Clinical, radiological and pathological features of idiopathic and secondary interstitial pneumonia with pleuroparenchymal fibroelastosis in patients undergoing lung transplantation.

AIMS: Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a rare type of idiopathic interstitial pneumonia, and pathological PPFE is also observed in patients with secondary interstitial pneumonia. This study aimed to evaluate the pathological findings associated with radiological PPFE-like lesions and the clinical and morphological features of patients with pathological PPFE. METHODS AND RESULTS: We retrospectively reviewed the pathology of the explanted lungs from 59 lung transplant recipients with radiological PPFE-like lesions. Pathological PPFE lesions were identified in 14 patients with idiopathic disease and in 12 patients with secondary disease. Pathological PPFE was associated with previous pneumothorax, volume loss in the upper lobes, and a flattened chest. Patients with idiopathic disease and those with secondary disease with pathological PPFE had similar clinical, radiological and pathological findings, whereas fibroblastic foci were more common in patients with idiopathic disease, and patients with secondary disease more frequently showed alveolar septal thickening with elastosis or fibrosis. Post-transplantation survival did not differ between patients with idiopathic and secondary disease with pathological PPFE (log-rank; P = 0.57) and was similar between patients with idiopathic disease with pathological PPFE and those with idiopathic pulmonary fibrosis (IPF) (log-rank; P = 0.62). CONCLUSIONS: Not all patients with interstitial pneumonia with radiological PPFE-like lesions have pathological PPFE. Characteristic clinical features can suggest the presence of pathological PPFE, and idiopathic and secondary cases with pathological PPFE are similar except for fibroblastic foci in idiopathic cases and alveolar septal thickening with elastosis or fibrosis in secondary cases. Patients with pathological PPFE have a similar prognosis to those with IPF after transplantation.

Cutaneous T-cell-attracting chemokine as a novel biomarker for predicting prognosis of idiopathic pulmonary fibrosis: a prospective observational study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease that leads to respiratory failure and death. Although there is a greater understanding of the etiology of this disease, accurately predicting the disease course in individual patients is still not possible. This study aimed to evaluate serum cytokines/chemokines as potential biomarkers that can predict outcomes in IPF patients. METHODS: A multi-institutional prospective two-stage discovery and validation design using two independent cohorts was adopted. For the discovery analysis, serum samples from 100 IPF patients and 32 healthy controls were examined using an unbiased, multiplex immunoassay of 48 cytokines/chemokines. The serum cytokine/chemokine values were compared between IPF patients and controls; the association between multiplex measurements and survival time was evaluated in IPF patients. In the validation analysis, the cytokines/chemokines identified in the discovery analysis were examined in serum samples from another 81 IPF patients to verify the ability of these cytokines/chemokines to predict survival. Immunohistochemical assessment of IPF-derived lung samples was also performed to determine where this novel biomarker is expressed. RESULTS: In the discovery cohort, 18 cytokines/chemokines were significantly elevated in sera from IPF patients compared with those from controls. Interleukin-1 receptor alpha (IL-1Rα), interleukin-8 (IL-8), macrophage inflammatory protein 1 alpha (MIP-1α), and cutaneous T-cell-attracting chemokine (CTACK) were associated with survival: IL-1Rα, hazard ratio (HR) = 1.04 per 10 units, 95% confidence interval (95% CI) 1.01-1.07; IL-8, HR = 1.04, 95% CI 1.01-1.08; MIP-1α, HR = 1.19, 95% CI 1.00-1.36; and CTACK, HR = 1.12 per 100 units, 95% CI 1.02-1.21. A replication analysis was performed only for CTACK because others were previously reported to be potential biomarkers of interstitial lung diseases. In the validation cohort, CTACK was associated with survival: HR = 1.14 per 100 units, 95% CI 1.01-1.28. Immunohistochemistry revealed the expression of CTACK and CC chemokine receptor 10 (a ligand of CTACK) in airway and type II alveolar epithelial cells of IPF patients but not in those of controls. CONCLUSIONS: CTACK is a novel prognostic biomarker of IPF. Trial registration None (because of no healthcare intervention).

Serum matrix metalloproteinase levels in polymyositis/dermatomyositis patients with interstitial lung disease.

OBJECTIVE: We aimed to clarify the clinical significance of serum levels of MMPs in interstitial lung disease (ILD) complicated with PM/DM (PM/DM-ILD). METHODS: We retrospectively analysed serum levels of seven subsets of MMPs in 52 PM/DM-ILD patients diagnosed at Kyoto University Hospital or Tenri Hospital from January 2005 to December 2014. The patients were sub-grouped based on the presence of anti-amimoacyl-tRNA synthetase antibody (anti-ARS antibody), anti-melanoma differentiation-associated protein 5 antibody (anti-MDA5 antibody) or lack of the antibodies (ARS-ILD, MDA5-ILD and other-ILD groups, respectively) and independently analysed. Eighteen PM/DM patients without ILD and 55 healthy control were also analysed. Associations between serum levels of MMPs and clinical findings including mortality were analysed. RESULTS: Among the MMPs analysed, MMP-7 serum levels in the ARS-ILD group were significantly higher compared with those in any of the other groups of PM/DM patients or in healthy controls. On the other hand, in the MDA5-ILD group, serum MMP-7 levels >5.08 ng/ml were associated with worse overall survival both in univariate (P = 0.017; odds ratio 18.0; 95% CI 1.69, 192.00) and multivariate (P = 0.027; odds ratio 14.60; 95% CI 1.11, 192.00) analyses. Immunohistochemical analysis suggested that MMP-7 was expressed in type II alveolar epithelial cells adjacent to the fibrotic lesions. CONCLUSION: Serum MMP-7 levels were higher in anti-ARS antibody-positive PM/DM-ILD patients, while higher serum MMP-7 levels among anti-MDA5 antibody-positive PM/DM-ILD patients were associated with a worse prognosis. Fibrotic processes may be associated with the elevation of serum MMP-7 levels.

Clinical significance of radiological pleuroparenchymal fibroelastosis pattern in interstitial lung disease patients registered for lung transplantation: a retrospective cohort study.

BACKGROUND: Radiological pleuroparenchymal fibroelastosis (PPFE) lesion is characterized by pleural thickening with associated signs of subpleural fibrosis on high-resolution computed tomography (HRCT). This study evaluated the clinical significance of radiological PPFE as an isolated finding or associated with other interstitial lung diseases (ILDs) in patients having fibrotic ILDs and registered for cadaveric lung transplantation (LT). METHODS: This retrospective study included 118 fibrotic ILD patients registered for LT. Radiological PPFE on HRCT was assessed. The impact of radiological PPFE on clinical features and transplantation-censored survival were evaluated. RESULTS: Radiological PPFE was observed in 30/118 cases (25%): definite PPFE (PPFE concentrated in the upper lobes, with involvement of lower lobes being less marked) in 12 (10%) and consistent PPFE (PPFE not concentrated in the upper lobes, or PPFE with features of coexistent disease present elsewhere) in 18 (15%). Of these, 12 had late-onset non-infectious pulmonary complications after hematopoietic stem-cell transplantation and/or chemotherapy (LONIPCs), 9 idiopathic PPFE, and 9 other fibrotic ILDs (idiopathic pulmonary fibrosis, IPF; other idiopathic interstitial pneumonias, other IIPs; connective tissue disease-associated ILD, CTD-ILD, and hypersensitivity pneumonia, HP). Radiological PPFE was associated with previous history of pneumothorax, lower body mass index, lower percentage of predicted forced vital capacity (%FVC), higher percentage of predicted diffusion capacity of carbon monoxide, less desaturation on six-minute walk test, and hypercapnia. The median survival time of all study cases was 449 days. Thirty-seven (28%) received LTs: cadaveric in 31 and living-donor lobar in six. Of 93 patients who did not receive LT, 66 (71%) died. Radiological PPFE was marginally associated with better survival after adjustment for age, sex, %FVC, and six-minute walk distance < 250 m (hazard ratio 0.51 [0.25-1.05], p = 0.07). After adjustment for covariates, idiopathic PPFE and LONIPC with radiological PPFE was associated with better survival than fibrotic ILDs without radiological PPFE (hazard ratio 0.38 [0.16-0.90], p = 0.03), and marginally better survival than other fibrotic ILDs with radiological PPFE (hazard ratio, 0.20 [0.04-1.11], p = 0.07). CONCLUSIONS: idiopathic PPFE and LONIPC with radiological PPFE has better survival on the wait list for LT than fibrotic ILDs without radiological PPFE, after adjustment for age, sex, %FVC, and six-minute walk distance.

Aqueous chromatographic system for separation of biomolecules using thermoresponsive polymer modified stationary phase.

We have investigated a new method for HPLC using packing materials modified with a functional polymer, such as thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm). PNIPAAm-modified silica exhibits temperature-controlled hydrophilic-hydrophobic surface property changes in aqueous systems. Temperature-responsive chromatography is performed with an aqueous mobile phase without using an organic solvent. We designed ternary copolymers of NIPAAm introduced 2-(dimethyl-amino) ethyl methacrylate (DMAEMA) as a cationic monomer and butyl methacrylate (BMA) as a hydrophobic monomer. A cationic thermoresponsive hydrogel grafted surface would produce an alterable stationary phase with both thermally regulated hydrophobicity and charge density for separation of bioactive compounds. In this study, we achieved successful separation of lysozyme without the loss of bioactivity by temperature-responsive chromatography. The electrostatic and hydrophobic interactions could be modulated simultaneously with the temperature in an aqueous mobile phase, thus the separation system would have potential applications in the separation of biomolecules.

Association of genetic variation of the adiponectin gene with body fat distribution and carotid atherosclerosis in Japanese obese subjects.

AIM: The aim of this study was to investigate the effect of SNP45 of the adiponectin gene on body fat distribution and carotid atherosclerosis in Japanese obese subjects. METHODS: A total of 64 obese subjects were investigated. Genotypes of SNP45 were assayed by polymerase chain reaction-restriction fragment length polymorphism. Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured using computed tomography. The progression of atherosclerosis was evaluated by plaque score (PS) of carotid artery using B-mode ultrasonography. RESULTS: Men carrying the G allele of SNP45 showed higher VFA (172.8+/-50.8 vs. 147.1+/-58.7, p=0.005), lower SFA (209.9+/-101.8 vs. 273.4+/-142.2, p=0.007), higher VFA/SFA (V/S) ratio (1.00+/-0.46 vs. 0.60+/-0.26, p <0.001) and higher PS (9.5+/-3.7 vs. 6.8+/-4.2, p=0.012) than those with TT genotype. Multivariate analysis showed that SNP45 was an independent determinant of V/S ratio and PS in men. In subgroup analysis, PS tended to be associated with V/S ratio only in the carrier of 45G allele. CONCLUSION: These results suggest that the G allele could be a risk factor of metabolic syndrome and the development of atherosclerosis in Japanese obese subjects.

Analysis of melatonin using a pH- and temperature-responsive aqueous chromatography system.

A new method for the qualitative and quantitative analysis of an intracerebral hormone, such as melatonin, has been proposed, utilizing newly designed copolymers that include ion-exchange groups. These copolymers responded to both the temperature and the pH, and the copolymers were modified with cross-linked hydrogel applied onto aminopropyl silica beads. The products were evaluated as HPLC packing materials for a pH- and temperature-responsive chromatography. The property of the surface of the stationary phase was altered from hydrophilic to hydrophobic, and from charged to non-charged by changes in both the temperature and the pH. In the chromatographic system, we investigated how to change the retention of melatonin by varying the temperature. A pH- and temperature-responsive chromatography is expected to be useful for the separation of pharmaceuticals and biomolecules.

Effect of substituents at the 5-position of the pyridine ring of imidacloprid on insecticidal activity against Periplaneta americana.

The insecticidal activities of imidacloprid derivatives with a wide range of substituents at the 5-position on the pyridine ring against American cockroaches, Periplaneta americana (L.), were measured by injection with and without synergists propyl 2-propynyl phenylphosphonate and piperonyl butoxide. The log(1/MLD) value (MLD = minimal lethal dose in mol) without synergists was 7.96 for the methyl derivative, and the values were lower for other derivatives. Synergists enhanced the potencies of all the compounds tested. Considering these compounds and those with other substituents at this position, the region for maximum activity was predicted to be in the conjunction of the pyridyl 6-chlorine atom with a lipophilic small group in the 5-position.

[The influence of cognitive appraisal on the duration of negative emotional experience and cardiovascular response].

The duration of a negative emotional experience is associated with delayed cardiovascular recovery. Cognitive appraisal is thought to play an important role in cutting off these responses, which are related to cardiovascular disease. This study examined the influence of cognitive appraisal on the duration of negative emotional experiences and cardiovascular responses. Before a speech task, participants were told that their performance would be evaluated by means of a video camera and that they would be given the score at the end of the experiment. To manipulate cognitive appraisal, participants were randomly assigned to a group that received one of three instructions following the speech task. The "non-threat" group was informed that there was no evaluation or feedback about the score; the "threat" group received that there were some obscurities in their speech and some questions were given while comparing with the video; the control group was given no instructions. After receiving their respective instructions, all groups were monitored for a post-task period of five minutes. The results showed that the "non-threat" group experienced a decreased negative emotional experience and had a speedy recovery for blood pressure, through the intermediary of a greater decline in total peripheral resistance, than the other groups in the post-task period. These results were discussed in connection with the function of cognitive reappraisal.

Effect of walking with a pedometer on serum lipid and adiponectin levels in Japanese middle-aged men.

OBJECTIVE: To clarify the effects of walking with a pedometer on metabolic parameters, including adiponectin (APN). METHODS: We recruited 44 male Japanese volunteers (age, 37 +/- 9 yrs; body mass index (BMI), 24.2 +/- 2.9 kg/m2; fasting plasma glucose (FPG), 96 +/- 11 mg/dL; total cholesterol (TC) 190 +/- 26 mg/dL; triglycerides (TG) 119 +/- 80 mg/dL; HDL-C56 +/- 14 mg/dL). Subjects were instructed to walk with a pedometer and record the number of steps they walked every day for 50 days. Serum adiponectin (APN) levels were measured by enzyme immunoassay. Treatment effects were examined by Wilcoxon's rank test. RESULTS: The average number of steps was 8211 +/- 2084 per day. There were significant reductions in BMI, sBP, TG and TNF-alpha levels after 50 days, but no changes in adiponectin levels. We then divided the subjects into 2 groups according to the steps walked per day, namely, more than 8000 steps (MT group, n = 22) and less than 8000 steps (LT group, n = 22) and found that the reduction in TG and BP was observed only in the MT group. CONCLUSIONS: Walking with a pedometer is effective for improving metabolic parameters, such as TG and blood pressure, but is not sufficient to increase adiponectin levels in Japanese men.

The relationship of percent body fat by bioelectrical impedance analysis with blood pressure, and glucose and lipid parameters.

The objective of this study was to clarify the clinical significance and usefulness of measuring percent body fat (PBF) when compared with body mass index (BMI) in the Japanese population. A total of 2,483 Japanese individuals (1,380 men and 1,103 women) who underwent a medical checkup from 1999-2002 were employed. PBF was determined using bioelectrical impedance analysis (BIA). Relationships of age, BMI and PBF with several metabolic parameters, including blood pressure, lipids and plasma glucose levels were assessed in both genders separately. In men, PBF was a stronger determinant of total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C) and triglycerides (TG) compared with age and BMI, whereas in women, age was the strongest determinant of TC and LDL-C. In both genders, BMI was the strongest determinant of serum HDL-C among age, PBF and BMI. Based on these data, we suggest that measuring PBF by BIA is superior to BMI for predicting TC, LDL-C and TG in Japanese men.

Raloxifene promotes adipocyte differentiation of 3T3-L1 cells.

To explore the possibility that raloxifene might influence an adipocyte differentiation and lipogenesis, we studied the effects of raloxifene on the expression of adiponectin and other peroxisome proliferator-activated receptor gamma targeting genes using the 3T3-L1 adipocytes. With standard adipogenic inducers, we added raloxifene at various doses for the adipocyte differentiation. Higher doses of raloxifene facilitated lipid accumulation of the 3T3-L1 cells. We next examined the differentiating and differentiated adipocytes and found that raloxifene augmented mRNA levels of adiponectin, adipocyte-specific fatty acid binding protein, and lipoprotein lipase dose-dependently in both. These effects were opposite those of 17beta-estradiol treatment. These findings suggest that raloxifene promotes adipocyte differentiation, providing a novel insight into the treatment of postmenopausal metabolic syndrome with hypoadiponectinemia.

Effects of fenofibrate therapy on plasma ubiquinol-10 and ubiquinone-10 levels in Japanese patients with hyperlipidemia and type 2 diabetes mellitus.

STUDY OBJECTIVE: To assess the effects of fenofibrate therapy on concentrations of plasma ubiquinol-10 and ubiquinone-10-the reduced and oxidized forms, respectively, of coenzyme Q(10). DESIGN: Prospective, open-label, non-controlled study. SETTING: University clinic and laboratory. PATIENTS: Eighteen patients with hyperlipidemia and type 2 diabetes mellitus. INTERVENTION: Patients received fenofibrate 150 mg/day for 12 weeks. MEASUREMENTS AND MAIN RESULTS: Metabolic parameters were assessed 4, 8, and 12 weeks after the start of fenofibrate treatment. Plasma ubiquinol-10 and ubiquinone-10 levels were measured by reverse-phase high-performance liquid chromatography. At 4, 8, and 12 weeks, significant reductions in fasting triglyceride levels and significant increases in high-density lipoprotein cholesterol levels were noted. Total cholesterol, low-density lipoprotein cholesterol, fasting plasma glucose, and adiponectin levels, however, did not change significantly. Plasma ubiquinol-10 concentrations significantly increased after 8 and 12 weeks (p<0.05 for both), whereas ubiquinone-10 concentrations tended to decrease, especially at 12 weeks. CONCLUSION: Our findings suggest that fenofibrate may help produce energy or prevent oxidation by increasing plasma ubiquinol-10 concentration; this effect may protect against the development and progression of atherosclerosis. In addition, treatment with fenofibrate demonstrated a favorable effect on serum lipid parameters.

[Sick-day management in elderly patients with diabetes mellitus].

Sick-day is defined as a state of common illness like cold or flu, which can reduce oral intake and make blood sugars hard to control in diabetic patients. The symptoms associated with hyper- or hypoglycemia may be atypical in the geriatric population, therefore, elderly patients need to take extra precautions on sick days to avoid diabetic crises. The elderly are particularly vulnerable to hyperglycemia and dehydration, the key components of hyperosmolar hyperglycemic syndrome, because insulin sensitivity and thirst mechanisms decrease with increasing age. Frequent monitoring of blood glucose is recommended and an individualized sick-day plan in considering the heterogeneity of older patients is important.

Association of coronary artery ectasia with plasma insulin levels in Japanese men of heterozygous familial hypercholesterolemia with the low-density lipoprotein receptor gene mutation K790X.

BACKGROUND: Hyperinsulinemia is widely believed to be an important coronary risk factor. We investigated the effect of plasma insulin levels on the development of coronary ectasia in Japanese men with heterozygous familial hypercholesterolemia (FH). METHODS: A cross-sectional study was conducted in 20 FH men with the LDL receptor mutation (K790X) [age 42.3+/-2.8 years old, body mass index (BMI) 24.6+/-0.7 kg/m2, total cholesterol (TC) 8.68+/-0.36 mmol/l, triglycerides (TG) 1.76+/-0.23 mmol/l, high-density lipoprotein cholesterol (HDL-C) 0.977+/-0.065 mmol/l]. Subjects with diabetes mellitus were excluded. Plasma insulin levels, either fasting or during oral glucose tolerance test, were compared between subjects with and without coronary artery ectasia. RESULTS: FH subjects with coronary ectasia had significantly higher fasting plasma insulin levels than those without (12.6+/-1.4 vs. 7.7+/-0.5 mU/l; p<0.05). Also, plasma insulin levels during oral glucose tolerance test tended to be higher in the former than in the latter. CONCLUSIONS: Plasma insulin level could be an important determinant of the development of coronary artery ectasia in Japanese heterozygous FH men.

An LMNA variant is associated with dyslipidemia and insulin resistance in the Japanese.

Nuclear lamins A and C are encoded by LMNA and are present in terminally differentiated cells. Rare mutations in LMNA were shown to cause familial partial lipodystrophy, a syndrome characterized by regional loss of adipose tissue, glucose intolerance, and dyslipidemia, making LMNA a candidate gene for insulin-resistant diabetes. The aim of this study was to investigate whether genetic variation in LMNA can influence the risk of type 2 diabetes in a Japanese cohort. First, we performed mutational screening of LMNA by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and sequence analysis in 8 insulin-resistant males with acanthosis nigricans who were not lipodystrophic. One known single nucleotide polymorphism, 1908C/T, was found in exon 10. We subsequently screened samples of 171 nondiabetic and 164 type 2 diabetic male subjects for the presence of the 1908C/T polymorphism by PCR-restriction fragment length polymorphism (RFLP). The frequency of subjects with the 1908T allele tended to be higher in the diabetic group than in the nondiabetic group; however, the difference was not significant (43.9% v 32.2%) (P =.084). Carriers of the 1908T allele, both among diabetics and nondiabetics, showed significantly higher fasting insulin, triglycerides (TG), total cholesterol (TC), and lower high-density lipoprotein-cholesterol (HDL-C) levels than those of the 1908C/C subjects. These results suggest the LMNA 1908C/T single nucleotide polymorphism (SNP) is not associated with the prevalence of type 2 diabetes, although it may be a factor predisposing to insulin resistance and dyslipidemia in some Japanese.

Does the use of insulin in a patient with liver dysfunction increase water retention in the body, i.e. cause insulin oedema?

A 68-year-old female with mild diabetes mellitus was admitted because of acute liver dysfunction due to autoimmune hepatitis. While 40 mg/day of prednisolone improved hepatic dysfunction dramatically, her diabetic milieu deteriorated seriously. The induced hyperglycaemia could not be controlled sufficiently, despite a high dose of insulin (> 110 units/day), suggesting the existence of insulin insensitivity and hyperinsulinaemia. Soon after introduction of insulin therapy, she developed severe anasarca, including marked peripheral oedema, ascites and pleural effusion. Anasarca eventually subsided within 4 weeks with the use of a diuretic agent. We conjectured that the side effects of insulin, such as anti-natriuresis and increased vascular permeability, might be pronounced in the presence of the hepatic dysfunction that accompanies insulin insensitivity, hyperinsulinaemia and hypoalbuminaemia.

Lispro is superior to regular insulin in transient intensive insulin therapy in type 2 diabetes.

OBJECTIVE: The optimal approach to relatively recent onset type 2 diabetes patients is still unknown. We speculated that the use of short-acting insulin analogs might be of particular benefit in this context. PATIENTS AND METHODS: To explore this possibility, we compared the effect on beta- and alpha-cell function of transient intensive insulin therapy using lispro versus human regular insulin in a total of 21 type 2 diabetic patients who were randomly assigned to 14-days intensive insulin therapy consisting of bedtime NPH insulin plus three injections of mealtime lispro (n=11) or regular insulin (n=10). The dosages of both types of insulin were adjusted to attain preprandial glucose levels of <6.1 mmol/l within 1 week with similar rates of glucose decline. An oral glucose tolerance test (OGTT) was performed at day 0 (baseline), 7, and 14; plasma glucose, serum insulin, and plasma glucagon responses over 0-120 minutes were measured, and calculated as the area under the curve (AUC). RESULTS: Lispro led to a significant reduction in glucose-AUC and also an increase in insulin-AUC versus regular insulin on day 7. Glucagon secretion following OGTT was well suppressed with lispro on day 14 compared to regular insulin. CONCLUSION: Two-week intensive insulin therapy with lispro appeared to be more effective than that with regular insulin in type 2 diabetes in attaining both more rapid beta-cell rest and greater suppression of glucagon. These changes may provide significant long-term benefits.