Paricalcitol Pretreatment Attenuates Renal Ischemia-Reperfusion Injury via Prostaglandin E 2

The protective mechanism of paricalcitol remains unclear in renal ischemia-reperfusion (IR) injury. We investigated the renoprotective effects of paricalcitol in IR injury through the prostaglandin E2 (PGE2) receptor EP4. Paricalcitol was injected into IR-exposed HK-2 cells and mice subjected to bilateral kidney ischemia for 23 min and reperfusion for 24 hr. Paricalcitol prevented IR-induced cell death and EP4 antagonist cotreatment offset these protective effects. Paricalcitol increased phosphorylation of Akt and cyclic AMP responsive element binding protein (CREB) and suppressed nuclear factor-κB (NF-κB) in IR-exposed cells and cotreatment of EP4 antagonist or EP4 small interfering RNA blunted these signals. In vivo studies showed that paricalcitol improved renal dysfunction and tubular necrosis after IR injury and cotreatment with EP4 antagonist inhibited the protective effects of paricalcitol. Phosphorylation of Akt was increased and nuclear translocation of p65 NF-κB was decreased in paricalcitol-treated mice with IR injury, which was reversed by EP4 blockade. Paricalcitol decreased oxidative stress and apoptosis in renal IR injury. Paricalcitol also attenuated the infiltration of inflammatory cells and production of proinflammatory cytokines after IR injury. EP4 antagonist abolished these antioxidant, anti-inflammatory, and antiapoptotic effects. The EP4 plays a pivotal role in the protective effects of paricalcitol in renal IR injury

Physical activity and the risk of SARS-CoV-2 infection, severe COVID-19 illness and COVID-19 related mortality in South Korea: a nationwide cohort study.

PURPOSE: To determine the potential associations between physical activity and risk of SARS-CoV-2 infection, severe illness from COVID-19 and COVID-19 related death using a nationwide cohort from South Korea. METHODS: Data regarding 212 768 Korean adults (age ≥20 years), who tested for SARS-CoV-2, from 1 January 2020 to 30 May 2020, were obtained from the National Health Insurance Service of South Korea and further linked with the national general health examination from 1 January 2018 to 31 December 2019 to assess physical activity levels. SARS-CoV-2 positivity, severe COVID-19 illness and COVID-19 related death were the main outcomes. The observation period was between 1 January 2020 and 31 July 2020. RESULTS: Out of 76 395 participants who completed the general health examination and were tested for SARS-CoV-2, 2295 (3.0%) were positive for SARS-CoV-2, 446 (0.58%) had severe illness from COVID-19 and 45 (0.059%) died from COVID-19. Adults who engaged in both aerobic and muscle strengthening activities according to the 2018 physical activity guidelines had a lower risk of SARS-CoV-2 infection (2.6% vs 3.1%; adjusted relative risk (aRR), 0.85; 95% CI 0.72 to 0.96), severe COVID-19 illness (0.35% vs 0.66%; aRR 0.42; 95% CI 0.19 to 0.91) and COVID-19 related death (0.02% vs 0.08%; aRR 0.24; 95% CI 0.05 to 0.99) than those who engaged in insufficient aerobic and muscle strengthening activities. Furthermore, the recommended range of metabolic equivalent task (MET; 500-1000 MET min/week) was associated with the maximum beneficial effect size for reduced risk of SARS-CoV-2 infection (aRR 0.78; 95% CI 0.66 to 0.92), severe COVID-19 illness (aRR 0.62; 95% CI 0.43 to 0.90) and COVID-19 related death (aRR 0.17; 95% CI 0.07 to 0.98). Similar patterns of association were observed in different sensitivity analyses. CONCLUSION: Adults who engaged in the recommended levels of physical activity were associated with a decreased likelihood of SARS-CoV-2 infection, severe COVID-19 illness and COVID-19 related death. Our findings suggest that engaging in physical activity has substantial public health value and demonstrates potential benefits to combat COVID-19

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Cutoff Values for Providing the Ideal Intravenous Patient-Controlled Analgesia According to the Intensity of Postoperative Pain—A Retrospective Observational Study

Background and Objectives: The cutoff values were analyzed for providing the ideal intravenous patient-controlled analgesia (PCA) that could reduce rescue analgesics or antiemetics requirements, based on the grades of postoperative pain intensity (PPI). Materials and Methods: PCA regimens of 4106 patients were retrospectively analyzed, and they were allocated into three groups with low, moderate, and high PPI grades (groups L, M, and H, respectively) based on numeric rating scores obtained 6 h postoperatively. Opioid and non-opioid analgesic doses were converted into fentanyl-equivalent doses (DOSE-FEN-OP and DOSE-FEN-NONOP, respectively). The primary endpoint was the cutoff values of these parameters. Results: With respect to the PCA settings to reduce rescue analgesic and antiemetic requirements, group L required a background infusion rate (BIR) of 1.75–3 mL/h, bolus volume of 0.5–1.25 mL, and lockout interval of ≤12.5 min. Group M required a BIR of 1.75 mL/h, bolus volume of 0.5–1.75 mL, and lockout interval of ≤5 min. Group H required a BIR of 1.75 mL/h, bolus volume of 0.5 mL, and lockout interval of ≤5 min. In assessments of the analgesic doses to reduce rescue analgesic requirement, the DOSE-FEN-OP was at least 950 μg of fentanyl regardless of group, while the DOSE-FEN-NONOP was ≥250 μg, ≥550 μg, and ≥700 μg for the L, M, and H groups, respectively. In assessments of the analgesic doses to reduce rescue antiemetic requirement, DOSE-FEN-OP was ≤950 μg for groups L and M and ≤850 μg for Group H, while DOSE-FEN-NONOP was ≤50 μg, ≤450 μg, and ≤700 μg for groups L, M, and H, respectively. Conclusion: The ideal PCA for reduction in rescue analgesics or antiemetics can be achieved by adjustment of PCA settings and drug dosages carefully with these cutoff values depending on the expected grades of PPI. Especially, the ideal PCA can be provided by adjusting the lockout interval and bolus volume rather than BIR and by applying smaller bolus doses and shorter lockout intervals with an increasing PPI grade