SARS-CoV-2 ORF6 disturbs nucleocytoplasmic trafficking to advance the viral replication

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the coronavirus disease 2019 pandemic. ORF6 is known to antagonize the interferon signaling by inhibiting the nuclear translocation of STAT1. Here we show that ORF6 acts as a virulence factor through two distinct strategies. First, ORF6 directly interacts with STAT1 in an IFN-independent manner to inhibit its nuclear translocation. Second, ORF6 directly binds to importin 1, which is a nuclear transport factor encoded by KPNA2, leading to a significant suppression of importin 1-mediated nuclear transport. Furthermore, we found that KPNA2 knockout enhances the viral replication, suggesting that importin 1 suppresses the viral propagation. Additionally, the analyses of gene expression data revealed that importin 1 levels decreased significantly in the lungs of older individuals. Taken together, SARS-CoV-2 ORF6 disrupts the nucleocytoplasmic trafficking to accelerate the viral replication, resulting in the disease progression, especially in older individuals.

Effective intrathecal opioid analgesia in two patients refractory to high doses of systemic opioids

<b>Purpose</b>: We report two patients receiving high doses of systemic opioids in whom gradual switching of the opioid administration route from systemic to intrathecal provided satisfactory pain relief without excessive sedation or withdrawal symptoms. <b>Case reports</b>: In one of the patients, who was already receiving 500mg morphine intravenously but still suffered from right upper quadrant pain, it was difficult to increase the opioid dosage according to the WHO guidelines because of intolerable side effects. The other patient, in spite of taking a combination of systemic opioids equivalent to 760mg oral morphine, had inadequate pain relief and could not continue receiving home medical care. In both cases we could successfully change from systemic to intrathecal opioid administration in a step-wise manner without deterioration of pain control, adverse effects due to over dosage, or withdrawal symptoms. Intrathecal opioid administration also reduced drowsiness and improved daily activity. <b>Conclusion</b>: Currently, there are no guidelines for change of route of opioid administration from systemic to intrathecal administration and few published reports have concretely documented opioid route switching in Japan. A carefully planned, step-wise switching of opioid administration route from systemic to intrathecal should be considered in patients who are already taking high doses of systemic opioids. Palliat Care Res 2009; 4(1): 317-320