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Author(s): Yohei Ikezumi [sup.1] , Masatoshi Yoshikane [sup.1] , Tomomi Kondoh [sup.1] , Yuji Matsumoto [sup.1] , Naonori Kumagai [sup.1] , Masahiro Kaneko [sup.2] , Hiroya Hasegawa [sup.2] , Takeshi [...], Background The immunosuppressant mizoribine (Miz) can reduce progression of childhood IgA nephropathy (IgAN). This study examined whether Miz affects CD163.sup.+ M2-type macrophages which are associated with kidney fibrosis in childhood IgAN. Methods A retrospective cohort of 90 children with IgAN were divided into groups treated with prednisolone (PSL) alone (P group; n = 42) or PSL plus Miz (PM group; n = 48) for a 2-year period. Normal human monocyte-derived macrophages were stimulated with dexamethasone (Dex), or Dex plus Miz, and analyzed by DNA microarray. Results Clinical and histological findings at first biopsy were equivalent between patients entering the P and PM groups. Both treatments improved proteinuria and haematuria, and maintained normal kidney function over the 2-year course. The P group exhibited increased mesangial matrix expansion, increased glomerular segmental or global sclerosis, and increased interstitial fibrosis at 2-year biopsy; however, the PM group showed no progression of kidney fibrosis. These protective effects were associated with reduced numbers of glomerular and interstitial CD163.sup.+ macrophages in the PM versus P group. In cultured human macrophages, Dex induced upregulation of cytokines and growth factors, which was prevented by Miz. Miz also inhibited Dex-induced expression of CD300E, an activating receptor which can prevent monocyte apoptosis. CD300e expression by CD163.sup.+ macrophages was evident in the P group, which was reduced by Miz treatment. Conclusion Miz halted the progression of kidney fibrosis in PSL-treated pediatric IgAN. This was associated with reduced CD163.sup.+ and CD163.sup.+CD300e.sup.+ macrophage populations, plus in vitro findings that Miz can suppress steroid-induced macrophage expression of pro-fibrotic molecules. Graphical abstract

The lattice square degree, denoted by the c/a value, is a crucial factor that influences the slip mode of α-Ti alloys and thereby affects their plasticity. However, the relationship between the c/a value and the plasticity of α-Ti alloys has not been fully clarified. In this study, the powder metallurgy method (PM) was used to prepare Ti alloys with different square degrees by introducing interstitial O and substitutional Si solutes into α-Ti crystal. Then the mechanical properties, particularly plasticity, and lattice parameters of the resulted alloys were measured. By combining first-principles calculation with experimental studying, a plastic criterion based on the square degree was established. Subsequently, the mechanism of strength and plasticity was investigated by means of the density of states and charge density difference. Finally, the composition of α-Ti alloys with both O and Si solution atoms was designed, whose c/a values were calculated by the first-principles calculation and accorded with the proposed square degree criterion, and then the reliability of this criterion was verified by the experimental results. As a result, a high strength and plasticity α-Ti alloy with tensile strength 1106 MPa and elongation 23.2 % was successfully prepared. The findings of this research offer new insights into the alloying design of α-Ti alloys with high strength and moderate plasticity.

Al-matrix composites, reinforced with two different types of glassy particles and prepared by mechanical alloying, were consolidated via Spark Plasma Sintering (SPS) and hot extrusion to produce high-strength Al–5%Al65Cu20Ti15 and Al–5%Al84Ni7Co3Nb6 composites, along with pure Al sample for comparison. TEM observation and XRD analysis were used to investigate the crystal structure of the prepared powders. Metallurgical analysis tools, including SEM, TEM, XRD and EBSD, were used to investigate the effect of consolidation temperature and processing on the amorphous phase and the distribution of reinforcing particles in the composite. Also, the effect of the consolidation process on the grain morphology and size of the prepared composite was studied. Al-5% Al65Cu20Ti15 was fully densified, compared to nearly 98 % relative density for Al-5% Al84Ni7Co3Nb6 and pure Al sample prepared by hot extrusion. Moreover, Al-5% Al65Cu20Ti15 composite showed the highest hardness and ultimate tensile strength values, which are 63Hv and 226 MPa, respectively. An acceptable elongation of 15 % was also achieved. After SPS, hot extrusion process improved the strength of the composite compared with previously reported Al composites containing higher percents of Al-based glassy articles manufactured using various processing techniques. Homogenous reinforcement distribution, grain refinement and improved wettability between matrix and reinforcement are the key factors on improving the strength of Al–5%Al65Cu20Ti15 composite. The coefficient of thermal expansion (CTE) decreased by adding glassy particles to the Al-matrix, while Al-5% Al65Cu20Ti15 had the lowest values.

Abstract Lympho-hematopoiesis is regulated by cytokines; however, it remains unclear how cytokines regulate hematopoietic stem cells (HSCs) to induce production of lymphoid progenitors. Here, we show that in mice whose CXC chemokine ligand 12 (CXCL12) is deleted from half HSC niche cells, termed CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells, HSCs migrate from CXCL12-deficient niches to CXCL12-intact niches. In mice whose CXCL12 is deleted from all Ebf3+/leptin receptor (LepR)+ CAR cells, HSCs are markedly reduced and their ability to generate B cell progenitors is reduced compared with that to generate myeloid progenitors even when transplanted into wild-type mice. Additionally, CXCL12 enables the maintenance of B lineage repopulating ability of HSCs in vitro. These results demonstrate that CAR cell-derived CXCL12 attracts HSCs to CAR cells within bone marrow and plays a critical role in the maintenance of HSCs, especially lymphoid-biased or balanced HSCs. This study suggests an additional mechanism by which cytokines act on HSCs to produce B cells.

Objective: To assess the clinical characteristics and endocrinological background of women with vascular retained products of conception (RPOC) after miscarriage or abortion and evaluate the effect of estrogen–progestogen therapy (EPT) as an initial treatment on this population based on their endocrinological background. Materials and methods: Women with vascular RPOC after miscarriage or abortion at less than 20 weeks of pregnancy who were given EPT (conjugated estrogen and norethisterone) were retrospectively reviewed. Their clinical characteristics, hormonal parameters, ultrasonographic findings, and outcomes were evaluated. Results: Of 35 women with vascular RPOC, 30 (86%) presented with vaginal bleeding at a visit, and 6 (17%) required inpatient management due to heavy bleeding. Among women who presented with vaginal bleeding, serum progesterone levels were significantly lower (0.25 vs. 6.5 ng/mL, p = 0.004) than those in women who did not present with vaginal bleeding. There were no differences in serum hCG levels (10.5 vs. 3.1 mIU/mL) or serum estradiol levels (65.4 vs. 162.3 pg/mL). After withdrawal bleeding following the first course of EPT, vaginal bleeding was stopped in 27 of the 30 women (90%), and 23 (66%) of all women had a thin and linear endometrium. All women could be treated by up to two courses of EPT and did not require additional interventions. The median duration to hCG normalization after the initial EPT was 24.5 (9–88) days. Conclusion: Women with vascular RPOC who have no bleeding had significantly higher levels of serum progesterone, indicating that administration of progestogen may have an effect on hemostasis. Endometrial bleeding can be prevented or stopped, and retained tissues can be conservatively expelled by oral administration of EPT, including norethisterone, in women with vascular RPOC.

Objective: In patients with ischemic cardiomyopathy, coronary artery bypass grafting ensures better survival than medical therapy. However, the long-term clinical impact of complete revascularization remains unclear. This observational study aimed to evaluate the effects of complete revascularization on long-term survival and left ventricular functional recovery in patients with ischemic cardiomyopathy undergoing coronary artery bypass grafting. Methods: We retrospectively reviewed outcomes of 498 patients with ischemic cardiomyopathy who underwent complete (n = 386) or incomplete (n = 112) myocardial revascularization between 1993 and 2015. The baseline characteristics were adjusted using inverse probability of treatment weighting to reduce the impact of treatment bias and potential confounding. The mean follow-up duration was 77.2 ± 42.8 months in survivors. Results: The overall 5-year survival rate (complete revascularization, 72.5% vs incomplete revascularization, 57.9%, P = .03) and freedom from all-cause death and/or readmission due to heart failure (54.5% vs 40.1%, P = .007) were significantly greater in patients with complete revascularization than those with incomplete revascularization. After adjustments using inverse probability of treatment weighting, the complete revascularization group demonstrated a lower risk of all-cause death (hazard ratio, 0.61; 95% confidence interval, 0.43-0.86; P = .005) and composite adverse events (hazard ratio, 0.59; 95% confidence interval, 0.44-0.79; P

Abstract Fish aquaculture potentially affects the local ecosystem through feed (leftovers) and feces. However, evaluation of its impacts on biodiversity, especially those of mobile organisms such as fish, is not straightforward. Here, we report a case study in which environmental DNA (eDNA) metabarcoding with MiFish universal primers for the 12S rRNA region of fish is used to detect and assess the impact of aquaculture on local fish communities. In Shizugawa Bay, Minamisanriku Town, Miyagi Prefecture, Japan, Oncorhynchus kisutch (coho salmon) is aquacultured in sea cages from November to July, but is absent from August to October. We conducted eDNA surveys in June, August, October, and December 2021 of water at depths of 5 m and 1 m above the bottom obtained from two sites, one approximately 100 m and the other approximately 2500 m from the nearest aquaculture site. The total number of operational taxonomic units (OTUs) detected was 122, with a maximum of 50 and a minimum of 10. With distance‐based redundancy analysis (dbRDA) and PERMANOVA applied to the eDNA‐based community compositional data, we detected a significant effect of the presence of O. kisutch aquaculture on fish biodiversity. The generalized linear model (GLM) applied to each detected OTUs indicated that the aquaculture was associated positively with Leucopsarion petersii (ice goby), and Oncorhynchus spp. and negatively with Chaenogobius annularis (forktongue goby). Environmental DNA metabarcoding surveys, combined with multivariate statics, are a promising tool to identify the dimension of biodiversity that human activity affects and would serve as a basic survey for sustainable use of the sea.

Abstract An enantioselective addition reaction for the construction of 1,3‐nonadjacent stereogenic centers is developed by means of a chiral strong Brønsted base catalyst. The chiral sodium ureate catalyst efficiently promoted the reaction of α‐thioacetamides as less acidic pronucleophiles with vinyl sulfones having a variety of α‐substituents including aryl, alkyl and halo groups, and α‐phenylacrylates, accomplishing the construction of various 1,3‐nonadjacent stereogenic centers in highly diastereo‐ and enantioselective manners. This is a rare example of the construction of 1,3‐nonadjacent stereogenic centers with less acidic pronucleophiles. In addition, the application of Michael acceptors having various types of α‐substituents in a single catalyst system is achieved for the first time, demonstrating the utility of the present catalyst system for the construction of 1,3‐nonadjacent stereogenic centers.

Objective: Preterm prelabor rupture of fetal membranes (pPROM) is a leading cause of preterm birth. When pPROM occurs around the pre- and periviable period, the perinatal outcome is unfavorable. However, there have been a few cases in which the leakage of amniotic fluid ceases and the ruptured fetal membranes are spontaneously sealed. Materials and methods: The prognosis of 38 cases of pPROM at less than 27 weeks of gestation in Kyoto University Hospital were studied. The clinical factors related to the sealing of fetal membranes were investigated. Results: Spontaneous sealing was confirmed in five patients (13%), and sealing occurred within 14 days of pPROM. Women in the no sealing group delivered at 26.3 ± 0.5 weeks of gestation, whereas women in the sealing group delivered at term at 38.8 ± 0.4 weeks (p

ABSTRACTSelective laser melted (SLMed) AlSi10Mg alloys usually fail before necking during tensile tests, which results in inadequate ductility. To overcome this problem, here we introduced Al4C3 nanorods into the primary Al cells of SLMed AlSi10Mg via in-situ chemical reaction. Tensile tests revealed that those in-cell Al4C3 nanorods not only increased the strain-hardening ability of SLMed AlSi10Mg but also delayed the fracture beyond necking. Consequently, 15% of tensile strength increase and 78% of ductility increase were achieved simultaneously. Post-tensile TEM analysis revealed that those in-cell Al4C3 nanorods pinned and accumulated dislocations within cells and thus alleviated stress concentration along cell boundaries.

Abstract It was reported that the 2020 guideline for hypersensitivity pneumonitis (HP) might result in the overdiagnosis of fibrotic HP (fHP). fHP and other types of interstitial pneumonias have several overlapping characteristics, and a high diagnostic concordance rate of fHP is rarely obtained. Therefore, we investigated the impact of the 2020 HP guideline on the pathological diagnosis of cases previously diagnosed as interstitial pneumonia. We identified 289 fibrotic interstitial pneumonia cases from 2014 to 2019 and classified them into four categories according to the 2020 HP guideline: typical, probable, and indeterminate for fHP and alternative diagnosis. The original pathological diagnosis of 217 cases were compared to their classification as either typical, probable, or indeterminate for fHP according to the 2020 guideline. The clinical data, including serum data and pulmonary function tests, were compared among the groups. Diagnoses changed from non-fHP to fHP for 54 (25%) of the 217 cases, of which, 8 were typical fHP and 46 were probable fHP. The ratio of typical and probable fHP cases to the total number of VATS cases was significantly lower when using transbronchial lung cryobiopsy (p

Abstract Background Since it was first reported in December 2019, coronavirus disease 2019 (COVID‐19) spread rapidly across the globe resulting in a pandemic. As of August 2022, seven outbreak peaks have been confirmed in Tokyo, and the numbers of new cases in the fifth and later outbreak periods have been far greater than in the preceding periods. This retrospective study examined the impact of the COVID‐19 pandemic on perioperative chemotherapy for breast cancer. Methods Patients with breast cancer who received perioperative chemotherapy at the National Cancer Center Hospital East were divided into 2 groups: 120 and 384 patients who started chemotherapy before and during the pandemic, respectively. The incidence of critical events that had potential detrimental effects on the prognosis, such as start of adjuvant chemotherapy ≥91 days after surgery and relative dose intensity of chemotherapy

The specification of the embryonic central nervous system (CNS) into future brain (forebrain, midbrain, or hindbrain) and spinal cord (SC) regions is a critical step of CNS development. A previous chicken embryo study indicated that anterior epiblast cells marked by Sox2 N2 enhancer activity are specified to the respective brain regions during the transition phase of the epiblast to the neural plate-forming neural primordium. The present study showed that the SC precursors positioned posterior to the hindbrain precursors in the anterior epiblast migrated posteriorly in contrast to the anterior migration of brain precursors. The anteroposterior specification of the CNS precursors occurs at an analogous time (∼E7.5) in mouse embryos, in which an anterior-to-posterior incremental gradient of Wnt signal strength was observed. To examine the possible Wnt signal contribution to the anteroposterior CNS primordium specification, we utilized mouse epiblast stem cell (EpiSC)-derived neurogenesis in culture. EpiSCs maintained in an activin- and FGF2-containing medium start neural development after the removal of activin, following a day in a transitory state. We placed activin-free EpiSCs in EGF- and FGF2-containing medium to arrest neural development and expand the cells into neural stem cells (NSCs). Simultaneously, a Wnt antagonist or agonist was added to the culture, with the anticipation that different levels of Wnt signals would act on the transitory cells to specify CNS regionality; then, the Wnt-treated cells were expanded as NSCs. Gene expression profiles of six NSC lines were analyzed using microarrays and single-cell RNA-seq. The NSC lines demonstrated anteroposterior regional specification in response to increasing Wnt signal input levels: forebrain-midbrain-, hindbrain-, cervical SC-, and thoracic SC-like lines. The regional coverage of these NSC lines had a range; for instance, the XN1 line expressed Otx2 and En2, indicating midbrain characteristics, but additionally expressed the SC-characteristic Hoxa5. The ranges in the anteroposterior specification of neural primordia may be narrowed as neural development proceeds. The thoracic SC is presumably the posterior limit of the contribution by anterior epiblast-derived neural progenitors, as the characteristics of more posterior SC regions were not displayed.

Musical compositions are distinguished by their unique rhythmic patterns, determined by subtle differences in how regular beats are subdivided. Precise perception of these subdivisions is essential for discerning nuances in rhythmic patterns. While musical rhythm typically comprises sound elements with a variety of timbres or spectral cues, the impact of such spectral variations on the perception of rhythmic patterns remains unclear. Here, we show that consistency in spectral cues affects perceptual accuracy in discriminating subdivided rhythmic patterns. We conducted online experiments using rhythmic sound sequences consisting of band-passed noise bursts to measure discrimination accuracy. Participants were asked to discriminate between a swing-like rhythm sequence, characterized by a 2:1 interval ratio, and its more or less exaggerated version. This task was also performed under two additional rhythm conditions: inversed-swing rhythm (1:2 ratio) and regular subdivision (1:1 ratio). The center frequency of the band noises was either held constant or alternated between two values. Our results revealed a significant decrease in discrimination accuracy when the center frequency was alternated, irrespective of the rhythm ratio condition. This suggests that rhythm perception is shaped by temporal structure and affected by spectral properties.

Laser powder bed fused (LPBFed) AlSi10Mg is recognised for its superior mechanical properties. However, its thermal stability has never been justified. Herein, we exposed as-built AlSi10Mg to different temperatures (200–500°C) for only 3 min to evaluate its thermal stability. Results showed that LPBFed AlSi10Mg had relatively low thermal stability. Only 3 min of thermal exposure at 200°C would deteriorate its tensile strength dramatically. Microstructural analysis revealed that with increasing thermal input, as-built AlSi10Mg exhibited a microstructural evolution similar to annealing of cold-worked metals, namely recovery, recrystallisation followed by grain-growth. The excessive energy stored in as-built microstructure due to fast cooling during LPBF was deduced as the driving force for this phenomenon. Therefore, such microstructural change was at the expense of dislocations stored in the as-built material, which in turn caused deterioration in tensile strength. The present findings may provide guidance for the application of LPBFed AlSi10Mg.

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a severe complication associated with a high mortality. However, evidence and guidance on management is sparse. The aim of this international survey was to assess differences in prevention, diagnostic and treatment strategies for AE-IPF in specialised and non-specialised ILD centres worldwide. Material and Methods: Pulmonologists working in specialised and non-specialised ILD centres were invited to participate in a survey designed by an international expert panel. Responses were evaluated in respect to the physicians institutions. Results: Three hundred and two (65%) of the respondents worked in a specialised ILD centre, 134 (29%) in a non-specialised pulmonology centre. Similarities were frequent with regards to diagnostic methods including radiology and screening for infection, treatment with corticosteroids, use of high-flow oxygen and non-invasive ventilation in critical ill patients and palliative strategies. However, differences were significant in terms of the use of KL-6 and pathogen testing in urine, treatments with cyclosporine and recombinant thrombomodulin, extracorporeal membrane oxygenation in critical ill patients as well as antacid medication and anaesthesia measures as preventive methods. Conclusion: Despite the absence of recommendations, approaches to the prevention, diagnosis and treatment of AE-IPF are comparable in specialised and non-specialised ILD centres, yet certain differences in the managements of AE-IPF exist. Clinical trials and guidelines are needed to improve patient care and prognosis in AE-IPF.

BackgroundChronic hypersensitivity pneumonitis (CHP) is an immune-mediated interstitial lung disease (ILD) caused by inhalational exposure to environmental antigens, resulting in parenchymal fibrosis. By definition, a diagnosis of CHP assumes a history of antigen exposure, but only half of all patients eventually diagnosed with CHP will have a causative antigen identified. Individual clinician variation in eliciting a history of antigen exposure may affect the frequency and confidence of CHP diagnosis.MethodsA list of potential causative exposures were derived from a systematic review of the literature. A Delphi method was applied to an international panel of ILD experts to obtain consensus regarding technique for the elicitation of exposure to antigens relevant to a diagnosis of CHP. The consensus threshold was set at 80% agreement, and median ≤ 2, interquartile range = 0 on a 5-point Likert scale (1, strongly agree; 2, tend to agree; 3, neither agree nor disagree; 4, disagree; 5, strongly disagree).ResultsIn two rounds, 36/40 experts participated. Experts agreed on 18 exposure items to ask every patient with suspected CHP. Themes included CHP inducing exposures, features that contribute to an exposure's relevance, and quantification of a relevant exposure. Based on the results from the literature review and Delphi process, a CHP exposure assessment instrument was derived. Using cognitive interviews, the instrument was revised by patients with ILD for readability and usability.ConclusionsThis Delphi survey provides items that ILD experts agree are important to ask in all patients presenting with suspected CHP and provides basis for a systematically derived CHP exposure assessment instrument. Clinical utility of this exposure assessment instrument may be affected by different local prevalence patterns of exposures. Ongoing research is required to clinically validate these items and consider their impact in more geographically diverse settings.

Objective: We aimed to elucidate the pathogenesis of ovarian cancer through the loss of mismatch repair (MMR) proteins in women with Lynch syndrome (LS) in this report. Case report: Two women with LS underwent surgery for synchronous endometrial cancer and ovarian cancer. In both cases, immunohistochemical examination showed concomitant MMR protein deficiency in endometrial cancer, ovarian cancer, and contiguous ovarian endometriosis. In Case 1, the macroscopically normal ovary included multiple endometrioses with MSH2 and MSH6 expression, and FIGO grade 1 endometrioid carcinoma and contiguous endometriosis without MSH2 and MSH6 expression. In Case 2, all endometriotic cells contiguous with carcinoma in the lumen of the ovarian cyst showed loss of the expression of MSH2 and MSH6. Conclusion: Ovarian endometriosis with MMR protein deficiency may progress to endometriosis-associated ovarian cancer in women with LS. Diagnosing endometriosis in women with LS during surveillance is important.