Search

Asthma and chronic obstructive pulmonary disease (COPD) are respiratory diseases associated with airway inflammation, which is the main pathogenesis. Although their causes and characteristics differ, in some cases, asthma and COPD may coexist in the same patient in a condition called asthma-COPD overlap (ACO). The prognosis of ACO is more unfavourable than those of asthma or COPD alone, without any treatment strategies demonstrating efficacy. Owing to its intricate spectrum of features, the detailed pathogenesis of how ACO exacerbates respiratory features remains unclear. In this study, we exposed papain-induced asthma model mice to tobacco smoke to establish an ACO mouse model, in which features of airway inflammation observed in both asthma and COPD were incorporated. This model exhibited distinctive mixed and corticosteroid-resistant airway inflammation and emphysematous changes that are characteristic of ACO. The novel mouse model established here is expected to significantly contribute to elucidating the mechanisms of the broad pathologies of ACO and identifying potential therapeutic targets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Asthma is characterized by phenotypes of different clinical, demographic, and pathological characteristics. Identifying the profile of exhaled volatile organic compounds (VOCs) in asthma phenotypes may facilitate establishing biomarkers and understanding asthma background pathogenesis. This study aimed to identify exhaled VOCs that characterize severe asthma phenotypes among patients with asthma., Methods: This was a multicenter cross-sectional study of patients with severe asthma in Japan. Clinical data were obtained from medical records, and questionnaires were collected. Exhaled breath was sampled and subjected to thermal desorption gas chromatography-mass spectrometry (GC/MS)., Results: Using the decision tree established in the previous nationwide asthma cohort study, 245 patients with asthma were divided into five phenotypes and subjected to exhaled VOC analysis with 50 healthy controls (HCs). GC/MS detected 243 VOCs in exhaled breath samples, and 142 frequently detected VOCs (50% of all samples) were used for statistical analyses. Cluster analysis assigning the groups with similar VOC profile patterns showed the highest similarities between phenotypes 3 and 4 (early-onset asthma phenotypes), followed by the similarities between phenotypes 1 and 2 (late-onset asthma phenotypes). Comparisons between phenotypes 1-5 and HC revealed 19 VOCs, in which only methanesulfonic anhydride showed p < 0.05 adjusted by false discovery rate (FDR). Comparison of these phenotypes yielded several VOCs showing different trends (p < 0.05); however, no VOCs showed p < 0.05 adjusted by FDR., Conclusions: Exhaled VOC profiles may be useful for distinguishing asthma and asthma phenotypes; however, these findings need to be validated, and their pathological roles should be clarified., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Introduction: TAS-115 is an oral multikinase inhibitor targeting the MET proto-oncogene, vascular endothelial growth factor receptor, and colony-stimulating factor 1 receptor. We evaluated the efficacy and safety of TAS-115 in castration-resistant prostate cancer (CRPC) patients with bone metastases., Patients and Methods: This phase II study, conducted in Japan, comprised 2 cohorts of CRPC patients. Cohort A included patients with bone metastasis and no history of docetaxel; TAS-115 200 to 400 mg/d was administered with abiraterone and prednisone. Cohort B included patients with symptomatic multiple bone metastases, post- or unfit for docetaxel, randomized 1:1 to receive TAS-115 400 or 600 mg/d orally, once daily, in a repeated weekly schedule of 5 days on/2 days off. The primary endpoint was bone scan index (BSI) response rate at Week 12 in each dose group., Results: Cohorts A and B included 24 and 26 patients, respectively. The 12-week BSI response rates for 200, 300, and 400 mg were 0%, 33.3%, and 16.7% in Cohort A, and for 400 and 600 mg were 7.1% and 25.0% in Cohort B. The best BSI response rates for 200, 300, and 400 mg were 0%, 66.7%, and 16.7% in Cohort A, and for 400 and 600 mg were 7.1% and 33.3% in Cohort B. A ≥ 30% reduction in BPI-SF score was shown in 57.7% of patients in Cohort B. The most frequent Grade ≥ 3 adverse drug reactions were hypophosphatemia (20.8%) in Cohort A and anemia (23.1%) in Cohort B., Conclusion: TAS-115 appears to demonstrate anti-tumor activity and acceptable tolerability in CRPC patients with bone metastases., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The prevalence of Mycobacterium avium complex (MAC) pulmonary disease (PD) is increasing significantly in Japan. Among the patterns of MAC-PD, a solitary pulmonary nodule (SPN) is less common and often resembles lung cancer. The aim of this study was to identify the clinical features of MAC-SPN., Methods: SPNs culture-positive for MAC (definite cases) and culture-negative SPNs showing nucleic acid amplification test (NAAT)-positive status (probable cases) that presented between January 2007 and December 2017 were enrolled. The patients' clinical, laboratory, radiological, and microbiological findings and outcomes were investigated., Results: This study included 28 patients (median age, 66 years; 16 men, 12 women). All patients were asymptomatic when the disease was detected. Median SPN size was 23.5 mm. Twenty-six patients underwent video-assisted thoracoscopic surgery, while the others underwent percutaneous needle biopsy for diagnosis. Granulomatous inflammation was confirmed in all cases. Microbiologically, the 28 cases were divided into 17 in the definite group and 11 in the probable group. In both groups, M. avium was predominant. There were no significant differences in clinical and radiological findings and follow-up periods between the 2 groups. After diagnosis, 6 patients received medical treatment, while the others did not. The median follow-up period was 42 months, and no recurrence was observed in both groups., Conclusions: MAC should be considered in the differential diagnosis of SPNs in asymptomatic patients. To overcome the difficulties in diagnosing MAC-SPN, this study underscores the importance of diagnostic interventions and identification of MAC by culture and/or NAAT in biopsied specimens., (Copyright © 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

The close association between dietary salt and hypertension is well established. However, previous studies generally assessed salt intake without adjustment for body weight. Herein, we investigated the significance of body weight-adjusted salt intake in the general population. The present cross-sectional study included 7629 participants from our yearly physical checkup program, and their salt intake was assessed using a spot urine test to estimate 24-hour urinary salt excretion. Total salt intake increased with increasing body weight. Body weight-adjusted salt intake was greater in participants with hypertension than in those without hypertension. Systolic blood pressure, estimated glomerular filtration rate, and urinary albumin were independently correlated with body weight-adjusted salt intake after adjustment for possible cardiovascular risk factors. Excessive body weight-adjusted salt intake could be related to an increase in blood pressure and hypertensive organ damage. Adjustment for body weight might therefore provide clinically important information when assessing individual salt intake., (Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Primarily the sodium-glucose cotransporter 2 (SGLT2) inhibitors suppress the cotransport of glucose and sodium from the tubular lumen of proximal tubules to the blood and enhance the glucose excretion into urine. Therefore, glucose and caloric balances become negative, making the blood glucose level as well as insulin secretion both reduced. On the other hand, the proximal tubular fluid, constituting with low chloride concentration because of SGLT2 inhibition, is transferred to the loop of Henle. On the low chloride conditions, the reabsorption mechanisms in the loop of Henle do not work, as if loop diuretics are given. Finally, blood pressure is also lowered secondarily due to the loop diuretic action by SGLT2 inhibitions. Thus, the metabolic and hemodynamic combined systems synergistically interact further to suppress the risks leading to atherosclerosis and organs damage. Precise mechanisms for SGLT2 inhibitors to work in various aspects especially in preventing organ damage and cardiovascular events must be clarified further., (Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Rates of renal cell carcinoma (RCC) morbidity and mortality vary widely by geography, with increasing incidence in most countries. Interestingly, RCC incidence is significantly lower in Asian countries relative to other regions, which is attributed to environmental and genetic influences. Additionally, it has been demonstrated that different ethnic groups differ in their RCC characteristics which might lead to varied responses to therapy. In this review, physicians drawn from countries across the Asia-Pacific region--China, Japan, Taiwan, Republic of Korea, and Australia--take all available data into consideration to develop the first opinion statement on treatment of advanced RCC in the region. We have sought to determine what factors influence treatment patterns and availability of therapeutic agents in our respective countries, discussed whether these factors are fully justified or should be modified, and considered what additional efforts should be undertaken to optimize treatment outcomes in RCC. Additionally, we have addressed the limitations on treatment of RCC in the region, capturing the restrictive situations of targeted therapy use in the Asia-Pacific region, mainly because of drug availability and treatment reimbursement. Often this illustrates the gap between Western and regional or even among local guidelines, the opinions of leading physicians regarding the treatment, and the realistic access to agents for most patients. Proposals made in this document are based on clinical experience and data from clinical trials of RCC therapies in which Asian patients have been included., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The cemented femoral stem with a distally straight cylindrical shape was designed to fill the distal femoral canal to facilitate higher cement pressurization and stability. We examined the mid-term outcomes of a stem made of titanium alloy and the efficacy of this shape., Methods: Four hundred and twenty-nine consecutive patients (505 hips), who underwent a total hip arthroplasty with the distally straight cylindrical stem made of titanium alloy as their primary hip arthroplasty at two institutes, were followed for a minimum 2 years. Loosening was defined as subsidence of over 3 mm, tilting of the femoral component, or fracture of the cement or the stem. A continuous radiolucent line along the entire interface was considered to indicate loosening, too. We examined the interface stresses on the distally straight cylindrical stem compared with a newly manufactured femoral prosthesis with a double-taper design using a finite element model study., Results: The mean follow-up was 101.3 months after surgery. Thirty patients (30 hips) had aseptic loosening of the stems. Of these 30 hips, 18 had osteolysis, 17 showed subsidence, and 11 had cement fractures at the tip of the stem. These 11 hips had osteolysis and ectasia in the same place: the stem tip. The stem survival rate with stem loosening as the end-point was 94.4 % at 10 years and 66.9 % at 15 years. A finite element model study revealed higher stress around the tip of the cylindrical stem compared with that in the double-taper stem., Conclusions: The straight cylindrical stem is potentially subject to early failure because of high stress around the tip of the stem, and showed a characteristic loosening with osteolysis and ectasia at the tip of the stem.

Background: The purpose of this study was to investigate the usefulness of a hydrocolloid dressing containing ceramide for hand-foot skin reaction (HFSR) on the soles of the feet in metastatic renal cell carcinoma (RCC) patients treated with sorafenib., Patients and Methods: Patients with grade 1 HFSR on the soles of the feet were randomly assigned in to two groups. One group received a hydrocolloid dressing containing ceramide (arm A) and the other received 10% urea cream (arm B). Patients in both groups applied treatment to the affected sites on the soles of the feet, but not to the hands. The primary end point was the incidence of grade 2 or 3 HFSR on the soles of the feet in the first 4 weeks., Results: Thirty-three patients were assessed (17 in arm A and 16 in arm B), and there were no significant differences in baseline characteristics between the two groups. During the observation period of this study, grade 2 or 3 HFSR on the soles of the feet was found in 29% of patients in arm A and was significantly less than the 69% in arm B (P=0.03). The incidence of HFSR on the hands, however, was similar in both arms. The median time to grade 2 or 3 HFSR on the soles of the feet was also significantly longer in arm A than in arm B (P=0.03)., Conclusions: These results indicate that a hydrocolloid dressing containing ceramide prevented the worsening of HFSR caused by sorafenib in metastatic RCC patients., Clinical Trial Registration Number: UMIN000002016.

Background: This study sought to evaluate the prevalence of coronary artery disease (CAD) and the impact of epicardial fat volume (EFV) on CAD in symptomatic patients with a zero calcium score (CS) using multislice computed tomography (MSCT)., Methods: In this study, 1308 consecutive symptomatic patients who underwent 64-slice MSCT with a zero CS were evaluated. EFV was quantified with CS data sets. Presence of an obstructive plaque (diameter stenosis >50%) and a CT-derived vulnerable plaque, which was defined as a plaque with remodeling index >1.10 and mean CT density value <3 0HU, was assessed with a CT coronary angiography., Results: Obstructive plaques were detected in 86 patients (7%) and CT-derived vulnerable plaques in 63 (5%). EFV was larger in patients with obstructive plaques than no plaque (124.3 ± 43.2 cm(3) vs. 95.1 ± 40.3 cm(3); p<0.01). Patients with CT-derived vulnerable plaques had a greater amount of EFV than no plaque (133.0 ± 40.2 cm(3) vs. 95.1 ± 40.3 cm(3); p<0.01). Multivariate analysis revealed EFV as a predictor of the presence of an obstructive and a CT-derived vulnerable plaque (per 10 cm(3); Odds ratio (OR) 1.10; 95% confidence interval (CI), 1.04-1.16; p<0.01 and OR 1.19; 95% CI, 1.12-1.27; p<0.01). The combination of EFV and Framingham risk score (FRS) resulted in an area under the receiver-operating characteristic curve for prediction of obstructive and CT-derived vulnerable plaque of 0.75 and 0.75, which was significantly higher than 0.68 and 0.64 for FRS alone (p=0.02 and p<0.01)., Conclusions: A zero CS doesn't exclude CAD and EFV can be a useful marker of CAD in symptomatic zero CS patients., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: RNA virus infections, such as rhinovirus and respiratory syncytial virus, induce exacerbations in patients with COPD and asthma, and the inflammation is corticosteroid refractory. The main aim of this study is to establish a murine model induced by a Toll-like receptor 3 (TLR3) agonist, an RNA virus mimic, and investigate the response to corticosteroid., Methods: A/J mice were given polyinosinic-polycytidylic acid (poly[I:C]), a TLR3 agonist, intranasally, in the presence or absence of cigarette smoke exposure. Inflammatory cell accumulation and C-X-C motif chemokine (CXCL) 1, interferon (IFN), and CXCL10 production in BAL fluid (BALF) were determined by flow cytometry and enzyme-linked immunosorbent assay, respectively, and airway hyperresponsiveness (AHR) to histamine/methacholine was determined by a two-chambered, double-flow plethysmography system. BALB/c and C57BL/6J mice were also used for comparisons., Results: Intranasal treatment of poly(I:C) significantly induced airway neutrophilia; production of CXCL1, IFN-β, and CXCL10; and necrotic cell accumulation in BALF. It also increased airway responsiveness to histamine or methacholine inhalation. This poly(I:C)-dependent airway inflammation and AHR was not inhibited by the corticosteroid fluticasone propionate (FP) (up to 0.5 mg/mL intranasal), although FP strongly inhibited lipopolysaccharide (TLR4 agonist)-induced airway neutrophilia. Furthermore, cigarette smoke exposure significantly increased TLR3 expression in murine lung tissue and exacerbated poly(I:C)-induced neutrophilia and AHR., Conclusions: These results suggest that TLR3 stimulation is involved in corticosteroid-refractory airway inflammation in lung, which is enhanced by cigarette smoking, and this may provide a model for understanding virus-induced exacerbations in COPD and their therapy.

Based on a Quality by Design (QbD) approach, it is important to follow International Conference on Harmonization (ICH) guidance Q8 (R2) recommendations to explore the design space. The application of an experimental design is, however, not sufficient because of the fact that it is necessary to take into account the effects of percolation theory. For this purpose, an adequate software needs to be applied, capable of detecting percolation thresholds as a function of the distribution of the functional powder particles. Formulation-computer aided design (F-CAD), originally designed to calculate in silico the drug dissolution profiles of a tablet formulation is, for example, a suitable software for this purpose. The study shows that F-CAD can calculate a good estimate of the disintegration time of a tablet formulation consisting of mefenamic acid. More important, F-CAD is capable of replacing expensive laboratory work by performing in silico experiments for the exploration of the formulation design space according to ICH guidance Q8 (R2). As a consequence, a similar workflow existing as best practice in the automotive and aircraft industry can be adopted by the pharmaceutical industry: The drug delivery vehicle can be first fully designed and tested in silico, which will improve the quality of the marketed formulation and save time and money., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Endothelial damage is an early component of atherosclerosis; however, the impact of cardiovascular risk factors on endothelial function is not clearly understood. We investigated the impact of lipid profiles and high blood pressure on damage., Objective: Japanese male outpatients with grade I or II hypertension, along with gender and age-matched normotensive subjects (both n = 25), were enrolled. Subjects with severe cardiovascular risk factors or illness or those taking medications were excluded. Blood was sampled for laboratory analysis and endothelial function was assessed by flow-mediated dilation (FMD)., Results: Total cholesterol to high-density lipoprotein cholesterol ratio (total-C/HDL-C) was inversely correlated with the FMD value and positively correlated with both malondialdehyde-modified low-density lipoprotein and high-sensitivity C-reactive protein values. Stepwise regression analysis revealed total-C/HDL-C and systolic blood pressure were significant determinants of FMD. Hypertensive subjects had lower FMD values and similar lipid profiles to normotensive subjects. Grouping subjects according to total-C/HDL-C levels showed that those with high values had lower FMD values. Hypertensive subjects with low total-C/HDL-C had similar endothelial index values to those in normotensive subjects with high total-C/HDL-C. Logistic regression indicated hypertension and high total-C/HDL-C were significantly associated with low FMD values., Conclusion: Impaired endothelial function was associated with increased total-C/HDL-C values, possibly as the result of increased vascular oxidative stress and inflammation. In the early stages of atherosclerosis, the impact of both total-C/HDL-C and BP may be similar in terms of endothelial damage., (Copyright © 2011 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

We reported a remarkable regional difference within Japan in the incidence of end-stage renal disease. Regional differences were also well-known for salt intake, blood pressure (BP), and mortality from stroke, which remains one of the leading causes of death. Noting these regional differences, we examined mutual relationships among salt intake, BP, and stroke mortality in 12 regions of Japan. Data of salt intake, BP, and stroke mortality in 12 regions were collected from National Nutrition Survey (NNS-J), reanalysis of NNS-J, and Vital Statistics of National Population Dynamic Survey (Ministry of Health, Labor and Welfare), respectively. Significant regional differences were found in salt intake (P < .0001), mean arterial BP (P = .0001), and stroke mortality (P < .0001). Although annual changes in these parameters were also significant, their regional differences persisted. Salt intake had positive relationships with both mean arterial BP (r = 0.26, P = .0009) and stroke mortality (r = 0.26, P < .0001) across 12 regions, whereas mean arterial BP was not correlated with stroke mortality. Multiple regression analysis further identified salt intake as an independent factor to increase stroke mortality, but mean arterial BP was not a determinant. Compared with the four regions with lowest salt intake, odds ratios of stroke mortality adjusted by mean arterial BP were 1.04 (95% CI, 1.03-1.06) for the intermediate four regions and 1.25 (95% CI, 1.23-1.27) for the four regions with highest salt intake. These findings suggest that salt intake may have an adverse effect on stroke mortality independently of BP., (Copyright © 2011 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Background: Although obesity has been reported to be associated with decreased plasma B-type natriuretic peptide (BNP) levels, it is unknown whether the reduced BNP levels in obesity results from decreased left ventricular (LV) hemodynamic load., Methods: We examined the relationships between body mass index (BMI), plasma BNP levels, and LV systolic and diastolic function (ejection fraction [EF] and end-diastolic pressure [EDP]) in 271 consecutive patients undergoing cardiac catheterization for coronary artery disease. When patients were grouped by tertile of BMI, with increasing tertiles of BMI, there was a progressive increase in EDP (lower, middle, and upper tertiles of BMI, 13.5 ± 5.8, 14.9 ± 5.3, and 16.3 ± 5.4 mmHg, respectively; p for trend <0.01) and a progressive decrease in log BNP levels (lower, middle, and upper tertiles of BMI, 3.52 ± 1.29, 2.96 ± 1.08, and 2.87 ± 1.21 ln[pg/ml], respectively, p for trend < 0.001). There was no clear difference in EF across BMI tertiles (p for trend >0.1). Plasma BNP levels correlated positively with EDP (r = 0.38, p < 0.001). In multivariate linear regression including EDP and known correlates of plasma BNP levels, BMI correlated negatively with BNP levels (standardized β = -0.31, p < 0.001)., Conclusions: We found that increased BMI was associated with LV diastolic abnormalities without change in systolic function and that patients with increased BMI had reduced plasma BNP levels despite having elevated EDP. These results suggest that the reduced BNP levels in obesity are not explained by altered LV hemodynamics., (© 2011 Asian Oceanian Association for the Study of Obesity . Published by Elsevier Ltd. All rights reserved.)

Some cardiovascular disorders disturb circadian variation of endothelial function. We investigated whether deterioration of renal function alters circadian variation of endothelial function in patients with hypertension. Endothelial function was assessed by the peak forearm blood flow (FBF) response to reactive hyperemia, and 24-hour ambulatory blood pressure monitoring was performed in 25 patients with essential hypertension (61 ± 17 years). Relationships among renal function, 24-hour blood pressure, and endothelial function were analyzed. The ratio of nighttime to daytime mean arterial pressure was inversely correlated with estimated glomerular filtration rate (eGFR) (r = -0.43, P = .03). The FBF response to reactive hyperemia examined at 21:00, but not at 6:30 or 11:30, was significantly correlated with eGFR (r = 0.44, P = .03). Furthermore, the ratio of FBF response measured at 21:00 to that measured at 6:30 was independently correlated with eGFR (β = 0.47, P = .02). Renal dysfunction is associated with the derangement of circadian variation of both endothelial function and blood pressure. Nocturnal blood pressure is elevated, and evening endothelial function deteriorates in parallel with a decline in renal function in hypertensive patients., (American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of the present study was to identify genetic variants that confer susceptibility to myocardial infarction (MI) in Japanese individuals., Methods: The study population comprised 5014 Japanese individuals, including 1444 subjects with MI and 3570 controls. The 150 polymorphisms examined in the present study were selected by a genome-wide association study for ischemic stroke with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix), and were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology., Results: An initial screen by the chi-square test revealed that the A-->G polymorphism of SEMA3F (rs12632110), the C-->T polymorphism of CLEC16A (rs9925481), the A-->G polymorphism of LAMA3 (rs12373237), and the C-->G polymorphism of PCSK2 (rs6080699) were significantly (false discovery rate for allele frequencies of <0.05) associated with MI. Subsequent multivariable logistic regression analysis with adjustment for covariates and a stepwise forward selection procedure revealed that the A-->G polymorphism of SEMA3F (dominant model; P=0.0014; odds ratio, 0.76), the C-->T polymorphism of CLEC16A (dominant model; P=0.0009; odds ratio, 0.75), the A-->G polymorphism of LAMA3 (recessive model; P=0.0099; odds ratio, 0.80), and the C-->G polymorphism of PCSK2 (recessive model; P=0.0155; odds ratio, 1.19) were significantly (P<0.05) associated with the prevalence of MI., Conclusion: Determination of these genotypes may prove informative for assessment of the genetic risk for MI in Japanese individuals., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

To study the properties and structure of aquatic silk, nest-spinning hydropsychid caddisfly (Stenopsyche marmorata) larva were collected from a Japanese river and the silk glands were removed from the larva by dissecting and dried on the glass plate at room temperature. The silk fibers were obtained by removing fibrous materials, which the aquatic insects spun at the bottom of glass container and the microstructure and physical properties of aquatic silk protein fibres and their solid silk protein gland were evaluated. Silk fiber produced by the caddisfly larvae is composed of two filament embedded in a layer of glue. The results of Fourier transform infrared spectroscopy and X-ray diffraction measurements suggested the existence of binary structure containing random coil conformation and additional minor beta-molecular structure. Differential scanning calorimetry results are characterized by two broad endothermic transitions, at 230 degrees C and 320 degrees C, which corresponds to the decomposition of silk glue and silk fiber from caddis fly, respectively. The storage modulus (E') remained almost unchanged and nearly constant at above 60 degrees C until about 214 degrees C, where it began to show a sharp drop. A prominent relaxation peak appeared in the imaginary part of the modulus (loss peak at 230 degrees C), in response to the strong motional transitions exhibited by the silk fiber at this temperature. There was significant difference of tensile strength of single solid silk protein gland in dry and wet state. The results obtained are quite promising as a basis for possible future biotechnological and adhesive applications of aquatic silk., (Copyright 2009 Elsevier B.V. All rights reserved.)

Expression of ATP binding cassette transporter A1 (ABCA1), a major regulator of high density lipoprotein (HDL) biogenesis, is known to be up-regulated by the transcription factor liver X receptor (LXR) alpha, and expression is further enhanced by activation of the peroxisome proliferator activated receptors (PPARs). We investigated this complex regulatory network using specific PPAR agonists: four fibrates (fenofibrate, bezafibrate, gemfibrozil and LY518674), a PPAR delta agonist (GW501516) and a PPAR gamma agonist (pioglitazone). All of these compounds increased the expression of LXRs, PPARs and ABCA1 mRNAs, and associated apoA-I-mediated lipid release in THP-1 macrophage, WI38 fibroblast and mouse fibroblast. When mouse fibroblasts lacking expression of PPAR alpha were examined, the effects of fenofibrate and LY518674 were markedly diminished while induction by other ligands were retained. The PPAR alpha promoter was activated by all of these compounds in an LXR alpha-dependent manner, and partially in a PPAR alpha-dependent manner, in mouse fibroblast. The LXR responsive element (LXRE)-luciferase activity was enhanced by all the compounds in an LXR alpha-dependent manner in mouse fibroblast. This activation was exclusively PPAR alpha-dependent by fenofibrate and LY518674, but nonexclusively by the others. We conclude that PPARs and LXRs are involved in the regulation of ABCA1 expression and HDL biogenesis in a cooperative signal transduction pathway.

The aim of the present study was to predict the prognosis of Chronic obstructive pulmonary disease (COPD) patients who underwent comprehensive pulmonary rehabilitation (PR). A total of 144 patients who performed PR between 1992 and 1999 was assessed. After PR, 67 patients underwent lung volume reduction surgery (LVRS). Baseline data before PR consisted of body mass index, serum albumin levels, use of supplement oxygen at home, pulmonary function, arterial blood gas analysis, and distance and fall of hemoglobin oxygen saturation (DeltaSpO(2)) in 6-min walk test. In addition to pre-PR factors, treatment with LVRS was taken into the analysis. The prognostic significance of variables influencing survival was determined by univariate analysis with Log rank test or multivariate analysis using Cox's proportional hazard model. By a median follow-up time of 8.4 years, the median survival time was 8.1 years (95% confidence interval: 6.9-9.4 years). Albumin level, PaCO(2), distance and DeltaSpO(2) were significant prognostic factors in univariate analysis. LVRS did not affect the prognosis. The multivariate analysis showed short distance and increase of DeltaSpO(2) as significant independent predictors of the risk of death. 6-min walk test was very useful for predicting the prognosis of the COPD patients.

A new classification for the severity of COPD was proposed at GOLD 2003: stage I: FEV(1) > or = 80% predicted; stage II: 50% < or = FEV(1)<80%; stage III: 30% < or = FEV(1)<50%; and stage IV: FEV(1) < 30%. To elucidate the acute effects of pulmonary rehabilitation (PR) on patients with different stages of COPD, data on pulmonary function, arterial blood gas analysis, the 6-min walk test, respiratory muscle strength, and activities of daily living were analyzed before and after our comprehensive 4- to 8-week inpatient PR program between 1992 and 2003. A total of 225 patients (201 men and 24 women; 21 with stage II, 79 with stage III, and 125 with stage IV COPD) was assessed. There were significant differences in FEV(1)% predicted and % residual volume in stages III and IV, in % vital capacity in stages II, III and IV, and in % total lung capacity in stage II when comparing the changes between pre- and post-PR. Significant differences of PaO(2) in stages III and IV and PaCO(2) in stage IV were found when comparing the changes between pre- and post-PR. The 6-min walk distance was significantly increased after PR by an average of approximately 50m for all staged patients. Respiratory muscle strength was also significantly increased in stages III and IV. Activities of daily living were significantly improved in all stages. These results showed that patients with COPD had benefited from PR regardless of disease severity. The effects included improvement in pulmonary function, arterial blood gas analysis, 6-min walk distance, respiratory muscle strength, and activities of daily living although there were some differences among the three stages.

Background: We reported that patients with sodium sensitive type of hypertension exhibited the lack of nocturnal fall in blood pressure with enhanced natriuresis during night. Sodium sensitivity is caused by diminished glomerular filtration capability and/or augmented tubular reabsorption of sodium, and seems tightly linked with glomerular capillary hypertension. In the present study, we investigated the relationship between glomerular filtration rate and circadian rhythms of these parameters in patients with glomerulopathy., Methods: Twenty six patients (15 men and 11 women; aged 17 to 72 years; mean age 47 +/- 3 years), whose diagnosis was confirmed as glomerulopathy with renal biopsy, were studied during hospitalization. Ambulatory blood pressure for 24 hours was monitored, while urinary samples were collected for both daytime (6:00 a.m. to 9:00 p.m.) and nighttime (9:00 p.m. to 6:00 a.m.) to estimate circadian rhythms of urinary sodium and protein excretion rates (UNaV, UproV). Then night/day ratios of mean arterial blood pressure (MAP), UNaV, and UproV were analyzed in relation to 24-hour creatinine clearance as a marker of glomerular filtration rate., Results: Serum creatinine and creatinine clearance were 1.1 +/- 0.1 mg/dL and 89 +/- 7 mL/min/1.73 m2. There were significant day-night differences in MAP (96 +/- 2 mm Hg vs. 92 +/- 2 mm Hg; P= 0.006), UNaV (6.7 +/- 0.9 mmol/hour vs. 3.6 +/- 0.3 mmol/hour; P= 0.003), and UproV (161 +/- 27 mg/hour vs. 128 +/- 28 mg/hour; P= 0.02). Creatinine clearance had significantly negative relationships with night/day ratios of MAP (r=-0.49; P= 0.01), UNaV (r=-0.43; P= 0.03,) and UproV (r=-0.41; P= 0.04). In addition, night/day ratio of MAP had significantly positive relationships with night/day ratios of UNaV (r= 0.49; P= 0.01) and UproV (r= 0.45; P= 0.02)., Conclusion: Our results show that as renal function deteriorates in glomerulopathy the nocturnal dip in blood pressure is lost, resulting in enhanced urinary sodium and protein excretions during night. These findings are compatible with our proposal that impaired natriuresis during daytime makes nocturnal blood pressure elevated to compensate for diminished natriuresis by pressure natriuresis. We speculate that nocturnal glomerular capillary hypertension contributes, at least in part, to enhanced urinary sodium and protein excretions during night.

Background: We recently found regional differences in the incidence of end-stage renal disease (ESRD) in Japan, which is generally ethnically homogeneous, suggesting that factors other than genetic may contribute to the difference. Here, we examined regional differences in the amounts of expenses spent on antihypertensives, especially angiotensin-converting enzyme (ACE) inhibitors, in our search for an explanation., Methods: Annually, the Japanese Society for Dialysis Therapy reports the numbers of patients entering maintenance dialysis in each prefecture of Japan since 1982. We used the findings for 1995 to 2000 to calculate the annual incidence of ESRD in each of the 11 regions of Japan. In addition, regional differences in annual amounts paid for antihypertensive drugs, presumably corresponding to the amounts used, during the same 6 years, corrected for population, were estimated., Results: As in our 1982 to 1998 study, the incidence of ESRD was high in Okinawa, Kyushu, and Shikoku, while low in Hokuriku, Koshinetsu, and Tohoku (P < 0.0001) [one-way repeated measures analysis of variance (ANOVA)]. We found regional differences in the corrected sum paid for total antihypertensive drugs, ACE inhibitors and calcium antagonists. Only ACE inhibitors were negatively correlated with the incidence of ESRD by linear and multiple regression analyses., Conclusion: The renal protective effects of ACE inhibitors have been established by results with animal models of progressive nephropathy and large-scale clinical trials. Our epidemiologic results for Japan as a whole show the same protective effects still more convincingly from a different approach.

Background: Although altered nonlinear heart rate dynamics predicts death in patients with coronary artery disease (CAD), its prognostic value in chronic hemodialysis patients with CAD is unknown., Methods: We analyzed 24-hour electrocardiogram for nonlinear heart rate dynamics and heart rate variability in a retrospective cohort of 81 chronic hemodialysis patients with CAD., Results: During a follow-up period of 31 +/- 20 months, 19 cardiac and 8 noncardiac deaths were observed. Cox hazards model, including diabetes, left ventricular ejection fraction, and the number of diseased coronary arteries, revealed that abnormal alpha2 (defined as both increase and decrease in alpha2 because of its J curve relationship with cardiac mortality), decreased approximate entropy and decreased heart rate variability (triangular index and ultra-low frequency power) were significant and independent predictors of cardiac death. No significant and independent predictive power for noncardiac death was observed in either the heart rate dynamics or the heart rate variability measures. The predictive power of alpha2 and approximate entropy was independent of that of triangular index and ultra-low frequency power. Combinations of two categories of measures improved the predictive accuracy; overall accuracy of approximate entropy + ultra-low frequency power for cardiac death was 87%., Conclusion: Altered nonlinear heart rate dynamics are independent predictors of cardiac death in chronic hemodialysis patients with CAD and their combinations with decreased heart rate variability provide clinically useful markers for risk stratification.

Study Objectives: We examined whether autonomic functions assessed by heart rate variability (HRV) during standardized head-up tilt testing (HUTT) predict risk for death in stable patients with coronary artery disease (CAD)., Design and Setting: Retrospective cohort study in medium-sized university general hospital., Measurements and Results: In a cohort of 250 patients with CAD who were undergoing elective coronary angiography, we analyzed HRV during standardized HUTT under paced breathing with discontinuation of treatment with all medications. During a subsequent mean follow-up period of 99 months, there were 13 cardiac deaths and 12 noncardiac deaths. Cox regression analysis adjusted for cardiovascular risks revealed that increased postural change (supine to upright) in the power of low-frequency component (LF) power predicted an increased risk for cardiac death (relative risk [per 1-ln ms(2) increment], 4.36; 95% confidence interval, 1.64 to 11.6), while neither the high-frequency component nor its response to HUTT predicted any form of death. When the patients were trichotomized by the level of postural LF change (large drop, < or = - 0.6 ln[ms(2)]; small drop and rise, > 0 ln[ms(2)]), the three groups did not differ in terms of clinical features or CAD severity at baseline or coronary interventions during the follow-up period; however, the 8-year cardiac mortality rates were 0%, 6%, and 12%, respectively (p = 0.008 [log rank test]). Additionally, the difference was enhanced when analyzed excluding 64 patients who had been treated with a beta-blocker during the follow-up period (0%, 7%, and 15%, respectively; p = 0.006 [log rank test])., Conclusions: The postural response of HRV predicts the risk for death in patients with CAD. Postural LF increase (LF rise), in particular, is an independent risk factor for cardiac death.

In our attempt to discover a potential cause for accumulation of cholesteryl ester transfer protein (CETP) deficiency in Eastern Asia, we studied the association of CETP deficiency with pathogenesis of Schistosoma japonicum, a life-threatening parasite peculiar to this region. The eggs of S. japonicum showed slow embryonation when cultured in CETP-deficient human plasma. Restoration of CETP to the deficient plasma rescued it, while inhibition of CETP in normal plasma did not cause slow embryonation of the cultured eggs. The egg embryonation was also retarded in the liver but not in the intestine of wild-type mice in comparison to the CETP-transgenic mice. The granulomatous lesion around the parasite eggs in the liver was less in the wild-type than in the CETP-transgenic mice. Thus, CETP deficiency may act against Schistosomiasis japonica by retarding egg embryonation, a potential cause of liver granulomatosis. It does not seem directly due to the lack of CETP activity in plasma but to abnormal lipoprotein generated by chronic CETP deficiency., (Copyright 2001 Academic Press.)

Background: In patients with sodium-sensitive hypertension, glomerular pressure is increased and microalbuminuria, a marker of glomerular hypertension, is a predictor of cardiovascular events. Similarly, the lack of a nocturnal decrease in blood pressure in these patients is also associated with an increased risk of cardiovascular events. We hypothesised that sodium sensitivity may be the common factor and carried out a retrospective study of cardiovascular events in patients with essential hypertension who had had sodium sensitivity measured in our clinic., Methods: Sodium sensitivity was assessed in about 350 patients with essential hypertension during the initial investigation of their disorder. The definition of sodium sensitivity was a 10% or greater difference in blood pressure on low-sodium or high-sodium diets. By alphabetical order, the records of 201 patients were obtained and 156 patients without pre-existing disorders were followed up. The records of patients who had a cardiovascular event or died were reviewed without knowledge of the patient's sodium-sensitivity status., Findings: 62 patients were deemed sodium sensitive and 94 non-sodium sensitive. Left-ventricular hypertrophy was found more frequently in the sodium-sensitive group than in the non-sodium-sensitive group (38 vs 16%; p < 0.01), whereas significantly fewer patients in this group smoked (23 vs 42%; p < 0.05). There were 17 cardiovascular events in the sodium-sensitive group and 14 in the non-sodium-sensitive group. The rate of total, non-fatal and fatal cardiovascular events, was 2.0 per 100 patient-years in the non-sodium-sensitive group and 4.3 per 100 patient-years in the sodium-sensitive group. Cox's proportional-hazards model identified sodium sensitivity (p < 0.01), mean arterial pressure (p < 0.01), and smoking (p < 0.01) as independent cardiovascular risk factors., Interpretation: Cardiovascular events occurred more frequently in patients with sodium-sensitive hypertension. Sodium sensitivity is an independent cardiovascular risk factor in Japanese patients with essential hypertension.

It has been postulated that glomerular capillary pressure is elevated in sodium-sensitive types of hypertension. In addition, the presence or absence of renal function reserve, in response to a chronic protein load, is thought to be useful in predicting the existence of glomerular hypertension. Intrarenal hemodynamic parameters in the sodium-sensitive type of essential hypertension were therefore calculated by analyzing the pressure-natriuresis curve, and the preservation of renal function reserve was evaluated. Fifteen patients with essential hypertension were maintained on a normal sodium diet for 1 week and a low-sodium diet for a second week in study 1. This protocol was repeated for low and high protein intake in 8 patients in study 2. Subjects in study 1 whose mean arterial pressure was reduced by more than 10% by sodium restriction were considered sodium sensitive (n = 7), with the remaining patients classified as non-sodium sensitive (n = 8). There were no significant differences in mean arterial pressure (125 +/- 2 mm Hg), glomerular filtration rate (80 +/- 3 ml/min), or renal plasma flow rate (355 +/- 24 ml/min) on the normal sodium diet between sodium-sensitive and non-sodium-sensitive patients. Glomerular capillary pressure (59 +/- 2 mm Hg vs 47 +/- 1 mm Hg, p < 0.0002) was estimated to be elevated in sodium-sensitive patients relative to that in non-sodium-sensitive patients, whereas the whole kidney ultrafiltration coefficient of glomerular capillary walls (0.068 +/- 0.009 (ml/sec)/mm Hg vs 0.221 +/- 0.042 (ml/sec)/mm Hg, p < 0.005) was decreased. Chronic protein loading increased both glomerular filtration and renal plasma flow rates in study 2. Although the sodium sensitivity of blood pressure showed no significant correlation with the increase in either glomerular filtration or renal plasma flow rate, it showed a weak negative correlation with the increase in filtration fraction (r = -0.69, p < 0.06), which is the ratio of the two rates. Taken together, these results suggest that glomerular capillary pressure is elevated and renal function reserve is impaired in patients with sodium-sensitive essential hypertension.

We examined the immunotherapeutic ability of activated B cells which bound to anti-CD3 monoclonal antibody (mAb) to enhance antitumor T cell immunity in vivo. A flow cytometric analysis revealed that LPS (lipopolysaccharide)-activated B cells (LPS blasts) expressed Fc receptor (FcR) which can bind to anti-CD3 mAb. LPS blasts were also stained with CTLA-4Ig, which can bind to costimulation molecules with high affinity, which suggested that LPS blasts expressed costimulation molecules on their surface. In an in vitro assay, T cells remarkably proliferated in the presence of LPS blasts and soluble anti-CD3 mAb, whereas this proliferation was blocked by the addition of CTLA-4Ig. In a model of metastasis established by the intravenous inoculation of melanoma cells, the in vivo administration of LPS blasts incubated with anti-CD3 mAb and followed by treatment with polyethylene glycol, to reinforce the binding, induced a low but significant antitumor activity against melanoma. The antitumor activity induced by the in vivo administration of LPS blasts which bound to anti-CD3 mAb was also detected in the spontaneously established model of metastasis. These results therefore suggest that the in vivo administration of activated B cells which bound to anti-CD3 mAb was able to enhance the antitumor T cell response against metastatic melanoma.

Recent data verified the role of thymocyte adhesion to thymic epithelial cells (TEC) in T cell development. In order to measure this cellular event as one of routine examinations in immunological studies, a simple quantitative assay in in vitro setting is required. Labeling thymocytes with fluorescein diacetate (FDA) was used to measure quickly and with certainty the adhesion ability of BALB/c thymocytes to TEC cells, a thymic epithelial cell line derived from BALB/c mouse thymic stroma. Thymocytes stained with FDA at the concentration of 2.5 micrograms/ml gave a strong fluorescent intensity (FI) easily detectable in a spectrophotometer and showed the same phenotypical and functional features as unstained cells. As it was confirmed that the cell number correlated well with FI, the number of cells adhering to TEC in wells of a 96-well microplate could be estimated. The major advantage of using FDA was that it took only a few seconds to measure FI of one sample. In contrast, to count the number of adherent cells with conventional methods using a light microscope or radioisotopes required much longer time and care to avoid radiological hazards. Moreover, cell viability and FI of FDA-labeled thymocytes changed little for 24 h, and lysates of FDA-positive cells demonstrated the same FI as living cells. These results indicate that many samples could be applied for FI measurement at the same time after in vivo or in vitro experiments.

Split intrarenal hemodynamics in stenotic and contralateral kidneys of unilateral renovascular hypertension (RVH) were estimated by Gomez's formulae. Forty patients with essential hypertension and 40 patients with RVH were studied. Split para-amino hippurate and inulin clearances were measured by ureteral catheterization as indexes for effective renal plasma flow and glomerular filtration rates, allowing the estimation of intrarenal hemodynamics such as afferent arteriolar resistance (RA), efferent arteriolar resistance (RE) and glomerular hydrostatic pressure (PG) in each kidney. Normal values of intrarenal hemodynamic parameters were obtained in 24 normotensive subjects without ureteral catheterization, assuming each kidney had the half function of both kidneys. Systemic mean arterial pressure did not differ between essential and renovascular hypertension (141 +/- 3 vs. 148 +/- 3 mm Hg). Effective renal plasma flow and glomerular filtration rates were decreased in the stenotic kidney of RVH (98 +/- 8, 24 +/- 2 ml/min/m2), while increased in the contralateral kidney (195 +/- 11, 48 +/- 2), compared with the right kidney of essential hypertension (162 +/- 8, 33 +/- 1). Although effective renal plasma flow rate was not different from normal (191 +/- 8), glomerular filtration rate was significantly higher in the contralateral kidney of RVH than in normal (38 +/- 1). RA was elevated due to the stenotic lesion in the stenotic kidney (28,500 +/- 1,900 dyns.sec.cm-5), while the elevation in the contralateral kidney (10,800 +/- 600) was less than in the right kidney of essential hypertension (14,900 +/- 1,200). RE (5,800 +/- 300) in both kidneys of RVH was higher than in the right kidney of essential hypertension (4,500 +/- 200).(ABSTRACT TRUNCATED AT 250 WORDS)

We have developed a new culture system (termed the JCC device) for the generation and expansion of human lymphokine-activated killer (LAK) cells. The JCC device was essentially based on dialysis culture. A dialysis membrane divided the culture vessel from the outside circulation of basal medium. Human lymph node lymphocytes were cultured in the culture vessel using a culture volume of 100 ml at an initial cell density of 1 X 10(6)/ml in the presence of recombinant human interleukin-2. The culture vessel was rotated for the proper dispersion of cells. The cell density reached up to 1.2 X 10(7)/ml on day 17 of culture. A modified JCC device supplying oxygen through a silicon tube prevented oxygen depletion in the culture vessel. With this modified JCC device cell densities up to 4.3 X 10(7)/ml were achieved without reduction of cytolytic activity. Cell viability was more than 90% throughout the culture. The use of this JCC device permitted the culturing of LAK cells at a high cell density. The procedure is relatively cheap, simple and less time consuming than previous methods.

We previously reported that lymphokine-activated killer (LAK) activity can be generated in human lymph node lymphocytes (LNL) at the same level as that in peripheral blood lymphocytes (PBL), despite the absence of active natural killer (NK) cells. In the present study, we investigated the surface phenotype of LNL-LAK cells by fractionation of lymphocytes, using a panning method. LNL isolated from lung cancer patients were cultured in the presence of recombinant interleukin 2 for 8 days and separated into T cells and non-T cells according to the expression of CD3 antigen. LAK effectors were enriched in the CD3- non-T cells. However, the CD3+ cells also mediated a low but substantial level of LAK activity, which was attributed to a CD8+ T-cell subset. Further investigation of the CD3- cells revealed that most of the CD3- effector cells expressed neither B-cell (CD20) nor NK-cell (CD16) markers. Precursors of this CD3-CD20-CD16- (null) population appeared to be also CD3-, CD20-, and CD16-. From these results, we would stress the significant contribution of CD3-CD20-CD16- null cells to the LAK phenomenon, which has not been focused on in PBL.

When 3Y1 cells resting at a saturation density were mitotically stimulated with serum, the c-fos mRNA level markedly increased in a short period of time and then decreased rapidly to an undetectable level. Subsequent serum deprivation followed by serum re-addition or subsequent cycloheximide addition caused a transient re-increase in the c-fos mRNA level. These results can be explained by assuming that the continuous expression of the c-fos gene at a minimum level is necessary for the eventual initiation of S phase, and that the over-expression of the c-fos gene occurs when the control of the gene expression is transiently disturbed by the change of the culture condition.

We have compared hypertensive target organ damage with home blood pressure readings (HBPs) and with office blood pressure readings (OBPs) in 100 patients with mild to moderate essential hypertension. The correlation between blood pressure levels and hypertensive target organ damage in HBPs and OBPs were similar (r = .42, p less than 0.001 for systolic HBPs; r = .33, p less than 0.001 for diastolic HBPs; r = .42, p less than 0.001 for systolic OBPs; r = .34, p less than 0.001 for diastolic OBPs). In most instances, HBPs were lower than corresponding OBPs. Among individual patients whose OBPs were identical, HBPs in some instances differed strikingly. Optic fundi abnormalities were significantly more severe in patients whose systolic HBPs were 150 mmHg or greater, than in those whose systolic HBPs were less than 150 mmHg (p less than 0.05). Hypertensive complications did not differ among office hypertensive patients who were normotensive or borderline hypertensive at home, from the differences of OBPs. We concluded that overall hypertensive complications were equally related to HBPs and OBPs, but patients with discrepancies between HBPs and OBPs had fewer hypertensive complications. Thus, both OBPs and HBPs should be considered in deciding therapy.