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Studies completed to date provide persuasive evidence that placental cell-derived exosomes play a significant role in intercellular communication pathways that potentially contribute to placentation and development of materno-fetal vascular circulation. The aim of this study was to establish the gestational-age release profile and bioactivity of placental cell-derived exosome in maternal plasma. Plasma samples (n = 20 per pregnant group) were obtained from non-pregnant and pregnant women in the first (FT, 6-12 weeks), second (ST, 22-24 weeks) and third (TT, 32-38 weeks) trimester. The number of exosomes and placental exosome contribution were determined by quantifying immunoreactive exosomal CD63 and placenta-specific marker (PLAP), respectively. The effect of exosomes isolated from FT, ST and TT on endothelial cell migration were established using a real-time, live-cell imaging system (Incucyte). Exosome plasma concentration was more than 50-fold greater in pregnant women than in non-pregnant women (p<0.001). During normal healthy pregnancy, the number of exosomes present in maternal plasma increased significantly with gestational age by more that two-fold (p<0.001). Exosomes isolated from FT, ST and TT increased endothelial cell migration by 1.9±0.1, 1.6±0.2 and 1.3±0.1-fold, respectively compared to the control. Pregnancy is associated with a dramatic increase in the number of exosomes present in plasma and maternal plasma exosomes are bioactive. While the role of placental cell-derived exosome in regulating maternal and/or fetal vascular responses remains to be elucidated, changes in exosome profile may be of clinical utility in the diagnosis of placental dysfunction.

In the last years, mesenchymal stem cell (MSC)-based therapies have become an interesting therapeutic opportunity for the treatment of rheumatoid arthritis (RA) due to their capacity to potently modulate the immune response. RA is a chronic autoimmune inflammatory disorder with an incompletely understood etiology. However, it has been well described that peripheral tolerance defects and the subsequent abnormal infiltration and activation of diverse immune cells into the synovial membrane, are critical for RA development and progression. Moreover, the imbalance between the immune response of pro-inflammatory and anti-inflammatory cells, in particular between memory Th17 and memory regulatory T cells (Treg), respectively, is well admitted to be associated to RA immunopathogenesis. In this context, MSCs, which are able to alter the frequency and function of memory lymphocytes including Th17, follicular helper T (Tfh) cells and gamma delta (γδ) T cells while promoting Treg cell generation, have been proposed as a candidate of choice for RA cell therapy. Indeed, given the plasticity of memory CD4 T cells, it is reasonable to think that MSCs will restore the balance between pro-inflammatory and anti-inflammatory memory T cells populations deregulated in RA leading to prompt their therapeutic function. In the present review, we will discuss the role of memory T cells implicated in RA pathogenesis and the beneficial effects exerted by MSCs on the phenotype and functions of these immune cells abnormally regulated in RA and how this regulation could impact RA progression.

In the general population, up to 10% of children treated by antibiotics have cutaneous adverse drug reaction, but allergy is confirmed in less than 20% of patients. Most of the non-allergic reactions are probably due to virus, such as enterovirus acute infection or Ebstein-Barr Virus (EBV) acute infection or reactivation. Especially in children, viruses have the propensity to induce skin lesions (maculopapular rash, urticaria) due to their skin infiltration or immunologic response. In drug-related skin eruptions, a virus can participate by activating an immune predisposition. The culprit antibiotic is then the trigger for reacting. Even in severe drug-induced reactions, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, viruses take part in immune phenomena, especially herpes viruses. Understanding the mechanisms of both virus- and drug-induced skin reaction is important to develop our clinical reflection and give an adaptive care to the patient. Our aim is to review current knowledge on the different aspects and potential roles of viruses in the different type of drug hypersensitivity reactions (DHR). Although major advances have been made those past year, further studies are needed for a better understanding of the link between viruses and DHR, to improve management of those patients.

To investigate food allergy-tolerance mechanisms induced through allergen-specific immunotherapy we used RNA-Sequencing to measure gene expression in lymph-node-derived dendritic cells from Pru p 3-anaphylactic mice after immunotherapy with glycodendropeptides at 2 nM and 5 nM, leading to permanent tolerance and short-term desensitization, respectively. Gene expression was also measured in mice receiving no immunotherapy (anaphylaxis); and in which anaphylaxis could never occur (antigen-only). Compared to anaphylaxis, the antigen-only group showed the greatest number of expression-changes (411), followed by tolerant (186) and desensitized (119). Only 29 genes changed in all groups, including Il12b , Cebpb and Ifngr1 . The desensitized group showed enrichment for genes related to chronic inflammatory response, secretory granule, and regulation of interleukin-12 production; the tolerant group showed genes related to cytokine receptor activity and glucocorticoid receptor binding, suggesting distinct pathways for similar outcomes. We identified genes and processes potentially involved in the restoration of long-term tolerance via allergen-specific immunotherapy, representing potential prognostic biomarkers.

Background: Intradermal tests (IDTs) are performed and interpreted differently in drug allergy centers making valid comparison of results difficult.Objective: To reduce method-related and intercenter variability of IDTs by the introduction of a standardized method.Materials and methods: In 11 centers of the European Network for Drug Allergy, IDTs were prospectively performed with saline and with amoxicillin (20 mg/ml) using (1) the local method and (2) the standardized European Network in Drug Allergy (ENDA) method (0.02 ml). The diameters of the initial injection wheal (Wi) for the different volumes and sites injected obtained from each center were analyzed.Results: The most reproducible method was to fill a syringe with test solution, then expel the excess fluid to obtain exactly 0.02 ml. The median Wi diameter with 0.02 ml injection using the standardized method was 5 mm [range 2–10 mm; interquartile range (IQR) 5–5 mm; n = 1,096] for saline and 5 mm (range 2–9 mm; IQR = 4.5–5 mm; n = 240) for amoxicillin. IDT injection sites did not affect the Wi diameter. Training improved precision and reduced the variability of Wi diameters.Conclusion: Using the standardized IDT method described in this multicenter study helped to reduce variability, enabling more reliable comparison of results between individuals and centers.

Nuclear vacuoles are specific structures present on the head of the human sperm of fertile and non-fertile men. Human sperm head vacuoles have been previously studied using motile sperm organelle morphology examination (MSOME) and their origin related to abnormal morphology, abnormal chromatin condensation and DNA fragmentation. However, other studies argued that human sperm vacuoles are physiological structures and consequently, to date, the nature and origin of the nuclear vacuoles remains to be elucidated. Here, we aim to define the incidence, position, morphology and molecular content of the human sperm vacuoles using transmission electron microscopy (TEM) and immunocytochemistry techniques. The results showed that ~50% of the analyzed human sperm cells (n = 1908; 17 normozoospermic human donors) contained vacuoles mainly located (80%) in the tip head region. A significant positive correlation was found between the sperm vacuole and nucleus areas. Furthermore, it was confirmed that nuclear vacuoles were invaginations of the nuclear envelope from the perinuclear theca and containing cytoskeletal proteins and cytoplasmic enzyme, discarding a nuclear or acrosomal origin. According to our findings, these human sperm head vacuoles are cellular structures originating from nuclear invaginations and contain perinuclear theca (PT) components, allowing us to define a new term of ‘nuclear invaginations’ rather than ‘nuclear vacuoles’.

A series of 2,6,9-trisubstituted purine derivatives have been synthesized and investigated for their potential role as antitumor agents. Twelve compounds were obtained by a three step synthetic procedure using microwave irradiation in a pivotal step. All compounds were evaluated in vitro to determine their potential effect on cell toxicity by the MTT method and flow cytometry analysis on four cancer cells lines and Vero cells. Three out of twelve compounds were found to be promising agents compared to a known and effective anticancer drug, etoposide, in three out of four cancer cell lines assayed with considerable selectivity. Preliminary flow cytometry data suggests that compounds mentioned above induce apoptosis on these cells. The main structural requirements for their activity for each cancer cell line were characterized with a preliminary pharmacophore model, which identified aromatic centers, hydrogen acceptor/donor center and a hydrophobic area. These features were consistent with the cytotoxic activity of the assayed compounds.

Over the last decade there has been growing evidence that neuropsychological deficits, principally in the executive functions, may be involved in the pathogenesis of Chiari Type I disease. The aim of this study is to compare changes in cognitive function in patients with Chiari Type I and healthy subjects. The neuropsychological profile of these patients was compared with healthy controls. Three neuropsychological tests were administered to both Chiari Type I patients and healthy controls to assess the frontal executive functions of vigilance or selective attention, mental flexibility, planning and concept formation. The results suggest that Chiari Type I patients are affected in the processes of inhibition and self-control as well as in attention capacity and maintaining a course of thought and action. These results provide evidence of possible deficits or anomalies in the cognitive executive functions of patients with Chiari Type I.

Background/Objectives: Systemic lupus erythematosus is an autoimmune disease. The musculoskeletal system is affected in 90% of patients. The most common symptoms are myalgia, arthralgia, and arthritis. The objective was to analyze the efficacy of an intervention using myofascial techniques and proprioceptive neuromuscular facilitation in patients with systemic lupus erythematosus. Methods: A randomized, single-blind, crossover clinical trial. Seventeen patients with systemic lupus erythematosus were randomly assigned to two sequences: Sequence A–B (intervention phase first, then control phase) and Sequence B–A (control phase first, then intervention phase). The intervention lasted for four weeks, with two weekly sessions lasting 50 min each. The intervention consisted of myofascial and proprioceptive neuromuscular facilitation techniques. The variables were: pain intensity (Visual Analog Scale), functional capacity of lower limbs (2-Minute Walk Test), physical function (Timed Up and Go Test), and fatigue (Fatigue Assessment Scale). After a 2-week follow-up and a 2-week washout period, the patients switched groups, and the methodology was replicated. Results: None of the patients developed injury or adverse effects as a direct consequence of the intervention. There were statistically significant differences between groups (p < 0.001) in the intensity of ankle (η2p = 0.38) and knee (η2 = 0.37) pain, functional capacity (η2 = 0.33), and physical function (η2 = 0.56). There were also intergroup changes in fatigue (η2 = 0.52), and the relevant mental (η2 = 0.26) and physical (η2 = 0.45) components. Conclusions: Proprioceptive myofascial and neuromuscular facilitation techniques are safe in patients with systemic lupus erythematosus. This physical therapy protocol can improve the intensity of knee and ankle joint pain in these patients. This intervention can improve functional capacity, physical function, and fatigue in people with systemic lupus erythematosus.

Heavy metals are endocrine disruptors which interfere with processes mediated by endogenous hormones of the organism, negatively affecting endocrine functions. Some studies have correlated heavy metal exposure with male infertility. However, the number of studies conducted on humans are limited. Therefore, the aim of this study is to summarize the current knowledge on how heavy metals influence human male fertility. Hence, three distinct databases were consulted—PubMed, Scopus and Web of Science—using single keywords and combinations of them. The total number of identified articles was 636. Nevertheless, by using the inclusion and exclusion criteria, 144 articles were finally included in this work. Results display that the development of adequate instruments for heavy metal assessment may play an important function in human male fertility diagnosis and treatment. Furthermore, clinical trials could be useful to confirm the role of heavy metals in human male fertility diagnosis. Overall, further research is required to fully understand the molecular and cellular basis of the influence of environmental and occupational exposure to heavy metals on human male infertility and reproductive outcomes.