後天性血友病A (抗C2 自己抗体)の凝固機能低下におけるFX 複合体阻害様式の解明

Acquired haemophilia A (AHA) is caused by the development of factor (F)VIII autoantibodies, demonstrating type 1 or type 2 inhibitory behaviour, and results in more serious haemorrhagic symptoms than in congenital severe HA. The reason(s) for this remains unknown, however. The global coagulation assays, thrombin generation tests and clot waveform analysis, demonstrated that coagulation parameters in patients with AHA-type 2 inhibitor were more significantly depressed than those in patients with moderate HA with similar FVIII activities. Thrombin and intrinsic FXa generation tests were significantly depressed in AHA-type 1 and AHA-type 2 compared to severe HA, and more defective in AHA-type 1 than in AHA-type 2. To investigate these inhibitory mechanism(s), anti-FVIII autoantibodies were purified from AHA plasmas. AHA-type 1 autoantibodies, containing an anti-C2 ESH4-epitope, blocked FVIII(a)-phospholipid binding, whilst AHA-type 2, containing an anti-C2 ESH8-epitope, inhibited thrombin-catalysed FVIII activation. The coagulation function in a reconstituted AHA-model containing exogenous ESH4 or ESH8 was more abnormal than in severe HA. The addition of anti-FIX antibody to FVIII-deficient plasma resulted in lower coagulation function than its absence. These results support the concept that global coagulation might be more suppressed in AHA than in severe HA due to the inhibition of FIXa-dependent FX activation by steric hindrance in the presence of FVIII-anti-C2 autoantibodies. Additionally, AHA-type 1 inhibitors prevented FVIIIa-phospholipid binding, essential for the tenase complex, whilst AHA-type 2 antibodies decreased FXa generation by inhibiting thrombin-catalysed FVIII activation. These two distinct mechanisms might, in part, contribute to and exacerbate the serious haemorrhagic symptoms in AHA.博士（医学）・乙第1298号・平成24年5月28日© Schattauer Publishers, Stuttgart, 201

Far-infrared rays control prostate cancer cells _in vitro_ and _in vivo_

We introduce a new effective method to control hormone refractory prostate cancer cells by using an activated rubber/resin form (RB), far-infrared ray emitter, with or without sodium butyrate (SB). The growth of three human prostate cancer cell lines (Du145, PC-3 and LNCaP) was suppressed _in vitro_ and _in vivo_ by using RB, and the cells were eradicated with RB + 3 mM SB. G1 arrest and apoptotic pathway proteins were induced by RB with intensified expressions of apoptosis - related mRNA on cDNA microarray. RB radiates the infra-red rays of the 4 to 25 [mu]m wavelengths to an object which exert a favorable influence on a cancer control. These results may render us a new therapeutic modality in hormone refractory prostate cancer

Systemic Lymphadenectomy Cannot Be Recommended for Low-Risk Corpus Cancer

Objective. The objective of this study is to ascertain whether omission of lymphadenectomy could be possible when uterine corpus cancer is considered low-risk based on intraoperative pathologic indicators. Patient and Methods. Between 1998 and 2007, a total of 83 patients with low risk corpus cancer (endometrioid type, grade 1 or 2, myometrial invasion ≦50%, and no intraoperative evidence of macroscopic extrauterine spread, including pelvic and paraaortic lymph node swelling and adnexal metastasis) underwent the total abdominal hysterectomy and bilateral salpingo-oophorectomy without lymphadenectomy. A retrospective review of the medical records was performed, and the disease-free survival (DFS), overall survival (OS), peri- and postoperative morbidities and complications were evaluated. Results. The 5-year DFS rates and the 5-year OS rates were 97.6% and 98.8%, respectively. No patient presented postoperative leg lymphedema and deep venous thrombosis. Conclusion. Omission of lymphadenectomy did not worsen the DFS or OS. The present findings suggest that systemic lymphadenectomy could be omitted in low-risk endometrial carcinoma

New Paradigm in the Role of Regulatory T Cells During Pregnancy

Semi-allogenic fetuses are not rejected by the maternal immune system because feto-maternal tolerance induced by CD4+CD25+FoxP3+ regulatory T (Treg) cells is established during pregnancy. Paternal antigen-specific Treg cells accumulate during pregnancy, and seminal plasma priming plays an important role in expanding paternal antigen-specific Treg cells in mouse models. Although paternal-antigen specific Treg cells have not been identified in humans, recent studies suggest that antigen-specific Treg cells exist and expand at the feto-maternal interface in humans. Studies have also revealed that reduction of decidual functional Treg cells occurs during miscarriage with normal fetal chromosomal content, whereas insufficient clonal expansion of decidual Treg cells is observed in preeclampsia. In this review, we will discuss the recent advances in the investigation of mechanisms underlying Treg cell-dependent maintenance of feto-maternal tolerance

包括的凝固機能検査による急性期川崎病における止血動態の評価

Introduction: Kawasaki disease (KD) is a systemic vasculitis involving coronary arteries, sometimes resulting in aneurysms and myocardial infarction. Hyper-coagulability in the acute-phase of KD is indicated in some circumstances based on changes of individual clotting factors. Comprehensive coagulation assays, clot waveform analysis (CWA) and thrombin/plasmin generation assay (T/P-GA), have been developed to assess physiological hemostasis, but these techniques have not been applied in KD. Methods: We utilized both assays to analyze coagulation function in KD children (n = 42) prior to intravenous-immunoglobulin (IVIG) treatment (Pre), 1-week (1W) and 1-month (1M) post-IVIG. Results: In CWA, the clot time (CT) pre-treatment was prolonged, and was significantly shortened at 1W and 1M. However, the maximum coagulation velocity (|min1|) and acceleration (|min2|) were ~2-fold greater relative to controls, indicating an overall hypercoagulable tendency. These parameters were related to fibrinogen concentration, and were decreased at 1W and declined to normal at 1M. In T/P-GA, the endogenous potentials of thrombin and plasmin were greater relative to control at each of three time-points, and measurements at 1W were greater than those Pre-treatment. The ratios of TG and PG relative to control were similar, however, suggesting well-balanced dynamic coagulation and fibrinolysis. In non-responders to IVIG, the |min1| and |min2| measurements were greater than those in responders at 1W and 1M, suggesting that non-responders remained hypercoagulable after primary treatment. Conclusion: The coagulation data observed in KD were consistent with hypercoagulability, although fibrinolytic function appeared to be well-balanced. Comprehensive assays of this nature could provide valuable information on coagulation potential in KD.博士（医学）・乙第1441号・令和元年12月5日Copyright © 2018 Elsevier Ltd. All rights reserved

エミシズマブは凝固第VIII因子と同様にフィブリン構造およびその安定性を向上させる

Introduction: Emicizumab is an antifactor (F)IXa/FX bispecific antibody, mimicking FVIIIa cofactor function. Emi prophylaxis effectively reduces bleeding events in patients with haemophilia A. The physical properties of emicizumab-induced fibrin clots remain to be investigated, however. Aim: We have investigated the stability and structure of emicizumab-induced fibrin clots. Methods: Coagulation was initiated by activated partial thromboplastin time (aPTT) trigger and prothrombin time (PT)/aPTT-mixed trigger in FVIII-deficient plasma with various concentrations of emicizumab or recombinant FVIII. The turbidity and stability of fibrin clots were assessed by clot waveform and clot-fibrinolysis waveform analyses, respectively. The resulting fibrin was analysed by scanning electron microscopy (SEM). Results: Using an aPTT trigger, the turbidity was decreased and the fibrinolysis times were prolonged in the presence of emicizumab dose-dependently. Scanning electron microscopy imaging demonstrated that emicizumab improved the structure of fibrin network with thinner fibres than in its absence. Although emicizumab shortened the aPTT dramatically, the nature of emicizumab-induced fibrin clots did not reflect the hypercoagulable state. Similarly, using a PT/aPTT-mixed trigger that could evaluate potential emicizumab activity, emicizumab improved the stability and structure of fibrin clot in a series of experiments. In this circumstance, fibrin clot properties with emicizumab at 50 and 100 µg/mL appeared to be comparable to those with FVIII at ~12 and ~24-32 IU/dL, respectively. Conclusion: Emicizumab effectively improved fibrin clot stability and structure in FVIII-deficient plasma, and the physical properties of emicizumab-induced fibrin clots were similar to those with FVIII.博士（医学）・甲第787号・令和3年3月15日© 2020 John Wiley & Sons Ltd.This is the peer reviewed version of the following article: https://onlinelibrary.wiley.com/doi/10.1111/hae.13961, which has been published in final form at https://doi.org/10.1111/hae.13961. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions

包括的凝固/線溶動態に基づく敗血症性DIC（播種性血管内凝固）の病態解明

Background: The functional dynamics of coagulation and fibrinolysis in patients with disseminated intravascular coagulation (DIC) vary due to the pathology and severity of various underlying diseases. Conventional measurements of hemostasis such as thrombin-antithrombin complex, plasmin-α2-plasmin-inhibitor complex, and fibrinogen-fibrin degradation products may not always reflect critical pathophysiologic mechanisms in DIC. This article aims to clarify the pathology of sepsis-associated DIC using assessment of comprehensive coagulation and fibrinolysis. Methods: Plasma samples were obtained from 57 patients with sepsis-associated DIC at the time of initial diagnosis. Hemostasis parameters were quantified by clot-fibrinolysis waveform analysis (CFWA) and thrombin/plasmin generation assays (T/P-GA). The results were expressed as ratios relative to normal plasma. Results: CFWA demonstrated that the maximum coagulation velocity (|min1|) ratio modestly increased to median 1.40 (min - max: 0.10 - 2.60) but the maximum fibrinolytic velocity (|FL-min1|) ratio decreased to 0.61 (0 - 1.19). T/P-GA indicated that the peak thrombin (Th-Peak) ratio moderately decreased to 0.71 (0.22 - 1.20), whereas the peak plasmin (Plm-Peak) ratio substantially decreased to 0.35 (0.02 - 1.43). Statistical comparisons identified a correlation between |min1| and Th-Peak ratios (ρ = 0.55, p < 0.001), together with a strong correlation between |FL-min1| and Plm-Peak ratios (ρ = 0.71, p < 0.001), suggesting that CFWA reflected the balance between thrombin and plasmin generation. With |min1| and |FL-min1| ratios, DIC was classified as follows: coagulation-predominant, coagulation/fibrinolysis-balanced, fibrinolysis-predominant, and consumption-impaired coagulation. The majority of patients in our cohort (80.7%) were coagulation-predominant. Conclusion: A pathological clarification of sepsis-associated DIC based on the assessment of coagulation and fibrinolysis dynamics may be useful for the hemostatic monitoring and management of optimal treatment in these individuals.博士（医学）・甲第786号・令和3年3月15日© 2020. Thieme. All rights reserved.This is a non-final version of an article published in final form in "http://dx.doi.org/10.1055/s-0040-1713890

1-year tolvaptan efficacy in ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) develops into end-stage kidney disease by 65 years of age in an estimated 45%-70% of patients. Recent trials revealed that tolvaptan inhibits disease progression both in early-stage or late-stage ADPKD ; however, stratified analysis showed a difference of favorable factors correlated with tolvaptan efficacy between early-stage and late-stage ADPKD. Thus, we examined the efficacy of tolvaptan in ADPKD with a wide range of estimated glomerular filtration rates (eGFR). We enrolled 24 patients with eGFR 35.3 (28.0-65.5) ml / min / 1.73m2 and evaluated treatment effect as ΔΔeGFR (ml / min / 1.73m2 / year) or ΔΔtotal kidney volume (TKV) (% / year) that was calculated as post-treatment annual change - pre-treatment annual change. Pre ΔeGFR was significantly low in eGFR responders, defined as ΔΔeGFR > 0 ml / min / 1.73m2 / year. In eGFR responders, pre ΔeGFR, post ΔeGFR, eGFR, TKV, and proteinuria were significantly correlated with ΔΔeGFR. In TKV responders defined as ΔΔTKV > 5 % / year, we identified hypertension history, proteinuria, TKV, and post ΔTKV as significantly correlated factors with ΔΔTKV. In conclusion, pre ΔeGFR may be a predictive factor of therapeutic efficacy on kidney function. Tolvaptan may have greater efficacy in early-stage ADPKD with rapid GFR decline or with well-controlled blood pressure

Preventative Effect of a Flavonoid, Enzymatically Modified Isoquercitrin on Ocular Symptoms of Japanese Cedar Pollinosis

ABSTRACTBackgroundFlavonoids are nutrients that exert anti-allergic effects. We investigated the preventative effect of enzymatically modified isoquercitrin (EMIQ), a flavonoid, to relieve the symptoms of Japanese cedar pollinosis.MethodsIn a parallel-group, double-blind placebo-controlled study design, 24 subjects with Japanese cedar pollinosis took 100 mg EMIQ or a placebo for 8 weeks, starting 4 weeks prior to the onset of pollen release. Subjective symptoms, ADL scores and the usage of drugs were recorded daily, and the QOL score was obtained every 4 weeks. Blood sampling was performed before and after the study to measure serum levels of IgE and flavonoids.ResultsDuring the entire study period, ocular symptom + medication score for the EMIQ group was significantly lower (p < 0.05) than that of the placebo group. When limited to the period, ocular symptom scores (p < 0.05, weeks 5–6), and ocular congestion scores (p < 0.05, weeks 5–6) for the EMIQ group was significantly lower than that for the placebo group while other scores for the EMIQ group, such as ocular itching scores (p = 0.09, weeks 4–5), lacrimation scores (p = 0.07, weeks 5–6), and ocular congestion scores (p = 0.06, weeks 45), all tended to be lower. However no significant differences were found in nasal symptoms between the two groups. Serum concentrations of IgE were not significantly downregulated but the serum concentrations of quercetin and its derivatives were elevated significantly by the intake of EMIQ.ConclusionsIntake of the quercetin glycoside EMIQ proved to be effective for the relief of ocular symptoms caused by Japanese cedar pollinosis

Mutant analyses reveal different functions of fgfr1 in medaka and zebrafish despite conserved ligand–receptor relationships

AbstractMedaka (Oryzias latipes) is a small freshwater teleost that provides an excellent developmental genetic model complementary to zebrafish. Our recent mutagenesis screening using medaka identified headfish (hdf) which is characterized by the absence of trunk and tail structures with nearly normal head including the midbrain–hindbrain boundary (MHB). Positional-candidate cloning revealed that the hdf mutation causes a functionally null form of Fgfr1. The fgfr1hdf is thus the first fgf receptor mutant in fish. Although FGF signaling has been implicated in mesoderm induction, mesoderm is induced normally in the fgfr1hdf mutant, but subsequently, mutant embryos fail to maintain the mesoderm, leading to defects in mesoderm derivatives, especially in trunk and tail. Furthermore, we found that morpholino knockdown of medaka fgf8 resulted in a phenotype identical to the fgfr1hdf mutant, suggesting that like its mouse counterpart, Fgf8 is a major ligand for Fgfr1 in medaka early embryogenesis. Intriguingly, Fgf8 and Fgfr1 in zebrafish are also suggested to form a major ligand–receptor pair, but their function is much diverged, as the zebrafish fgfr1 morphant and zebrafish fgf8 mutant acerebellar (ace) only fail to develop the MHB, but develop nearly unaffected trunk and tail. These results provide evidence that teleost fish have evolved divergent functions of Fgf8–Fgfr1 while maintaining the ligand–receptor relationships. Comparative analysis using different fish is thus invaluable for shedding light on evolutionary diversification of gene function