Abstract-Clinical reports indicate that patients with primary aldosteronism commonly have impaired glucose tolerance; however, the relationship between aldosterone and insulin signaling pathway has not been clarified. In this study, we examined the effects of aldosterone treatment on insulin receptor substrate-1 expression and insulin signaling pathway including Akt phosphorylation and glucose uptake in rat vascular smooth muscle cells. Insulin receptor substrate-1 protein expression and Akt phosphorylation were determined by Western blot analysis with anti-insulin receptor substrate-1 and phosphorylated-Akt antibodies, respectively. Glucose metabolism was evaluated using 3 H-labeled 2-deoxy-D-glucose uptake. Aldosterone (1-100 nmol/L) dose-dependently decreased insulin receptor substrate-1 protein expression with a peak at 18 hours (nϭ4). Aldosterone-induced degradation of insulin receptor substrate-1 was markedly attenuated by treatment with the selective mineralocorticoid receptor antagonist eplerenone (10 mol/L; nϭ4). Furthermore, degradation was blocked by the Src inhibitor PP1 (20 mol/L; nϭ4). Treatment with antioxidants, N-acetylcysteine (10 mmol/L), or ebselen (40 mol/L) also attenuated aldosterone-induced insulin receptor substrate-1 degradation (nϭ4). In addition, proteasome inhibitor MG132 (1 mol/L) prevented insulin receptor substrate-1 degradation (nϭ4). Aldosterone treatment abolished insulin-induced Akt phosphorylation (100 nmol/L; 5 minutes; nϭ4). Furthermore, aldosterone pretreatment decreased insulin-stimulated (100 nmol/L; 60 minutes; nϭ4) glucose uptake by 50%, which was reversed by eplerenone (10 mol/L; nϭ4). These data indicate that aldosterone decreases insulin receptor substrate-1 expression via Src and reactive oxygen species stimulation by proteasome-dependent degradation in vascular smooth muscle cells; thus, aldosterone may be involved in the pathogenesis of vascular insulin resistance via oxidative stress. Key Words: aldosterone Ⅲ oxidative stress Ⅲ insulin receptor substrate-1 Ⅲ insulin resistance Ⅲ type 2 diabetes mellitus Ⅲ metabolic syndrome Ⅲ eplerenone I nsulin resistance is a key attribute of type 2 diabetes and the metabolic syndrome. 1,2 Systemic glucose metabolism is maintained in the liver and skeletal muscle, and in the insulin resistant state, insulin-stimulated glucose uptake is attenuated and accompanied with subsequent increases in blood glucose concentration. High blood glucose concentration induces secretion of insulin from the pancreas and results in hyperinsulinemia. Both hyperglycemia and hyperinsulinemia affect the vasculature and are associated with microangiopathy, including retinopathy and nephropathy, and macroangiopathy, including cardiovascular disease and atherosclerosis. 3 Insulin resistance in the vasculature might also affect systemic glucose metabolism. However, the involvement of normal insulin signaling contributes to arteriosclerosis. 4,5 On the other hand, serine phosphorylation and degradation of insulin receptor substrate-1 (IRS-1) is a possible...

Background: Thrombosis is a characteristic complication in coronavirus disease 2019 (COVID-19). Since coagulopathy has been observed over the entire clinical course, thrombosis might be a clue to understanding the specific pathology in COVID-19. Currently, there is limited epidemiological data of COVID-19-associated thrombosis in the Japanese population and none regarding variant strains of SARS-CoV-2. Here, we elucidate the risk factors and the pattern of thrombosis in COVID-19 patients.Methods: The patients consecutively admitted to Tokyo Medical and Dental University Hospital with COVID-19 were retrospectively analyzed. SARS-CoV-2 variants of concern/interest (VOC/VOI) carrying the spike protein mutants E484K, N501Y, or L452R were identified by PCR-based analysis. All thrombotic events were diagnosed by clinical symptoms, ultrasonography, and/or radiological tests.Results: Among the 516 patients, 32 patients experienced 42 thromboembolic events. Advanced age, severe respiratory conditions, and several abnormal laboratory markers were associated with the development of thrombosis. While thrombotic events occurred in 13% of the patients with a severe respiratory condition, those events still occurred in 2.5% of the patients who did not require oxygen therapy. Elevated D-dimer and ferritin levels on admission were independent risk factors of thrombosis (adjusted odds ratio 9.39 and 3.11, 95% confidence interval 2.08–42.3, and 1.06–9.17, respectively). Of the thrombotic events, 22 were venous, whereas 20 were arterial. While patients with thrombosis received anticoagulation and antiinflammatory therapies with a higher proportion, the mortality rate, organ dysfunctions, and bleeding complications in these patients were higher than those without thrombosis. The incidence of thrombosis in COVID-19 became less frequent over time, such as during the replacement of the earlier strains of SARS-CoV-2 by VOC/VOI and during increased use of anticoagulatory therapeutics.Conclusion: This study elucidated that elevated D-dimer and ferritin levels are useful biomarkers of thrombosis in COVID-19 patients. The comparable incidence of arterial thrombosis with venous thrombosis and the development of thrombosis in less severe patients required further considerations for the management of Japanese patients with COVID-19. Further studies would be required to identify high-risk populations and establish appropriate interventions for thrombotic complications in COVID-19.

BackgroundIn Japan, nafamostat mesylate (NM) is frequently used as an anticoagulant during continuous renal replacement therapy (CRRT). The dialyzer membrane AN69ST has been reported to adsorb NM and affect the management of anticoagulant therapy. However, the adsorbed amount has not yet been quantitatively assessed. Therefore, in this study, we evaluated the pre- and post-hemofilter prolongation of the activated clotting time (ACT) in patients with AN69ST and PS membranes. We also measured the adsorption of NM in three types of CRRT membranes using an experimental model.MethodsIn a study of patients who underwent CRRT using AN69ST or PS membranes in 2015 at the Advanced Emergency and Critical Care Center, Okayama University Hospital, pre- and post-hemofilter ACT measurements were extracted retrospectively, and the difference was calculated. In addition, AN69ST (sepXiris100), PS (HEMOFEEL SHG-1.0), and PMMA membranes (HEMOFEEL CH-1.0N) were used in an in vitro model of a dialysis circuit, and the concentrations of NM were measured in pre- and post-hemofilter membranes and filtrates.ResultsThe ACT difference was significantly lower in the group using AN69ST membranes (p < 0.01). In the in vitro model (n = 4) with adsorption and filtration, the post-hemofilter and filtrate concentrations of NM in AN69ST membranes were significantly lower than those in the PS and PMMA membranes (p < 0.01). The NM adsorption clearance of the AN69ST membrane was significantly higher than that of the PS and PMMA membranes.ConclusionsThe AN69ST membrane had higher NM adsorption than the PS and PMMA membranes. This may have resulted in the lower ACT difference in patients undergoing CRRT using the AN69ST membrane than in patients undergoing CRRT using PS or PMMA membranes.

HighlightsMassive bleeding from the thyroid without direct neck trauma rarely causes airway compromise.Physicians should regard possible thyroid gland rupture in patients with swelling of the neck or acute respiratory failure after direct/indirect trauma to the neck.Airway management is the most important consideration in such patients with thyroid injury.

IntroductionAeromonas hydrophila sometimes causes bacteremia, which can be fatal in compromised patients, such as those with liver cirrhosis. We present a case of septic shock due to Aeromonas hydrophila bacteremia in a patient with liver cirrhosis, which was successfully treated with rapid resuscitation and critical care.Case presentationA 71-year-old Japanese man with liver cirrhosis was transported to our emergency center by ambulance after presenting with gait difficulties and fever. On arrival, he exhibited shock and severe lactic acidosis, which was suggestive of sepsis, and was immediately resuscitated and administered empiric antibiotic therapy. He also displayed catecholamine-resistant hypotension, which was successfully treated with critical care including supportive therapies, such as polymyxin B hemoperfusion and cytokine-absorbing hemofiltration. Aeromonas hydrophila was detected in his initial blood cultures.ConclusionsAeromonas septicemia should be considered in patients with alcoholic liver cirrhosis who have profound shock. In addition to goal-directed therapy and the prompt administration of empiric antibiotic therapy, aggressive critical care involving multiple supportive therapies can save such patients.