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High pre-treatment serum soluble interleukin-2 receptor (sIL-2R) levels are associated with poor overall survival (OS) of patients with newly diagnosed follicular lymphoma (FL). We evaluated the usefulness of pre-treatment sIL-2R levels in selecting a treatment regimen for advanced-stage FL with low tumor burden (FL-LTB). This retrospective, multicenter observational study enrolled consecutive patients who received a rituximab-containing regimen for newly diagnosed advanced stage FL-LTB (grade 1-3a) between 2008 and 2018. We applied a previously reported cut-off value of 1800 IU/mL for sIL-2R. A total of 211 patients were eligible for the analysis. Among patients with high sIL-2R (47 patients, 22.3%), the OS rates for patients treated by rituximab monotherapy (R-mono) (11 patients) were significantly lower than those treated by rituximab-combination chemotherapy (R-chemo) (36 patients): 5-year OS rates were 66.7% and 94.4%, respectively (P = 0.007). Among patients with low sIL-2R (164 patients, 77.7%), OS rates were comparably good between the R-mono group (34 patients) and the R-chemo group (130 patients): 5-year OS rates were 100% and 98.3%, respectively (P = 0.38). Our results suggest that R-chemo may yield better OS than R-mono for patients with newly diagnosed advanced-stage FL-LTB and high pre-treatment serum sIL-2R levels.

Providing a normal diet to a care recipient who is unable to form an adequate bolus may cause suffocation or aspiration pneumonia. We investigated whether differences in kinematic data of mandibular movements during mastication can be used as an indicator of the need for a dysphagia diet in the elderly in long-term care facilities. We included 63 participants who were provided with solid food in two long-term care facilities. The primary outcome variable was the kinematic data on mandibular movement during cracker chewing. The analysis results were compared between the normal and dysphagia diet groups. Logistic regression analysis and receiver operating characteristic curve analyses were performed. Significant differences were observed in the masticatory time, cycle frequency, total change amount, number of linear motions, and circular motion frequency between the normal and modified diet groups. The odds ratio for the circular motion frequency was −0.307, and the calculated cutoff value was 63%, with a sensitivity of 71.4%, a specificity of 73.5%, and an area under the curve of 0.714. Thus, these characteristics may be useful for detecting care recipients who need to be provided with a dysphagia diet. Moreover, the circular motion frequency could be used as a screening test to identify people who need a dysphagia diet.

Purpose To examine the relationship between oral intake function and oral health status in convalescent inpatients. Methods Subjects were 222 patients admitted to a convalescent hospital between 1 January and 30 June 2018. Investigation items were age, sex, causative disease, body mass index, functional oral intake scale (FOIS), functional independence measure, occlusal contact, assistance with oral cleaning, and oral health assessment tool (OHAT) scores. Multiple regression analysis was performed with FOIS as the dependent variable, and investigation items were related to FOIS as independent variables. Results Results of multiple regression analysis for all patients suggested that saliva and denture scores were significantly associated with FOIS. However, analysis excluding non-oral feeding patients did not show a significant association between FOIS and OHAT scores. Conclusion The results of this study suggest that oral health status is associated with oral intake function. In addition, the oral health status of inpatients may be strongly related to whether or not they are eating orally. Therefore, it is necessary to take good care of oral health in non-oral feeding patients in the convalescent ward.

We retrospectively analyzed 51 patients with solitary plasmacytoma diagnosed from October 2002 to September 2018 from a cohort of 3575 patients with plasma cell dyscrasias registered in the Kansai Myeloma Forum. Twenty-seven patients had solitary bone plasmacytoma (SBP) and 24 had extramedullary plasmacytoma (EMP), with prevalence of 0.8% and 0.7%, respectively. The most frequent M protein was IgG (40%) in SBP, whereas non-secretory proteins were most frequent (50%) in EMP. Five-year overall survival was 78.2% in SBP and 80.8% in EMP (P = 0.894). Among patients with SBP, 44% progressed to MM with a median time of 10.5 months (2.4–93.3 months), whereas 8% of EMP patients progressed to MM with a median time of 18.6 months (13.0–24.2 months). The most frequent treatment was radiotherapy (41%) or observation (41%) in SBP, and chemotherapy (54%) in EMP. No statistically significant difference was observed upon univariate analysis of prognostic factors including age, sex, performance status, and IgG M protein. Our results suggest that there are biological differences between SBP and EMP in real-world settings.

Radiation doses to the heart are potentially high in patients undergoing radiotherapy for thymoma or thymic carcinoma because of their origin site and propensity for pericardial invasion. We investigated potential relationships between radiation pneumonitis (RP) and the dosimetric parameters of lung and heart substructures in patients with thymic epithelial tumors. This retrospective study included 70 consecutive patients who received definitive or postoperative radiotherapy at a median dose of 58.3 Gy. Heart substructures were delineated according to a published atlas. The primary end point of ≥ grade 2 RP was observed in 13 patients (19%) despite a low lung dose; median lung V20 (i.e. percentage of the volume receiving at least 20 Gy) was only 16.6%. In a univariate analysis, four lung parameters, heart V35, three pulmonary artery (PA) parameters, two left ventricle parameters, and left atrium V35 were associated with the development of RP. In a multivariate analysis, only PA V35 remained significant (hazard ratio 1.04; 95% CI 1.01–1.07, p = 0.007). PA V35 of the RP versus non-RP groups were 84.2% versus 60.0% (p = 0.003). The moderate dose sparing of PA could be a candidate as a planning constraint for reducing the risk of RP in thoracic radiotherapy.

Inter-arm differences of SBP ≧5 mmHg have been associated with all-cause and cardiovascular mortalities in hypertensive subjects. Inter-arm differences of SBP appears to be mediated by arterial stiffness. We hypothesized inter-arm differences of SBP ≧5 mmHg may be related to higher pulse pressure/stroke volume index, a surrogate marker of arterial stiffness.To obtain inter-arm differences of SBP (the absolute difference of right and left arm) and ankle-brachial index, bilateral blood pressures were measured simultaneously at the four limbs using an automated oscillometric device in patients with treated hypertension (n = 234) and in normotensive subjects (n = 40). Pulse pressure was calculated as SBP-DBP. Stroke volume was obtained by time-velocity integral method using echocardiography. Left ventricular mass and relative wall thickness were calculated by the conventional methods.All hypertensive patients were medically treated and had average blood pressure levels of 135/85 mmHg. Inter-arm differences of SBP ≧5 mmHg was detected in 26.5% of hypertensive patients. Hypertensive patients with inter-arm differences of SBP ≧5 mmHg had higher pulse pressure/stroke volume index, lower ankle-brachial index, higher BMI, and higher relative wall thickness, higher prevalence of female than those with inter-arm differences of SBP5 mmHg. Multiple linear regression analysis confirmed inter-arm differences of SBP ≧5 mmHg was associated with higher pulse pressure/stroke volume index, higher relative wall thickness, and lower ankle-brachial index.Inter-arm difference of SBP measured by automated double-cuff device was related to large artery stiffness in patients with hypertension.

For breast cancer (BC) patients who refused surgery, we developed a definitive treatment employing modern sophisticated radiation techniques. Thirty-eight operable BC patients were treated by conventionally fractionated whole-breast (WB) radiotherapy in combination with stereotactic (for primary tumor) or intensity-modulated (for primary tumor with/without regional lymph nodes [LN]) radiotherapy (IMRT) boost. Standard doses were 50 Gy/25 fractions, 21 Gy/3 fractions and 20 Gy/8 fractions, respectively, for the three radiation modalities. Disease stages were 0 (ductal carcinoma in situ [DCIS]) in seven patients, I in 12, II in 16 and III in three. In 26 patients, intratumoral hydrogen peroxide injection or hyperthermia with oral tegafur-gimeracil-oteracil potassium (S-1) was also used to sensitize the tumors to radiation. Hormonal and standard systemic therapy were administered in 25 and 13 patients, respectively. Complete and partial responses were obtained in 19 patients each; in patients with partial response, no further regrowth of the residual mass was observed, except for two patients who developed local recurrence. During a follow-up of 8–160 months (median, 50 months for living patients), two, one and two patients developed local relapse, sub-clavicular node metastasis and distant metastasis, respectively. The 5-year rates for overall, progression-free and local relapse-free survival were 97.2, 90.9 and 93.4%, respectively. Fourteen patients developed Grade 3 radiation dermatitis but all recovered after treatment. In 47%, the affected breast became better-rounded, and the nipple of the irradiated breast became higher by ≥1 cm than the contralateral nipple. Our method might be a treatment option for operable BC patients.

Prediabetes defined by HbA1c 5.7-6.4 has been shown to be associated with left ventricular (LV) hypertrophy and diastolic dysfunction in hypertensive patients. We hypothesized HbA1c prediabetes may be related to the alterations of LA contractility or volume in nondiabetic hypertension.Nondiabetic individuals on sinus rhythm were enrolled; 107 patients with never-treated hypertension, 134 patients with treated hypertension, and 71 normotensive subjects. Participants were classified as normal glucose tolerance (NGT, HbA1c5.7), prediabetes (HbA1c 5.7-6.4) according to the ADA criteria. They underwent echocardiography to measure left atrial (LA) phasic volumes and functions, as well as mitral E/e' and mitral e'.In nondiabetic patients with never-treated hypertension, prediabetes saw lower LA total emptying fraction (53.7 ± 8.2 vs. 48.3 ± 9.9*) and mitral e' (7.38 ± 2.18 vs. 6.17 ± 1.50*) than NGT, implicating that the association of prediabetes with reduced LA contractility and LV stiffness. On the other hand, in nondiabetic patients with treated hypertension, prediabetes saw higher maximum LA volume/BSA (29.7 ± 7.1 vs. 32.9 ± 6.2* ml/mmPrediabetes may be involved in the progression of LA structural and functional alterations in nondiabetic hypertensive patients.

This retrospective, multicenter observational study investigated the prognostic value of pretreatment serum soluble interleukin-2 receptor (sIL-2R) level for outcomes of newly diagnosed follicular lymphoma (FL) grade 1-3a who required treatment at diagnosis. A total of 628 patients were recorded, and 502 of these were eligible for analysis. Patients were divided into four quartiles, based on their serum sIL-2R levels as follows: Q1 (sIL-2R520 IU/mL), Q2 (520 ≤ sIL-2R1030 IU/mL), Q3 (1030 ≤ sIL-2R2530 IU/mL) and Q4 (sIL-2R ≥ 2530 IU/mL). Using a multivariable Cox proportional-hazards model, we showed the adjusted probability of overall survival (OS) decreased with increasing serum sIL-2R levels (

We retrospectively analyzed 51 patients with solitary plasmacytoma diagnosed from October 2002 to September 2018 from a cohort of 3575 patients with plasma cell dyscrasias registered in the Kansai Myeloma Forum. Twenty-seven patients had solitary bone plasmacytoma (SBP) and 24 had extramedullary plasmacytoma (EMP), with prevalence of 0.8% and 0.7%, respectively. The most frequent M protein was IgG (40%) in SBP, whereas non-secretory proteins were most frequent (50%) in EMP. Five-year overall survival was 78.2% in SBP and 80.8% in EMP (P = 0.894). Among patients with SBP, 44% progressed to MM with a median time of 10.5 months (2.4-93.3 months), whereas 8% of EMP patients progressed to MM with a median time of 18.6 months (13.0-24.2 months). The most frequent treatment was radiotherapy (41%) or observation (41%) in SBP, and chemotherapy (54%) in EMP. No statistically significant difference was observed upon univariate analysis of prognostic factors including age, sex, performance status, and IgG M protein. Our results suggest that there are biological differences between SBP and EMP in real-world settings.

Recently reaction–diffusion approximation has been intensively studied. This paper reviews the studies in reaction–diffusion approximation and is based on Iida and Ninomiya (Sugaku 66:225–248, 2014) added recent studies to. This paper explains reaction–diffusion approximation of the Stefan problem, nonlinear diffusion, nonlocal dispersal and wave equations. Moreover, some instabilities of equations mentioned above will be explained by the Turing instability through reaction–diffusion approximations.

We consider a type of singular limit problem called the fast reaction limit. The problem of the fast reaction limit involves studying the behaviour of solutions of reaction–diffusion systems when the reaction speeds are very fast. Fast reaction limits of two-component systems have been studied in recent decades. In most of these systems, the fast reaction terms of each component are represented by the same function. Fast reaction limits of systems with different fast reaction terms are still far from being well understood. In this paper, we focus on a reaction–diffusion system for which the reaction terms consist of monomial functions of various powers. The behaviour of interfaces arising in the fast reaction limit of this system is studied. Depending on the powers, three types of behaviour are observed: (i) the initial interface vanishes instantaneously, (ii) the interface propagates at a finite speed, and (iii) the interface does not move.

A one-dimensional semi-linear elliptic system with constraint to the growth of its solutions at respective infinities is discussed. This system appears in a rescaling limit of a competition-diffusion system which describes very strong inter-specific competition between two biological species. A necessary and sufficient condition for the existence of solutions is characterized in terms of the constraint at respective infinities. Also the uniqueness of a solution and several asymptotic estimates of its derivatives at infinities are stated. Moreover similar problems are discussed for an associated inhomogeneous linear elliptic system with constraint to the growth of its solutions at infinities.

Tricuspid regurgitation (TR) with the maximum velocity 2.8m/s has been newly integrated into the diagnostic criteria for left ventricular (LV) diastolic dysfunction. Although the maximum velocity of TR within the normal range (TR 2.8m/s) is frequently detected in hypertensive patients and is associated with enlarged left atrial (LA) volumes, the influence of TR 2.8m/s on LV diastolic dysfunction remains unknown in uncomplicated hypertension.Echocardiography was performed to assess the mitral annular velocity (e'), E/e', LV mass, and LA phasic volumes and emptying fractions (total, passive, and active) in 100 patients with uncomplicated hypertension with TR within the normal range and in 77 of those without measurable TR. Patients were defined as having normal, inclusive, or dysfunction of LV diastolic function, according to how many parameters met the cut-off levels (maximum LA volume index34ml/mmThe maximum velocity of TR or PASP saw a positive correlation, and LA total or passive emptying fractions saw an inverse correlation with LV diastolic dysfunction in hypertensive patients with TR 2.8. In contrast, pulse pressure and LV mass saw positive correlation in hypertensive patients without TR. A stepwise ordinal logistic regression analysis indicated that PASP and LA passive emptying fractions were associated with LV diastolic dysfunction in hypertensive patient with TR 2.8m/s.The presence of TR may be related to the development of LV diastolic dysfunction in hypertensive patients with TR 2.8m/s.

Determinants of the efficacy and safety of pomalidomide (POM) monotherapy or POM plus dexamethasone (DEX) (POM/DEX) for relapsed and refractory multiple myeloma (RRMM) were examined retrospectively in a real-world clinical practice setting in Japan. The subjects were 108 patients registered with the Kansai Myeloma Forum, who were treated with either POM or POM/DEX. Of these, 79 (73%), 73 (68%), and 58 (54%) were resistant to bortezomib (BTZ), lenalidomide (LEN), and both BTZ and LEN, respectively. The median overall survival (OS) was not reached. The median time to treatment failure (TTF) was 4.4 months. The best response was recorded in 96 patients, with a 31% overall response rate (ORR) and a 79% rate of achieving at least stable disease. Number of pre-POM regimens ≥ 5, non-IgG-type M-protein, and time from initial therapy to POM or POM/DEX therapy 2 years were associated with shorter TTF and OS. Frequent ( 10%) severe adverse events included neutropenia (55.1%), thrombocytopenia (33.7%), anemia (30.6%), febrile neutropenia (12.2%), fatigue (11.2%), and anorexia (10.2%). In conclusion, POM and POM/DEX showed substantial efficacy against RRMM, but new combination therapies with POM are needed to improve efficacy further without causing hematologic toxicities.

Introduction: Serum soluble interleukin-2 receptor (sIL-2R) is recognized as a tumor-related biomarker of malignant lymphomas, including follicular lymphoma (FL). The objective of this study is to assess the prognostic significance of pretreatment serum sIL-2R level for disease-specific overall survival (DSS) in patients with FL. Methods: We retrospectively analyzed medical records of our 10 individual institutions to identify all patients (pts) ≥ 18 years old with newly diagnosed FL between 01/01/2008 and 12/31/2018. Only pts with FL grade 1-3b, confirmed at pathological review, were included. Pts with histological transformation at diagnosis were excluded. Serum sIL-2R was determined by sandwich enzyme-linked immunosorbent assay. Clinical characteristics, therapies, response, relapse patterns and follow up status were collected and analyzed in the cohort. DSS was defined from the time of initial diagnosis to death due to lymphoma or last follow up. DSS was analyzed according to Kaplan Meier method and differences between subgroups were compared with log-rank test. Multivariate cox regression analysis was used to investigate associations of sIL-2R, FL International Prognostic Index (FLIPI) and progression or relapse within 24 months after diagnosis (POD24) with DSS. Serum levels of sIL-2R was measured before initiation of treatment and the data on the nearest date of the diagnostic biopsy within six months was adopted. Results: We recorded 565 pts and 535 pts of them with pretreatment serum sIL-2R levels available were included in the analysis with median age 64 years (range: 30-90) and 305 females (57%). Clinical characteristics are summarized in Table 1. The median of the serum sIL-2R level was 896 IU/mL (range: 145 - 23800). We decided an optimal cutoff value of 1800 IU/mL by using receiver operating characteristic (ROC) analysis, which showed it was 1830 IU/mL (AUC : 0.76, 95%CI : 0.67 - 0.84). Various poor prognostic indicators, such as bulky mass, increased LDH, ≥5 nodal lesions, poor performance status (PS), bone marrow invasion, FLIPI and FLIPI-2 high-risk, decreased Hb, advanced disease, high tumor burden, increased β2MG and existence of B symptoms, were strongly associated with high serum sIL-2R level (≥1800 IU/mL), and high sIL-2R level correlated with POD24 (P Conclusions: High sIL-2R level ( ≥1800 IU/mL) is a significant and independent adverse prognostic factor for DSS in pts with newly diagnosed FL. This study provides us useful information to predict population with worse DSS before initiation of treatment. Disclosures Nozaki: Chugai: Honoraria; Celgene: Honoraria. Kida:Eisai Co., Ltd: Honoraria. Kosugi:Novartis Pharma Co.: Honoraria; Bristol-Myers Squibb Co.: Honoraria; Eisai Co., Ltd: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Celgene K.K.: Honoraria; Pfizer Inc.: Honoraria. Shibayama:Astellas, Teijin, MSD, Shionogi, Eisai, Sumitomo Dainippon, Taiho, Nippon Shinyaku: Research Funding; Celgene, Chugai, Eisai, AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Takeda, Novartis, Janssen, Chugai, Eisai, Mundi Pharma, Ono, Otsuka, Kyowa Kirin, Sumitomo Dainippon, AstraZeneca, Avvie, DaiichiSankyo, Fujimoto, Nippon Shinyaku, Sanofi, Bristol-Myers Squibb, Pfizer: Honoraria.

A 90-year-old female complaining of severe upper abdominal pain was transferred to our institution. The patient had been prescribed with calcium polystyrene sulfonate (CPS) for the treatment of hyperkalemia following myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) associated glomerulonephritis. Physical examination revealed diffuse tenderness over the abdomen, with signs of peritoneal irritation. Abdominal computed tomography (CT) revealed the retention of ascites, free air in the abdominal cavity, and the retention of hard stools in the left-sided colon. The diagnosis of intestinal perforation was immediately confirmed; thereafter, the patient underwent emergency surgical treatment. Surgical findings revealed a perforated site in the descending colon surrounded with hard stools. Histopathology of the perforated colon revealed crystalline materials, suggestive of association with CPS. CPS is a cation-exchange resin used to treat hyperkalemia; the major adverse effect in patients receiving CPS is constipation. When CPS is administered to patients with frequent constipation or the elderly, the risk of intestinal perforation should be considered.

Left atrial (LA) phasic volumes consist of reservoir, conduit and booster pump volumes. Arterial stiffness is linked to lower systemic arterial compliance (SAC) contributing to cardiac afterload. Arterial stiffness may be a modulator of LA phasic volumes. Echocardiography was performed in 161 hypertensive patients and in 50 normotensive subjects in order to assess biplane LA volumes (maximum, before atrial contraction, minimum), early and late diastolic mitral annular velocity (e' and a'), and LV stroke volume. LA emptying volumes (total, passive, active) were calculated from these LA volumes. Blood pressures were measured using an automated oscillometric device simultaneously at the four limbs for evaluating pulse pressure (PP) and ankle-brachial index (ABI). SAC was estimated by the ratio of LV stroke volume indexed by body surface area (BSA) divided by PP. All three LA volumes, LA total volume and LA active emptying volume were greater in hypertensive patients than in normotensive subjects. A multiple linear regression analysis indicated that LA passive emptying volume (reservoir=early diastole)/BSA correlated positively with ABI after being adjusted for age, gender, BSA, LV mass, max LA volume, e' and SAC in hypertensive patients. LA active emptying volume (booster=late diastole)/BSA correlated positively with SAC after being adjusted for age, gender, BSA, LV mass, LA volume before atrial contraction, a' and ABI. LA reservoir volume was associated with ABI, and LA booster volume was related to systemic arterial stiffness in hypertensive patients, suggesting the LA-arterial coupling in this clinical setting.

Background Patients with aortic valve sclerosis (AVS) have an increased risk of cardiovascular events. Patients with atherosclerotic renal artery stenosis (RAS) develop resistant hypertension and heart failure. We hypothesized AVS may be copresent with RAS in hypertensive patients. Methods Hypertensive patients with AVS (n = 167) underwent magnetic resonance (MR) angiography using nonenhanced steady-state free precession (SSFP) technique. More than 75% luminal narrowing in the proximal region of main renal artery was regarded as significant RAS. Peak aortic jet velocity was obtained by Doppler echocardiography. We measured brain natriuretic peptide (BNP), and estimated glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease equation. Results Unilateral or bilateral RAS was detected in 40 patients. AVS patients with RAS were older (78 +/- 6 vs. 74 +/- 8 years), and had higher levels of aortic jet velocity (162 +/- 4 vs. 144 +/- 3 cm/s), and lower levels of GFR (55 +/- 13 vs. 62 +/- 14 ml/min/1.73 m(2)) than those without RAS. Higher aortic jet velocity (odds ratio (OR) = 1.58, 95% confidence interval (CI) = 1.09-2.31) and lower GFR (OR = 0.54, 95% CI = 0.33-0.38) were associated with the presence of RAS, after being adjusted for age, systolic blood pressure, and BNP. Conclusions RAS was detected in hypertensive patients with AVS, particularly in patients with higher aortic jet velocity and lower GFR. Higher aortic jet velocity and lower GRF may be useful as a potential indicator for those needing assessment of RAS for risk stratification and deserves further study.

Polo-like kinase 1 (Plk1) is a serine/threonine kinase that plays an important role in M phase progression by regulating various downstream substrates via phosphorylation. Here, we identified beta-catenin as a novel substrate of Plk1 and determined that Ser-718 is a phosphorylation site for Plk1 by using a phospho-specific antibody that cross-reacts with Plk1-dependent phosphorylation sites. Ser-718 of beta-catenin was directly phosphorylated by recombinant Plk1 in vitro, with the phosphorylation signal in cells increasing with overexpression of Plk1 and decreasing when endogenous Plk1 was depleted by small interfering RNA. The phosphorylation at Ser-718 was correlated with the cell cycle-dependent expression of Plk1 which reached a maximum in M phase. We also confirmed that there is a physical interaction between beta-catenin and Plk1 using coimmunoprecipitation and a GST pull-down assay. These results demonstrate that beta-catenin is a physiological substrate of Plk1 in cells, which may provide a novel insight into the role of beta-catenin in M phase.

Aortic valve sclerosis (AVS) may predispose to a prothrombotic state, as AVS is predictor of cardiovascular events in hypertensive populations. Thrombin exerts non-thrombotic effects such as vessel tone regulation, progression of atherosclerosis and stimulation of atrial natriuretic peptide (ANP) secretion. We hypothesized that hypertensive patients with AVS may have a persistently activated thrombin generation. We studied 234 asymptomatic never-treated hypertensive patients (73 of them with AVS). Prothrombin F1+2 (F1+2), as a marker of thrombin generation and fibrin D-dimer, as a marker of thrombus formation, ANP and brain natriuretic peptide (BNP) were measured. Presence of AVS, aortic jet velocity and left ventricular diameter at diastole were determined by echocardiography. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease formula. F1+2 (median and interquartile range (IQR) = 1.05, 0.87-1.38 nM vs. 0.93, 0.72-1.16) and ANP (22, 14-37 pg ml(-1) vs. 17, 11-25) levels were greater, and glomerular filtration rate values (65+/-9 ml min(-1)/1.73 m2 vs. 68+/-11) were lower in hypertensive patients with AVS than in those without AVS. F1+2 (odds ratio, 95% CI = 2.94, 1.07-8.6) was independently associated with AVS after being adjusted for age, gender and the variables of cardiorenal functions measured. After 6 months of treatment using valsartan, F1+2 levels remained elevated in hypertensive patients with AVS (1.14, 0.83-1.42 nM vs. 1.07, 0.84-1.5, n=19), but decreased in those without AVS (1.01, 0.85-1.31 vs. 0.8, 0.84-1.78, n=27). Thrombin generation was associated with AVS in untreated hypertensive patients, and this association was persistent after blood-pressure-lowering treatment using valsartan.

The Plk (polo-like kinase) family is involved in cell-cycle machinery. Despite the possible overlapping involvement of Plk1 and Plk3 in cell-cycle distribution, the precise role of each Plk might be different. To investigate mechanisms that may differentiate their physiological roles, we compared the substrate specificities of Plk1 and Plk3 using synthetic peptides. Among these substrate peptides, topoisomerase IIalpha EKT(1342)DDE-containing synthetic peptide was strongly phosphorylated by Plk3 but not by Plk1. By modulating the topoisomerase IIalpha peptide, we identified residues at positions +1, +2 and +4 as determinants of differential substrate recognition between Plk1 and Plk3. Acidic residues at positions +2 and +4 appear to be a positive determinant for Plk3 but not Plk1. Variation at position +1 appears to be tolerated by Plk3, while a hydrophobic residue at +1 is critical for Plk1 activity. The direct phosphorylation of Thr(1342) of topoisomerase IIalpha by Plk3 was demonstrated with an in vitro kinase assay, and overexpression of Plk3 induced the phosphorylation of Thr(1342) in cellular topoisomerase IIalpha. Furthermore, the physical interaction between Plk3 and topoisomerase IIalpha was also demonstrated in cells in addition to phosphorylation. These data suggest that topoisomerase IIalpha is a novel physiological substrate for Plk3 and that Plk1 and Plk3 play different roles in cell-cycle regulation.

We consider a class of $2m$ components competition-diffusion systems which involve $m$ parabolic equations as well as $m$ ordinary differential equation, and prove the strong convergence in $L^p$ of a subsequence of each component as the reaction coefficient tends to infinity. In the special case of $4$ components the solution of this system converges to that of a Stefan problem.

Plasma levels of von Willebrand factor (vWF), a marker of endothelial dysfunction/damage, are elevated in high-risk hypertensive patients and in patients with severe aortic regurgitation (AR). Patients with mild-to-moderate AR, frequently detected in hypertensive elderly, have additional left ventricular morphological and functional dysfunctions. We hypothesized that hypertensive patients with mild-to-moderate AR may have enhanced endothelial and/or left ventricular dysfunctions that may lead to a deteriorated prognosis. We measured vWF, prothrombin F1+2 (F 1+2) as a marker of thrombin generation, brain natriuretic peptide (BNP) in 104 hypertensive patients with mild-to-moderate AR and 66 hypertensive patients without AR. The left ventricular diameter at systole (LVDs) and left ventricular posterior wall thickness (LVWT) were determined by echocardiography and indexed by body surface area (LVDs/BSA and LVWT/BSA). VWF (median, interquartile range (IQR) 154, 120-196%) and BNP (34.7 pg ml(-1), 15-65%) levels were greater in patients with AR than in those without AR (135, 98-175% and 20, 10.3-49 pg ml(-1)). All patients were prospectively followed up for cardiac events during the period of median 43 months (IQR 31-81). Patients with AR had an increased risk of cardiac events (regression ratio (RR) 1.87, 95% confidence interval 1.28-2.87) when compared to those without AR. A multivariate Cox hazard analysis indicated that log vWF (RR 4.93) and log BNP (RR 1.9) were independent predictors in patients with AR. VWF was an independent predictor of clinical outcome in hypertensive patients with mild-to-moderate AR.

The cross-diffusion competition systems were introduced by Shigesada et al. [J. Theor. Biol. 79, 83-99 (1979)] to describe the population pressure by other species. In this paper, introducing the densities of the active individuals and the less active ones, we show that the cross-diffusion competition system can be approximated by the reaction-diffusion system which only includes the linear diffusion. The linearized stability around the constant equilibrium solution is also studied, which implies that the cross-diffusion induced instability can be regarded as Turing's instability of the corresponding reaction-diffusion system.

46歳女性. C型慢性肝炎に対し Interferon (以下IFN)・リバビリン療法を施行. 発熱・失見当識・構音障害を認め入院となる. 頭部CTやMRI検査では異常なく, 尿所見より腎盂腎炎と診断した. IFN・リバビリン治療を中止したが, 患者は disseminated intravascular coagulation (以下DIC) を併発し出血性梗塞を発症した. 内服中止2日目でも血中リバビリン濃度は高値であった. IFN・リバビリン療法中にDICを発症し死亡した例は初で, 今後注意が必要と考える.

Aim Urinary type IV collagen is an early biomarker of diabetic nephropathy. Concomitant prediabetes (the early stage of diabetes) was associated with left ventricular (LV) diastolic dysfunction and increased brain natriuretic peptide (BNP) in hypertensive patients. We hypothesized that urinary type IV collagen may be related to these cardiac dysfunctions. Methods We studied hypertensive patients with early prediabetes (HbA1c 110, n=18), those with prediabetes (HbA1c 5.7–6.4, n=98), and those with diabetes (HbA1c>6.5 or on diabetes medications, n=92). The participants underwent echocardiography to assess left atrial volume/body surface area (BSA) and the ratio of early mitral flow velocity to mitral annular velocity (E/e'). Left ventricular diastolic dysfunction (LVDD) was defined if patients had E/e'≥15, or E/e'=9–14 accompanied by left atrial volume/BSA≥32ml/mm 2 . Urinary samples were collected for type IV collagen and albumin, and blood samples were taken for BNP and HbA1c. Results Urinary type IV collagen and albumin increased in parallel with the deterioration of glycemic status. In hypertensive patients with prediabetes, subjects with LVDD had higher levels of BNP and urinary type IV collagen than those without LVDD. In contrast, in hypertensive patients with diabetes, subjects with LVDD had higher urinary albumin and BNP than those without LVDD. Urinary type IV collagen correlated positively with BNP in hypertensive patients with prediabetes, whereas it correlated with HbA1c in those with diabetes. Conclusions In hypertensive patients with prediabetes, urinary type IV collagen was associated with LV diastolic dysfunction and BNP.

A new type of competition-diffusion system with a small parameter is proposed. By singular limit analysis, it is shown that any solution of this system converges to the weak solution of the two-phase Stefan problem with reaction terms. This result exhibits the relation between an ecological population model and water-ice solidification problems.

This paper discusses the dynamics of bi-stable competition systems. It is assumed that in the initial state one species is numerically superior to the other species at every point of their habitat. If the two species do not migrate, then the superior species will wipe out the inferior one. It is shown, however, that the superior species may become extinct if the diffusion is taken into consideration.

Consider the equationut = e2 div(D(x)∇u) +f(u; e) in ℝn, whereD(x) is a positive functionx ∈ ℝn,f is the derivative of a bistable potential, and e>0 is a small parameter. Let Γ(T),T∈[0,T0], be a one-parameter family of smooth hypersurfaces which move with the time scaleT = e2t according to a certain generalized mean curvature flow. It is shown that, if the initial data have an interface which is close to Γ(0), then the interface remains close to Γ(e2t fort ∈ [0,T0/e2]. Moreover, ifT0=∞ and Γ(T) converges to a stable stationary hypersurface asT→∞, then the interface remains close to Γ(e2t) for allt≥0.

A 50-year-old female patient, who had been followed for 15 years for protein-losing enteropathy, was hospitalized due to epigastric pain. Examination on admission revealed that the patient was in the sub-ileus state. On the 26th day after admission, she complained of severe abdominal pain and shortly after she went into shock. The emergency laparotomy documented intestinal perforation and a tumor. The perforated site was right at the middle of tumor. The histological and histochemical studies identified the tumor as malignant lymphoma of B lymphocyte lineage. As far as we know, this is the third case of malignant lymphoma occurring in the jejunum in a patient with protein-losing enteropathy in Japan. The possible relationship between lymphomas and protein-losing enteropathy is discussed.

Background Cystatin C, a cathepsin inhibitor, is involved in the remodeling of human aortic valve and left ventricle (LV). Objective Cystatin C may be related to the severity of aortic regurgitation (AR). Methods We measured cystatin C and CRP in hypertensive patients with mild-to-moderate AR (n = 120) and in those without AR (n = 128). Echocardiography was performed to assess the vena contracta width (the narrowest region of regurgitant jet, VCW) as a marker of the severity of AR, relative wall thickness as a marker of LV concentric remodeling, and the ratio of early peak mitral flow to early diastolic mitral annular velocity (E/e′) as an index of LV diastolic function. Glomerular filtration rate (GFR) was estimated using the MDRD methods. Results Cystatin C levels were greater in hypertensive patients with AR than in those without AR. A multiple linear regression analysis indicated cystatin C levels correlated with the VCW independent of GFR, body mass index, CRP, relative wall thickness, and E/e′ in hypertensive patients with AR. Conclusions Cystatin C was associated with the severity of regurgitation independent of renal function body composition chronic inflammation LV remodeling and diastolic function in hypertensive patients with mild-to-moderate AR.

An 82-year-old female presented to our institution with mild dyspnea. Her medical history included effort angina pectoris, which was treated with stent placement in the coronary artery at the age of 78, and congestive heart failure, which was improved by oxygen inhalation and administration of diuretic agents. Chest radiography revealed evidence of swollen lymph nodes at the level of the left pulmonary hilar lesion. Contrast-enhanced chest computed tomography revealed a mass at the pulmonary hilar lesion site extending into the left pulmonary artery and left lower pulmonary vein, swollen lymph nodes proximal to the left pulmonary hilar lesion and bilateral mediastinum, and pleural dissemination. Bronchoscopy revealed almost total occlusion of the left upper bronchial trunk. Biopsied specimen confirmed the diagnosis of small-cell lung carcinoma (SCLC). Although the standard chemotherapy regimen for extended SCLC is a combination therapy of cisplatin (CDDP) and etoposide (ETP), that regimen was considered intolerable for the patient because of chronic heart and renal failure. Therefore, the regimen of amrubicin hydrochloride (AMR) monotherapy was decided. After the first cycle of chemotherapy, the tumor was remarkably reduced. Despite mild digestive symptoms, including nausea and loss of appetite, and mild myelosuppression, the patient was well tolerated with AMR monotherapy. The patient has been kept partial response during the fifth cycle of chemotherapy until the patient developed pneumonia.

A 80-year-old female was referred to our hospital for hematomesis. An abdominal CT revealed a heterogeneous giant tumor of about 11 cm, rich in vascularity, extending from the gastric fundus, beyond the upper side of the spleen, to the left thoracic diaphragm. Gastroscopy showed a 5 cm submucosal tumor with a visible vessel at the gastric fundus. After biopsy was performed, she was diagnosed with a c-kit-positive gastrointestinal stromal tumor (GIST)of the stomach. Following endoscopic hemostasis for gastric bleeding, imatinib mesilate was administered. The tumor reduced markedly, and vascularity in the tumor was diminished, the visible vessels of the tumor disappeared. For curative resection, total gastrectomy with a distal pancreato -splenectomy and a left diaphgram resection is necessary, but surgery was high-risk for this patient because she was advanced in age. She is now achieving a good partial response without surgery.

Thyroid hormone amplifies hypertrophy of cardiac myocytes. The heart is influenced by the minimal changes of thyroid hormone levels. We hypothesized that thyroid hormone within the normal reference range may be associated with left ventricular (LV) mass in hypertensive subjects. We performed echocardiography to assess LV mass indexed by body surface area (LVMI), and measured thyroid stimulating hormone (TSH), free triiodo-thyronine (fT3), free thyroxine (fT4), and brain natriuretic peptide (BNP) in 318 hypertensive patients without known thyroidal diseases. Glomerular filtration rate (GFR) was estimated using the MDRD formula. Relationship between each thyroid hormone and LVMI in hypertensive patients with euthyroidism were investigated using a multiple linear regression model entering age, gender, height, weight, GFR, log BNP, systolic BP, the use of more than 2 different types of antihypertensive medications, and HbA1c as covariates. Thyroid hormone and TSH levels were within the normal range in 293 patients. In these patients, fT3 (standard β = 0.13) and fT4 (standard β = 0.11) positively, and TSH (standard β = -0.15) inversely correlated with LVMI in the multiple linear regression model. Thyroid hormone may be associated with LV remodeling independent of renal and LV dysfunctions in hypertensive patients with euthyroidism.

One of the challenges to develop time-resolved fluorescence resonance energy transfer (TR-FRET) assay for serine/threonine (Ser/Thr) protein kinase is to select an optimal peptide substrate and a specific phosphor Ser/Thr antibody. This report describes a multiplexed random screen-based development of TR-FRET assay for ultra-high-throughput screening (uHTS) of small molecule inhibitors for a potent cancer drug target polo-like kinase 1 (Plk1). A screen of a diverse peptide library in a 384-well plate format identified several highly potent substrates that share the consensus motif for phosphorylation by Plk1. Their potencies were comparable to FKD peptide, a designed peptide substrate derived from well-described Plk1 substrate Cdc25C. A specific anti-phosphor Ser/Thr antibody p(S/T)F antibody that detects the phosphorylation of FKD peptide was screened out of 87 antibodies with time-resolved fluorometry technology in a 96-well plate format. Using FKD peptide and p(S/T)F antibody, we successfully developed a robust TR-FRET assay in 384-well plate format, and further miniaturized this assay to 1,536-well plate format to perform uHTS. We screened about 1.2 million compounds for Plk1 inhibitors using a Plk1 deletion mutant that only has the kinase domain and subsequently screened the same compound library using a full-length active-mutant Plk1. These uHTSs identified a number of hit compounds, and some of them had selectivity to either the deletion mutant or the full-length protein. Our results prove that a combination of random screen for substrate peptide and phospho-specific antibodies is very powerful strategy to develop TR-FRET assays for protein kinases.

本研究では, 歯周病患者での初診, 治療中からメインテナンスにかけてのプラークコントロールレベルの経時的な動態や病態との関連について検討を行った。対象者は, 初診からメインテナンスまで歯周治療が継続された35名 (平均年齢46.4歳) とした。被検項目としては, O'LearyのPlaque Control Record (PCR) とProbing Depth (PD) を用い, 以下の結果を得た。1) 対象者の初診時や初期治療中のプラークスコアの改善度とメインテナンス時のプラークスコアとは, 直接関連していなかった。2) 対象者のメインテナンス時ではプラークスコアが低い人ほどその変動が大きく表れることが示唆された。3) 対象者の初診時PCRあるいは初期治療によるPCRの改善と4mm以上のPD所有率とに関連は見られなかった