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Various transcatheter interventions for the right ventricular outflow tract (RVOT) have been introduced and developed in recent decades. Transcatheter pulmonary valve perforation was first introduced in the 1990s. Radiofrequency wire perforation has been the approach of choice for membranous pulmonary atresia in newborns, with high success rates, although complication rates remain relatively common. Stenting of the RVOT is a novel palliative treatment that may improve hemodynamics in neonatal patients with reduced pulmonary blood flow and RVOT obstruction. Whether this option is superior to other surgical palliative strategies or early primary repair of tetralogy of Fallot remains unclear. Transcatheter pulmonary valve replacement has been one of the biggest innovations in the last two decades. With the success of the Melody and SAPIEN valves, this technique has evolved into the gold standard therapy for RVOT abnormalities with excellent procedural safety and efficacy. Challenges remain in managing the wide heterogeneity of postoperative lesions seen in RVOT, and various technical modifications, such as pre-stenting, valve ring modification, or development of self-expanding systems, have been made. Recent large studies have revealed outcomes comparable to those of surgery, with less morbidity. Further experience and multicenter studies and registries to compare the outcomes of various strategies are necessary, with the ultimate goal of a single-step, minimally invasive approach offering the best longer-term anatomical and physiological results., (Copyright ©2024 The Author(s).)

Background: Transradial access (TRA) is not a common vascular access in children. We have been performing TRA actively to reduce puncture complications, and the purpose of this study was to investigate the safety and efficacy of TRA in young children., Methods: The study included 29 patients aged 5-12 years who underwent diagnostic catheterization at Kurume University Hospital. Vascular access was placed through TRA in 11 of these patients and through transfemoral access (TFA) in 18 patients with comparable ages. We compared TRA with TFA using various demographic data., Results: The median age of TRA was 10 years (5-12 years) and that of TFA was 7 years (5-11 years). They were not significantly different. Transradial access showed an acceptably high success rate (91%), which was comparable with that of TFA (100%), although we had to switch to TFA in one patient in which the radial artery diameter was too small to puncture and due to failure of appropriate sedation and local anesthesia. A comparison between the two groups showed no significant differences in weight, puncture success rate, total time to completion of both arterial and venous puncture, or fluoroscopy time. However, none of the patients with TRA required post-catheter bed rest after removal of the arterial sheath, whereas patients with TFA required 6 h of bed rest. Although there were no puncture complications in group TRA, one patient with TFA had a subcutaneous hematoma., Conclusion: Transradial access can be performed safely in young children and may be more beneficial than TFA., (© 2024 Japan Pediatric Society.)

Background: This study aimed to determine whether ongoing vascular inflammation presents in patients who had coronary artery aneurysms (CAAs) caused by Kawasaki disease (KD)., Methods: Subjects were 26 patients with a history of KD; 15 had giant CAA (gCAA) ≥ 8.0 mm and 11 had smaller CAA (smCAA) < 8 mm in the acute phase. They underwent X-ray computed tomography and 18 F-fluorodeoxyglucose positron emission tomography. We determined the maximum coronary target-to-background ratio (CaTBR) and the mean thoracic aorta TBR (TaTBR) in each patient. They were compared between groups, and their correlation with various variables was determined., Results: CaTBR and TaTBR were significantly higher in gCAA than in smCAA (P < .005 for both values) and were significantly higher even in patients without any metabolic risk factor (P < .05 for both values). The CAA size in acute phase significantly positively correlated with CaTBR (R 2 = 0.32) as well as TaTBR (R 2 = 0.28). Also, TaTBR significantly positively correlated with CaTBR (R 2 = 0.32) as well as cumulative number of metabolic risk factors (trend, P = .03)., Conclusions: Ongoing vascular inflammation may present long after KD, especially in patients with severe inflammation expressed as gCAA in the acute phase., (© 2022. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Introduction: Metastatic urothelial carcinomas are common in lung, liver, and lymph nodes. We present rare secondary tumor of the prostate metastasized from upper tract urothelial carcinoma., Case Presentation: An 87-year-old man was diagnosed as urothelial carcinoma of left upper tract and bladder. Only transurethral resection of bladder tumor was performed as palliative therapy to control hematuria. Thereafter, the tumor of left upper tract showed aggressive progression with multiple metastases involving lymph nodes and bilateral lungs. Finally, autopsy revealed swelling of left kidney due to tumor growth and systemic cancer disseminations involving bilateral lungs and renal hilar lymph nodes. In addition, prostate tumor was found incidentally. Histological examination including immunohistochemistry revealed the prostate tumor as metastatic tumor from urothelial carcinoma of left renal pelvis., Conclusion: We reported rare secondary tumor of the prostate, derived from upper tract urothelial carcinoma. Further consideration would be required to provide better knowledge of the disease., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.)

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin's lymphoma, which is characterized by overexpression of cyclin D1. Although novel drugs, such as ibrutinib, show promising clinical outcomes, relapsed MCL often acquires drug resistance. Therefore, alternative approaches for refractory and relapsed MCL are needed. Here, we examined whether a novel inhibitor of enhancer of zeste homologs 1 and 2 (EZH1/2), OR-S1 (a close analog of the clinical-stage compound valemetostat), had an antitumor effect on MCL cells. In an ibrutinib-resistant MCL patient-derived xenograft (PDX) mouse model, OR-S1 treatment by oral administration significantly inhibited MCL tumor growth, whereas ibrutinib did not. In vitro growth assays showed that compared with an established EZH2-specific inhibitor GSK126, OR-S1 had a marked antitumor effect on MCL cell lines. Furthermore, comprehensive gene expression analysis was performed using OR-S1-sensitive or insensitive MCL cell lines and showed that OR-S1 treatment modulated B-cell activation, differentiation, and cell cycle. In addition, we identified Cyclin Dependent Kinase Inhibitor 1C (CDKN1C, also known as p57, KIP2), which contributes to cell cycle arrest, as a direct target of EZH1/2 and showed that its expression influenced MCL cell proliferation. These results suggest that EZH1/2 may be a potential novel target for the treatment of aggressive ibrutinib-resistant MCL via CDKN1C-mediated cell cycle arrest., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Transcatheter closure of patent ductus arteriosus (TC-PDA), conventionally guided by aortography, has become the standard treatment of this disease. The purposes of this study were to evaluate whether intracardiac echocardiography (ICE) may be used for measuring PDA size and be used as a guide for TC-PDA., Methods: This study had 2 phases. In phase 1, we compared the measurements of PDA size: pulmonary artery side diameter (PA-D), length, and aortic side diameter (Ao-D) of PDA, as measured by ICE with those measured by aortography or cardiac computed tomography (AoG/CCT) in 23 patients who underwent TC-PDA. In phase 2, we compared the demographics, fluoroscopic time, contrast volume, and complications of the TC-PDAs between 10 adult patients with ICE guidance and 16 without it., Results: In phase 1, we found great correlation and agreement between ICE and AoG/CCT in PA-D ( r  = 0.985, bias -0.077 to 0.224), but moderate to poor correlation and agreement in length ( r  = 0.653, bias -0.491 to 3.065) and Ao-D ( r  = 0.704, bias 0.738 to 4.732), respectively. Nevertheless, all patients underwent successful TC-PDA with ICE guidance that allowed us to continuously monitor the whole process. In phase 2, TC-PDA required a significantly lower contrast volume with ICE guidance than without it, and there was no significant difference in the remaining variables between the 2 groups., Conclusion: ICE is comparable to AoG/CCT in providing accurate PA-D of the PDA and may be a safe alternative to guide TC-PDA as compared to conventional aortography., Competing Interests: The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2020 Hironaga Yoshimoto et al.)

Background: Growth differentiation factor 15 (GDF 15) is a member of the transforming growth factor-beta superfamily and is considered to be a useful biomarker for severity of heart failure (HF) in repaired congenital heart disease (CHD). The aim of this study was to determine the clinical implication of GDF 15 in children with unrepaired CHD., Methods: Subjects included 69 patients (≤14 years old) who had unrepaired CHD with left to right shunt and underwent cardiac catheterization. Demographic and hemodynamic data, including oxygen demand-supply relationship, were collected from medical records. Severity of HF was evaluated using modified Ross score. Serum GDF 15 levels were determined using enzyme-linked immunosorbent assay and correlated with patients' demographics, hemodynamic data, and blood chemistry data., Results: Subjects had median age of 71 (range 1-173) months and simple acyanotic CHDs with mean pulmonary to systemic flow ratio of 2.0 (1.0-5.6), median N-terminal pro type Brain natriuretic peptide (NT-pro-BNP) of 162.8 (17.1-8789) pg/mL, and median GDF 15 of 242.1 (13.6-1116.7) pg/mL. GDF 15 significantly positively correlated with the modified Ross score, mean pulmonary artery pressure, oxygen extraction rate (OER), and Ln NT-pro-BNP, but negatively correlated with age, oxygen delivery and its components, and estimated glomerular filtration rate (eGFR). Multiple linear regression analysis revealed significant correlation of GDF 15 levels with the modified Ross score, OER, and eGFR., Conclusions: GDF 15 mainly reflects oxygen demand-supply relationship and can be used as a diagnostic marker of HF in unrepaired CHD with left to right shunt for a wide range of age and diagnoses., (Copyright © 2019. Published by Elsevier Ltd.)

Chronic myelomonocytic leukemia (CMML) constitutes a hematopoietic stem cell (HSC) disorder characterized by prominent monocytosis and myelodysplasia. Although genome sequencing has revealed the CMML mutation profile, the mechanism of disease development remains unclear. Here we show that aberrant histone acetylation by nucleoporin-98 (NUP98)-HBO1, a newly identified fusion in a patient with CMML, is sufficient to generate clinically relevant CMML pathogenesis. Overexpression of NUP98-HBO1 in murine HSC/progenitors (HSC/Ps) induced diverse CMML phenotypes, such as severe leukocytosis, increased CD115 + Ly6C high monocytes (an equivalent subpopulation to human classical CD14 + CD16 - monocytes), macrocytic anemia, thrombocytopenia, megakaryocyte-lineage dysplasia, splenomegaly, and cachexia. A NUP98-HBO1-mediated transcriptional signature in human CD34 + cells was specifically activated in HSC/Ps from a CMML patient cohort. Besides critical determinants of monocytic cell fate choice in HSC/Ps, an oncogenic HOXA9 signature was significantly activated by NUP98-HBO1 fusion through aberrant histone acetylation. Increased HOXA9 gene expression level with disease progression was confirmed in our CMML cohort. Genetic disruption of NUP98-HBO1 histone acetyltransferase activity abrogated its leukemogenic potential and disease development in human cells and a mouse model. Furthermore, treatment of azacytidine was effective in our CMML mice. The recapitulation of CMML clinical phenotypes and gene expression profile by the HBO1 fusion suggests our new model as a useful platform for elucidating the central downstream mediators underlying diverse CMML-related mutations and testing multiple compounds, providing novel therapeutic potential., (© 2019 by The American Society of Hematology.)

Multiple myeloma (MM) is an incurable hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs as a result of a remaining population of drug-resistant myeloma stem cells. Side population (SP) cells show cancer stem cell-like characteristics in MM; thus, targeting these cells is a promising strategy to completely cure this malignancy. Herein, we showed that SP cells expressed higher levels of enhancer of zeste homolog (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non-SP cells, suggesting that EZH1 as well as EZH2 contributes to the stemness maintenance of the MM cells and that targeting both EZH1/2 is potentially a significant therapeutic approach for eradicating myeloma stem cells. A novel orally bioavailable EZH1/2 dual inhibitor, OR-S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including a unique patient-derived xenograft model. Moreover, long-term continuous dosing of OR-S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling in MM, and overactivation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells and negatively affected tumorigenesis, suggesting that repression of WNT signaling by PRC2 plays an important role in stemness maintenance of MM cells. Our results show the role of EZH1/2 in the maintenance of myeloma stem cells and provide a preclinical rationale for therapeutic application of OR-S1, leading to significant advances in the treatment of MM., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

A 20-year-old patient, who had double outlet right ventricle, mitral atresia, pulmonary atresia, and bilateral superior vena cava and underwent successful lateral tunnel total cavo-pulmonary connection at 6 years old, presented with frequent watery diarrhea, general malaise, and tetany. He was known to have intractable protein-losing enteropathy (PLE) from 7 years of age that was resistant to various treatments. To keep hemodynamics stable, he required intravenous albumin infusion every day. Fontan fenestration partially improved his condition and allowed to stop albumin infusion, however still he showed muddy stool and cachexia with low serum albumin <20 g/L and immunoglobulin <3 g/L. Because of serious risk of infection, we placed him on regular subcutaneous immunoglobulin supplementation with rescue intravenous immunoglobulin that improved his PLE within a month and allowed him to be discharged. This case illustrates that immunoglobulin supplementation can be one of the choices of treatment for intractable PLE. < Learning objective: Combined subcutaneous and intravenous immunoglobulin infusion therapy can be one of the choices of treatment for intractable protein-losing enteropathy that does not respond to multiple medications.>.

RUNX1a , but not RUNX1b , is overexpressed in CD34 + cells from patients with myelodysplastic/myeloproliferative neoplasms. SRSF2 P95H mutation induces RUNX1a overexpression and a monocytic phenotype in TF-1 cells., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.

Purpose: This study describes the use of CT images in atlas-based automated planning methods for acetabular cup implants in total hip arthroplasty (THA). The objective of this study is to develop an automated cup planning method considering the statistical distribution of the residual thickness., Methods: From a number of past THA planning datasets, we construct two statistical atlases that represent the surgeon's expertise. The first atlas is a pelvis-cup merged statistical shape model (PC-SSM), which encodes global spatial relationships between the patient anatomy and implant. The other is a statistical residual thickness map (SRTM) of the implant surface, which encodes local spatial constraints of the anatomy and implant. In addition to PC-SSM and SRTM, we utilized the minimum thickness as a threshold constraint to prevent penetration., Results: The proposed method was applied to the pelvis shapes segmented from CT images of 37 datasets of osteoarthritis patients. Automated planning results with manual segmentation were compared to the plans prepared by an experienced surgeon. There was no significant difference in the average cup size error between the two methods (1.1 and 1.2 mm, respectively). The average positional error obtained by the proposed method, which integrates the two atlases, was significantly smaller (3.2 mm) than the previous method, which uses single atlas (3.9 mm). In the proposed method with automated segmentation, the size error of the proposed method for automated segmentation was comparable (1.1 mm) to that for manual segmentation (1.1 mm). The average positional error was significantly worse (4.2 mm) than that using manual segmentation (3.2 mm). If we only consider mildly diseased cases, however, there was no significance between them (3.2 mm in automated and 2.6 mm in manual segmentation)., Conclusion: We infer that integrating PC-SSM and SRTM is a useful approach for modeling experienced surgeon's preference during cup planning.

Recent progress in high-speed sequencing technology has revealed that tumors harbor novel mutations in a variety of genes including those for molecules involved in epigenetics and splicing, some of which were not categorized to previously thought malignancy-related genes. However, despite thorough identification of mutations in solid tumors and hematological malignancies, how these mutations induce cell transformation still remains elusive. In addition, each tumor usually contains multiple mutations or sometimes consists of multiple clones, which makes functional analysis difficult. Fifteen years ago, it was proposed that combination of two types of mutations induce acute leukemia; Class I mutations induce cell growth or inhibit apoptosis while class II mutations block differentiation, co-operating in inducing acute leukemia. This notion has been proven using a variety of mouse models, however most of recently found mutations are not typical class I/II mutations. Although some novel mutations have been found to functionally work as class I or II mutation in leukemogenesis, the classical class I/II theory seems to be too simple to explain the whole story. We here overview the molecular basis of hematological malignancies based on clinical and experimental results, and propose a new working hypothesis for leukemogenesis., (© The Authors 2015. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

IDH1 and IDH2 mutations occur frequently in acute myeloid leukemia (AML) and other cancers. The mutant isocitrate dehydrogenase (IDH) enzymes convert α-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), which dysregulates a set of α-KG-dependent dioxygenases. To determine whether mutant IDH enzymes are valid targets for cancer therapy, we created a mouse model of AML in which mice were transplanted with nucleophosmin1 (NPM)(+/-) hematopoietic stem/progenitor cells cotransduced with four mutant genes (NPMc, IDH2/R140Q, DNMT3A/R882H, and FLT3/ITD), which often occur simultaneously in human AML patients. Conditional deletion of IDH2/R140Q blocked 2-HG production and maintenance of leukemia stem cells, resulting in survival of the AML mice. IDH2/R140Q was necessary for the engraftment or survival of NPMc(+) cells in vivo. Gene expression analysis indicated that NPMc increased expression of Hoxa9. IDH2/R140Q also increased the level of Meis1 and activated the hypoxia pathway in AML cells. IDH2/R140Q decreased the 5hmC modification and expression of some differentiation-inducing genes (Ebf1 and Spib). Taken together, our results indicated that IDH2 mutation is critical for the development and maintenance of AML stem-like cells, and they provided a preclinical justification for targeting mutant IDH enzymes as a strategy for anticancer therapy., (©2015 American Association for Cancer Research.)

High levels of HES1 expression are frequently found in BCR-ABL(+) chronic myelogenous leukemia in blast crisis (CML-BC). In mouse bone marrow transplantation (BMT) models, co-expression of BCR-ABL and Hes1 induces CML-BC-like disease; however, the underlying mechanism remained elusive. Here, based on gene expression analysis, we show that MMP-9 is upregulated by Hes1 in common myeloid progenitors (CMPs). Analysis of promoter activity demonstrated that Hes1 upregulated MMP-9 by activating NF-κB. Analysis of 20 samples from CML-BC patients showed that MMP-9 was highly expressed in three, with two exhibiting high levels of HES1 expression. Interestingly, MMP-9 deficiency impaired the cobblestone area-forming ability of CMPs expressing BCR-ABL and Hes1 that were in conjunction with a stromal cell layer. In addition, CMPs expressing BCR-ABL and Hes1 secreted MMP-9, promoting the release of soluble Kit-ligand (sKitL) from stromal cells, thereby enhancing proliferation of the leukemic cells. In accordance, mice transplanted with CMPs expressing BCR-ABL and Hes1 exhibited high levels of sKitL as well as MMP-9 in the serum. Importantly, MMP-9 deficiency impaired the development of CML-BC-like disease induced by BCR-ABL and Hes1 in mouse BMT models. The present results suggest that Hes1 promotes the development of CML-BC, partly through MMP-9 upregulation in leukemic cells., (© 2014 by The American Society of Hematology.)

Myeloid malignancies consist of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasm (MPN). The latter two diseases have preleukemic features and frequently evolve to AML. As with solid tumors, multiple mutations are required for leukemogenesis. A decade ago, these gene alterations were subdivided into two categories: class I mutations stimulating cell growth or inhibiting apoptosis; and class II mutations that hamper differentiation of hematopoietic cells. In mouse models, class I mutations such as the Bcr-Abl fusion kinase induce MPN by themselves and some class II mutations such as Runx1 mutations induce MDS. Combinations of class I and class II mutations induce AML in a variety of mouse models. Thus, it was postulated that hematopoietic cells whose differentiation is blocked by class II mutations would autonomously proliferate with class I mutations leading to the development of leukemia. Recent progress in high-speed sequencing has enabled efficient identification of novel mutations in a variety of molecules including epigenetic factors, splicing factors, signaling molecules and proteins in the cohesin complex; most of these are not categorized as either class I or class II mutations. The functional consequences of these mutations are now being extensively investigated. In this article, we will review the molecular basis of hematological malignancies, focusing on mouse models and the interfaces between these models and clinical findings, and revisit the classical class I/II hypothesis.

This paper describes a method for automated optimization of total hip arthroplasty (THA) planning incorporating joint functionalities. The optimal planning is formulated as maximum a posterior (MAP) estimation, which ensures the best-balance of joint functionalities and bone-implant spatial relations based on their statistical models derived from the training datasets prepared by an experienced surgeon. According to the performance evaluation, four of the six functionalities of the automatically optimized plans were almost equivalent to those of surgeon's plans, and two of them were improved. We consider these results showed a potential usefulness of the proposed method.

Activating mutations of c-Kit are frequently found in acute myeloid leukemia (AML) patients harboring t(8;21) chromosomal translocation generating a fusion protein AML1-ETO. Here we show that an active mutant of c-Kit cooperates with AML1-ETO to induce AML in mouse bone marrow transplantation models. Leukemic cells expressing AML1-ETO with c-Kit(D814V) were serially transplantable. Transplantation experiments indicated that lineage(-)c-Kit(+)Sca-1(+) (KSL) leukemic cells, but not lineage(+) leukemic cells, were enriched for leukemia stem cells (LSCs). Comparison of gene expression profiles between KSL leukemic and normal cells delineated that CD200R1 was highly expressed in KSL leukemic cells as compared with KSL normal cells. Upregulation of CD200R1 was verified in lineage(-) leukemic cells, but not in lineage(+) leukemic cells. CD200R1 expression in the lineage(-) leukemic cells was not correlated with the frequency of LSCs, indicating that CD200R1 is not a useful marker for LSCs in these models. Interestingly, CD200R1 was upregulated in KSL cells transduced with AML1-ETO, but not with other leukemogenic mutants, including c-Kit(D814V), AML1(D171N), and AML1(S291fsX300). Consistently, upregulation of CD200R1 in lineage(-) leukemic cells was observed only in the BM of mice suffering from AML1-ETO-positive leukemia. In conclusion, AML1-ETO upregulated CD200R1 in lineage(-) cells, which was characteristic of AML1-ETO-positive leukemia in mice.

Atlas-based methods for automated preoperative planning of the femoral stem implant in total hip arthroplasty are described. Statistical atlases are constructed from a number of past preoperative plans prepared by experienced surgeons in order to represent the surgeon's expertise of the planning. Two types of atlases are considered. One is a statistical distance map atlas, which represents surgeon's preference of the contact pattern between the femoral canal (host bone) and stem (implant) surfaces. The other is an optimal reference plan, which is selected as the best representative plan expected to minimize the deviation from the surgeon's preferred contact pattern. These atlases are fitted to the patient data to automatically generate the preoperative plan of the femoral stem. In this paper, we formulate a general framework of atlas-based implant planning, and then describe the methods for construction and utilization of the two proposed atlases. In the experiments, we used 40 cases to evaluate the proposed methods and compare them with previous methods by defining the errors as differences between automated and surgeon's plans. By using the proposed methods, the positional and orientation errors were significantly reduced compared with the previous methods and the size error was superior to inter-surgeon variability in size selection using 2D templates on an X-ray image reported in previous work., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The Bcr-Abl oncogene causes human Philadelphia chromosome-positive (Ph(+)) leukemias, including B-cell acute lymphoblastic leukemia (B-ALL) and chronic myeloid leukemia (CML) with chronic phase (CML-CP) to blast crisis (CML-BC). Previous studies have demonstrated that Src family kinases are required for the induction of B-ALL, but not for CML, which is induced by Bcr-Abl in mice. In contrast, it has been reported that Fyn is up-regulated in human CML-BC compared with CML-CP, implicating Fyn in the blast crisis transition. Here, we aimed to delineate the exact role of Fyn in the induction/progression of Ph(+) leukemias. We found that Fyn is expressed in mouse hematopoietic cells at varying stages of development, including c-kit(+)Sca-1(+)Lin(-) cells. Notably, Fyn is highly expressed in some of human lymphomas, but not in human Ph(+) leukemias including CML-BC. In mouse bone marrow transplantation models, mice transplanted with wild-type or Fyn-deficient bone marrow cells transduced with Bcr-Abl showed no differences in the development of B-ALL or CML-like diseases. Similarly, Fyn deficiency failed to impact the development of myeloid CML-BC induced by Bcr-Abl and Hes1. Elevated expression of Fyn was not found in mouse samples of Bcr-Abl-mediated CML- and CML-BC-like diseases. Thus, Fyn is not required for the pathogenesis of Bcr-Abl-mediated leukemias.

The indigenous bacteria create natural cohabitation niches together with mucosal Abs in the gastrointestinal (GI) tract. Here we report that opportunistic bacteria, largely Alcaligenes species, specifically inhabit host Peyer's patches (PPs) and isolated lymphoid follicles, with the associated preferential induction of antigen-specific mucosal IgA Abs in the GI tract. Alcaligenes were identified as the dominant bacteria on the interior of PPs from naïve, specific-pathogen-free but not from germ-free mice. Oral transfer of intratissue uncultured Alcaligenes into germ-free mice resulted in the presence of Alcaligenes inside the PPs of recipients. This result was further supported by the induction of antigen-specific Ab-producing cells in the mucosal (e.g., PPs) but not systemic compartment (e.g., spleen). The preferential presence of Alcaligenes inside PPs and the associated induction of intestinal secretory IgA Abs were also observed in both monkeys and humans. Localized mucosal Ab-mediated symbiotic immune responses were supported by Alcaligenes-stimulated CD11c(+) dendritic cells (DCs) producing the Ab-enhancing cytokines TGF-beta, B-cell-activating factor belonging to the TNF family, and IL-6 in PPs. These CD11c(+) DCs did not migrate beyond the draining mesenteric lymph nodes. In the absence of antigen-specific mucosal Abs, the presence of Alcaligenes in PPs was greatly diminished. Thus, indigenous opportunistic bacteria uniquely inhabit PPs, leading to PP-DCs-initiated, local antigen-specific Ab production; this may involve the creation of an optimal symbiotic environment on the interior of the PPs.

Intraoperative robotic and computer-guided assistances are now commonly used in total hip arthroplasty (THA) for accurate execution of the preoperative plan. Although the preoperative plan to be accurately executed is critical, it is still interactively prepared in a time-consuming and subjective manner. In this paper, atlas-based approach to automated surgical planning of the acetabular cup in THA is described to stabilize its quality as well as reduce its time-consuming nature. Surgeon's expertise is embedded in two types of statistical atlases, which are constructed from training datasets of CT-based 3D plans prepared by experienced surgeons. One is a statistical shape model which encodes global spatial relationships between the patient anatomy and implant. The other is the statistical map of residual bone thickness on the implant surface, which encodes local spatial constraints of the anatomy and implant. Given the 3D pelvis shape of the patient, we formulate a procedure to determine the best size and position of the acetabular cup which satisfy the constraints derived from the two statistical atlases. We validated the proposed planning method by retrospective study using the datasets which were actually used in the THA surgery.

It is well established that Peyer's patches (PPs) are sites for the differentiation of IgA plasma cell precursors, but molecular and cellular mechanisms in their trafficking remain to be elucidated. In this study, we show that alterations in type 1 sphingosine 1-phosphate (S1P) receptor expression during B cell differentiation in the PPs control the emigration of IgA plasma cell precursors. Type 1 S1P receptor expression decreased during the differentiation of IgM(+)B220(+) B cells to IgA(+)B220(+) B cells, but recovered on IgA(+)B220(-) plasmablasts for their emigration from the PPs. Thus, IgA(+)B220(-) plasmablasts migrated in response to S1P in vitro. Additionally, IgA(+) plasmablasts selectively accumulated in lymphatic regions of PPs when S1P-mediated signaling was disrupted by FTY720 treatment. This accumulation of IgA(+) plasmablasts in the PPs led to their reduction in the intestinal lamina propria and simultaneous impairment of Ag-specific intestinal IgA production against orally administered Ag. These findings suggest that S1P regulates the retention and emigration of PP B cells and plays key roles in the induction of intestinal IgA production.

The problem of automating preoperative planning of the femoral component (stem) for total hip arthroplasty (THA) is addressed. In our previous method, time-consuming trial-and-error processes were involved in parameter tuning of the objective function. This problem prevents application in different stem systems. To overcome this problem, a statistical surgical plan atlas (SSPA) is constructed from training datasets of stem planning. The SSPA represents the average and variance of the distance distribution on the stem surface to the femoral canal surface. That is, it encodes the distribution of the degree of contact preferred by the surgeon. Automated planning is performed by minimizing the squared difference between distributions of the SSPA and planning solution. The proposed method involves no parameter tuning to define the objective function that evaluates differences from the planning the surgeon prefers. Experimental evaluations showed that the proposed method renders parameter tuning unnecessary while it still provides comparable accuracy to the previous method.

Dorsal-ventral (DV) specification in the early optic vesicle plays a crucial role in the proper development of the eye. To address the questions of how DV specification is determined and how it affects fate determination of the optic vesicle, isolated optic vesicles were cultured either in vitro or in ovo. The dorsal and ventral halves of the optic vesicle were fated to develop into retinal pigment epithelium (RPE) and neural retina, respectively, when they were separated from each other and cultured. In optic vesicles treated with collagenase to remove the surrounding tissues, the neuroepithelium gave rise to cRax expression but not Mitf, suggesting that surrounding tissues are necessary for RPE specification. This was also confirmed in in ovo explant cultures. Combination cultures of collagenase-treated optic vesicles with either the dorsal or ventral part of the head indicated that head-derived factors have an important role in the fate determination of the optic vesicle: in the optic vesicles co-cultured with the dorsal part of the head Mitf expression was induced in the neuroepithelium, while the ventral head portion did not have this effect. The dorsal head also suppressed Pax2 expression in the optic vesicle. These observations indicate that factors from the dorsal head portion have important roles in the establishment of DV polarity within the optic vesicle, which in turn induces the patterning and differentiation of the neural retina and pigment epithelium.

The comprehensive bioconversion of aromatic compounds with a benzene ring to a picolinic acid was achieved with a recombinant Escherichia coli strain that expressed the six genes involved in biphenyl catabolism, these being the bphA1(2072)A2A3A4 genes encoding the evolved biphenyl dioxygenase, the bphB gene encoding dihydrodiol dehydrogenase, and the bphC gene encoding catechol 2,3-dioxygenase.

A case of acute myocardial infarction associated with primary coronary dissection was followed up angiographically. A 46-year-old woman complained of chest oppression. Electrocardiogram on admission showed ST-segment elevation in V1-5. Urgent coronary angiography was performed under a diagnosis of acute anterior myocardial infarction, and showed a significant stenosis with multiple filling defects in segments 7-8 (99% with severe delay) in the left anterior descending artery. There was no organic lesion in the right coronary artery. Intracoronary thrombolytic therapy was unsuccessful, and thereafter she was treated with aspirin, warfarin and isosorbide dinitrate. Coronary angiography performed 1 month later revealed a long dissection with double lumens in segments 7-8. The septal branches emerged from the smaller lumen. Two months later, the 2 lumens were almost equal in size. These findings indicated that coronary dissection produced a false lumen with an entry in segment 7 and a reentry in segment 8, and that the false lumen was responsible for the greater flow. Four months later, the flow in the true lumen had improved remarkably while that in the false lumen had almost disappeared. She remained in stable condition during the follow-up period of 4 months.

Since it is very rare that cardiac tamponade due to myocardial rupture caused by infective endocarditis, occurs we are reporting this case. A 62 year old man, who had underlying diseases of pneumoconiosis and hypertensive heart disease, visited Chikuho Rosai Hospital complaining of chest oppression and general fatigue on Feb. 7, 1987. He was diagnosed as having ischemic heart disease by electrocardiogram. Two days later, he suddenly had chills and a fever, and the laboratory data showed leukocytosis and a positive C-reactive protein (CRP). The echo cardiogram showed mitral regurgitation (MR) and aortic regurgitation (AR), but neither vegetation nor pericardial effusion was observed. On Feb. 16, he was admitted with shock, and he died the next day. The blood cultures grew gram-positive cocci, respectively. From the clinical symptoms, chest roentgenogram and electrocardiogram, we suspected a cardiac tamponade. On autopsy findings, though coronary arteries were intact, the aortic valves had severe valvular adhesions, calcifications and hypertrophies. The rupture hole was observed in the left ventricles, which was just under the aortic valve through the pericardiac space. It seemed that he died of a cardiac tamponade due to the outflow of blood from this hole. On histopathologic findings of the cardiac wall, gram-positive cocci and many of neutrophils were observed.

Ion-selective electrodes designed in our laboratory have been employed to determine the characteristics of the changes in extracellular K+ and pH associated with acute coronary artery ligation and release. These studies have defined major inhomogeneities in the rate and magnitude of change of extracellular K+ and pH not only at the lateral margin of the ischemic zone but also between the subepicardium and subendocardium, between the subendocardium and endocardium, and even between closely spaced electrodes throughout the ischemic zone. The inhomogeneities during reperfusion were as great as or greater than those induced by coronary ligation. We have used papillary muscles of guinea pigs to determine the effect of the various combinations of extracellular pH and K+ observed at any point in time in an intact heart to study the anticipated changes in conduction and have found both a speeding and a slowing of conduction, which can be expected to occur simultaneously in an intact heart. These results indicate that significant inhomogeneities exist in the ionic and electrical consequences of acute coronary artery ligation and release and that these inhomogeneities can be expected to result in disorders of conduction leading to reentry.