. Recent evidence suggests that early neurodevelopmental defects might play a role in cellular susceptibility to neurodegeneration. To study the early developmental contribution of GBA mutations in PD we used patient-derived iPSCs carrying a heterozygous N370S mutation in the GBA gene. Patient-specific midbrain organoids displayed GBA-PD relevant phenotypes such as reduction of GCase activity, autophagy impairment, and mitochondrial dysfunction. Genome-scale metabolic (GEM) modeling predicted changes in lipid metabolism which were validated with lipidomics analysis, showing significant differences in the lipidome of GBA-PD. In addition, patient-specific midbrain organoids exhibited a decrease in the number and complexity of dopaminergic neurons. This was accompanied by an increase in the neural progenitor population showing signs of oxidative stress-induced damage and premature cellular senescence. These results provide insights into how GBA mutations may lead to neurodevelopmental defects thereby predisposing to PD pathology.

Extra-Neural Metastases of Glioblastoma: A Case Series.

Glioblastoma (GBM) is the most common brain tumor and has a median survival of less than two years. The current standard of care consists of surgery followed by concomitant radio and chemotherapy with temozolomide. Although it is an aggressive tumor, distant metastases are extremely rare. The dissemination mechanisms are not fully understood and currently there is no standard of care for its treatment. In this study, the authors present a comprehensive analysis of all the existing cases of extra-neural metastases of GBM in a tertiary care center over the last five years, along with the procedures carried out in each case.

Innovative three-dimensional models for understanding mechanisms underlying lung diseases: powerful tools for translational research.

Chronic lung diseases result from alteration and/or destruction of lung tissue, inevitably causing decreased breathing capacity and quality of life for patients. While animal models have paved the way for our understanding of pathobiology and the development of therapeutic strategies for disease management, their translational capacity is limited. There is, therefore, a well-recognised need for innovative in vitro models to reflect chronic lung diseases, which will facilitate mechanism investigation and the advancement of new treatment strategies. In the last decades, lungs have been modelled in healthy and diseased conditions using precision-cut lung slices, organoids, extracellular matrix-derived hydrogels and lung-on-chip systems. These three-dimensional models together provide a wide spectrum of applicability and mimicry of the lung microenvironment. While each system has its own limitations, their advantages over traditional two-dimensional culture systems, or even over animal models, increases the value of in vitro models. Generating new and advanced models with increased translational capacity will not only benefit our understanding of the pathobiology of lung diseases but should also shorten the timelines required for discovery and generation of new therapeutics. This article summarises and provides an outline of the European Respiratory Society research seminar "Innovative 3D models for understanding mechanisms underlying lung diseases: powerful tools for translational research", held in Lisbon, Portugal, in April 2022. Current in vitro models developed for recapitulating healthy and diseased lungs are outlined and discussed with respect to the challenges associated with them, efforts to develop best practices for model generation, characterisation and utilisation of models and state-of-the-art translational potential.

RUFY3 regulates endolysosomes perinuclear positioning, antigen presentation and migration in activated phagocytes.

Endo-lysosomes transport along microtubules and clustering in the perinuclear area are two necessary steps for microbes to activate specialized phagocyte functions. We report that RUN and FYVE domain-containing protein 3 (RUFY3) exists as two alternative isoforms distinguishable by the presence of a C-terminal FYVE domain and by their affinity for phosphatidylinositol 3-phosphate on endosomal membranes. The FYVE domain-bearing isoform (iRUFY3) is preferentially expressed in primary immune cells and up-regulated upon activation by microbes and Interferons. iRUFY3 is necessary for ARL8b + /LAMP1+ endo-lysosomes positioning in the pericentriolar organelles cloud of LPS-activated macrophages. We show that iRUFY3 controls macrophages migration, MHC II presentation and responses to Interferon-γ, while being important for intracellular Salmonella replication. Specific inactivation of rufy3 in phagocytes leads to aggravated pathologies in mouse upon LPS injection or bacterial pneumonia. This study highlights the role of iRUFY3 in controlling endo-lysosomal dynamics, which contributes to phagocyte activation and immune response regulation.

Corrigendum: Ionic-liquid-based approaches to improve biopharmaceuticals downstream processing and formulation.

[This corrects the article DOI: 10.3389/fbioe.2023.1037436.].

Impact of Donor Age on Long-Term Outcomes in Simultaneous Pancreas-Kidney Transplantation.

BACKGROUND: Simultaneous pancreas-kidney transplantation (SPKT) is the treatment of choice for type 1 diabetes patients with end-stage renal disease. Donor characteristics are determinants of graft and patient survival. We aimed to study the impact of donor age on outcomes in SPKT. METHODS: We retrospectively studied 254 patients submitted to SPKT between 2000 and 2021. Patients were classified as "younger donor" (donor age <40 years) and "older donor" (donor age ≥40 years). RESULTS: Fifty-three patients received grafts from older donors. Pancreas graft survival rates at 1, 5, 10, and 15 years were 89%, 83%, 77%, and 73% in the younger donor group, respectively, and 77%, 73%, 67%, and 62% in the older donor group, respectively (P = .052). Older donors and previous major adverse cardiovascular events (MACEs) were associated with pancreas graft failure at 15 years. Kidney transplant survival (1, 5, 10, and 15 years) was lower in the older donor cohort (94%, 92%, 69%, 60% vs 97%, 94%, 89%, and 84%, respectively; P = .004). Older donor, recipient age, and previous MACE predicted kidney graft failure at 15 years. Patient survival rates at 1, 5, 10, and 15 years were 98%, 95%, 91%, and 81% in the younger donor group, respectively, versus 92%, 90%, 84%, and 72% in the older donor group, respectively (P = .127). CONCLUSIONS: The kidney graft survival rate was lower in the older donor group, whereas pancreas graft survival and patient survival did not differ significantly. Multivariate analysis showed that a donor age of ≥40 years was an independent predictor of pancreas and kidney graft failure at 15 years in SPKT patients.

Alterations of bovine nucleus pulposus cells with aging.

Aging is one of the major etiological factors driving intervertebral disc (IVD) degeneration, the main cause of low back pain. The nucleus pulposus (NP) includes a heterogeneous cell population, which is still poorly characterized. Here, we aimed to uncover main alterations in NP cells with aging. For that, bovine coccygeal discs from young (12 months) and old (10-16 years old) animals were dissected and primary NP cells were isolated. Gene expression and proteomics of fresh NP cells were performed. NP cells were labelled with propidium iodide and analysed by flow cytometry for the expression of CD29, CD44, CD45, CD146, GD2, Tie2, CD34 and Stro-1. Morphological cell features were also dissected by imaging flow cytometry. Elder NP cells (up-regulated bIL-6 and bMMP1 gene expression) presented lower percentages of CD29+, CD44+, CD45+ and Tie2+ cells compared with young NP cells (upregulated bIL-8, bCOL2A1 and bACAN gene expression), while GD2, CD146, Stro-1 and CD34 expression were maintained with age. NP cellulome showed an upregulation of proteins related to endoplasmic reticulum (ER) and melanosome independently of age, whereas proteins upregulated in elder NP cells were also associated with glycosylation and disulfide bonds. Flow cytometry analysis of NP cells disclosed the existence of 4 subpopulations with distinct auto-fluorescence and size with different dynamics along aging. Regarding cell morphology, aging increases NP cell area, diameter and vesicles. These results contribute to a better understanding of NP cells aging and highlighting potential anti-aging targets that can help to mitigate age-related disc disease.

Synthesis, In Vitro Biological Evaluation of Antiproliferative and Neuroprotective Effects and In Silico Studies of Novel 16E-Arylidene-5α,6α-epoxyepiandrosterone Derivatives.

Steroids constitute an important class of pharmacologically active molecules, playing key roles in human physiology. Within this group, 16E-arylideneandrostane derivatives have been reported as potent anti-cancer agents for the treatment of leukemia, breast and prostate cancers, and brain tumors. Additionally, 5α,6α-epoxycholesterol is an oxysterol with several biological activities, including regulation of cell proliferation and cholesterol homeostasis. Interestingly, pregnenolone derivatives combining these two modifications were described as potential neuroprotective agents. In this research, novel 16E-arylidene-5α,6α-epoxyepiandrosterone derivatives were synthesized from dehydroepiandrosterone by aldol condensation with different aldehydes followed by a diastereoselective 5α,6α-epoxidation. Their cytotoxicity was evaluated on tumoral and non-tumoral cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Furthermore, the assessment of the neuroprotective activity of these derivatives was performed in a dopaminergic neuronal cell line (N27), at basal conditions, and in the presence of the neurotoxin 6-hydroxydopamine (6-OHDA). Interestingly, some of these steroids had selective cytotoxic effects in tumoral cell lines, with an IC50 of 3.47 µM for the 2,3-dichlorophenyl derivative in the breast cancer cell line (MCF-7). The effects of this functionalized epoxide on cell proliferation (Ki67 staining), cell necrosis (propidium iodide staining), as well as the analysis of the nuclear area and near neighbor distance in MCF-7 cells, were analyzed. From this set of biological studies, strong evidence of the activation of apoptosis was found. In contrast, no significant neuroprotection against 6-OHDA-induced neurotoxicity was observed for the less cytotoxic steroids in N27 cells. Lastly, molecular docking simulations were achieved to verify the potential affinity of these compounds against important targets of steroidal drugs (androgen receptor, estrogen receptor α, and 5α-reductase type 2, 17α-hydroxylase-17,20-lyase and aromatase enzymes). This in silico study predicted a strong affinity between most novel steroidal derivatives and 5α-reductase and 17α-hydroxylase-17,20-lyase enzymes.

Cerebral Air Embolism: A Case of a Rare Transthoracic Needle Biopsy Complication.

Transthoracic needle biopsy (TNB) is a fundamental procedure in the diagnosis of a wide spectrum of thoracic diseases replacing more invasive surgical procedures. The procedure may be performed with computed tomography (CT) or ultrasound imaging guidance, with CT being the more commonly utilized. Although less invasive than surgery, there is still a complication risk associated with this procedure. These can be local such as pneumothorax, parenchymal hemorrhage, tumor seeding, and hemoptysis, or systemic such as air embolism. The authors report a case of cerebral circulation air embolism as a complication of TNB in a 54-year-old male with suspected lung tumor followed by a brief review of the current literature.

Ionic-liquid-based approaches to improve biopharmaceuticals downstream processing and formulation.

The emergence of biopharmaceuticals, including proteins, nucleic acids, peptides, and vaccines, revolutionized the medical field, contributing to significant advances in the prophylaxis and treatment of chronic and life-threatening diseases. However, biopharmaceuticals manufacturing involves a set of complex upstream and downstream processes, which considerably impact their cost. In particular, despite the efforts made in the last decades to improve the existing technologies, downstream processing still accounts for more than 80% of the total biopharmaceutical production cost. On the other hand, the formulation of biological products must ensure they maintain their therapeutic performance and long-term stability, while preserving their physical and chemical structure. Ionic-liquid (IL)-based approaches arose as a promise alternative, showing the potential to be used in downstream processing to provide increased purity and recovery yield, as well as excipients for the development of stable biopharmaceutical formulations. This manuscript reviews the most important progress achieved in both fields. The work developed is critically discussed and complemented with a SWOT analysis.

Glycemic Control in Type 1 Diabetes Mellitus and COVID-19: What We Learned From the Lockdown Experience.

INTRODUCTION: Confinement measures that were imposed during the COVID-19 pandemic drastically changed the routines of the population. Some studies on the impact of confinement on glycemic control suggest a reduction of 0.1 to 0.5% in glycated hemoglobin. The objective of this study was to evaluate the impact of the COVID-19 pandemic lockdown on glycemic control in adult patients with type 1 diabetes mellitus. METHODS: An observational retrospective cohort study of patients with type 1 diabetes mellitus followed in a Diabetes Unit was performed. The study compared the metabolic control of these patients before (between January 1st and March 18th, 2020) and after (between May 3rd and July 31st, 2020) the lockdown. RESULTS: The study included 102 patients with type 1 diabetes mellitus (51% females), with a median age of 36 years (interquartile range 18.75, (24.25-43)) and a median duration of diabetes of 15 years (interquartile range 13, (8-21)). After lockdown, a significant decrease of 0.28±0.71% in glycated hemoglobin was observed (7.88±1.33% vs 7.59±1.23%, p=<0.001). In patients using continuous glucose monitoring a significant improvement in time in range was also noted (47.25±17.33% vs 49.97±18.61%, p=0.008). CONCLUSIONS: This study demonstrated an improvement in glycemic control after the lockdown. This might be explained by the positive impact of stable schedules, healthy meals and greater availability to make therapeutic adjustments to glycemic control. The fact that diabetes was considered a risk factor for the development of severe COVID-19 disease might also influence patients to increase their efforts to optimize their glycemic control.

IgA Vasculitis with scrotal involvement - a rare presentation in adults.

IgA vasculitis (IgAV) is a small-vessel vasculitis common in children but rare in adults. It is usually an auto-limited disease in children but has a more severe course and worse prognosis in adults. The classical manifestations are non-thrombocytopenic purpura, arthralgias, gastrointestinal involvement and renal involvement. Herein we report a case of a 39-year-old man with a rash of the lower limbs associated with testicular and lower abdominal pain. The initial study revealed increased inflammatory biomarkers and enlarged left testis with bilateral ischemic areas on doppler ultrasound. A cutaneous biopsy later revealed leukocytoclastic vasculitis, confirming the diagnosis of IgAV with scrotal involvement. The patient started prednisolone, with improvement in the first week and sustained remission after two years of follow-up. This case report describes an adult with IgAV and scrotal involvement, which is rarely reported in adults and appears to be different from the one in children. The prevalence of scrotal involvement is presumably underestimated. In all men with IgAV, a scrotal examination should be performed and ultrasonography accordingly since it affects the treatment and follow-up. Recommendations for IgAV diagnosis and treatment in adults are still lacking and more research is needed.

Molecular Mechanisms Behind the Role of Plasmacytoid Dendritic Cells in Systemic Sclerosis.

Systemic sclerosis (SSc) is a debilitating autoimmune disease that affects multiple systems. It is characterized by immunological deregulation, functional and structural abnormalities of small blood vessels, and fibrosis of the skin, and, in some cases, internal organs. Fibrosis has a devastating impact on a patient's life and lung fibrosis is associated with high morbimortality. Several immune populations contribute to the progression of SSc, and plasmacytoid dendritic cells (pDCs) have been identified as crucial mediators of fibrosis. Research on murine models of lung and skin fibrosis has shown that pDCs are essential in the development of fibrosis, and that removing pDCs improves fibrosis. pDCs are a subset of dendritic cells (DCs) that are specialized in anti-viral responses and are also involved in autoimmune diseases, such as SSc, systemic lupus erythematosus (SLE) and psoriasis, mostly due to their capacity to produce type I interferon (IFN). A type I IFN signature and high levels of CXCL4, both derived from pDCs, have been associated with poor prognosis in patients with SSc and are correlated with fibrosis. This review will examine the recent research on the molecular mechanisms through which pDCs impact SSc.