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TAFRO syndrome is a systemic inflammatory, lymphoproliferative disorder, but the pathophysiology of the disease is unknown. It is typically characterized by thrombocytopenia, anasarca, a fever, reticulin fibrosis, renal dysfunction, and organomegaly. However, other manifestations have been also reported. We encountered a 43-year-old man with TAFRO syndrome who showed mediastinal panniculitis, liver damage, and adrenal lesions in addition to the core signs. He achieved complete remission with combination therapy of corticosteroids, tocilizumab, and cyclosporin, and remission was maintained even after drug discontinuation at 15 months. Atypical manifestations and complete remission of TAFRO syndrome were remarkable features of our case.

Coagulation and fibrinolytic mechanisms are enhanced in patients with coronavirus (COVID-19), but disturbances in the balance of both functions in COVID-19 patients remain unclear. We assessed global coagulation and fibrinolysis in plasma from 167 COVID-19 patients (mild/moderate/severe: 62/88/17, respectively) on admission using clot-fibrinolysis waveform analysis (CFWA). Maximum coagulation velocity (|min1|) and maximum fibrinolysis velocity (|FL-min1|) were expressed as ratios relative to normal plasma. Ten patients (6.0%) developed thrombosis, 5 (3.0%) had bleeding tendency, and 13 (7.8%) died during admission. FDP levels increased with severity of COVID-19 symptoms (mild/moderate/severe; median 2.7/4.9/9.9 μg/mL, respectively). The |min1| ratios were elevated in all categories (1.27/1.61/1.58) in keeping with enhanced coagulation potential, with significant differences between mild cases and moderate to severe cases. The |FL-min1| ratios were also elevated in all groups (1.19/1.39/1.40), reflecting enhanced fibrinolytic potential. These data identified coagulation dominance in moderate to severe cases, but balanced coagulation and fibrinolysis in mild cases. There were significant differences in FDP and TAT, but no significant differences in |min1| or |FL-min1| ratios, between patients with and without thrombosis. CFWA monitoring of coagulation and fibrinolysis dynamics could provide valuable data for understanding hemostatic changes and disease status in COVID-19 patients.

Hot water bathing – a Japanese traditional practice – has not been evaluated for its association with night- and sleep-time blood pressure (BP) in large population. In this longitudinal analysis, bathing parameters and ambulatory BP were repeatedly measured for 2 nights in 758 Japanese elderly individuals. Participants were divided into three groups according to tertile values of time soaked in the bathtub (Duration: tertile value, 11 and 15 min), time from bathing-end to bedtime (Time before bedtime: tertile value, 42 and 106 min), and temperature of hot water in the bathtub (Water temp: tertile value, 40.3 and 41.2 °C). Participants’ mean age was 70.9 years, and mean night- and sleep-time systolic BP (SBP) and dipping were 115.1 ± 16.1, 114.2 ± 16.2 mmHg, and 14.2 ± 8.8%, respectively. Multivariable mixed-effect linear regression models adjusted for potential confounding factors suggested that nighttime SBP was significantly lower in the intermediate Time before bedtime group by 1.7 mmHg (95% CI, 0.2–3.1) and in the short group by 1.9 mmHg (95% CI, 0.1–3.7) than that in the long group. Dipping was significantly greater in the intermediate Time before bedtime group by 1.8% (95% CI, 0.7–2.9) and in the short group by 1.8% (95% CI, 0.6–3.1) than that in the long group. These associations were consistent regarding sleep-time SBP. Conversely, Water temp and Duration did not significantly associate with any ambulatory BP parameter. Remarkably, Time before bedtime significantly prolonged with increases in tertiles of Water temp (P for trend = 0.006). In conclusion, the findings of this study revealed that Japanese hot water bathing, especially the short time from bathing-end to bedtime, was associated with lower night- and sleep-time BP and greater dipping in an elderly population., 博士（医学）・甲第751号・令和2年9月30日, This is a post-peer-review, pre-copyedit version of an article published in Chronobiology international. The final authenticated version is available online at: https://doi.org/10.1080/07420528.2019.1675685.

STUDY OBJECTIVES: Passive body heating in controlled settings could shorten sleep onset latency (SOL). The hypothesized mechanism is vasodilation-induced heat loss before bedtime. However, this evidence is based on small sample–sized studies in specific populations. Thus, we analyzed the association of hot-water bathing and its before-bedtime timing with SOL and heat loss in a large study population of older adults. METHODS: We conducted a longitudinal analysis using repeated measurements of hot-water bathing and sleep among 1,094 older adults (mean age, 72.0 years). SOL was recorded using actigraphy and self-reported sleep estimates and was categorized into conditions (intervals of 1–60, 61–120, 121–180, and > 181 minutes between hot bath and bedtime) and compared with the control condition of no bathing. The heat-loss indicator, distal-proximal skin temperature gradient, was examined in the same categorization. RESULTS: Mixed-effects linear regression models suggested that the bathing conditions of 61–120 minutes and 121–180 minutes showed significantly shorter log-transformed actigraphic SOL by 0.23 log-minutes (95% confidence interval (CI), 0.03–0.42) and 0.32 log-minutes (95% CI, 0.09–0.56), shorter self-reported SOL by 0.16 log-minutes (95% CI, 0.02–0.30) and 0.18 log-minutes (95% CI, 0.01–0.35), and higher distal-proximal skin temperature gradient for 30 minutes before bedtime by 0.49°C (95% CI, 0.22–0.75) and 0.51°C (95% CI, 0.20–0.83), respectively, independent of potential confounders. CONCLUSIONS: Hot-water bathing before bedtime is significantly associated with shorter SOL and higher distal-proximal skin temperature gradient among the large-scale older population. This finding could enhance the generalizability of hot-water bathing habits for ameliorating sleep initiation difficulty. CITATION: Tai Y, Obayashi K, Yamagami Y, et al. Hot-water bathing before bedtime and shorter sleep onset latency are accompanied by a higher distal-proximal skin temperature gradient in older adults. J Clin Sleep Med. 2021;17(6):1257–1266.

Introduction: Patients with systemic autoimmune rheumatic diseases (SARDs) such as rheumatoid arthritis, systemic lupus erythematosus (SLE), Sjögren syndrome, and systemic sclerosis, which are chronic inflammatory diseases, are prone to develop renal dysfunction, which is related to vascular endothelial cell damage. Material and Methods: We evaluated plasma levels of von Willebrand factor (VWF), VWF propeptide (VWF-pp), disintegrin-like and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), and VWF multimer pattern in patients with SARDs at diagnosis and investigated whether they may serve as markers to identify patients destined to develop renal dysfunction within 1 year. Renal dysfunction was defined as subsequent reduced estimated glomerular filtration rate (eGFR) by >25% or the new appearance of abnormal urine findings such as proteinuria (protein > 30 mg/dL) or hematuria (red blood cells >20/HPF in urine sediments). Overall, 63 patients with SARDs were studied. Results and Conclusions: We observed a significant increase of VWF-pp and a significant decrease of ADAMTS13 in patients with SARDs compared with normal healthy controls. The highest level of VWF-pp was observed in patients with SLE among the groups. The levels of VWF and multimer pattern of VWF were not different compared with normal healthy controls. Von Willebrand factor propeptide predicted a subsequent decrease in eGFR at a cutoff point of 210% (sensitivity, 78.6%; specificity, 73.5%) and new urinary abnormal findings at a cutoff point of 232% (sensitivity, 77.8%; specificity, 77.8%) Using these cutoff points, multivariable analysis revealed that VWF-pp was a significant risk factor for renal dysfunction at an odds ratio of 8.78 and 22.8, respectively, and may lead to a new therapeutic approach to prevent vasculitis and renal dysfunction.

Hepatic ischaemia–reperfusion (I/R) injury is a serious liver damage that critically influences the clinical outcome of liver surgery or transplantation. Since recent studies indicated the critical involvement of von Willebrand factor (VWF) in reperfusion injuries of brain and myocardium, we hypothesized that VWF-dependent thrombotic or inflammatory responses also play a role in hepatic I/R injury. Using a mouse model of hepatic I/R injury, we explored the functional relevance of the VWF–ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) axis in this pathologic condition. Time-course studies during hepatic I/R revealed significantly lower alanine aminotransferase (ALT) values, as well as greater hepatic blood flow, in VWF gene-deleted (KO) mice in comparison with wild-type (WT) mice. Histological analysis revealed a significantly lesser extent of neutrophil infiltration and hepatocellular necrosis in liver tissues of VWF-KO mice. Human recombinant ADAMTS13 significantly improved the impairment in ALT values and hepatic blood flow and decreased neutrophil infiltration within the liver tissue of WT mice. Real-time intravital imaging successfully visualized significantly reduced leukocyte–vessel wall interactions in I/R liver of VWF-KO mice. Taken together, our results indicate that VWF promotes neutrophil recruitment in ischaemic mouse liver, critically aggravating reperfusion injury, and suggest that functional regulation of VWF by ADAMTS13 represents a promising therapeutic option for hepatic I/R injury.

Acute kidney injury (AKI), an abrupt loss of renal function, is often seen in clinical settings and may become fatal. In addition to its hemostatic functions, von Willebrand factor (VWF) is known to play a role in cross-talk between inflammation and thrombosis. We hypothesized that VWF may be involved in the pathophysiology of AKI, major causes of which include insufficient renal circulation or inflammatory cell infiltration in the kidney. To test this hypothesis, we studied the role of VWF in AKI using a mouse model of acute ischemia-reperfusion (I/R) kidney injury. We analyzed renal function and blood flow in VWF-gene deleted (knock-out; KO) mice. The functional regulation of VWF by ADAMTS13 or a function-blocking anti-VWF antibody was also evaluated in this pathological condition. Greater renal blood flow and lower serum creatinine were observed after reperfusion in VWF-KO mice compared with wild-type (WT) mice. Histological analysis also revealed a significantly lower degree of tubular damage and neutrophil infiltration in kidney tissues of VWF-KO mice. Both human recombinant ADAMTS13 and a function-blocking anti-VWF antibody significantly improved renal blood flow, renal function and histological findings in WT mice. Our results indicate that VWF plays a role in the pathogenesis of AKI. Proper functional regulation of VWF may improve the microcirculation and vessel function in the kidney, suggesting a novel therapeutic option against AKI.

Sjogren’s syndrome, an autoimmune disease characterized by exocrine gland dysfunction leading to dry mouth and dry eye diseases, is typified by lymphoplasmacytic infiltrations and a progressive destruction of the salivary and lacrimal glands. Despite an ever-increasing focus on identifying the underlying etiology of Sjogren’s syndrome, the factors that initiate this autoimmune disease and the mechanisms that cause the subsequent exocrine gland dysfunction remain a mystery. The original explanatory concept for the pathogenesis of Sjogren’s syndrome proposed a specific, self-perpetuating, immune-mediated loss of acinar and ductal cells as the principal cause of salivary gland dysfunction. We highlight the possible involvement of regenerating gene (Reg) in the regeneration and destruction of salivary gland acinar and ductal cells in Sjogren’s syndrome. The Reg gene was originally isolated as a gene specifically overexpressed in regenerating pancreatic islets and constitutes a growth factor family (Reg family). We describe how salivary gland dysfunction is initiated and maintained and how it can be regenerated or progressed, mediated by the Reg gene, Reg protein, and anti-REG autoantibodies in Sjogren’s syndrome.

Aims Although accumulating evidence suggests the associations between sleep apnea syndrome (SAS) and type 2 diabetes, the direct effect of intermittent hypoxia (IH) on pancreatic β cell proliferation remains a missing piece of the puzzle. Main methods Rat RINm5F β cells, hamster HIT-T15 β cells, and human 1.1B4 β cells were exposed to normoxia (21% O2, 5% CO2, and balance N2), to sustained hypoxia (SH: 1% O2, 5% CO2, and balance N2), or to intermittent hypoxia (IH: 64 cycles of 5 min SH and 10 min normoxia) for 24 h. After the treatment, cellular proliferation and apoptosis were measured by WST-8 assay and TUNEL method, respectively. The expression of regenerating gene (Reg) family, interleukin (IL)-6, and hepatocyte growth factor (HGF) was determined by real-time RT-PCR. Key findings The cellular proliferation of HIT-T15, RINm5F and 1.1B4 cells by IH was significantly increased, whereas apoptosis of these cells was unchanged. Real-time RT-PCR revealed that the mRNA levels of Reg family genes, IL-6, a typical Reg family gene inducer, and HGF, an inhibitor of high-concentration of Reg protein-induced apoptosis, were increased in IH-treated cells. In addition, siRNAs against rat Reg family genes except for PAP I/Reg 2 attenuated IH-induced β cell proliferation. Significance IH stress stimulates pancreatic β cell to induce IL-6 gene expression. By the IL-6 stimulation, β cells over-express Reg family genes as well as HGF gene. Reg family proteins stimulate β cell proliferation and HGF inhibits apoptosis of β cells. As a result, β cell numbers are increased by IH.

Summary The regenerating gene (Reg) was isolated originally as a gene specifically over-expressed in regenerating pancreatic islets and constitute a growth factor family. Reg gene product (Reg) is important in the pathophysiology of various human inflammatory diseases. Recently, the possible involvement of human REG in the regeneration of salivary ductal epithelial cells of patients with primary Sjögren's syndrome (SS) was reported. However, the expression of the REG family genes in minor salivary glands (MSG) and the occurrence of anti-REG Iα autoantibodies in SS patients were obscured. In this study, we examined the expression of REG family genes in the MSG of SS and screened anti-REG Iα autoantibodies in SS. The mRNA levels of REG family genes in MSG were quantified using real-time reverse transcription–polymerase chain reaction (RT–PCR) and REG Iα expression in the MSG was analysed by immunohistochemistry. The mRNA level of REG Iα in the MSG of SS patients was significantly higher than that of control. REG Iα protein was expressed highly in SS ductal epithelial cells. Anti-REG Iα autoantibodies in the sera were found in 11% of SS. All the MSG in the anti-REG Iα autoantibody-positive group showed REG Iα expression, whereas only 40% showed REG Iα expression in the anti-REG Iα autoantibody-negative group. The anti-REG Iα autoantibody-positive group showed significantly lower saliva secretion and a higher ratio of grade 4 (by Rubin–Holt) in sialography. These data suggest strongly that autoimmunity to REG Iα might play a role in the degeneration of MSG ductal epithelial cells in primary SS.

Reg (regenerating gene) product, Reg protein, is induced in pancreatic β-cells and acts as autocrine/paracrine growth factor for regeneration via the cell surface Reg receptor. However, high concentrations of Reg I protein induced β-cell apoptosis. In the present study, we found that hepatocyte growth factor (HGF) attenuated the β-cell apoptosis induced by the high concentrations of Reg I protein and that the combined stimulation of interleukin-6 (IL-6) and dexamethasone (Dx) induced the accumulation of HGF mRNA as well as Reg I mRNA in β-cells. The accumulation of the HGF mRNA was caused by the activation of the HGF promoter. Deletion analysis revealed that the region of −96 to −92 of the HGF gene was responsible for the promoter activation by IL-6+Dx. The promoters contain a consensus transcription factor binding sequence for signal transducer and activator of transcription (STAT). Site-directed mutations of STAT-binding motif in the region markedly attenuated the HGF promoter activity. Chromatin immunoprecipitation assay showed that STAT3 is located at the active HGF promoter in response to IL-6+Dx stimulation. These results strongly suggest that the combined stimulation of IL-6 and glucocorticoids induces the activation of both Reg and HGF genes and that the anti-apoptotic effects of HGF against the Reg I-induced apoptosis may help β-cell regeneration by Reg I protein.

The regenerating gene, Reg, was originally isolated from a rat regenerating islet cDNA library, and its human homolog was named REG Iα. Recently, we reported that REG Iα mRNA as well as its product were overexpressed in ductal epithelial cells in the minor salivary glands of Sjögren׳s syndrome (SS) patients. This study was undertaken to elucidate the role of cytokines and the subsequent intracellular mechanism for induction of REG Iα in the salivary glands of SS patients. We prepared a reporter plasmid containing REG Iα promoter (−1190/+26) upstream of a luciferase reporter gene. The promoter plasmid was introduced by lipofection into human NS-SV-DC and rat A5 salivary ductal cells. The cells were treated with interleukin (IL)-6, IL-8, and a combination of the two. Thereafter transcriptional activity of REG Iα was measured by luciferase assay. We found that IL-6 stimulation, but not IL-8, significantly enhanced the REG Iα promoter activity in salivary ductal cells. Deletion analysis revealed that the region of −141 to −117 of the REG Iα gene was responsible for the promoter activation by IL-6, which contains a consensus sequence for signal transduction and activation of transcription (STAT). The introduction of siRNA for human STAT3 abolished IL-6-induced REG Iα transcription. These results showed that IL-6 stimulation induced REG Iα transcription through STAT3 activation and binding to the consensus sequence of REG Iα promoter in salivary ductal cells. This IL-6/STAT dependent REG Iα induction might play a role in the pathogenesis of SS., Graphical abstract, Highlights • REG Iα was overexpressed in salivary ductal cells of patients with Sjögren׳s syndrome. • IL-6 stimulation enhanced the REG Iα gene transcription in salivary ductal cells. • STAT3 mediated IL-6-induced REG Iα transcription in salivary ductal cells.