Prevalence of peripheral arterial disease: persistence of excess risk in former smokers

Objective: To determine the age-standardised prevalence of peripheral arterial disease (PAD) and associated risk factors, particularly smoking. Method: Design: Cross-sectional survey of a randomly selected population. Setting: Metropolitan area of Perth, Western Australia. Participants: Men aged between 65-83 years. Results: The adjusted response fraction was 77.2%. Of 4,470 men assessed, 744 were identified as having PAD by the Edinburgh Claudication Questionnaire and/or the ankle-brachial index of systolic blood pressure, yielding an age-standardised prevalence of PAD of 15.6% (95% confidence intervals (CI): 14.5%, 16.6%). The main risk factors identified in univariate analyses were increasing age, smoking current (OR=3.9, 95% CI 2.9-5.1) or former (OR=2.0, 95% CI 1.6-2.4), physical inactivity (OR=1.4, 95% CI 1.2-1.7), a history of angina (OR=2.2, 95% CI 1.8-2.7) and diabetes mellitus (OR=2.1, 95% CI 1.7-2.6). The multivariate analysis showed that the highest relative risk associated with PAD was current smoking of 25 or more cigarettes daily (OR=7.3, 95% CI 4.2-12.8). In this population, 32% of PAD was attributable to current smoking and a further 40% was attributable to past smoking by men who did not smoke currently. Conclusions: This large observational study shows that PAD is relatively common in older, urban Australian men. In contrast with its relationship to coronary disease and stroke, previous smoking appears to have a long legacy of increased risk of PAD. Implications: This research emphasises the importance of smoking as a preventable cause of PAD.

A comparison of lipid variables as predictors of cardiovascular disease in the Asia Pacific Region

PURPOSE: Many guidelines advocate measurement of total or low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), and triglycerides (TG) to determine treatment recommendations for preventing coronary heart disease (CHD) and cardiovascular disease (CVD). This analysis is a comparison of lipid variables as predictors of cardiovascular disease. METHODS: Hazard ratios for coronary and cardiovascular deaths by fourths of total cholesterol (TC), LDL, HDL, TG, non-HDL, TC/HDL, and TG/HDL values, and for a one standard deviation change in these variables, were derived in an individual participant data meta-analysis of 32 cohort studies conducted in the Asia-Pacific region. The predictive value of each lipid variable was assessed using the likelihood ratio statistic. RESULTS: Adjusting for confounders and regression dilution, each lipid variable had a positive (negative for HDL) log-linear association with fatal CHD and CVD. Individuals in the highest fourth of each lipid variable had approximately twice the risk of CHD compared with those with lowest levels. TG and HDL were each better predictors of CHD and CVD risk compared with TC alone, with test statistics similar to TC/HDL and TG/HDL ratios. Calculated LDL was a relatively poor predictor. CONCLUSIONS: While LDL reduction remains the main target of intervention for lipid-lowering, these data support the potential use of TG or lipid ratios for CHD risk prediction. (c) 2005 Elsevier Inc. All rights reserved.

Lipopolysaccharide and lipoteichoic acid induce different innate immune responses in bovine mammary epithelial cells

The objective of the present study was to characterize the innate immune responses induced by in vitro stimulation of bovine primary mammary epithelial cells (bMEC) using gram-negative lipopolysaccharide (LPS) and gram-positive lipoteichoic acid (LTA) bacterial cell wall components. Quantitative real-time PCR (qRT-PCR) was employed to examine the mRNA expression of a panel of 22 cytokines, chemokines, beta-defensins and components of the Toll-Like Receptor signaling pathway. Stimulation of bMEC with LPS for 24 h elicited a marked increase in mRNA expression for IL-1 beta, IL-8, TNF alpha, CXCL6 and beta-defensin while members of the Toll-Like Receptor pathway.. although present, were largely unaffected. Surprisingly, stimulation of these cells with LTA for 24 h did not significantly alter the expression of these genes. A time course of the expression of IL-1 beta, IL-8, TNF alpha, CXCL6 and beta-defensin was subsequently performed. The mRNA levels of all genes increased rapidly after stimulation for 2-4 h with both LPS and LTA but only the former treatment resulted in sustained responses. In contrast, the increased gene expression for LTA stimulated cells returned to resting levels after 8-16 h with the exception of beta-defensin, which remained up-regulated. The limited and unsustained cytokine response to LTA may explain why mastitis caused by gram-positive bacteria has greater potential for chronic intra-mammary infection than gram-negative infection. It was concluded that bovine mammary epithelial cells have a strong but differential capacity to mount innate immune responses to bacterial cell wall components. Crown Copyright (c) 2005 Published by Elsevier Ltd. All rights reserved.

Bovine mammary epithelial cells, initiators of innate immune responses to mastitis

Innate immunity plays a vital role in the protection of the bovine mammary gland against mastitis. Until recently, the migration of effector cells such as neutrophils and monocytes into the mammary gland was thought to provide the only defence against invading pathogens. However, mammary epithelial cells may also play an important role in the immune response, contributing to the innate defence of the mammary tissue through secretion of antimicrobial peptides and attraction of circulating immune effector cells. This paper reviews the innate immune pathways in mammary epithelial cells and examines their role in the initiation of an innate immune response to Gram-positive and Gram-negative bacteria.

Effect of Diode-Laser and AC Magnetic Field of Bovine Serum Albumin Nanospheres Loaded with Phthalocyanine and Magnetic Particles

This study reports on the development and characterization of bovine serum albumin (BSA) nanospheres containing Silicon(IV) phthalocyanine (NzPc) and/or maghemite nanoparticles (MNP), the latter introduced via ionic magnetic fluid (MF). The nanosized BSA-loaded samples were designed for synergic application while combining Photodynamic Therapy and Hyperthermia. Incorporation of MNP in the albumin-based template, allowing full control of the magnetic content, was accomplished by adding a highly-stable ionic magnetic fluid sample to the albumin suspension, following heat denaturing. The material`s evaluation was performed using Zeta potential measurements and scanning electron microscopy. The samples were characterized by steady-state techniques and time-resolved fluorescence. The in vitro assay, using human fibroblasts, revealed no cytotoxic effect in all samples investigated, demonstrating the potential of the tested system as a synergistic drug delivery system.

An fMRI study indicating increased cortical recruitment during a cognitive interference task in Huntington's disease patients

We used an event related fMRI design to study the BOLD response in Huntington’s disease (HD) patients during performance of a Simon interference task. We hypothesised that HD patients will demonstrate significantly slower RTs than controls, and that there will be significant differences in the pattern of brain activation between groups. Seventeen HD patients and 15 age and sex matched controls were scanned using 3T GE scanner (FOV = 24 cm2; TE = 40 ms; TR = 3 s; FA = 60°; slice thickness = 6 mm; in-plane resolution = 1.88x1.88 mm2). The task involved two activation conditions, namely congruent (for example, left pointing arrow appearing on the left side of the screen) and incongruent (for example, left pointing arrow appearing on the right side of the screen), and a baseline condition. Each stimulus was presented for 2500 ms followed by a blank screen for 500 ms. Subjects were instructed to press a button using the same hand as indicated by the direction of the arrow head and were given 3000 ms to respond. Data analysis was performed using SPM2 with a random effects analysis model. For each subject parameter estimates for combined task conditions (congruent and incongruent combined) were calculated. Comparisons such as these, based on block designs, have superior statistical power for detecting subtle changes in the BOLD response anywhere in the brain. The activations reported are significant at PFDR_corr

Prognostic Significance of Myocardial Fibrosis Quantification by Histopathology and Magnetic Resonance Imaging in Patients With Severe Aortic Valve Disease

Objectives We sought to determine whether the quantitative assessment of myocardial fibrosis (MF), either by histopathology or by contrast-enhanced magnetic resonance imaging (ce-MRI), could help predict long-term survival after aortic valve replacement. Background Severe aortic valve disease is characterized by progressive accumulation of interstitial MF. Methods Fifty-four patients scheduled to undergo aortic valve replacement were examined by ce-MRI. Delayed-enhanced images were used for the quantitative assessment of MF. In addition, interstitial MF was quantified by histological analysis of myocardial samples obtained during open-heart surgery and stained with picrosirius red. The ce-MRI study was repeated 27 +/- 22 months after surgery to assess left ventricular functional improvement, and all patients were followed for 52 +/- 17 months to evaluate long-term survival. Results There was a good correlation between the amount of MF measured by histopathology and by ce-MRI (r = 0.69, p < 0.001). In addition, the amount of MF demonstrated a significant inverse correlation with the degree of left ventricular functional improvement after surgery (r = -0.42, p = 0.04 for histopathology; r = -0.47, p = 0.02 for ce-MRI). Kaplan-Meier analyses revealed that higher degrees of MF accumulation were associated with worse long-term survival (chi-square = 6.32, p = 0.01 for histopathology; chi-square = 5.85, p = 0.02 for ce-MRI). On multivariate Cox regression analyses, patient age and the amount of MF were found to be independent predictors of all-cause mortality. Conclusions The amount of MF, either by histopathology or by ce-MRI, is associated with the degree of left ventricular functional improvement and all-cause mortality late after aortic valve replacement in patients with severe aortic valve disease. (J Am Coll Cardiol 2010; 56: 278-87) (c) 2010 by the American College of Cardiology Foundation

Expression of the iron regulatory peptide hepcidin is reduced in patients with chronic liver disease

Disturbances in iron metabolism often accompany liver disease in humans and hepatic iron deposition is a frequent finding. Since the peptide hepcidin, a major regulator of body iron homeostasis, is synthesised in the liver, alterations in hepcidin expression could be responsible for these effects. To investigate this possibility, we studied hepcidin expression in liver biopsies from patients with hepatitis C virus (HCV) infection, non-alcoholic fatty liver disease (NAFLD) and hemochromatosis (HC). Total RNA was extracted from the liver tissue of 24 HCV, 17 NASH and 5 HC patients, and 17 liver transplant donors (controls). The levels of mRNA for hepcidin and several other molecules involved in iron metabolism (DMT1, Dcytb, hephaestin, ferroportin, TfR1, TfR2, HFE and HJV) were examined by ribonuclease protection assay and expressed relative to the housekeeping gene GAPDH. The expression of hepcidin was significantly decreased in HCV and NASH patients relative to control liver (109±16 and 200±44 versus 325±26 respectively; P=0.008 and 0.02). We have previously reported similar findings in patients with HC, and this was confirmed in the current analysis (176±21; P=0.003). In both HCV and NAFLD patients the expression of the iron reductase Dcytb and the transferrin binding regulatory molecule TfR2 was also decreased, while the cellular iron exporter ferroportin showed a significant increase. Levels of the mRNA for the iron oxidase hephaestin were lower in HCV patients alone, while expression of the major transferrin binding molecule TfR1 was decreased only in NAFLD patients. Of particular interest was the finding that the expression of HJV (which is mutated in patients with juvenile HC) was significantly increased in NAFLD patients. No changes were seen in the expression of the iron importer DMT1 or the regulatory molecule HFE. Decreased expression of hepcidin in patients with HCV and NAFLD provides an explanation why iron homeostasis could be perturbed in these disorders. Reduced hepcidin levels would increase intestinal iron absorption and iron release from macrophages, which could contribute to hepatic iron accumulation. This in turn could lead to alterations in the expression of various proteins involved in iron transport and its regulation. Indeed most of the changes in the expression of such molecules observed in this study are consistent with this. However, the mechanisms leading to changes in the expression of hepcidin in these diseases remain to be elucidated.

Local inflammation is crucial for T cell mediated rejection of skin graft expressing foreign antigen

Most of the skin grafts from (K14hGH.FVB C57BL/6) F1 mice, which express foreign antigen (human growth hormone, hGH) in skin keratinocytes driven by keratin 14 promoter, were spontaneously rejected by syngeneic wild type F1 recipients and hGH-specific immune responses such as antibody and hGHspecific T cells were generated in these recipients. Interestingly, a 2nd F1 hGH-expressing skin graft was rejected by graft primed recipients, but was not rejected from such recipients if CD4+ or CD8+ T cells were depleted prior to the placement of the 2nd graft. Surprisingly, this 2nd graft retained healthy even after CD4+ or CD8+ T cells were allowed to recover so that the animal could reject a freshly placed 3rd F1 hGH-expressing graft. Furthermore, inflammatory response induced by topical treatment with imiquimod could lead to the rejection of some well-healed 2nd grafts. This result indicates that both CD4+ and CD8+ T cells are required for the rejection and the ability of effector T cells to reject a graft is determined by local factors in the graft which are presumably determined by inflammation induced by surgery or imiquimod treatment. Taken together, our results suggest that in addition to CD4+ and CD8+ T cells, local environmental factors induced by inflammation are also crucial for effector T cell functions leading to graft destruction. The understanding of these local factors will lead to more effective immunotherapy for established, epithelial cancer in the future.