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Despite similar infection rates, COVID-19 has resulted in more deaths in men than women. To understand the underlying mechanisms behind this sex-biased difference in disease severity, we infected K18-human angiotensin converting enzyme 2 (ACE2) mice of both sexes with SARS-CoV-2. Our study revealed a unique protein expression profile in the lung microenvironment of female mice. As a result, they were less vulnerable to severe infection, with higher ACE2 expression and a higher estrogen receptor α (ERα)/androgen receptor (AR) ratio that led to increased antiviral factor levels. In male mice, inhaling recombinant ACE2 neutralized the virus and maintained the ERα/AR ratio, thereby protecting the lungs. Our findings suggest that inhaling recombinant ACE2 could serve as a decoy receptor against SARS-CoV-2 and protect male mice by offsetting ERα-associated protective mechanisms. Additionally, our study supports the potential effectiveness of recombinant ACE2 therapy in human lung organoids infected with the Delta variant., Competing Interests: GW is an employee, JP a shareholder, and AS an advisor of Apeiron Biologics AG developing soluble ACE2 as a therapy for COVID-19. The other authors declare no competing interests., (© 2023 The Authors.)

BACKGROUND Positron emission tomography/computed tomography (PET/CT) has become one of the most prominent modalities worldwide for the diagnosis and surveillance of malignancies. Current clinical imaging guidelines report adverse reactions following PET/CT, especially due to contrast-induced toxicities, such as contrast-induced nephropathy and other rare reactions attributed to a hypersensitivity immune response, such as bronchospasm. Other rare lung toxicities were reported in a few case reports. Herein, we report repeated episodes of alveolar hemorrhage, a novel adverse response to PET/CT, occurring on 2 separate occasions 5 months apart. CASE REPORT A 57 year-old female patient with breast carcinoma managed by mastectomy, adjuvant chemotherapy, irradiation, and hormonal therapy presented with massive alveolar hemorrhage following PET/CT performed for surveillance 13 years after completion of chemotherapy and irradiation. An additional episode of massive alveolar hemorrhage occurred 5 months later following PET/CT, with respiratory failure requiring mechanical ventilation. Fluorine-18 fluorodeoxyglucose ([¹⁸F] FDG) and iohexol were used for imaging on both occasions. Common causes of alveolar hemorrhage, including malignancy, were excluded. CONCLUSIONS The repeated episodes immediately following PET/CT and the earlier and more intense respiratory failure following the second event raise the possibility of an immune-mediated alveolar hemorrhage in response to either the administration of iodinated radiocontrast agent or to [¹⁸F] FDG.

Introduction: In recent years, the status of Internal Medicine has been constantly wearing down. There has been a dramatic decrease in the number of internal medicine students and residents planning to pursue careers in internal medicine. This is mainly due to a higher workload, as well as physical and professional exhaustion leading to work dissatisfaction and provision of suboptimal patient care. Therefore, an increased tendency towards selecting a career in internal medicine sub-specialties has been noted. In this paper, we will present an open and sincere talk with three young internal medicine specialists, who willingly decided to keep working in internal medicine departments despite the challenging work environment. We will discuss the burnout associated with poor work-life/home balance and disruptive work environment and suggest measurements that may enhance the educational and professional experience and career satisfaction and increase the well-being of internal medicine specialists in the future. We aim to promote awareness to the importance of maintaining high-quality senior physicians working in Internal Medicine departments.

The major variant of concerns (VOCs) have shared mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins, mostly on the S1 unit and resulted in higher transmissibility rate and affect viral virulence and clinical outcome. The spike protein mutations and other non-structural protein mutations in the VOCs may lead to escape approved vaccinations in certain extend. We will discuss these VOC mutations and discuss the need for combination therapeutic strategies targeting viral cycle and immune host responses., (© 2021. The Author(s).)

Background: Diabetes mellitus is a systemic disorder associated with inflammation and oxidative stress which may target many organs such as the kidney, retina, and the vascular system. The pathophysiology, mechanisms, and consequences of diabetes on these organs have been studied widely. However, no work has been done on the concept of the lung as a target organ for diabetes and its implications for lung diseases., Aim: In this review, we aimed to investigate the effects of diabetes and hypoglycemic agent on lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, pulmonary hypertension, and lung cancer. We also reviewed the potential mechanisms by which these effects may affect lung disease patients., Results: Our results suggest that diabetes can affect the severity and clinical course of several lung diseases., Conclusions: Although the diabetes-lung association is epidemiologically and clinically well-established, especially in asthma, the underlying mechanism and pathophysiology are not been fully understood. Several mechanisms have been suggested, mainly associated with the pro-inflammatory and proliferative properties of diabetes, but also in relation to micro- and macrovascular effects of diabetes on the pulmonary vasculature. Also, hypoglycemic drugs may influence lung diseases in different ways. For example, metformin was considered a potential therapeutic agent in lung diseases, while insulin was shown to exacerbate lung diseases; this suggests that their effects extend beyond their hypoglycemic properties.

Objective: The atherosclerotic lesion is characterized by lipid peroxide accumulation. Paraoxonase 1 (PON1) reduces atherosclerotic lesion oxidative stress, whereas urokinase-type plasminogen activator (uPA) increases oxidative stress in atherosclerotic lesions and contributes to the progression and complications of atherosclerosis. We hypothesized that uPA may promote oxidative stress in the arterial wall via modulation of PON1 activity. Because the liver is the main site for PON1 production, in the present study, we tested whether uPA influences PON1 expression in hepatocytes., Methods and Results: HuH7 hepatocytes were incubated in culture with increasing concentrations of uPA. uPA decreased PON1 gene expression and activity in a dose-dependent manner and accordingly suppressed PON1 secretion from hepatocytes. This effect required uPA/uPA receptor interaction. uPA downregulated PON1 gene expression via inactivation of peroxisome proliferator-activated receptor-γ (PPARγ) activity, and this effect was dependent on uPA-mediated mitogen-activated protein kinase kinase activation. Mechanistic studies showed that uPA enhanced mitogen-activated protein kinase kinase-PPARγ interaction, resulting in PPARγ nuclear export to the cytosol., Conclusions: This study provides the first evidence that uPA interferes with PPARγ transcriptional activity in hepatocytes, resulting in downregulation of PON1 expression and its secretion to the medium. This may explain, at least in part, the prooxidative effect of uPA in the vascular wall.

Background: The aim of this investigation was to assess the effect of prior statin use on the 30-day in-hospital mortality among bacteraemic patients and to determine the impact of long-term versus short-term statin use on the mortality of bacteraemic patients., Patients and Methods: A retrospective study of 342 bacteraemic patients who presented to the emergency department (ED) within a period of 7 years was undertaken. Twenty-three patients did not meet the inclusion criteria. The remaining 319 patients were divided into three groups according to statin use and duration of therapy prior to the bacteraemic episode: group 1 (n = 123) had long-term statin use ≥ 12 weeks, group 2 (n = 35) had short-term statin use < 12 weeks, and group 3 (n = 161) had no statin use., Results: The overall 30-day in-hospital all-cause mortality of patients with statins was lower than patients without statin therapy (13 vs. 24%, p = 0.001). The mortality rate in group 1 was lower than in group 2 (11 vs. 17%, p = 0.04). After adjusting for confounding variables, the results of a multiple Cox regression analysis revealed that the absence of statin use (hazard ratio [HR] = 2.98; 95% confidence interval [CI] 1.59-5.56, p = 0.001) was associated with increased 30-day in-hospital all-cause mortality in bacteraemic patients., Conclusions: Statins reduce the 30-day in-hospital all-cause mortality of bacteraemic patients. Long-term statin use prior to the bacteraemia improves the survival of bacteraemic patients more than short-term statin use.

Background: Diabetes mellitus and obesity are important components of metabolic syndrome (MetS) which are associated with infections. MetS is frequent in nonalcoholic fatty liver disease (NAFLD)., Aims: The objective of this study was to examine whether patients with NAFLD are at higher risk of recurrent bacterial infections (RBIs)., Methods: Two-hundred and forty-seven from 296 hospitalized NAFLD patients were assessed over a three-year period for the occurrence of RBIs and were compared with 100 age and gender-matched patients without NAFLD, who were hospitalized over the same period because of a bacterial infection. An RBI was defined as: ≥2 episodes of bacterial infections per year for a period of three consecutive years. NAFLD was diagnosed by ultrasonography. Biomarkers of inflammation, the level of oxidative stress, insulin resistance, and serum vitamin D levels were measured., Results: NAFLD patients had significantly more RBIs than the patients without NAFLD (22% vs. 8%; P < 0.001). Univariate analysis showed that age, BMI, male waist circumference, serum 25(OH)D, triglycerides, serum malondialdehyde, and paraoxonase-1 are associated with RBIs in NAFLD patients. Multivariate analysis showed that NAFLD (odds ratio (OR) = 3.0, 95% confidence interval (CI) = 2.6-4.2, P < 0.001), serum 25(OH)D level <20 ng/mL (OR = 2.6; 95% CI 2.4-3.1, P = 0.01), obesity (BMI >30 kg/m(2) (OR = 2.2, 95% CI 1.8-2.9, P = 0.02) were associated with RBIs, irrespective of MetS., Conclusions: NAFLD is associated with increased risk of RBIs irrespective of MetS. Vitamin D insufficiency is frequent in NAFLD and is associated with increased risk of RBIs.

Comamonas testosteroni has rarely been implicated as a human pathogen. In general, the outcome of C. testosteroni infections is favorable. We report a case of fatal bacteremia caused by C. testosteroni in a 64-year-old woman on hemodialysis., (© 2011 The Authors. Hemodialysis International © 2011 International Society for Hemodialysis.)

Background: Helicobacter pylori (H. pylori) is a major cause of chronic gastritis. Statins have several pleotropic effects and their mechanisms of action could be related to anti-inflammatory, antioxidants, and immunomodulatory effects., Aim: To determine whether statin therapy affects the severity of chronic gastritis., Materials and Methods: In a retrospective study, we evaluated 516 patients who underwent upper endoscopy. One-hundred and ninety-eight patients had chronic gastritis, The 198 patients with chronic gastritis were divided into two groups: group 1 comprised patients with a history of statin therapy and group 2 comprised patients with no history of statin therapy. Both groups were compared for age, gender, body mass index (BMI), underlying diseases, drug therapy, alcohol consumption, smoking and the serum levels of C-reactive protein (CRP). The presence of H. pylori was determined by gastric biopsy and rapid urease test. The grade and severity of gastritis were assessed using the updated Sydney classification system in two gastric biopsy specimens that were taken from each participant in each group., Results: Of the 198 patients with chronic gastritis, 49% of the patients had mild gastritis and 51% had moderate to severe gastritis. From the results of a multiple logistic regression analysis after adjusting for confounding variables that included age, gender, and BMI, we found that elevated serum CRP levels (odds ratio (OR) 2.33; 95% confidence interval (CI) = 0.8-2.6, p = .02), H. pylori (OR 1.99; CI 0.14-2.4, p = .04), and the use of statin (OR 1.64; CI = 0.71-1.77, p = .05) independently predict the severity of chronic gastritis., Conclusion: Long-standing statin therapy may reduce the severity of chronic gastritis. Mild increased CRP levels in absence of obvious source can predict the severity of chronic gastritis. Further researches are needed to assess the effect of statin in chronic gastritis., (© 2010 Blackwell Publishing Ltd.)

Objective: Serum paraoxonase-1 (PON1) expression is regulated by polyphenols, shown to activate the peroxisome proliferator-activated receptor gamma (PPARgamma). Pomegranate juice (PJ) is a polyphenol-rich fruit. Because promoter sequence of PON1 gene indicates that it could be regulated by nuclear receptors, we investigated the effect of PJ polyphenols on PON1 gene expression in HuH7 hepatocytes., Methods and Results: PON1 protein or mRNA expression, determined by immunocytochemistry, or quantitative PCR, respectively, as well as PON1 gene promoter activation, was significantly increased in hepatocytes incubated with PJ or with its major polyphenols punicalagin, or gallic acid (GA). Ellagic acid (EA) elicited only modest stimulatory effect. Accordingly, PJ, punicalagin, GA, and less so EA, dose-dependently increased cell-associated and hepatocyte-secreted PON1 arylesterase activity. Functionally, the secreted PON1 exhibited biological activity by protecting LDL and HDL from oxidation. Finally, PJ polyphenols upregulated the hepatocyte PON1 expression, at least in part, via the intracellular signaling cascade PPARgamma-PKA-cAMP., Conclusions: This study shows for the first time that PJ polyphenols have a specific transcriptional role in hepatocyte PON1 expression upregulation, and its secretion to the medium. We conclude that the anti-atherogenic characteristics of PJ polyphenols are modulated, at least in part, via hepatocyte PON1 upregulation and its subsequent release to the medium., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Aims: We have recently shown that urokinase plasminogen activator (uPA) increases oxidative stress (OS), cholesterol biosynthesis, and paraoxonase 2 (PON2) expression in macrophages via binding to its receptor, the uPAR. Since PON2 is regulated by both OS and cholesterol content, we hypothesized that uPA elicits a cascade of signal transduction events shared by NADPH oxidase and cholesterol biosynthesis that culminates in PON2 gene expression. Here, we investigated the signalling pathway that leads to the expression of PON2 in macrophages in response to uPA., Methods and Results: The increase in macrophage PON2 mRNA levels in response to uPA was shown to depend on PON2 gene promoter activation and mRNA transcription. LDL abolished these effects, suggesting a possible role for a transcription factor involved in cellular cholesterogenesis. Indeed, uPA upregulated PON2 expression in a sterol regulatory binding protein-2 (SREBP-2)-dependent manner, since blocking SREBP-2 maturation by 4-(2-aminoethyl)-benzenesulfonyl fluoride abolished uPA-stimulation of PON2, whereas inhibition of SREBP-2 catabolism by N-acetyl-leucyl-norleucinal had an opposite effect. The upstream signalling mechanisms include uPA activation of extracellular signal-regulated kinases (ERK1/2), which was dependent on NADPH oxidase and phosphatidylinositol 3-kinase activation, and these latter effects were mediated by the tyrosine kinase activity of the platelet-derived growth factor receptor-beta., Conclusion: These findings provide a framework linking interactions among cellular signalling pathways associated with reactive oxygen species production, macrophage cholesterol biosynthesis, and cellular PON2 expression in vascular pathophysiology.

Objective: Macrophage foam cells are characterized by increased oxidative stress. Macrophage urokinase plasminogen activator (uPA) was shown to contribute to atherosclerosis progression. We hypothesized that uPA atherogenicity is related to its ability to increase macrophage oxidative stress. Increased macrophage oxidative stress in turn was shown to enhance PON2 expression. In the present study we investigated the effect of uPA on macrophage PON2 expression in relation to cellular oxidative stress., Methods and Results: uPA increased PON2 expression in THP-1 macrophages in a dose-dependent manner. This effect required uPA/uPAR interaction and was abolished by cell treatment with antioxidants. uPA increased macrophage oxidative stress, measured by increased lipid peroxides, reactive oxygen species formation, superoxide anion release, and cell-mediated LDL oxidation. These effects were related to uPA-mediated activation of NADPH oxidase, and could not be reproduced in mouse peritoneal macrophages (MPM) harvested from p47(phox)-/- mice, suggesting a causal relationship between NADPH oxidase activation and the effects of uPA on macrophage oxidative stress and PON2 expression. Finally, MPM from PON2(-/-) mice were more susceptible to uPA-induced cellular oxidative stress than wild-type MPM, suggesting that PON2 protects against uPA-stimulated macrophage oxidative stress., Conclusions: Upregulation of macrophage PON2 may provide a compensatory protective mechanism against uPA-stimulation of macrophage oxidative stress during atherogenesis.