What is the Role of Computer Game Addiction in the Sleep Disturbance Risk Among Children of COVID Lock Down? A Cross-sectional Study

Objective:In this study, it was aimed to examine the risk of sleep disturbance in children and its relationship with computer game addiction during the Coronavirus disease-2019 lock down.Materials and Methods:In our cross-sectional observational study, 343 children and their mothers who applied family medicine clinics of a tertiary hospital between 1 October 2020 and 1 January 2021 were included. A structured questionnaire including the socio-demographic data of the mother and the child, and the Children’s Sleep Disturbance Scale and the Children’s Computer Game Addiction Scale were applied.Results:One-hundred sixty-five (48.1%) girls and 178 (51.9%) boys aged 8-12 years and their mothers participated in the study. The risk of sleep disturbance was observed at a rate of 74.1% (n=254) and it was strongly correlated with computer game addiction (p<0.001, r=0.787). Game addiction scores of boys (58.66±16.68) and primary school children (60.37±16.41) were higher than game addiction of girls (52.91±17.57), and of secondary school children (55.06±17.39) (p=0.023, p=0.040, respectively). Computer game addiction score (61.89±14.77) of children with sleep disturbance risk was significantly higher (p<0.001) than children without sleep disturbance risk (38.79±11.84). Among the children with a risk of sleep disturbance, the proportion of time spent on the computer compared to the pre-pandemic period (70.1%), the proportion of going late to bed-time (70.0%), and the proportion of being own computer or tablet (71.7%) were found to be higher than the proportions in children (48.3%, 58.4%, 37.1%, respectively) without sleep disturbance (p<0.001, p=0.004, p<0.001, respectively). The level of computer game addiction was significantly increased in children who spent less time with their mothers (58.68±16.97) and less time for games (58.05±18.11) compared to other children (p=0.002). In the logistic regression analysis, it was shown that the game addiction score was 1.128 times higher in children with sleep disturbance risk [Odds ratio=1.128 (1.094-1.162; p<0.001)].Conclusion:Our study showed that three of four children had a risk of sleep disorders during the pandemic period and were associated with an increased level of computer game addiction and drew attention to the importance of the time spent with the mother

Consequences of cathepsin C inactivation for membrane exposure of proteinase 3, the target antigen in autoimmune vasculitis

Membrane-bound proteinase 3 (PR3(m)) is the main target antigen of anti-neutrophil cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis, a systemic small-vessel vasculitis. Binding of ANCA to PR3(m) triggers neutrophil activation with the secretion of enzymatically active PR3 and related neutrophil serine proteases, thereby contributing to vascular damage. PR3 and related proteases are activated from pro-forms by the lysosomal cysteine protease cathepsin C (CatC) during neutrophil maturation. We hypothesized that pharmacological inhibition of CatC provides an effective measure to reduce PR3(m) and therefore has implications as a novel therapeutic approach in granulomatosis with polyangiitis. We first studied neutrophilic PR3 from 24 patients with Papillon-Lefevre syndrome (PLS), a genetic form of CatC deficiency. PLS neutrophil lysates showed a largely reduced but still detectable (0.5-4%) PR3 activity when compared with healthy control cells. Despite extremely low levels of cellular PR3, the amount of constitutive PR3(m) expressed on the surface of quiescent neutrophils and the typical bimodal membrane distribution pattern were similar to what was observed in healthy neutrophils. However, following cell activation, there was no significant increase in the total amount of PR3(m) on PLS neutrophils, whereas the total amount of PR3(m) on healthy neutrophils was significantly increased. We then explored the effect of pharmacological CatC inhibition on PR3 stability in normal neutrophils using a potent cell-permeable CatC inhibitor and a CD34(+) hematopoietic stem cell model. Human CD34(+) hematopoietic stem cells were treated with the inhibitor during neutrophil differentiation over 10 days. We observed strong reductions in PR3(m), cellular PR3 protein, and proteolytic PR3 activity, whereas neutrophil differentiation was not compromised

Therapeutic targeting of cathepsin C::from pathophysiology to treatment

Cathepsin C (CatC) is a highly conserved tetrameric lysosomal cysteine dipeptidyl aminopeptidase. The best characterized physiological function of CatC is the activation of pro-inflammatory granule-associated serine proteases. These proteases are synthesized as inactive zymogens containing an N-terminal pro-dipeptide, which maintains the zymogen in its inactive conformation and prevents premature activation, which is potentially toxic to the cell. The activation of serine protease zymogens occurs through cleavage of the N-terminal dipeptide by CatC during cell maturation in the bone marrow. In vivo data suggest that pharmacological inhibition of pro-inflammatory serine proteases would suppress or attenuate deleterious effects of inflammatory/auto-immune disorders mediated by these proteases. The pathological deficiency in CatC is associated with Papillon-Lefèvre syndrome. The patients however do not present marked immunodeficiency despite the absence of active serine proteases in immune defense cells. Hence, the transitory pharmacological blockade of CatC activity in the precursor cells of the bone marrow may represent an attractive therapeutic strategy to regulate activity of serine proteases in inflammatory and immunologic conditions. A variety of CatC inhibitors have been developed both by pharmaceutical companies and academic investigators, some of which are currently being employed and evaluated in preclinical/clinical trials

Pharmacological targeting of cathepsin C in novel therapeutic approach in granulomatosis with polyangiitis

Les protéases à serine du neutrophile (PSN), maturées par une protéase à cystéine nommée la cathepsine C (CatC), sont des acteurs majeurs dans la dégradation tissulaire et la réponse immunitaire médiées par les polynucléaires neutrophiles (PNN). La protéinase 3 (PR3), l’une des PSN, est l’auto-antigène majeur de la granulomatose avec polyangéite (GPA) qui est une vascularite systémique auto-immune. Le ciblage pharmacologique des PSN par des inhibiteurs est une approche intéressante pour le traitement de la GPA mais également pour toutes les maladies inflammatoires chroniques impliquant les PSN mais reste sans résultat jusqu’à maintenant. L’inactivation génétique de la CatC chez les patients atteints du syndrome de Papillon-Lefèvre est associée à une élimination presque totale des PSN. Au cours de ce travail de thèse, nous avons ciblé la CatC à l’aide d’un inhibiteur de type nitrile dans un modèle de cellules souches différenciées en PNN et nous avons obtenu une élimination presque complète de la PR3 intracellulaire et membranaire. Dans un deuxième temps, nous avons identifié la cathepsine S (CatS) comme la protéase activatrice majeure de la CatC dans les précurseurs neutrophiliques. Nous avons donc ciblé la CatS avec un inhibiteur de type nitrile pendant la différentiation des PNN ce qui a diminué significativement les taux de PSN. L’inhibition pharmacologique de la CatC pourrait donc éliminer l’auto- antigène de la GPA et constituer une nouvelle stratégie thérapeutique innovante pour contrôler l’auto-immunité et l’inflammation associée dans cette pathologie. Une combinaison d’inhibiteurs de CatS et de CatC pourrait s’avérer plus efficace pour éliminer la PR3 ainsi que les PSN pro-inflammatoires dans la GPA et dans d’autres pathologies inflammatoires chroniques.Neutrophil serine proteases (NSP), maturated by cathepsin C (CatC), are the major players in neutrophil-mediated tissue degradation and immune response. Proteinase 3 (PR3) is the main target antigen of anti-neutrophil cytoplasmic auto-antibodies (ANCA) in granulomatosis with polyangiitis (GPA), a systemic small-vessel vasculitis. The pharmacological targeting of NSP by proteinase inhibitors is promising approach for GPA treatment but also for all chronic inflammatory diseases involving NSP but remains unsuccessful until now. The genetic inactivation of CatC in patients with Papillon-Lefèvre syndrome is associated with almost complete elimination of NSP in blood neutrophils. In this work, we targeted CatC using a nitrile inhibitor in neutrophil generated from umbilical cord stem cells and we observed strong reductions in intracellular and membrane- bound PR3. Among the five-proCatC activating proteases, we found CatS in neutrophilic precursor cells and in mature neutrophils. Pharmacological inhibition of CatS in neutrophils generated from stem cells resulted in significant reduction of cellular NSP. The pharmacological inhibition of CatC could help eliminate the auto- antigen of GPA and constitute a novel therapeutic strategy to reduce auto-immune inflammation in this pathology. Pharmacological targeting of both CatS and CatC might help to efficient inhibition and elimination of NSP in GPA and in chronic inflammatory diseases

Does a microfluidic chip for sperm sorting have a positive add-on effect on laboratory and clinical outcomes of intracytoplasmic sperm injection cycles? A sibling oocyte study

The most recent technologies for sperm sorting involve microfluidics. However, the most important question whether their use is of any advantage in terms of laboratory and clinical IVF/ICSI outcomes still remains controversy. In this study, we aimed to investigate whether a microfluidic sperm sorting device (Fertile Plus (R)) has a positive add-on effect on laboratory and clinical outcomes. Sibling oocytes of 81 patients were assigned to two sperm sorting groups including swim up and Fertile Plus (R). All embryos were cultured until day 5/6. Fertilisation, embryo quality and blastocyst development were assessed as primary outcomes among 81 patients; clinical pregnancy, implantation and live birth rates were analysed as secondary outcomes as a subgroup analysis due to transfer cancellations. No statistically significant differences were found between groups in terms of all outcomes analysed in laboratory and clinical terms (p > .05 for all). The results of this study suggest that sorting spermatozoa through Fertile chip does not improve laboratory outcomes significantly and does not seem to have a positive contribution to clinical outcomes

Neutrophil Elastase-Activatable Prodrugs Based on an Alkoxyamine Platform to Deliver Alkyl Radicals Cytotoxic to Tumor Cells

&lt;p&gt;Current chemotherapies suffer low specificity and sometimes drug resistance. Neutrophil elastase activity in cancer is associated with poor prognosis and metastasis settlement. More generally, tumors harbor various and persistent protease activities unseen in healthy tissues. In an attempt to be more specific, we designed prodrugs that are activatable by neutrophil elastase. Upon activation, these alkoxyamine-based drugs release cytotoxic alkyl radicals that act randomly to prevent drug resistance. As a result, U87 glioblastoma cells displayed high level caspase 3/7 activation during the first hour of exposure in the presence of human neutrophil elastase and the prodrug in vitro. The apoptosis process and cell death occurred between 24 and 48 h after exposure with a half lethal concentration of 150 μM. These prodrugs are versatile and easy to synthetize and can be adapted to many enzymes.&lt;/p&gt

The effect of antioxidants on angiogenesis in uterine transplantation

The aim of this study was to investigate the effect of antioxidants on angiogenesis in uterine transplantation. We used 24 female rats equally divided into four groups: Group 1 had the uterus stored in HTK (Histidine–Tryptophan–Ketoglutarate) solution at 4 °C cold storage for 4 h. Group 2 had the uterine tissue stored in HTK solution combined with acetyl L-carnitine (10−8 M) for 4 h at +4 °C. The same procedures with Group 1 and 2 were repeated for 24 h for Groups 3 and 4, respectively. Histological investigation and immunohistochemical analysis were performed. Histological findings showed that storing donor uterus in HTK solution at +4° C for 24 h results in histological alteration in uterus. We also found that immunoreactivity of VEGFR-2 in all layers of rat uterus in Group 2 was lower than that in Group 1, and the expression of the uterus in Group 4 was lower than that in Group 3. We concluded that antioxidant acetyl L-carnitine, which was added to the organ preservation solution HTK, had prevented the formation of free radicals, and thus protected the uterus that was stored in short and long cold storage periods.Impact statement What is already known on this subject? Ischemia–reperfusion is a complex pathophysiological process involve in hypoxia and/or reoxygenation, ionic imbalance-induced oedema and acidosis, oxidative stress, mitochondrial uncoupling, coagulation and endothelium activation. The composition of preservation solutions must be adapted to the severity of ischaemia–reperfusion injuries to reduce cellular damage and inflammation and preserve graft functionality and integrity, thus improving short-term and long-term graft outcome. Clinicians use three types of composition of solution for static cold preservation: intracellular, intermediate and extracellular. HTK will be used frequently, especially with the consideration of lower price and more easy handling aspects. L-carnitine acts as an antioxidant, protects against free radicals and prevents mitochondrial damage. VEGFR-2 plays an important role in angiogenesis, chemotaxis, proliferation and migration of endothelial cells. What this study adds? In this study, we investigate the effect of antioxidants on angiogenesis in uterus transplantation. Our results showed that antioxidant acetyl L-carnitine that added to the organ preservation solution HTK, has prevented the formation of free radicals, thus protect the uterus that was stored in short and long cold storage periods. What the implications are for future studies? Therefore, we will contribute to the literature with the results of this study

J Med Chem

Current chemotherapies suffer low specificity and sometimes drug resistance. Neutrophil elastase activity in cancer is associated with poor prognosis and metastasis settlement. More generally, tumors harbor various and persistent protease activities unseen in healthy tissues. In an attempt to be more specific, we designed prodrugs that are activatable by neutrophil elastase. Upon activation, these alkoxyamine-based drugs release cytotoxic alkyl radicals that act randomly to prevent drug resistance. As a result, U87 glioblastoma cells displayed high level caspase 3/7 activation during the first hour of exposure in the presence of human neutrophil elastase and the prodrug in vitro. The apoptosis process and cell death occurred between 24 and 48 h after exposure with a half lethal concentration of 150 μM. These prodrugs are versatile and easy to synthetize and can be adapted to many enzymes