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The factors controlling earthquake swarm duration are remain unclear, especially in the long‐living ones. A severe earthquake swarm struck the tip of the Noto peninsula, Japan. Ten M > 4.0 earthquakes occurred, and the sequence has continued more than 4 years. We investigated the spatiotemporal characteristics of the swarm using relocated hypocenters to elucidate the factors causing this long duration. The swarm consists of four seismic clusters—northern, northeastern, western, and southern—the latter of which began first. Diffusive hypocenter migrations were observed in the western, northern, and northeastern clusters with moderate to low diffusivities, implying a low‐permeability environment. Rapid diffusive migration associated with intermittent seismicity deep within the southern cluster suggests the presence of a highly pressurized fluid supply. We conclude that the nature of this fluid supply combined with intermittent seismicity from the southern cluster and a low‐permeability environment are the key causes of this long‐living swarm. Plain Language Summary: Earthquake swarms are sequences of several earthquakes occurring in a concentrated area over a given period. Unlike other major earthquakes, which have one main shock and several subsequent aftershocks, swarms lack a clear mainshock event. The causes of long‐lasting earthquake swarms are not sufficiently understood. In the northeastern tip of the Noto Peninsula in Japan, more than 20,000 earthquakes occurred between May 2018 and June 2022, including 10 events over magnitude 4.0. To understand the controlling factors of this long‐living earthquake swarm, we investigated the spatiotemporal characteristics of the swarm using high‐resolution relocated hypocenter locations. The hypocenters of the swarm are spatially separated in four clusters and initiated from the southern cluster. We also observed a diffusive pattern in hypocenter distribution, which is typical of earthquake swarms surrounding volcanoes or fluid injection wells, implying the existence of fluid as a driving factor of the swarm. In the southern cluster specifically, we found several intermittent seismic activities with rapid diffusive changes in hypocenter distribution, suggesting the presence of a highly pressurized, deep‐source fluid supply. The intermittent fluid supply from the southern cluster toward the others and the relatively low‐permeability environment are key factors in the longevity of this earthquake swarm. Key Points: An energic and long‐living earthquake swarm has been observed in the northeastern tip of the Noto peninsula, JapanObserved diffusive hypocenter migrations suggest that pore fluid pressure migration is a driving factor of the swarmIntermittent seismicity at the bottom of the initial cluster suggests that a geyser‐like fluid supply is a key factor in swarm longevity [ABSTRACT FROM AUTHOR]

Currently, biological disease-modifying anti-rheumatic drugs (bDMARDs) with different modes of action [tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL-6Ri), or cytotoxic T-lymphocyte antigen 4–immunoglobulin (CTLA4-Ig)] are used in clinical practice to treat rheumatoid arthritis (RA). However, it is unclear which type of bDMARD is the most efficacious for a specific clinical situation. C-reactive protein (CRP) is an acute-phase reactant driven by IL-6 signalling. Here, we aimed to establish whether therapeutic efficacy differs between IL-6Ri and other bDMARDs with alternative modes of action in RA patients according to their CRP level. RA patients treated with bDMARDs were enrolled from an observational multicentre registry in Japan. Patients were classified into three groups according to baseline CRP tertiles. The overall 3 year retention rates of each bDMARD category were assessed. The Clinical Disease Activity Index (CDAI) was also assessed before and 3, 6, and 12 months after bDMARD initiation. A total of 1438 RA patients were included and classified into three groups according to tertiles of baseline CRP levels (CRP1, 0–0.3; CRP2, 0.3–1.8; CRP3, 1.8–18.4 mg/dL). In CRP3, the overall 3 year drug retention rates were significantly higher for IL-6Ri than for TNFi and CTLA4-Ig (77.5 vs 48.2 vs 67.3, respectively). No significant difference was evident in terms of CDAI 12 months after bDMARD initiation in CRP1–CRP3. IL-6Ri may be a favourable therapeutic option over TNFi and CTLA4-Ig in RA patients with high CRP levels. [ABSTRACT FROM AUTHOR]

The COO subtypes were assigned as follows: 308 patients (51%) with activated B-cell-like (ABC)-DLBCL, 196 (33%) with germinal center B-cell-like (GCB)-DLBCL, 32 (5%) with DZsig-pos DLBCL and 66 (11%) with unclassified (UNC). H-score of CD79B was the lowest in patients with ABC-DLBCL followed by GCB-DLBCL and DZsig-pos DLBCL in ascending order (Kruskal-Wallis test I P i <.00001; Figure A). B Introduction: b CD79B is a target of polatuzumab vedotin, an antibody-drug conjugate, which may improve the prognosis of both previously untreated and relapsed/refractory patients with diffuse large B-cell lymphoma (DLBCL). [Extracted from the article]

Objectives We investigated the efficacy and safety of tacrolimus (TAC) by monitoring its serum concentration for mothers and infants in pregnant patients with systemic lupus erythematosus (SLE). Methods We measured trough concentrations of TAC in 25 pregnant patients with SLE to assess influence of TAC on the disease activity. Additionally, we measured the concentrations of TAC in umbilical arterial blood, breast milk, and breastfed infants to investigate the safety of TAC for the mothers and infants. Results The trough concentrations of TAC in the mothers significantly decreased in the second trimester as compared with those before pregnancy. However, the decrease in the trough concentrations of TAC did not lead to the deterioration of SLE. When examined, the doses of TAC were significantly lower in the second trimester and postpartum in the deteriorating group than those in the non-deteriorating group. There were no adverse events by TAC in mothers and fetuses. The concentrations of TAC in the umbilical cord blood were lower than those in the maternal blood. The relative infant dose in breastfed infants of TAC was < 1%. The level of TAC in infant bloods was below detectable limits. Conclusion These findings suggest that TAC is one of the most effective and safest immunosuppressive drugs for use in pregnant patients with SLE. [ABSTRACT FROM AUTHOR]

The clinical and genetic spectrum of hereditary sensory and autonomic neuropathy ( HSAN) is still unknown in Japan. We collected a broad cohort of 33 unrelated patients with predominant sensory and/or autonomic dysfunctions, who were referred to our genetic laboratory. A gene panel sequencing targeting 18 HSAN-related genes was performed using a next-generation sequencing system. A recurrent frame shift mutation in the WNK1/ HSN2 gene, c.3237_3238insT (p.Asp1080*), was detected in 5 patients. This mutation was homozygous in 4 cases and of a compound heterozygous genotype in 1 case. Geographic and haplotype analysis of all 5 patients suggested a founder event. In addition, a novel heterozygous nonsense variant, c. 2615C>G (p.Ser872*), was identified. All the 5 patients presented with severe sensory and autonomic dysfunctions at birth or during adolescence. In 2 patients, an uncommon phenotype of acute pathological pain presented at ~50 years of age. Here, we present the first founder mutation of WNK1/ HSN2, in addition to French Canadian, which accounts for ~15.2% of Japanese patients with HSAN in our cohort. We have also reviewed all previously described mutations in WNK1/ HSN2 and reconciled their nomenclature strategy on the basis of the current longest transcript. [ABSTRACT FROM AUTHOR]

Abstract: Constitutive androstane receptor (CAR) has been reported to decrease insulin resistance, while obesity and insulin resistance may also be involved in the pathogenesis of preeclampsia. We examined whether a CAR ligand, 1,4-bis(2-(3,5-dichloropyridyloxy)) benzene (TCPOBOP), can ameliorate the signs of preeclampsia in high-fat diet (HFD)-induced obese pregnant mice to examine a possibility of CAR as a therapeutic target. We employed six groups including non-pregnant, HFD-fed or control diet-fed pregnant mice with or without TCPOBOP treatment (n =6). In HFD pregnant mice, insulin resistance increased with increasing expression of gluconeogenic and lipogenic genes and abnormal adipocytokine levels. TCPOBOP treatment, which was once-weekly intraperitoneal injections (0.5mg/kg) and started at day 0.5 of pregnancy, improved glucose tolerance with significant changes of gluconeogenic, lipogenic and adipocytokine genes. HFD pregnant mice had hypertension and proteinuria, while TCPOBOP treatment ameliorated these signs. Our data suggested CAR might be a potential therapeutic target for obese preeclampsia patients with insulin resistance. [Copyright &y& Elsevier]

Advanced glycation end products (AGEs) are known to cause oxidative damage in various cells by binding with its receptor, RAGE. We measured the serum level of AGEs and examined the AGEs, RAGE, and the other biomarkers of oxidative stress in the placentas from preeclamptic women. Competitive ELISA was carried out to measure the AGEs in serum. Western blotting was performed to analyze AGEs and RAGE in the placenta. Immunohistochemical analyses were performed to examine the localization of AGEs, RAGE, and other biomarkers of oxidative stress in the placenta. The mean level of serum AGEs in preeclamptic women was significantly higher than that in healthy non-pregnant women or healthy pregnant women. Western blotting revealed that the level of AGEs or RAGE in preeclamptic placenta was significantly higher than that in normal placenta. Immunohistochemical analyses showed that levels of nitrotyrosine and nitroguanosine, which are formed by reactive nitrogen species, in preeclamptic placenta were higher than those in normal placenta. Accumulation of 4-hydroxy-2-nonenal and 8-hydroxy-2′-deoxyguanosine indicated enhanced oxidative modifications of lipids and DNA in preeclamptic placenta. The AGE–RAGE system, which is upregulated in preeclampsia, is likely to be involved in the oxidative stress of preeclampsia. [Copyright &y& Elsevier]

Objective: To determine whether patient characteristics and presenting symptoms could be prognostic indicators for endometrial cancer in Japanese women.Methods: Review of the medical charts, which included presenting symptoms and other patient characteristics, of 242 women who underwent surgical treatment for FIGO stage I-IV endometrial cancer.Results: FIGO stage, histologic grade, and lower abdominal pain were found to be significant independent factors for progression-free and overall survival. In contrast, abnormal uterine bleeding, comorbidities, and prior malignancy were not found to be prognostic factors.Conclusion: Lower abdominal pain was found to be an independent prognostic factor in endometrial cancer among Japanese women. [ABSTRACT FROM AUTHOR]

Background: Enumeration of CD34+ cells in peripheral blood (PB) before apheresis predicts the number of CD34+ cells collected, although flow cytometric techniques used are complex and expensive. In an attempt to determine the optimal timing for peripheral blood progenitor cell (PBPC) collection, the usefulness of circulating immature cell (CIC) counts in PB was evaluated.Study Design and Methods: CIC counts in PB and CD34+ cell counts in the apheresis product from 249 collections were assessed, and the relationship between these two parameters was evaluated by with the Pearson rank correlation analysis, the Fisher exact test, and the U-test.Results: CIC counts were correlated significantly with the number of CD34+ cells per kg of patient's body weight in the apheresis product (Pearson rank correlation analysis: r = 0.635, p < 0.0001). When a level of 1 x 10(9) CICs per L was selected as a cutoff value, the sensitivity and specificity for collecting more than 1 x 10(6) CD34+ cells per kg of body weight were 75.7 and 85.5 percent, respectively.Conclusion: The present study strongly suggests that the number of CICs in PB may estimate the number of CD34+ cells collected. The data indicate that CIC counts above 1 x 10(9) per L can be used as a good predictor for PBPC collections containing more than 1 x 10(6) CD34+ cells per kg of body weight in a single apheresis procedure. [ABSTRACT FROM AUTHOR]

The salivary gland is considered to be a reservoir of many growth factors in rodents. In humans, the epidermal growth factor, basic fibroblast growth factor, and insulin and insulin-like growth factor family have also been detected in this gland, but their physiological role remains unclear. In this study, we focused on bFGF, which is a well-known mitogen for various types of cells, and is present in the salivary gland as well as in saliva. The roles of bFGF in the salivary gland were investigated by three different procedures. First, the effects of bFGF on the salivary gland cells were investigated with a monolayer culture of normal submandibular gland cells. The effects of different concentrations of bFGF on the second passage of these cultured cells were examined. In both human and rat cultured submandibular gland cells, bFGF accelerated the cell proliferation at a concentraion of 100 ng/mL or higher. Next, an atrophic model of the rat submandibular gland was used to examine the ability of bFGF to accelerate tissue repair. Two weeks after ductal ligation, the ligature was removed, and various amounts of bFGF, isoproterenol, or saline were administered via a retrograde duct instillation. Both isoproterenol and bFGF increased acinar and ductal cell proliferation significantly. To determine the role of bFGF in saliva, we investigated its effect on the healing process of oral mucosal defects. Four-millimeter mucosal defects were made to the depth of the periosteum in the rat palate under anesthesia. bFGF or vehicle alone was applied once only at the time of surgery as a suspension. At days 3, 5, and 7 in the bFGF group, significant increases in the degree of re-epithelialization were found in treated groups. These results indicate that its action as a mitogen stimulus is the major effect of bFGF on salivary gland cells and mucosal epithelium. [ABSTRACT FROM AUTHOR]