Evaluation of Right Ventricular overload by ^<123>I-MIBG, ^<123>I-BMIPP , and ^<99m>Tc-MIBI

It is important to evaluate the severity of right ventricular (RV) overload in patients with chronic pulmonary diseases or pulmonary thromboembolism because their prognosis depend on the severity of RV overload. Various examination methods have been used to non-invasively evaluate the severity of RV overload. We evaluated the usefulness of recently developed novel radiopharmaceuticals 123I-MIBG, 123I-BMIPP, and 99mTc-MIBI) in patients with chronic respiratory diseases or pulmonary thromboembolism. Myocardial scintigraphy using 1231-MIBG revealed that the ratio of scintillation counts in the interventricular septum (IVS) to those in the left ventricle (LV) correlated negatively with the mean pulmonary arterial pressure (MPAP), suggesting the presence of sympathetic neuropathy due to RV overload. Myocardial scintigraphy using 123I-BMIPP revealed that the ratio of scintillation counts in the RV to those in LV (RV/LV uptake ratio) correlated with MPAP. There was a negative correlation between RV metabolic index [RVMI = (RV/LV ratio of 123I-BMIPP uptake)(RV/LV ratio of 201T1 uptake)] and MPAP. These findings suggested the presence of RV overload-induced fatty acid metabolic disorder. 99iTc-MIBI allows the simultaneous performance of both cardiac pool scintigraphy and myocardial single photon emission computed tomography. RV/LV ratio of 99Tc-MIBI uptake correlated with MPAP. Moreover, RV ejection fraction (RVEF) obtained by right cardiac pool scintigraphy correlated with the RVEF determined by the thermodilution method, suggesting the usefulness of 99mTc-MIBI. Our findings suggest that these radiopharmaceuticals are useful for evaluating the severity of RV overload in patients with chronic respiratory diseases or pulmonary thromboembolism, as well as for evaluating RV overloadinduced metabolic disorders

Determination of a phosphorylation site in Nipah virus nucleoprotein and its involvement in virus transcription

Many viruses use their host’s cellular machinery to regulate the functions of viral proteins. The phosphorylation of viral proteins is known to play a role in genome transcription and replication in paramyxoviruses. The paramyxovirus nucleoprotein (N), the most abundant protein in infected cells, is a component of the N–RNA complex and supports the transcription and replication of virus mRNA and genomic RNA. Recently, we reported that the phosphorylation of measles virus N is involved in the regulation of viral RNA synthesis. In this study, we report a rapid turnover of phosphorylation in the Nipah virus N (NiV-N). The phosphorylated NiV-N was hardly detectable in steady-state cells, but was detected after inhibition of cellular protein phosphatases. We identified a phosphorylated serine residue at Ser451 of NiV-N by peptide mass fingerprinting by electrospray ionization–quadrupole time-of-flight mass spectrometry. In the NiV minigenome assay, using luciferase as a reporter gene, the substitution of Ser451 for alanine in NiV-N resulted in a reduction in luciferase activity of approximately 45 % compared with the wild-type protein. Furthermore, the substitution of Ser451 for glutamic acid, which mimics a phosphoserine, led to a more significant decrease in luciferase activity – approximately 81 %. Northern blot analysis showed that both virus transcription and replication were reduced by these mutations. These results suggest that a rapid turnover of the phosphorylation of NiV-N plays an important role in virus transcription and replication

Matrix-Embedded Osteocytes Regulate Mobilization of Hematopoietic Stem/Progenitor Cells

The bone marrow (BM) niche comprises multiple cell types that regulate hematopoietic stem/progenitor cell (HSPC) migration out of the niche and into the circulation. Here, we demonstrate that osteocytes, the major cellular component of mature bone, are regulators of HSPC egress. Granulocyte colony-stimulating factor (G-CSF), used clinically to mobilize HSPCs, induces changes in the morphology and gene expression of the osteocytic network that precedes changes in osteoblasts. This rapid response is likely under control of the sympathetic nervous system, since osteocytes express the β2-adrenergic receptor and surgical sympathectomy prevents it. Mice with targeted ablation of osteocytes or a disrupted osteocyte network have comparable numbers of HSPCs in the BM but fail to mobilize HSPCs in response to G-CSF. Taken together, these results indicate that the BM/bone niche interface is critically controlled from inside of the bone matrix and establish an important physiological role for skeletal tissues in hematopoietic function

Multicenter, single-blind, randomized controlled study of the efficacy and safety of favipiravir and nafamostat mesilate in patients with COVID-19 pneumonia

Objectives: To evaluate the efficacy and safety of nafamostat combined with favipiravir for the treatment of COVID-19. Methods: We conducted a multicenter, randomized, single-blind, placebo-controlled, parallel assignment study in hospitalized patients with mild-to-moderate COVID-19 pneumonia. Patients were randomly assigned to receive favipiravir alone (n = 24) or nafamostat with favipiravir (n = 21). The outcomes included changes in the World Health Organization clinical progression scale score, time to improvement in body temperature, and improvement in oxygen saturation (SpO2). Results: There was no significant difference in the changes in the clinical progression scale between nafamostat with favipiravir and favipiravir alone groups (median, -0.444 vs -0.150, respectively; least-squares mean difference, -0.294; P = 0.364). The time to improvement in body temperature was significantly shorter in the combination group (5.0 days; 95% confidence interval, 4.0-7.0) than in the favipiravir group (9.0 days; 95% confidence interval, 7.0-18.0; P =0.009). The changes in SpO2 were greater in the combination group than in the favipiravir group (0.526% vs -1.304%, respectively; least-squares mean difference, 1.831; P = 0.022). No serious adverse events or deaths were reported, but phlebitis occurred in 57.1% of the patients in the combination group. Conclusion: Although our study showed no differences in clinical progression, earlier defervescence, and recovery of SpO2 were observed in the combination group

Osteocytes Regulate Primary Lymphoid Organs and Fat Metabolism

Osteocytes act as mechanosensors to control local bone volume. However, their roles in the homeostasis of remote organs are largely unknown. We show that ablation of osteocytes in mice (osteocyte-less [OL] mice) leads to severe lymphopenia, due to lack of lymphoid-supporting stroma in both the bone marrow and thymus, and complete loss of white adipose tissues. These effects were reversed when osteocytes were replenished within the bone. In contrast, neither in vivo supply of T cell progenitors and humoral factors via shared circulation with a normal parabiotic partner nor ablation of specific hypothalamic nuclei rescued thymic atrophy and fat loss in OL mice. Furthermore, ablation of the hypothalamus in OL mice led to hepatic steatosis, which was rescued by parabiosis with normal mice. Our results define a role for osteocytes as critical regulators of lymphopoiesis and fat metabolism and suggest that bone acts as a central regulator of multiple organs