Inflammatory markers are associated with ventilatory limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects

Background: Inflammatory markers are increased in chronic obstructive pulmonary disease ( COPD) and are hypothesised to play an important part in muscle dysfunction and exercise intolerance. Methods: The Health Aging and Body Composition ( Health ABC) study is a prospective observational cohort of well functioning individuals aged 70 - 79 years. A cross sectional analysis of the baseline data was conducted to examine the association between inflammatory markers and ventilatory limitation, muscle strength, and exercise capacity. These associations were compared in participants with and without obstructive lung disease ( OLD). Results: Of the 3075 participants enrolled in the Health ABC cohort, OLD was identified by spirometric testing in 268 participants and 2005 participants had normal spirometric results. Of the participants with OLD, 35%, 38%, and 27% participants had mild, moderate, and severe OLD, respectively. Participants with OLD had lower quadriceps strength (102.5 Nm v 108.9 Nm, p = 0.02), lower maximum inspiratory pressure (64.7 cm H2O v 74.2 cm H2O, p< 0.0001), higher systemic interleukin (IL)-6 levels (2.6 pg/ml v 2.2 pg/ml, p< 0.0001), and higher C-reactive protein (CRP) levels (3.5 mg/l v 2.5 mg/l, p< 0.0001) than those with normal spirometry. In participants with OLD and those with normal spirometry, forced expiratory volume in 1 second (FEV1) was associated with IL-6 ( adjusted regression coefficients (beta) = -5.3 (95% CI -9.1 to -1.5) and -3.1 (95% CI -4.3 to -1.9), respectively). IL-6 and TNF were also associated with quadriceps strength among participants with OLD and those with normal spirometry (beta = -6.4 (95% CI -12.8 to -0.03) and -3.4 (95% CI -5.4 to -1.3), respectively, for IL-6 and beta = -10.1 (95% CI -18.7 to -1.5) and -3.8 (95% CI -7 to -0.6), respectively, for TNF). IL-6, quadriceps strength, and maximum inspiratory pressures were independent predictors of reduced exercise capacity in both groups. Conclusions: In well functioning elderly subjects with or without OLD, IL-6 is associated with reduced FEV1, quadriceps strength, and exercise capacity.

Kidney dysfunction and hypertension: Role for cadmium, P450 and heme oxygenases?

Cadmium (Cd) is a metal toxin of continuing worldwide concern. Daily intake of Cd, albeit in small quantities, is associated with a number of adverse health effects which are attributable to distinct pathological changes in a variety of tissues and organs. In the present review, we focus on its renal tubular effects in people who have been exposed environmentally to Cd at levels below the provisional tolerable intake level set for the toxin. We highlight the data linking such low-level Cd intake with tubular injury, altered abundance of cytochromes P450 (CYPs) in the kidney and an expression of a hypertensive phenotype. We provide updated knowledge on renal and vascular effects of the eicosanoids 20-hydroxyeicosatetraenoic acid (20-HETE) and eicosatrienoic acids (EETs), which are biologically active metabolites from arachidonate metabolism mediated by certain CYPs in the kidney. We note the ability of Cd to elicit oxidative stress and to alter metal homeostasis notably of zinc which may lead to augmentation of the defense mechanisms involving induction of the antioxidant enzyme heme oxygenase-1 (HO-1) and the metal binding protein metallothionein (MT) in the kidney. We hypothesize that renal Cd accumulation triggers the host responses mediated by HO-I and MT in an attempt to protect the kidney against injurious oxidative stress and to resist a rise in blood pressure levels. This hypothesis predicts that individuals with less active HO-1 (caused by the HO-1 genetic polymorphisms) are more likely to have renal injury and express a hypertensive phenotype following chronic ingestion of low-level Cd, compared with those having more active HO-1. Future analytical and molecular epidemiologic research should pave the way to the utility of induction of heme oxygenases together with dietary antioxidants in reducing the risk of kidney injury and hypertension in susceptible people.

Rosuvastatin attenuates hypertension-induced cardiovascular remodeling without affecting blood pressure in DOCA-salt hypertensive rats

The pleiotropic effects of statins represent potential mechanisms for the treatment of end-organ damage in hypertension. This study has investigated the effects of rosuvastatin in a model of cardiovascular remodeling, the DOCA-salt hypertensive rat. Male Wistar rats weighing 300 to 330 g were uninephrectomized (UNX) or UNX and treated with DOCA (25 mg subcutaneously every fourth day) and 1% NaCl in the drinking water. Compared with UNX controls, DOCA-salt rats developed hypertension, cardiovascular hypertrophy, inflammation with perivascular and interstitial cardiac fibrosis, endothelial dysfunction, and prolongation of ventricular action potential duration at 28 days. Rosuvastatin-treated rats received 20mg/kg/d of the drug in 10% Tween 20 by oral gavage for 32 days commencing 4 days before uninephrectomy. UNX and DOCA-salt controls received vehicle only. Rosuvastatin therapy attenuated the development of cardiovascular hypertrophy, inflammation, fibrosis, and ventricular action potential prolongation, but did not modify hypertension or vascular dysfunction. We conclude that the pleiotropic effects of rosuvastatin include attenuation of aspects of cardiovascular remodeling in the DOCA-salt model of hypertension in rats without altering systolic blood pressure.

The key role of CD40 ligand in overcoming tumor-induced dendritic cell dysfunction

Overcoming dendritic cell (DC) dysfunction is a prerequisite for successful active immunotherapy against breast cancer. CD40 ligand (CD40L), a key molecule in the interface between T-lymphocytes and DCs, seems to be instrumental in achieving that goal. Commenting on our data that CD40L protects circulating DCs from apoptosis induced by breast tumor products, Lenahan and Avigan highlighted the potential of CD40L for immunotherapy. We expand on that argument by pointing to additional findings that CD40L not only rescues genuine DCs but also functionally improves populations of immature antigen-presenting cells that fill the DC compartment in patients with breast cancer.

B-type natriuretic peptide concentrations and myocardial dysfunction in critical illness

B-type natriuretic peptide (BNP) is the first biomarker of proven value in screening for left ventricular dysfunction. The availability of point-of-care testing has escalated clinical interest and the resultant research is defining a role for BNP in the investigation and treatment of critically ill patients. This review was undertaken with the aim of collecting and assimilating current evidence regarding the use of BNP assay in the evaluation of myocardial dysfunction in critically ill humans. The information is presented in a format based upon organ system and disease category. BNP assay has been studied in a spectrum of clinical conditions ranging from acute dyspnoea to subarachnoid haemorrhage. Its role in diagnosis, assessment of disease severity, risk stratification and prognostic evaluation of cardiac dysfunction appears promising, but requires further elaboration. The heterogeneity of the critically ill population appears to warrant a range of cut-off values. Research addressing progressive changes in BNP concentration is hindered by infrequent assay and appears unlikely to reflect the critically ill patient's rapidly changing haemodynamics. Multi-marker strategies may prove valuable in prognostication and evaluation of therapy in a greater variety of illnesses. Scant data exist regarding the use of BNP assay to alter therapy or outcome. It appears that BNP assay offers complementary information to conventional approaches for the evaluation of cardiac dysfunction. Continued research should augment the validity of BNP assay in the evaluation of myocardial function in patients with life-threatening illness.

Prognostic value of intraventricular dyssynchrony according to clinical stage of left ventricular impairment

Intraventricular dyssynchrony has prognostic implications in patients who have severe functional limitation and decreased ejection fraction. Patients with less advanced cardiac disease often exhibit intraventricular dyssynchrony, but there is little available information about its prognostic relevance in such patients. We investigated the prognostic effect of intraventricular dyssynchrony on outcome in 318 patients with known or suspected coronary artery disease who were classified according to the presence or absence of left ventricular dysfunction and heart failure symptoms. Mortality was considered the primary end point over a median follow-up of 56 months, and a Cox proportional hazards model was used for survival analysis. Despite a low prevalence (8%) of left bundle branch block, there was a high prevalence of intraventricular dyssynchrony even in patients without symptomatic heart failure. The magnitude of intraventricular dyssynchrony correlated poorly with QRS duration (r = 0.25),end-systolic volume index (r = 0.27), and number of scar segments (r = 0.25). There,were 58 deaths during follow-up. Ventricular volume, ischemic burden, and magnitude of intraventricular dyssynchrony predicted outcome, but magnitude of intraventricular dyssynchrony was an independent predictor of survival only in patients with asymptomatic left ventricular dysfunction. In conclusion, patients with known or suspected coronary artery disease have a high prevalence of intraventricular dyssynchrony. Although ventricular volume, ischemic burden, and intraventricular dyssynchrony are potentially important prognostic markers, the relative importance of intraventricular dyssynchrony changes with the clinical setting and, may be greatest-in patients with preclinical disease. (c) 2006 Elsevier Inc. All rights reserved.

A comparison of the effect of high- and low-dose fentanyl on the incidence of postoperative cognitive dysfunction after coronary artery bypass surgery in the elderly

Background. Postoperative cognitive dysfunction (POCD) after coronary artery bypass graft surgery is a common complication for which, despite many clinical investigations, no definitive etiology has been found. The current use of both high and low-dose fentanyl as anesthetic techniques allowed us to investigate the effect of fentanyl on the incidence of POCD. Methods. Three hundred fifty patients scheduled to undergo elective coronary artery bypass graft surgery were randomized to receive either high-dose fentanyl (50 mu g/kg) or low-dose fentanyl (10 mu g/kg) as the basis of the anesthetic. All patients underwent neuropsychological testing before surgery and at 1 week, 3 months, and 12 months after surgery. Results. One hundred sixty-eight patients in the low-dose group and 158 patients in the high-dose group were included in the final analysis. Neuropsychological testing was performed on 88%, 93%, and 92% of patients at 1 week, 3 months, and 12 months, respectively. There was no difference between group mean scores at any of the three testing times. Analysis of individual patients by the 20% rule did not detect any differences between groups. The one SD rule, which has fewer false-positive results, detected significantly more patients with POCD in the low-dose group than in the high-dose group at 1 week (23.6% vs. 13.7%; P = 0.03) but not at the other testing times. Patients with POCD spent an average of 1.2 days longer in the hospital than those without POCD (P = 0.021). Conclusions: High-dose fentanyl is not associated with a difference in the incidence of POCD at 3 or 12 months after surgery. Low-dose fentanyl leads to shorter postoperative ventilation times and may be associated with a greater incidence of POCD 1 week after surgery. Early POCD is associated with an increased duration of stay in the hospital.