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Severe forms of chronic kidney disease can lead to a critical, end-stage condition, requiring renal replacement therapy, which may involve a form of dialysis or renal transplantation. Identification and characterization of novel markers and/or targets of therapy that could be applied in these critically ill patients remains the focus of the current research in the field of critical care medicine and has been the objective of our studies for some years past. To this end, we used models of renal vascular disease, Ang II, L-NAME or mice overexpressing renin, treated with AT1 antagonists at different stages of progression, to create cohorts of animals during progression, reversal or escape from therapy. Transcriptomic analysis and comparisons were performed and genes were selected according to the following criteria: a) not previously described in the kidney, b) highly upregulated during progression and returning to the normal levels during reversal, and c) producing proteins that are either circulating or membrane receptors.

Background: Isotretinoin is the drug of choice for severe acne. We sought to examine the potential link between isotretinoin and insulin resistance. Methods: We conducted a systematic review and meta-analysis in accordance with the PRISMA statement. A comprehensive search of the PubMed/MEDLINE, SCOPUS, and Cochrane databases was performed until 12 January 2022 utilizing the PICO (Patient, Intervention, Comparison, Outcome) tool. Fifteen English-language studies focusing on isotretinoin-treated acne patients were included. Serum levels of insulin, glucose, and adiponectin were evaluated before and after treatment, and insulin sensitivity was assessed using the HOMA–IR. A meta-analysis was conducted using RevMan 5.4.1 software, and a quality assessment was undertaken using the ROBINS-I tool. Results: The meta-analysis unveiled a statistically significant rise in the post-treatment levels of adiponectin, an anti-inflammatory agent, which inhibits liver glucose production while enhancing insulin sensitivity (SMD = 0.86; 95% confidence interval (95% CI) = 0.48–1.25, p-value < 0.0001; I2 = 58%). Our subgroup analysis based on study type yielded consistent findings. However, no statistically significant outcomes were observed for insulin, glucose levels, and the HOMA-IR. Conclusions: There is not a clear association between isotretinoin and insulin resistance, but it appears to enhance the serum levels of adiponectin, which participates in glucose metabolism.

Abstract Background Without a viable cure, chronic kidney disease is a global health concern. Inflammatory damage in and around the renal tubules dictates disease severity and is contributed to by multiple cell types. Activated in response to danger associated molecular patterns (DAMPs) including ATP, the NOD-like receptor protein-3 (NLRP3) inflammasome is integral to this inflammation. In vivo, we have previously observed that increased expression of Connexin 43 (Cx43) is linked to inflammation in chronic kidney disease (CKD) whilst in vitro studies in human proximal tubule cells highlight a role for aberrant Cx43 hemichannel mediated ATP release in tubule injury. A role for Cx43 hemichannels in priming and activation of the NLRP3 inflammasome in tubule epithelial cells remains to be determined. Methods Using the Nephroseq database, analysis of unpublished transcriptomic data, examined gene expression and correlation in human CKD. The unilateral ureteral obstruction (UUO) mouse model was combined with genetic (tubule-specific Cx43 knockout) and specific pharmacological blockade of Cx43 (Peptide5), to explore a role for Cx43-hemichannels in tubule damage. Human primary tubule epithelial cells were used as an in vitro model of CKD. Results Increased Cx43 and NLRP3 expression correlates with declining glomerular filtration rate and increased proteinuria in biopsies isolated from patients with CKD. Connexin 43-tubule deletion prior to UUO protected against tubular injury, increased expression of proinflammatory molecules, and significantly reduced NLRP3 expression and downstream signalling mediators. Accompanied by a reduction in F4/80 macrophages and fibroblast specific protein (FSP1+) fibroblasts, Cx43 specific hemichannel blocker Peptide5 conferred similar protection in UUO mice. In vitro, Peptide5 determined that increased Cx43-hemichannel activity primes and activates the NLRP3 inflammasome via ATP-P2X7 receptor signalling culminating in increased secretion of chemokines and cytokines, each of which are elevated in individuals with CKD. Inhibition of NLRP3 and caspase 1 similarly decreased markers of tubular injury, whilst preventing the perpetual increase in Cx43-hemichannel activity. Conclusion Aberrant Cx43-hemichannel activity in kidney tubule cells contributes to tubule inflammation via activation of the NLRP3 inflammasome and downstream paracrine mediated cell signalling. Use of hemichannel blockers in targeting Cx43-hemichannels is an attractive future therapeutic target to slow or prevent disease progression in CKD. Video Abstract

Background: Three years after the outbreak of the COVID-19 pandemic, psychological distress among college students remains increased. This study assesses stress, anxiety, and depression levels among students of the Aristotle University of Thessaloniki by the end of the third year of the pandemic (November 2022), revealing demographic characteristics and probable stressors. Methods: A questionnaire was distributed in November 2022 via the academic students’ e-mails. The evaluation was performed with the DASS21 survey tool. The correlation analysis and the effect size calculation were performed with the t-test. Results: The majority of participants were undergraduates, on their first or second academic year, female students (67%), age of 18 to 21, unmarried or single (91%), and vaccinated against COVID-19 infection (83.4%). Severely increased levels of stress, anxiety, and depression (21.3%, 23.3%, and 25.1%, respectively) were measured. The normal and mild levels of stress, anxiety, and depression were 64.0%, 66.5%, and 57.2%, respectively. Female and younger students were at a higher risk of extremely severe stress, anxiety and depression prevalence (ORs up to 2.07, p-Values < 0.00001). Participants who were receiving psychological or psychiatric treatment exhibited severe stress, anxiety, and depression levels (ORs above 2.9, p-Values < 0.00001). Conclusions: Despite the undeniable withdrawal of the COVID-19 pandemic, the community of the Aristotle University of Thessaloniki presents high stress, anxiety, and depression levels, similar to those reported during the first year of the pandemic (November 2020). Stressors and risk factors were according to the reported literature and previous studies on Greek students. Academic psychological support offices should consider the students’ “profile” in order to evaluate properly the potential risk for emotional and psychological distress. Evidence suggest that new technology (virtual reality, tele-psychiatry or tele-support apps and sessions) should also be implemented in universities.

Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most prevalent malignant entity with a significant fatality rate. The International Agency for Research on Cancer reported in 2018 that there are approximately 350,000 newly diagnosed instances of oral cancer per year, amounting to a cumulative incidence of 4.0 per 100,000 people. The aim of this review was to investigate the biomarkers associated with immunotherapy in head and neck cancer, and in particular oral cancer, as well as their respective immunotherapeutic agents. An extensive review of the literature was carried through. Relevant articles were searched in Medline Pubmed, Web of Science and Google scholar. The inclusion criterion was that the article should be written in English, whereas the exclusion criterion was the opposite. The current standard of care (SOC) for disease that recurs locally and/or metastatic disease was, until recently, platinum-based chemotherapy plus cetuximab. A potential treatment option is the monoclonal antibody cetuximab, which extends median progression-free survival (PFS) as it targets the epidermal growth factor (EGFR). Last decade, research has shown that there are two mechanisms of tumor's microenvironment (the immune escape and the T-cell exhaustion) which are related to total survival from cancer. Consequently, scientists focused on immunotherapy, a new therapeutic approach that activates a patient's immune system to fight tumor cells. Immune checkpoint inhibitors (ICIs) are a category of immunotherapies that are extremely effective at reactivating the immune system's defence against cancer. Oral cancer immunotherapy could target two significant immune checkpoints, cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) and programmed death-1 (PD-1).

Recurrent miscarriages affect up to 5% of couples. CD3+ (T-lymphocytes), CD4+ (helper T-lymphocytes), CD8+ (cytotoxic T-lymphocytes), and CD20+ (B-lymphocytes) cells may participate in the pathophysiology of recurrent pregnancy loss (RPL). The aim of this study was to investigate the complicity of these molecules in RPL. The experimental specimens were obtained from 20 females who underwent miscarriages in the first gestational trimester, while the control group’s specimens consisted of 20 females who proceeded with voluntary pregnancy termination during the same period. Tissue samples were taken from the decidua basalis, decidua parietalis, and trophoblast (placental chorionic villi) and were studied using immunohistochemical methods. Monoclonal antibodies were used against CD3, CD4, CD8, and CD20 cells. The lymphocyte levels in the decidua parietalis displayed profound disparities among the two groups. The decidua basalis and trophoblast exhibited almost the same disparities regarding positive CD cells. The comparison of CD4+ and CD8+ cells in the endometrial tissue revealed a significant difference between the two groups of study. The analysis uncovered a strong relationship between RPL and the presence of CD3+, CD4+, CD8+, and CD20+ cells in the decidua parietalis tissue. The number of positive T cells was decreased in the decidual basalis and chorionic villi, proving that their absence significantly disrupts the balance of the immunological environment.

Background: SARS–CoV–2 virus has undergone several mutations on its genome, since the onset of the pandemic. Multiple variants of concern (VOC) have emerged including Alpha, Beta, Gamma, and Delta with the more recent one being the Omicron (B.1.1.529). Specific rapid antigen tests (RADs) have been used for the detection of SARS–CoV–2. However, since the emergence of new VOCs, the performance characteristics of these RADs needs to be re–evaluated. Objectives: The main purposes of this clinical study were to determine the diagnostic sensitivity and specificity of the BOSON Rapid Antigen Test compared to the gold standard real time RT–PCR and to determine the ability of the RAD to accurately depict different VOC. Additionally, the cross reactivity to other viruses and pathogen, as well as, the possible interference of non Covid–19 hospitalized patients for various causes, were investigated. Results: A total of 623 individuals (symptomatic) were tested. The sensitivity, specificity and accuracy of the BOSON RAD was 95.27%, 100% and 98.45% (n = 448), meeting the WHO recommended standards. Additionally, the Delta (83.33%, Ct

Urban tunnelling can be highly challenging, especially in areas where limited ground settlements and environmental disturbance is required. Mechanised tunnelling is usually preferred in such ground environments, specifically Slurry or EPBM (Earth Pressure Balance Machine), depending on the ground properties. Being able to predict the anticipated tunnel behaviour at the preliminary stages of the project can be very beneficial in optimising not only the design, but also control the construction activities and completion times. In practice, the short-term excavation response and support performance focus primarily on design, since most site characterisation inputs are focused on material properties gained from short-term testing. Although the analysis of tunnelling is a three-dimensional (3D) problem, conventional approaches and design methods employed during the design and construction of underground openings are often based on the ground’s static response in two dimensions (2D). In this paper, an initial 2D model is generated in PLAXIS2D and RS2 (Rocscience) to test advanced constitutive models and compare transverse settlement profiles; subsequently, a complete 3D FEM numerical model in RS3 (Rocscience) was used to simulate an Earth Pressure Balance (EPB) excavation sequence. The 3D numerical model simulates the relevant EPB components such as face pressure, TBM shield, backfilling of the tail void (time-dependent hardening of the grout) and gradual segmental lining erections in the longitudinal direction. The presented numerical approach can be used by tunnel designers and engineers to predict the soil response in EPBM tunnelling.

Abstract Background Tubulointerstitial fibrosis represents the key underlying pathology of Chronic Kidney Disease (CKD), yet treatment options remain limited. In this study, we investigated the role of connexin43 (Cx43) hemichannel-mediated adenosine triphosphate (ATP) release in purinergic-mediated disassembly of adherens and tight junction complexes in early tubular injury. Methods Human primary proximal tubule epithelial cells (hPTECs) and clonal tubular epithelial cells (HK2) were treated with Transforming Growth Factor Beta1 (TGF-β1) ± apyrase, or ATPγS for 48 h. For inhibitor studies, cells were co-incubated with Cx43 mimetic Peptide 5, or purinergic receptor antagonists Suramin, A438079 or A804598. Immunoblotting, single-cell force spectroscopy and trans-epithelial electrical resistance assessed protein expression, cell-cell adhesion and paracellular permeability. Carboxyfluorescein uptake and biosensing measured hemichannel activity and real-time ATP release, whilst a heterozygous Cx43+/− mouse model with unilateral ureteral obstruction (UUO) assessed the role of Cx43 in vivo. Results Immunohistochemistry of biopsy material from patients with diabetic nephropathy confirmed increased expression of purinergic receptor P2X7. TGF-β1 increased Cx43 mediated hemichannel activity and ATP release in hPTECs and HK2 cells. The cytokine reduced maximum unbinding forces and reduced cell-cell adhesion, which translated to increased paracellular permeability. Changes were reversed when cells were co-incubated with either Peptide 5 or P2-purinoceptor inhibitors. Cx43+/− mice did not exhibit protein changes associated with early tubular injury in a UUO model of fibrosis. Conclusion Data suggest that Cx43 mediated ATP release represents an initial trigger in early tubular injury via its actions on the adherens and tight junction complex. Since Cx43 is highly expressed in nephropathy, it represents a novel target for intervention of tubulointerstitial fibrosis in CKD. Video Abstract Graphical abstract In proximal tubular epithelial cells (PTECs), tight junction proteins, including zona occuludens-1 (ZO-1), contribute to epithelial integrity, whilst the adherens junction protein epithelial (E)-cadherin (ECAD) maintains cell-cell coupling, facilitating connexin 43 (Cx43) gap junction-mediated intercellular communication (GJIC) and the direct transfer of small molecules and ions between cells. In disease, such as diabetic nephropathy, the pro-fibrotic cytokine transforming growth factor beta1 (TGF-β1) binds to its receptor and recruits SMAD2/3 signalling ahead of changes in gene transcription and up-regulation of Cx43-mediated hemichannels (HC). Uncoupled hemichannels permit the release of adenosine triphosphate (ATP) in to the extracellular space (↑[ATP]e), where ATP binds to the P2X7 purinoreceptor and activates the nucleotide-binding domain and leucine-rich repeat containing (NLR) protein-3 (NLRP3) inflammasome. Inflammation results in epithelial-to-mesenchymal transition (EMT), fibrosis and tubular injury. A major consequence is further loss of ECAD and reduced stickiness between cells, which can be functionally measured as a decrease in the maximum unbinding force needed to uncouple two adherent cells (Fmax). Loss of ECAD feeds forward to further lessen cell-cell coupling exacerbating the switch from GJIC to HC-mediated release of ATP. Reduction in ZO-1 impedes tight junction effectiveness and decreases trans-epithelial resistance (↓TER), resulting in increased paracellular permeability.

Background: COVID-19 has affected everyday clinical practice, having an impact on the quality of healthcare provided, even in eye clinic departments. The aim of this study is to evaluate the consequences of this worldwide pandemic on cataract surgery in a Greek tertiary university hospital. Methods: A total of 805 patients were included in this study. The number of cataract surgeries (CS), the type, the unilateral or bilateral appearance as well as the stage of cataract were recorded for the months between January and June 2019 (pre-COVID period) and compared with the same period in 2021 (during the pandemic outbreak) in the Department of Ophthalmology of Thessaloniki General Hospital G. Papanikolaou. Results: A significant reduction in the number of CS as well as a significant increase in advanced and/or bilateral cataracts in 2021 compared to the pre-COVID period were observed. Conclusions: The COVID-19 pandemic has affected equally the value of ophthalmic interventions as well as the patients’ quality of life, being a powerful reminder of the significant physical and psychological benefits of CS, especially for older adults and patients with comorbidities.

Chronic kidney disease is an incurable to date pathology with a continuously growing incidence that contributes to the increase of the number of deaths worldwide. With currently no efficient prognostic or therapeutic options being available, the only possibility for treatment of end-stage renal disease is renal replacement therapy through dialysis or transplantation. Understanding the molecular mechanisms participating in the progression of renal diseases and uncovering the pathways implicated will permit the identification of novel and more efficient targets of therapy. Connexin43 was recently identified as a novel player in the development of chronic kidney disease. It was found de novo expressed and/or differentially localized in various renal cell populations during progression of renal disease, indicating an abnormal connexin signaling, both in patients and animal models. Subsequent in vivo studies demonstrated that connexin43 is involved in mediating inflammatory and fibrotic processes contributing to renal damage. Genetic, pharmaco-genetic or peptide-based inhibition of connexin43 in animal models and cell culture systems was successful in preventing the progression of the pathology and preserving the cell phenotypes. This review will summarize the recent advances on connexin43 in the field of kidney diseases and discuss the potential of future connexin43-based therapies against chronic kidney disease.

Data security plays a crucial role in healthcare monitoring systems, since critical patient information is transacted over the Internet, especially through wireless devices, wireless routes such as optical wireless channels, or optical transport networks related to optical fibers. Many hospitals are acquiring their own metro dark fiber networks for collaborating with other institutes as a way to maximize their capacity to meet patient needs, as sharing scarce and expensive assets, such as scanners, allows them to optimize their efficiency. The primary goal of this article is to develop of an attack detection model suitable for healthcare monitoring systems that uses internet protocol (IP) virtual private networks (VPNs) over optical transport networks. To this end, this article presents the vulnerabilities in healthcare monitoring system networks, which employ VPNs over optical transport layer architecture. Furthermore, a multilayer network architecture for closer integration of the IP and optical layers is proposed, and an application for detecting DoS attacks is introduced. The proposed application is a lightweight implementation that could be applied and installed into various remote healthcare control devices with limited processing and memory resources. Finally, an analytical and focused approach correlated to attack detection is proposed, which can also serve as a tutorial oriented towards even nonprofessionals for practical and learning purposes.

The main hallmark of chronic kidney disease (CKD) is excessive inflammation leading to interstitial tissue fibrosis. It has been recently reported that NOV/CCN3 could be involved in kidney damage but its role in the progression of nephropathies is poorly known. NOV/CCN3 is a secreted multifunctional protein belonging to the CCN family involved in different physiological and pathological processes such as angiogenesis, inflammation and cancers. The purpose of our study was to determine the role of NOV/CCN3 in renal inflammation and fibrosis related to primitive tubulointerstitial injury. After unilateral ureteral obstruction (UUO), renal histology and real-time PCR were performed in NOV/CCN3-/- and wild type mice. NOV/CCN3 mRNA expression was increased in the obstructed kidneys in the early stages of the obstructive nephropathy. Interestingly, plasmatic levels of NOV/CCN3 were strongly induced after 7 days of UUO and the injection of recombinant NOV/CCN3 protein in healthy mice significantly increased CCL2 mRNA levels. Furthermore, after 7 days of UUO NOV/CCN3-/- mice displayed reduced proinflammatory cytokines and adhesion markers expression leading to restricted accumulation of interstitial monocytes, in comparison with their wild type littermates. Consequently, in NOV/CCN3-/- mice interstitial renal fibrosis was blunted after 15 days of UUO. In agreement with our experimental data, NOV/CCN3 expression was highly increased in biopsies of patients with tubulointerstitial nephritis. Thus, the inhibition of NOV/CCN3 may represent a novel target for the progression of renal diseases.

BACKGROUND: Several studies have shown that activation of the renin-angiotensin system may lead to hypertension, a major risk factor for the development of chronic kidney disease (CKD). The existing hypertension-induced CDK mouse models are quite fast and consequently away from the human pathology. Thus, there is an urgent need for a mouse model that can be used to delineate the pathogenic process leading to progressive renal disease. The objective of this study was dual: to investigate whether mice overexpressing renin could mimic the kinetics and the physiopathological characteristics of hypertension-induced renal disease and to identify cellular and/or molecular events characterizing the different steps of the progression of CKD. METHODOLOGY/PRINCIPAL FINDINGS: We used a novel transgenic strain, the RenTg mice harboring a genetically clamped renin transgene. At 3 months, heterozygous mice are hypertensive and slightly albuminuric. The expression of adhesion markers such as vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 are increased in the renal vasculature indicating initiation of endothelial dysfunction. At 5 months, perivascular and periglomerular infiltrations of macrophages are observed. These early renal vascular events are followed at 8 months by leukocyte invasion, decreased expression of nephrin, increased expression of KIM-1, a typical protein of tubular cell stress, and of several pro-fibrotic agents of the TGFβ family. At 12 months, mice display characteristic structural alterations of hypertensive renal disease such as glomerular ischemia, glomerulo- and nephroangio-sclerosis, mesangial expansion and tubular dilation. CONCLUSIONS/SIGNIFICANCE: The RenTg strain develops CKD progressively. In this model, endothelial dysfunction is an early event preceding the structural and fibrotic alterations which ultimately lead to the development of CKD. This model can provide new insights into the mechanisms of chronic renal failure and help to identify new targets for arresting and/or reversing the development of the disease.

[Figure: see text]. [ABSTRACT FROM AUTHOR]

A variety of tumors are sensitive to cell death by ferroptosis, a type of regulated necrosis characterized by iron accumulation, failure of cellular antioxidant defence systems, unrestrained accumulation of lipid peroxides and membrane rupture. Efficient removal of apoptotic and necrotic cells via tumor-associated phagocytes results in local immune suppression. Phagocytosis inhibition reduces tumor growth and metastasis. Here I hypothesize that accumulating iron nanoparticles, hemin, cytochrome c and preformed lipid peroxides in tumors combined with phagocytosis inhibition may induce the generation of oxidizing species to high levels within tumor tissue, thus causing increased oxidative damage and tumor cell death. I propose that C3d(g), the final degradation product of the third component of complement (C3) can be utilized to limit phagocytosis and stimulate anti-tumor responses. Furthermore, the plasticity and the multiple subtypes of tumor-associated myeloid cells mainly represented by tumor-associated macrophages and myeloid-derived suppressor cells hinder inhibition by targeted approaches or monotherapies. Here I provide insights into a novel, integrative therapeutic model that aims at both killing tumor cells and counteracting tumor-associated myeloid cells via the induction of excessive oxidative conditions in tumors. In conclusion, accumulating iron and lipid peroxides in both tumor- and myeloid cells and extracellularly in the tumor microenvironment combined with limiting phagocytosis due to C3d(g) may synergistically increase the oxidized burden and induce tumor cytotoxicity. Future directions include detailed suggestions on criteria for intermittent administration of the proposed therapeutics so that newly recruited myeloid cells could differentiate/be activated to functional anti-tumor phenotypes in a more antigenic tumor microenvironment. Furthermore, combination with other therapeutic forms might be promising. Optimizing the delivery of ION-containing liposomes at tumor sites is also important, thus enhancing their efficiency and safety profiles. [ABSTRACT FROM AUTHOR]

The article examines the apocalyptic section of the East Syrian monk Joseph Hazzaya's treatise entitled "On Divine Providence." It illustrates how the treatise reflects social developments during the time of Joseph in Mesopotamia, particularly the changing situation of the Christians in Northern Mesopotamia. It cites the consequences of the peculiarity of Joseph's apocalyptic disgression for his perception of contemporary historical developments that he connected with the preambles of apocalypse.

The article discusses the study that evaluates the effect of aliskiren on regression of renal fibrosis with the use a heterozygous transgenic mouse model expressing an artificial mouse renin gene (RenTg) in the liver at constantly high levels, wherein the effectivity of aliskiren has been proven. The study found significant amelioration of renal interstitial fibrosis and inflammation in aliskiren-treated mice with the decrease in proinflammatory and profibrotic markers.

The article examines the possible influences of Syriac Christian bishop Theodore of Mopsuestia on the pneumatology of Syriac theologian and bishop Isaac of Nineveh. Emphasis is given to Isaac's writings on the Holy Spirit's salvific activity as it pertains to humans and Biblical history. The relationship between Isaac and Theodore's trinitarian theology and their understandings of pneumatology is explored. The ways in which both theologians understood the connection between the Holy Spirit's activities and the Christian understanding of the afterlife are then detailed.