Change over Time in the Risk of Death among Japanese COVID-19 Cases Caused by the Omicron Variant Depending on Prevalence of Sublineages.

To assess temporal changes to the risk of death in COVID-19 cases caused by the Omicron variant, we calculated age-standardized case fatality rates (CFR) in patients aged ≥40 years over nine diagnostic periods (3 January to 28 August 2022) in ten Japanese prefectures (14.8 million residents). Among 552,581 study subjects, we found that there were 1836 fatalities during the isolation period (up to 28 days from date of onset). The highest age-standardized CFR (0.85%, 95% confidence interval (CI):0.78-0.92) was observed in cases diagnosed in the second 4-week period (January 31 to February 27), after which it declined significantly up to the 6th 4-week period (0.23%, 95% CI: 0.13-0.33, May 23 to June 19). The CFR then increased again but remained at 0.39% in the eighth period (July 18 to August 28). The CFR in cases with the BA.2 or BA.5 sublineages in the age range 60-80 years was significantly lower than that with BA.1 infections (60 years: 0.19%, 0.02%, 0.053%, respectively; 70 years: 0.91%, 0.33%, 0.39%; ≥80 years: 3.78%, 1.96%, 1.81%, respectively). We conclude that the risk of death in Japanese COVID-19 patients infected with Omicron variants declined through February to mid-June 2022.

Zinc-Excess Intake Causes the Deterioration of Renal Function Accompanied by an Elevation in Systemic Blood Pressure Primarily Through Superoxide Radical-Induced Oxidative Stress.

Using rats fed 22 g/d of a control diet containing 0.005% zinc (Zn) or 2 Zn-excess diets containing 0.05% or 0.2% Zn for 4 weeks, we examined the mechanisms involved in the deterioration of renal function induced by Zn-excess intake. An increase in Zn intake elevated mean blood pressure (BP) and reduced renal blood flow (RBF) and inulin clearance in a dose-dependent manner. This decline in inulin clearance may be derived from a fall in RBF. Administration of the nitric oxide (NO) synthase inhibitor, Nω-nitro-l-arginine methyl ester, markedly increased mean BP and significantly decreased RBF in the 3 groups of rats. Administration of the exogenous superoxide radical (OO-) scavenger, tempol, significantly decreased mean BP and substantially increased RBF in all groups of rats. These observations suggest that both an elevation in systemic BP and a reduction in RBF seen in the 2 Zn-excess diet groups result from a decrease in the action of the vasodilator, NO, through the formation of peroxynitrite based on the nonenzymatic reaction of NO and increased OO- Indeed, the activity of the endogenous OO- scavenger, copper/Zn-superoxide dismutase, was significantly reduced in the vessel wall of rats fed 2 Zn-excess diets versus a control diet. 8-Hydroxy-2'-deoxyguanosine formation caused by OO- generation was notably elevated in the kidneys of rats fed 2 Zn-excess diets relatively to rats fed a control diet. Thus, Zn-excess intake leads to the aggravation of renal function concomitantly with an increase in systemic BP predominantly through the oxidative stress caused by OO^.

Lipopolysaccharide-induced overproduction of nitric oxide and overexpression of iNOS and interleukin-1ß proteins in zinc-deficient rats.

Zinc deficiency leads to decreased cellular immune responses. The overproduction of nitrogen species derived from inducible nitric oxide synthase (iNOS), its enzyme, and interleukine-1 beta (IL-1ß), and inflammatory cytokine have been implicated in immune responses. The goal of this study was to investigate the effects of lipopolysaccharide (LPS)-induced changes in NO metabolites, iNOS, and IL-1ß protein expression in the lungs of zinc-deficient rats. Male Sprague-Dawley rats (body weight, 100 g) were divided into two groups and were fed either a zinc-deficient diet (ZnD) or a zinc-containing diet (Cont). After 4 weeks on these diets, rats received a 10-mg/kg dose of LPS injected via the tail vein and were then maintained for an additional 72 h. To determine total NO concentrations in the blood, serum zinc concentration, iNOS protein expression, IL-1ß, and iNOS immunohistochemistry, blood and lung samples were obtained at pre-LPS injection, 5, 24, and 72 h after injection. Total NO levels were significantly increased at 5, at 24, and at 72 h after LPS injection compared with pre-LPS injection level in ZnD group; significant changes in total NO levels was elevated at 5 h from at pre-LPS level but not significant changes from basal level at 24 and 72 h in the control group. Based on western blot analyses and immunohistochemistry, clear bands indicating iNOS and IL-1ß protein expression and iNOS antibody-stained inflammatory cells were detected at 5 and 24 h in the ZnD group and 5 h in the Cont group, not observed at 24 and 72 h in the control group. These results suggest that zinc deficiency induces overexpression of iNOS and IL-1ß proteins from inflammatory cells around the alveolar blood vessels, resulting in overproduction of total NO and persisted inflammatory response in the zinc-deficient rat lung. Taken together, overexpression of LPS-induced iNOS, overproduction of iNOS-derived NO, and overexpression of IL-1ß may induce nitrosative and oxidative stresses in the lung, and these stresses may be involved low immunity of zinc deficiency states.