Prevalence and distribution of coronary calcium in asymptomatic Japanese subjects in lung cancer screening computed tomography.

BACKGROUND: Coronary artery calcium (CAC) is associated with a risk of coronary heart disease. The prevalence and distribution of the CAC score have been examined in Western countries, but few studies have been performed in Asia, and especially in Japan. The goal of this study was to investigate CAC scores in an asymptomatic Japanese population. METHODS: CAC score and risk factors were analyzed in 1834 asymptomatic subjects who underwent lung cancer screening computed tomography. RESULTS: CAC was present in 26.9% of all the subjects, 29.8% of the males, and 17.1% of the females. In all age groups, the CAC score was higher in males. In multivariate analysis, male gender [odds ratio (OR) 2.461, 95% confidence interval (CI) 1.361-4.452, p=0.002], aging (OR 1.102, 95% CI 1.081-1.123, p<0.001), dyslipidemia (OR 1.740, 95% CI 1.216-2.490, p=0.002), and fasting glucose (OR 1.008, 95% CI 1.002-1.015, p=0.012) were significantly associated with a CAC score >100. CONCLUSION: The results of this study provide a pattern of CAC distribution based on age and gender in asymptomatic Japanese subjects. This pattern was similar to that in Western countries, although the absolute CAC scores were lower. High CAC scores were associated with male gender, aging, dyslipidemia, and fasting glucose.

Relationship between Alcohol Intake and Risk Factors for Metabolic Syndrome in Men.

OBJECTIVE: The precise relationship between alcohol intake and metabolic syndrome (MetS) is still unclear, and the results from previous studies have been inconclusive. Thus, we examined the effect of alcohol intake on the risk of MetS in men in order to gain more information on a potential relationship. METHODS: This study included 22,349 men who were divided into four groups according to their average alcohol intake [non-, light (less than 20 g ethanol/day), heavy (equal or more than 20 g and less than 60 g ethanol/day) and very heavy (equal and greater than 60 g ethanol/day) drinkers]. We measured each subject's body mass index (BMI), waist circumference and blood pressure (BP) and conducted a blood test to obtain a complete blood count and biochemical panel. These results were used to obtain the MetS prevalence. Additionally, fatty liver was diagnosed using abdominal ultrasonography. RESULTS: Light drinkers had smaller waist circumferences. Heavy and very heavy drinkers had larger waist circumferences, a higher BMI, a higher BP, higher fasting plasma glucose levels, higher triglycerides (TG) levels and higher high-density lipoprotein (HDL) cholesterol levels while they had lower low-density lipoprotein cholesterol levels than nondrinkers. The prevalence of high BP, hyperglycemia and high TG was significantly higher in heavy and very heavy drinkers than in nondrinkers. The prevalence of low HDL cholesterol levels decreased with an increase in alcohol consumption. The prevalence of MetS was significantly lower in light drinkers and higher in very heavy drinkers compared with nondrinkers. CONCLUSION: Alcohol intake significantly influences the risk of MetS in men. A significant association was seen between an alcohol intake of 60 g/day or higher and the prevalence of MetS.

Significance of oral glucose tolerance tests in non-alcoholic fatty liver disease patients with a fasting plasma glucose level of <126 mg/dL and HbA1c level of ≤ 6.4% in Japan.

OBJECTIVE: The aim of this study was to clarify the indications for oral glucose tolerance tests (OGTT) in non-alcoholic fatty liver disease (NAFLD) subjects with a HbA1c level of ≤6.4%, fasting plasma glucose (FPG) level of <126 mg/dL and no history of diabetes. PATIENTS: A total of 569 NAFLD subjects underwent 75-g OGTT. The plasma glucose and insulin levels were analyzed periodically for three hours during the OGTT examinations. Impaired fasting glucose (IFG) was defined as a plasma glucose level of ≥100 mg/dL to <126 mg/dL. Diabetes was defined as a two-hour post-load plasma glucose level of ≥200 mg/dL. Elevated insulin resistance was defined as a homeostasis model assessment-insulin resistance (HOMA-IR) of ≥2.5. Insulin secretory insufficiency was defined as an insulinogenic index of <0.4. RESULTS: The prevalence of diabetes on the OGTT was 7.7% (44/569) among the NAFLD patients with an HbA1c level of ≤6.4%, FPG level of <126 mg/dL and no history of diabetes. A multivariate analysis showed that diabetes occurred more frequently when the subjects had IFG [odds ratio (OR) 5.13; 95% confidential interval (CI) 3.01-8.76; p<0.001] and an HbA1c level of 5.7-6.4% (OR 5.45; 95% CI 3.33-8.93; p<0.001). Of the NAFLD subjects with both IFG and an HbA1c level of 5.7-6.4%, 22.8% (28/123) exhibited a pattern of diabetes on OGTT. Regarding insulin dynamics, among the NAFLD subjects with both IFG and an HbA1c level of 5.7-6.4%, 25.2% (31/123) had elevated IR alone, 25.2% (31/123) had insulin secretory deficiency alone and 27.6% (34/123) had both elevated insulin resistance and insulin secretory deficiency. CONCLUSION: NAFLD subjects with IFG and an HbA1c level of 5.7-6.4% should undergo OGTT in order to determine whether they have diabetes and/or abnormal insulin dynamics.

Potential impact of joint association of alanine aminotransferase and gamma-glutamyltransferase on insulin resistance in Japan: The Toranomon Hospital Health Management Center Study 19 (TOPICS 19).

AIM: To investigate the potential impact of joint association of alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) on insulin resistance and ß-cell dysfunction in healthy Japanese individuals with a normal range of liver enzymes. METHODS: This study included 1010 individuals (545 men and 465 women) aged 20-89 years who underwent an oral glucose tolerance test for health screening. Participants were divided into four groups on the basis of median values for ALT and GGT: (i) both ALT and GGT low (both-low); (ii) ALT high and GGT low (ALT-high); (iii) ALT low and GGT high (GGT-high); and (iv) both ALT and GGT high (both-high). Logistic regression analysis was used to investigate the relationship between liver enzyme and insulin dynamics, such as Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) and insulinogenic index (IGI). The insulin resistance was defined when HOMA-IR was 2.5 or more. IGI of less than 0.4 was considered to be decreased early-phase insulin secretion. RESULTS: Mean values of HOMA-IR in men was 1.5 in the both-low group, 1.8 in ALT-high, 1.8 in GGT-high and 2.8 in both-high. The mean HOMA-IR in women was 1.3 in the both-low group, 1.3 in ALT-high, 1.6 in GGT-high and 2.0 in both-high. HOMA-IR in the both-high group was significantly higher than that in the both-low group regardless of the difference of sex. Multivariate analysis showed that insulin resistance occurred when the patient had high liver enzymes. CONCLUSION: Combining the two liver function markers would be effective for identifying individuals with insulin resistance.

Prognostic factors for regression from impaired glucose tolerance to normal glucose regulation in Japanese patients with nonalcoholic fatty liver disease.

OBJECTIVE: The aim of this retrospective cohort study was to assess the predictive factors for the regression from impaired glucose tolerance (IGT) to normal glucose regulation (NGR) in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: A total of 164 NAFLD patients who had IGT in the first 75-g oral glucose tolerance test (OGTT) and underwent a repeated OGTT five years later were enrolled. A multivariate logistic regression analysis was carried out to identify factors predicting the regression from IGT to NGR. RESULTS: Out of the 164 patients, 29 regressed from IGT to NGR within five years after the first OGTT. The multivariate analysis by logistic regression showed that regression from IGT to NGR occurred when the patient was young (risk ratio for ten years: 0.38; 95% confidence interval [CI] 0.20-0.72; p=0.003), had a fasting plasma glucose (FPG) level of <100 mg/dL (risk ratio: 6.53; 95%CI 1.88-21.73; p=0.003), had a 2-hr post-load plasma glucose (PG) level of <160 mg/dL (risk ratio: 4.86; 95%CI 1.08-22.72; p=0.040), a body mass index (BMI) decrease of ≥1.5 (risk ratio: 5.20; 95% CI 1.41-19.24; p=0.014), physical activity of ≥2 Metabolic Equivalent of Task (MET) h/day (risk ratio: 5.57; 95%CI 1.68-18.44; p=0.005), and showed disappearance of the fatty liver by ultrasonography at five years (risk ratio: 9.92; 95%CI 2.87-34.34; p<0.001). CONCLUSION: Our results suggest that six factors: young age, FPG <100 mg/dL, 2-hr post-load PG of <160 mg/dL, BMI decrease of ≥1.5, physical activity of ≥2 MET h/day, and the disappearance of fatty liver predict the regression from IGT to NGR in NAFLD patients.

Giant coronary artery aneurysms associated with Kawasaki disease detected on whole-heart magnetic resonance coronary angiographic screening.

Kawasaki disease (KD) is one of the most important causes of coronary artery aneurysms in children and young adults. However, the natural course of the disease and the patient prognosis remain obscure. A 72-year-old asymptomatic man with undiagnosed KD underwent whole-heart magnetic resonance coronary angiography during a health checkup. The imaging disclosed giant aneurysms in the proximal portion of the right coronary artery and the left anterior descending artery. The patient was successfully treated with coronary artery bypass grafting. The present case suggests that there may be a substantial number of patients who have attained middle to old age with undiagnosed KD.

Efficacy and safety in sitagliptin therapy for diabetes complicated by non-alcoholic fatty liver disease.

AIM: The aim of this case-control study was to assess the efficacy and safety of dipeptidyl peptidase-4 inhibitor (sitagliptin) for type 2 diabetes mellitus (T2DM) with non-alcoholic fatty liver disease (NAFLD). METHODS: Twenty NAFLD patients with T2DM treated by sitagliptin were retrospectively enrolled as the sitagliptin group. These patients were given sitagliptin between January 2010 and July 2011. Another 20 NAFLD patients with T2DM treated only with diet and exercise for 48 weeks were selected as the control group. Serum levels of fasting plasma glucose (FPG), hemoglobin A1C (HbA1c), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured before and 12, 24, 36 and 48 weeks after the initiation of treatment. RESULTS: In the sitagliptin group, average HbA1c levels decreased approximately 0.7% at 48 weeks after the initiation of sitagliptin. Next, average FPG levels decreased approximately 15 mg/dL at 48 weeks after the initiation of sitagliptin. The serum levels of HbA1c and FPG in the sitagliptin group decreased with statistical significance compared to those in the control group (P < 0.05). All the patients could take sitagliptin of 50 mg/day without reduction necessitated by sitagliptin-related side-effects. There were no significant changes of average AST and ALT levels during follow up of 48 weeks in both sitagliptin and control groups. CONCLUSION: Our results indicate sitagliptin is effective and safe for the treatment of T2DM complicated with NAFLD.

Low lung function and risk of type 2 diabetes in Japanese men: the Toranomon Hospital Health Management Center Study 9 (TOPICS 9).

OBJECTIVE: To evaluate the effect of elevated fasting plasma glucose (FPG) and hemoglobin A(1c) (HbA(1c)) concentrations on lung dysfunction and to prospectively investigate whether reduced lung function would be independently predictive of diabetes. PARTICIPANTS AND METHODS: From January 6, 1997, through December 22, 2008, we observed 5346 men with no history of diabetes or lung dysfunction. Hazard ratios (HRs) for incident diabetes (FPG ≥126 mg/dL, HbA(1c) ≥6.5%, or self-reported clinician-diagnosed diabetes) were estimated for spirometry indices as continuous and categorical variables. RESULTS: Elevated HbA(1c) concentrations within the normal range were significantly and more strongly associated with reduced forced vital capacity and forced expiratory volume in the first second after expiration (FEV(1)) than were FPG concentrations. During a 4.0-year follow-up, diabetes developed in 214 individuals. A 10-point decrease in percentage of FEV(1) predicted value was associated with an increased HR of 1.21 (95% confidence interval [CI], 1.09-1.34; P=.001) for diabetes after adjustment for demographic factors and body mass index. This association remained significant even after adjustment for metabolic factors, smoking status, and FPG or HbA(1c) concentrations but was attenuated substantially after adjustment for baseline HbA(1c) values (HR, 1.13; 95% CI, 1.01-1.26; P=.03). Lower quartile (Q) categories of percentage of FEV(1) predicted value were associated with increased risk of diabetes independently of known predictors including HbA(1c) (HR, 1.73; 95% CI, 1.14-2.62 for Q1; and HR, 1.76; 95% CI, 1.15-2.69 for Q2). CONCLUSION: Reduced lung function was significantly related to chronic glycemic exposure within a normal range. Relatively low pulmonary function was an independent risk factor for diabetes in apparently healthy Japanese men.

Large-scale long-term follow-up study of Japanese patients with non-alcoholic Fatty liver disease for the onset of hepatocellular carcinoma.

OBJECTIVES: The aim of this study was to determine the incidence and risk factors of hepatocellular carcinoma (HCC), and to elucidate the utility of two non-invasive predictive procedures for liver fibrosis: the aspartate aminotransferase (AST) to platelet ratio index (APRI) and the BARD score (which includes the following three variables: body mass index, AST/alanine aminotransferase ratio, and diabetes) in the prediction of HCC in a large population of Japanese patients with non-alcoholic fatty liver disease (NAFLD). METHODS: This was a retrospective cohort study conducted at a public hospital. Study subjects included 6,508 patients with NAFLD diagnosed by ultrasonography. The median follow-up period was 5.6 years. The primary end point was the onset of HCC. Evaluation was performed using Kaplan-Meier methodology and Cox's proportional hazards analysis. RESULTS: In all, 16 (0.25%) new cases with HCC were diagnosed during the study. The cumulative rates of NAFLD-related HCC were 0.02% at year 4, 0.19% at year 8, and 0.51% at year 12. The annual rate of new HCC was 0.043%. Multivariate analysis identified serum AST level ≥40 IU/L (hazard ratio (HR): 8.20; 95% confidence interval (95% CI): 2.56-26.26; P<0.001), platelet count <150 × 10(3)/µl (HR: 7.19; 95% CI: 2.26-23.26; P=0.001), age ≥60 years (HR: 4.27; 95% CI: 1.30-14.01; P=0.017), and diabetes (HR: 3.21; 95% CI: 1.09-9.50; P=0.035) as independent risk factors for HCC. With regard to the APRI, 184 patients (2.83%) were considered to have significant fibrosis (equivalent to non-alcoholic steatohepatitis (NASH) stage 3-4). The cumulative rate of HCC was significantly higher in this group (HR: 25.03; 95% CI: 9.02-69.52; P<0.001). In contrast, regarding the BARD score, 3,841 (59%) patients were considered to have advanced fibrosis (NASH stage 3-4). However, no significant associations between the BARD score and the incidence of HCC were observed (HR: 1.16; 95% CI: 0.40-3.37; P=0.780). CONCLUSIONS: This retrospective study indicates that the annual incidence rate of HCC among Japanese NAFLD patients is low. Elderly NAFLD patients with diabetes, elevated serum AST, and especially thrombocytopenia (suggested to be associated with advanced liver fibrosis) should be monitored carefully during follow-up that includes using the APRI to ensure early diagnosis and treatment of HCC.

Difference in malignancies of chronic liver disease due to non-alcoholic fatty liver disease or hepatitis C in Japanese elderly patients.

AIM: Malignancies that include hepatocellular carcinoma often occurred in patients with chronic liver disease. The aim of this retrospective match control study was to assess the cumulative development incidence and predictive factors for total malignancies in elderly Japanese patients with non-alcoholic hepatic diseases (NAFLD) or hepatitis C virus (HCV). METHODS: A total of 1600 NAFLD patients with age of ≥60 years were enrolled, and 1600 HCV patients with age of ≥60 years were selected as control by matching 1:1 with NAFLD group for age, sex, and follow-up period. The primary goal is the first development of malignancies. Evaluation was performed by the use of the Wilcoxon rank sum test, the Kaplan-Meier method, and Cox proportional hazard model. The mean observation period is 8.2 years in both NAFLD and HCV group, respectively. RESULTS: The number of patients with the development of malignancies was 167 in the NAFLD group and 395 in the HCV group. The 10th development rate of malignancies was 13.9% in the NAFLD group and 28.2% in the HCV group (risk ratio 2.27; P < 0.001). The incident rates of hepatocellular carcinoma in all the malignancies were 6.0% (10/167) in the NAFLD group and 67.6% (267/395) in the HCV group (P < 0.001). The malignancies in the NAFLD group were observed in the following order: gastric cancer 34 cases (20.4%) > colon cancer 31 cases (18.6%) > prostate cancer 21 cases (12.6%). CONCLUSIONS: The incident rates of hepatocellular carcinoma in all the malignancies were approximately 6% in the NAFLD group and two-thirds in the HCV group.

High serum uric acid level and low urine pH as predictors of metabolic syndrome: a retrospective cohort study in a Japanese urban population.

The objective of this study was to evaluate whether hyperuricemia, acidic urine, or their combination predicts metabolic syndrome (MetS). In study 1, 69,094 subjects who received a general health checkup between 1985 and 2005 were included in a cross-sectional study of serum uric acid (SUA) and urine pH in relation to MetS. In study 2, the association of SUA and urine pH with MetS development over a 5-year period was evaluated in 5617 subjects with body mass index less than 25 kg/m(2) at the first examination. In study 1, higher SUA and lower urine pH were both positively correlated to MetS status (P < .001). The combination of high SUA and low urine pH was significantly associated with higher MetS prevalence compared with the combination of low SUA and high urine pH (odds ratio, 3.383; 95% confidence interval [CI], 3.034-3.784 in men; odds ratio, 4.000; 95% CI, 2.992-5.452 in women). In study 2, the top quartile of SUA levels was associated with higher MetS development compared with the bottom quartile during the 5-year period in men (hazard ratio [HR], 1.793; 95% CI, 1.084-2.966; P = .023). In women, the HR was 3.732 (95% CI, 0.391-35.62; P = .252) for the upper vs the lower half of SUA levels. For urine pH, the HR was 1.955 (95% CI, 1.089-3.509; P = .025) for the bottom vs the top quartile in men. A likelihood ratio test confirmed that high SUA and low urine pH act synergistically in the development of MetS. High SUA, low urine pH, and their combination are predictive risk factors for MetS development.

The development of chronic kidney disease in Japanese patients with non-alcoholic fatty liver disease.

Objective Chronic kidney disease (CKD) is present in patients with nonalcoholic fatty liver disease (NAFLD). The aim of this retrospective study was to assess the cumulative development incidence and predictive factors for new onset of CKD in Japanese patients with NAFLD. Methods A total of 5,561 NAFLD patients without CKD were enrolled. CKD was defined as either an estimated glomerular filtration rate of <60 mL/min/1.73 m(2) or dipstick proteinuria (≥+1). A blood sample and a urine sample were taken for routine analyses during follow-up. The mean observation period was 5.5 years. The primary goal is the new development of CKD. Independent factors associated with new development of CKD were analyzed by using the Kaplan-Meyer method and the Cox proportional hazards model. Results Of 5.561 NAFLD patients, 263 patients developed CKD. The cumulative development rate of CKD was 3.1% at the 5th year and 12.2% at the 10th year. Multivariate Cox proportional hazards analysis showed that CKD development in patients with NAFLD occurred when patient had low level of GFR of 60-75 mL/min/1.73 m(2) [hazard ratio:2.75; 95% confidence interval (CI)=1.93-3.94; p<0.001], age of ≥50 years (hazard ratio: 2.67; 95% CI=2.06-3.46; p<0.001), diabetes (hazard ratio: 1.92; 95% CI=1.45-2.54; p<0.001), hypertension (hazard ratio: 1.69; 95% CI=1.25-2.29; p<0.001), and elevated serum gamma-glutamyltransferase of ≥109 IU/L (hazard ratio: 1.35; 95% CI=1.02-1.78; p=0.038). Conclusion Our retrospective study indicates that the annual incidence of CKD in Japanese patients with NAFLD is about 1.2%. Five factors of low eGFR level, aging, type 2 diabetes, hypertension, and elevated gamma-glutamyltransferase, increases the risk of the development of CKD.

Efficacy and safety in sitagliptin therapy for diabetes complicated by chronic liver disease caused by hepatitis C virus.

AIM: Diabetes is present in patients with chronic liver disease caused by hepatitis C virus (HCV). The aim of this case-control study is to assess the efficacy and safety of dipeptidyl peptidase-4 inhibitor (sitagliptin) for type 2 diabetes mellitus (T2DM) with chronic liver disease caused by HCV. METHODS: Sixteen HCV positive patients with T2DM treated by sitagliptin were retrospectively enrolled. These patients were given sitagliptin between December 2009 and January 2010. Another 16 HCV patients with T2DM treated only with diet and excise for 48 weeks were selected as the control group. Serum levels of fasting plasma glucose (FPG), hemoglobin A1C (HbA1C), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured before and 12, 24, 36 and 48 weeks after the initiation of treatment. RESULTS: In the sitagliptin group, the average HbA1C level decreased approximately 0.8% at 48 weeks after the initiation of sitagliptin. Next, the average FPG level decreased approximately 20 mg/dL during follow up after the initiation of sitagliptin. All the patients were able to take sitagliptin of 50 mg/day without reduction because of sitagliptin-related side-effects. On the other hand, in the control group, the average HbA1C and FPG level did not change with statistical significance during follow up of 48 weeks. Regarding aminotransferase, there were no significant changes of average AST and ALT level during follow up of 48 weeks in both the sitagliptin group and control group. CONCLUSION: Our results indicate that sitagliptin is effective and safe for the treatment of T2DM complicated with HCV positive chronic liver disease.

Virus clearance reduces bone fracture in postmenopausal women with osteoporosis and chronic liver disease caused by hepatitis C virus.

Osteoporosis is often present in postmenopausal women. The aim of this retrospective cohort study was to assess the cumulative incidence and predictive factors for bone fracture after cessation of interferon (IFN) in postmenopausal women with osteoporosis and chronic liver disease caused by hepatitis C virus (HCV). A total of 420 postmenopausal women treated with IFN monotherapy were enrolled. The mean observation period was 7.2 years. The primary goal was the development of bone fracture. Evaluation was carried out by using the Kaplan-Meier method and the Cox proportional hazards analysis. Thirty-one out of 420 patients sustained bone fracture. The cumulative development rate of bone fracture was 3.6% at 5th year, 9.2% at 10th year, and 17.4% at 15th year. Multivariate Cox proportional hazards analysis showed that bone fracture after cessation of IFN therapy occurred when histological staging of the liver was advanced (hazard ratio (HR): 2.54; 95% confidence interval (CI) = 1.21-5.31; P = 0.013), serum albumin level was < 3.5g/dl (HR: 2.25; 95% CI = 1.10-4.59; P = 0.026), and virus clearance was not achieved (HR: 3.65; 95% CI = 1.11-12.05; P = 0.033). The results indicate that virus clearance causes a reduction of two-thirds in the risk of bone fracture after cessation of IFN therapy in postmenopausal women with osteoporosis and chronic liver disease caused by HCV. J. Med. Virol. 82:390-395, 2010. (c) 2010 Wiley-Liss, Inc.

Effects of diesel exhaust particles on human neutrophil activation.

Diesel exhaust particles (DEP) are associated with respiratory disease and exposure to diesel exhaust induces an inflammatory response associated with marked leukocytic infiltration in the lung. This study examined whether neutrophils are activated by the active component of DEP (methanol extract of DEP [me-DEP]). The authors demonstrated that neutrophils exposed to me-DEP had increased levels of the f-actin content, the surface expression of adhesion molecules, and the release of interleukin (IL-8) and leukotriene B4 (LTB4), superoxide, and matrix metalloproteinase (MMP-9). Thus, the author conclude that DEP exposure activates neutrophils and that these activated neutrophils could contribute to the adverse respiratory health effects associated with DEP and to the pathogenesis of chronic inflammatory lung diseases.

Effects of initial passage of endotoxin through the liver on the extent of acute lung injury in a rat model.

We hypothesized that the extent of acute lung injury (ALI) caused by lipopolysaccharide (LPS) is modified with its initial passage through the liver. We tested this hypothesis by administering LPS, 5 mg/kg, or saline to 120 male Wistar rats via the portal vein (PV) or the inferior vena cava (IVC) over 1 h. Four experimental groups of rats were administered saline into the PV, saline into the IVC, LPS into the PV (LPS-PV group), and LPS into the IVC (LPS-IVC group), respectively. At 15 and 30 min after onset of 51Chromium-LPS infusion, the gamma counts in the liver were higher in the LPS-PV group than that in the LPS-IVC group. The ratio of 125Iodine-albumin counts in lung tissue to that in plasma per unit of weight (as an assessment of pulmonary microvascular permeability) at 240 min after onset of LPS stimulation, the accumulation of polymorphonuclear cell (assessed by myeloperoxidase activity) and the concentration of tumor necrosis factor alpha in the lung at 60 and 240 min after onset of LPS infusion, were higher in the LPS-IVC group than in the LPS-PV group. Significant differences in several factors indicative of inflammation and in the extent of LPS-induced ALI were observed after the onset of LPS infusion, depending on whether it was delivered via the PV or the IVC. These observations suggest that the entrapping of LPS during its initial passage through the hepatic circulation may attenuate LPS-induced ALI within 4 h of initiation of LPS stimulation.

Suppressive effects of diesel exhaust particles on cytokine release from human and murine alveolar macrophages.

Epidemiological studies have shown an increase in the number of hospital admissions for respiratory diseases in association with high concentrations of particulate matter smaller than 10 micro m (PM(10)). Diesel exhaust particles (DEP) are important components of PM(10). This study was designed to test the effect of DEP on the release of cytokines from alveolar macrophages (AMs). Human and murine AMs were exposed to DEP for 24 hours, and the concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 were measured in the supernatants by enzyme-linked immunosorbent assay (ELISA). DEP (10 micro g/mL) suppressed the spontaneous release of TNF-alpha and IL-6 from murine AMs (P<.05). This suppression was not seen with exposure to carbon particles. Soluble components of DEP had a similar suppressive effect, suggesting that the chemical composition of DEP is responsible for the suppression. Lipopolysaccharide (LPS)- or IFN-gamma-induced TNF-alpha and IL-6 production by murine AMs were suppressed by DEP in a dose-dependent manner (P<.05). DEP also inhibited LPS-stimulated production of TNF-alpha, IL-6, and IL-8 from human AMs (P<.05). Pretreatment of AMs with superoxide dismutase (SOD) (300 IU/mL) prevented the suppressive effect of DEP on AM cytokine production (P<.05). The authors conclude that DEP exposure suppressed the release of cytokines from AMs, and speculate that this suppression could impair normal host defenses.

Correlation between cysteinyl leukotriene release from leukocytes and clinical response to a leukotriene inhibitor.

STUDY OBJECTIVES: Antileukotriene drugs are widely used in patients with bronchial asthma, but not all patients show significant clinical improvements, and no factors have been identified that are correlated with the clinical response to these drugs. This study was designed to examine the factors correlated with a response to a leukotriene receptor antagonist, pranlukast, in patients with asthma. DESIGN: WBC counts, IgE, and ex vivo leukotriene release from leukocytes were measured, and 31 patients with asthma were treated with pranlukast, a leukotriene receptor antagonist, for 4 weeks. MEASUREMENTS: Outcome measurements included twice-daily peak expiratory flow rate (PEFR), daytime and nocturnal symptoms, and frequency of beta(2)-agonist use. Subjects with a reduction of > 20% in symptom scores or beta(2)-agonist use, or an improvement of PEFR of > 10% were designated as responders; others were designated as nonresponders. Logistic regression analysis assessed the efficacy of models using various allergic markers correlated with the response to pranlukast. RESULTS: There were 16 responders and 15 nonresponders. The release of cysteinyl leukotrienes from the leukocytes of the responders was higher than that of the nonresponders (p < 0.05). There was a significant correlation between the clinical response and the release of cysteinyl leukotrienes, but not demographic features, WBC counts, percentage of eosinophils, or serum IgE levels (p < 0.05). Subjects with a release of cysteinyl leukotrienes of > 3,500 pg/mL were 11.0 times more likely to respond to pranlukast than those with < 3,500 pg/mL (95% confidence interval, 2.0 to 60.5). CONCLUSION: Cysteinyl leukotriene release from leukocytes is correlated with leukotriene receptor antagonist response.