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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jenvman.2007.03.001 Byline: Robert O. Strobl (a), Paul D. Robillard (b) Keywords: Water quality; Monitoring network; Design methodology; Monitoring objectives; Sampling location; Sampling frequency; Surface freshwaters Abstract: To date, many water quality monitoring networks for surface freshwaters have been rather haphazardly designed without a consistent or logical design strategy. Moreover, design practices in recent years indicate a need for cost-effective and logistically adaptable network design approaches. There are many variables that need to be included in a comprehensive yet practical monitoring network: a holistic appraisal of the monitoring objectives, representative sampling locations, suitable sampling frequencies, water quality variable selection, and budgetary and logistical constraints are examples. In order to investigate the factors which affect the development of an effective water quality monitoring network design methodology, a review of past and current approaches is presented. Author Affiliation: (a) Water Resources Department, International Institute for Geo-Information Science and Earth Observation (ITC), Enschede, The Netherlands (b) World Water Watch, Cambridge, MA, USA Article History: Received 3 May 2006; Revised 15 February 2007; Accepted 11 March 2007

We have previously shown a pathophysiological role for NGF in pulmonary hypertension, particularly in pulmonary arterial (PA) hyperreactivity. Our experiments have suggested different mechanisms activated by NGF depending on a short- or a long-term PA treatment. The aim of the present study was to determine the mechanisms activated by a short-term NGF treatment (1 h) to induce PA hyperreactivity. Contractions of rat PA were induced ex vivo by endothelin-1 (ET-1, 10-12-10-6 M) in the absence or presence of NGF (100 ng/mL, 1 h), with or without K252a (TrkA kinase inhibitor, 300 nM) or Y–27632 (ROCK inhibitor, 10 μM). NGF–induced phosphorylation of myosin phosphatase target subunit 1 (MYPT1) was evaluated in vitro by Western blotting in primary PA smooth muscle cells (PASMC) from both rat and human origin. Basal and ET–1–induced (10-7 M) calcium responses were evaluated in vitro in PASMC using calcium imaging (Fura2, Fluo-4), in the absence or presence of NGF (100 ng/mL, 1 h). Calcium sources involved in NGF-dependent increase in calcium levels and response to ET-1 were determined using Thapsigargin and Cyclopiazonic acid (SERCA inhibitors, 1 or 10 μM, respectively) or verapamil and Nicardipine (calcium L–Type channels blocker, 2 μM). Ex vivo, NGF (1 h) induced rat PA hyperreactivity to ET-1 in a TrkA- and ROCK-dependent manner. In vitro, in both rat and human PASMC, NGF (1 h) enhanced basal calcium levels through activation of calcium L-type channels. NGF also enhanced ET–1–induced increase in intracellular calcium levels, with endoplasmic reticulum (ER) being the main calcium source contributing to these effects. Finally, in both rat and human cells, NGF also induced phosphorylation of MYPT1 in a TrkA- and ROCK-dependent manner. In conclusion, our results show that NGF induces PA hyperreactivity to ET-1 through activation of its TrkA receptor, leading to both increased calcium intracellular levels and increased ER calcium loading. NGF also activates ROCK-dependent calcium sensitization mechanisms. Such mechanisms may therefore contribute to NGF-induced PA hyperreactivity in pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Background Familial hypercholesterolemia (FH) features elevated oxidative stress and accelerated atherosclerosis driven by elevated levels of atherogenic lipoproteins relative to subnormal levels of atheroprotective high-density lipoprotein (HDL). Small, dense HDL3 potently protects low-density lipoprotein (LDL) against proinflammatory oxidative damage. OBJECTIVE To determine whether antioxidative and/or anti-inflammatory activities of HDL are defective in FH and whether such defects are corrected by LDL apheresis. Methods Antioxidative and antiinflammatory activities of HDL were evaluated as protection of reference LDL from oxidative stress and capacity to prevent accumulation of proinflammatory oxidised lipids, respectively. Lipid surface rigidity of HDL was assessed using a fluorescent probe. HDL components were measured by analytical approaches. Systemic oxidative stress was characterized as plasma 8-isoprostanes. Results Pre-LDL-apheresis, FH patients (n = 10) exhibited elevated systemic oxidative stress (3.3-fold, P < 0.001) vs. sex- and age-matched normolipidemic controls (n = 10). Both antioxidative and antiinflammatory activity of HDL3 were impaired (up to −91%, P < 0.01) in FH. Sphingomyelin and saturated fatty acid contents were elevated in FH HDL3, resulting in enhanced lipid surface rigidity. The surface lipid content (phospholipids, free cholesterol) was reduced in FH (up to −15%, P < 0.001), whereas content of core lipids (cholesteryl esters, triglycerides) was elevated (up to +17%, P < 0.001). Molar apolipoprotein A-I content of HDL3 was subnormal in FH. A single LDL-apheresis session partially corrected (by up to 76%) deficient HDL antiatherogenic activities, attenuated systemic oxidative stress and partially normalised both the lipid composition and surface rigidity of HDL particles. Conclusions FH features elevated oxidative stress and deficient antioxidative and anti-inflammatory activities of small, dense HDL3; such functional deficiency is intimately linked to anomalies in lipid and protein composition, which may impair the capacity of HDL to acquire and inactivate oxidized lipids. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia is a common pathology of premature newborns caused by oxidative stress and mechanical ventilation, resulting in hypoalveolization and impaired angiogenesis. It can be complicated by pulmonary hypertension (HTP-DBP) with excess mortality. Celastrol has anti-inflammatory and antioxidant properties. So, we addressed its potential therapeutic interest in HTP-DBP. Different concentrations of celastrol were used in a murine model of hyperoxic HTP-DBP (14 days with 90% O 2) and we evaluated hemodynamic parameters with echocardiography and lung remodeling with histological methods. Pulmonary arterial (PA) reactivity was addressed with myograph. Cytoplasmic calcium (Ca2 + i) response to endothelin-1 (ET-1) was evaluated in human fetal PA smooth muscle cells (fPASMC) with spectrophotometry in normoxic (21% O 2) and hyperoxic conditions (48 h with 60% O 2). Inflammation was addressed with IL6 ELISA assay in fPASMC. Celastrol reduces mortality at doses of 1 and 0.5 mg/kg/d compared to the hyperoxic control group. At 1 mg/kg/d, it normalizes PAAT (PA acceleration time) (P < 0.001) and reduces vascular hyperreactivity to phenylephrine and ET-1 (P < 0.001) with no effect on the alteration of the response to acetylcholine induced by hyperoxia. At doses of 0.1, 0.5 and 1 mg/kg/d, it decreases right heart hypertrophy and vascular remodeling (wall thickness) but has no effect on alveolization and vascular density (vWF staining). Finally, although celastrol (0.1 and 0.3 μM) decreases the increased Ca2 + i response to ET-1 in hyperoxia in fPASMC, expression of ET-1 receptors (Western blotting and qPCR for ET-A and ET-B) was unchanged. However, celastrol 0.5 μM decreases ET-1 concentration measured with an ELISA assay in human umbilical arterial endothelial cells. An increased concentration of IL6 was also observed in fPASMC in hyperoxia and was decreased by celastrol 0.5 μM. Celastrol has a preventive dose-dependent effect on some hallmarks of HTP induced by hyperoxia and could thus be considered as an interesting new potential therapeutic option for HTP-DBP. [ABSTRACT FROM AUTHOR]

Background Niacin as an adjunct to statin treatment to reduce cardiovascular risk is questioned. Objective To evaluate interrelationships between the effects of niacin on mixed dyslipidemia and a spectrum of metabolic and inflammatory biomarkers. Methods Obese, nondiabetic, hypertriglyceridemic males ( n = 19) with low high-density lipoprotein–cholesterol levels received extended-release nicotinic acid for 8 weeks. Multiple biomarkers were measured using enzyme-linked immunosorbent assay, enzymatic/absorptiometric, or multiplex biochip assays. Treatment effects were determined for each variable and a differential correlation network created on the basis of univariate correlations between baseline and response to niacin treatment for all pairs of variables. Results Extended-release niacin treatment favoured normalization of plasma lipid and apolipoprotein profile. Plasma markers of inflammation, hepatic function, cellular adhesion and proliferation, and macrophage phenotype were attenuated; however, insulin resistance increased. Differential network analysis revealed that changes in triglycerides and high-density lipoprotein–cholesterol were closely linked; equally, niacin mediated reductions in total cholesterol, apolipoprotein B, low-density lipoprotein–cholesterol and lipoprotein(a) clustered together, as did homeostatic model assessment of insulin resistance, insulin, and interleukin-6 levels. Two clusters of inflammatory markers were identified, involving (1) intercellular adhesion molecule 1 and high-sensitive C-reactive protein and (2) soluble tumor necrosis factor receptors; and novel clusters involving matrix metallopeptidase 9 and apolipoprotein E, and adiponectin and cystatin C, respectively, were equally revealed. At lower stringency, lipid and insulin resistance clusters were linked; a C-reactive protein-centered cluster linked reduction in apolipoprotein CIII to intercellular adhesion molecule 1, gamma-glutamyltransferase, soluble tumor necrosis factor receptors, and E-selectin. Conclusion A niacin-mediated trend to normalize atherogenic mixed dyslipidemia was intimately linked to attenuation of biomarkers of inflammation, cell adhesion, hepatic dysfunction and cell proliferation, but to enhanced insulin resistance and plasma homocysteine elevation. [ABSTRACT FROM AUTHOR]

Background Statins impact the metabolism, concentrations, composition, and function of circulating lipoproteins. Objective We evaluated time course relationships between statin-mediated reduction in atherogenic apolipoprotein B (ApoB)–containing particles and dynamic intravascular remodeling of ApoAI-containing lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome. Methods Insulin-resistant, hypertriglyceridemic, hypercholesterolemic, obese males (n = 12) were treated with pitavastatin (4 mg/d) and response evaluated at 6, 42, and 180 days. Results Reduction in low-density lipoprotein (LDL) cholesterol, ApoB, and triglycerides (TGs) was essentially complete at 42 days (–38%, –32%, and –35%, respectively); rapid reduction equally occurred in remnant cholesterol, ApoCII, CIII, and E levels (day 6; –35%, –50%, –23%, and –26%, respectively). Small dense LDLs (LDL4 and LDL5 subpopulations) predominated at baseline and were markedly reduced on treatment (–29% vs total LDL mass). Cholesteryl ester (CE) transfer protein activity and mass decreased progressively (–18% and –16%, respectively); concomitantly, TG depletion (up to –49%) and CE enrichment occurred in all high-density lipoprotein (HDL) particle subpopulations with normalization of CE/TG mass ratio at 180 days. ApoAI was redistributed from LpAI to LpAI:AII particles in HDL2a and HDL3a subpopulations; ApoCIII was preferentially depleted from LpAI:AII–rich particles on treatment. Conclusion Overall, statin action exhibits duality in mixed dyslipidemia, as CE transfer protein–mediated normalization of the HDL CE/TG core lags markedly behind subacute reduction in elevated levels of atherogenic ApoB-containing lipoproteins. Normalization of the HDL neutral lipid core is consistent with enhanced atheroprotective function. The HDL CE/TG ratio constitutes a metabolomic marker of perturbed HDL metabolism in insulin-resistant states, equally allowing monitoring of statin impact on HDL metabolism, structure, and function. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is characterised by an increase in pulmonary arterial pressure, ultimately leading to right ventricular failure and death. We have previously shown that nerve growth factor (NGF) plays a critical role in PH. Our objectives here were to determine whether NGF controls Connexin-43 (Cx43) expression and function in the pulmonary arterial smooth muscle, and whether this mechanism contributes to NGF-induced pulmonary artery hyperreactivity. NGF activates its TrkA receptor to increase Cx43 expression, phosphorylation, and localization at the plasma membrane in human pulmonary arterial smooth muscle cells, thus leading to enhanced activity of Cx43-dependent GAP junctions as shown by Lucifer Yellow dye assay transfer and fluorescence recovery after photobleaching -FRAP- experiments. Using both in vitro pharmacological and in vivo SiRNA approaches, we demonstrate that NGF-dependent increase in Cx43 expression and activity in the rat pulmonary circulation causes pulmonary artery hyperreactivity. We also show that, in a rat model of PH induced by chronic hypoxia, in vivo blockade of NGF or of its TrkA receptor significantly reduces Cx43 increased pulmonary arterial expression induced by chronic hypoxia and displays preventive effects on pulmonary arterial pressure increase and right heart hypertrophy. Modulation of Cx43 by NGF in pulmonary arterial smooth muscle cells contributes to NGF-induced alterations of pulmonary artery reactivity. Since NGF and its TrkA receptor play a role in vivo in Cx43 increased expression in PH induced by chronic hypoxia, these NGF/Cx43-dependent mechanisms may therefore play a significant role in human PH pathophysiology. [Display omitted] • NGF increases Cx43 expression and activity in pulmonary arterial smooth muscle cells. • This effect is TrkA-dependent and contributes to pulmonary artery reactivity. • Such mechanism may contribute to human pulmonary hypertension pathophysiology. [ABSTRACT FROM AUTHOR]

Background Low plasma levels of high-density lipoprotein-cholesterol (HDL-C) are typical of acute myocardial infarction (MI) and predict risk of recurrent cardiovascular events. The potential relationships between modifications in the molecular composition and the functionality of HDL subpopulations in acute MI however remain indeterminate. Methods and results ST segment elevation MI (STEMI) patients were recruited within 24 h after diagnosis (n = 16) and featured low HDL-C (− 31%, p < 0.05) and acute-phase inflammation (determined as marked elevations in C-reactive protein, serum amyloid A (SAA) and interleukin-6) as compared to age- and sex-matched controls (n = 10). STEMI plasma HDL and its subpopulations (HDL2b, 2a, 3a, 3b, 3c) displayed attenuated cholesterol efflux capacity from THP-1 cells (up to − 32%, p < 0.01, on a unit phospholipid mass basis) vs. controls. Plasma HDL and small, dense HDL3b and 3c subpopulations from STEMI patients exhibited reduced anti-oxidative activity (up to − 68%, p < 0.05, on a unit HDL mass basis). HDL subpopulations in STEMI were enriched in two proinflammatory bioactive lipids, lysophosphatidylcholine (up to 3.0-fold, p < 0.05) and phosphatidic acid (up to 8.4-fold, p < 0.05), depleted in apolipoprotein A-I (up to − 23%, p < 0.05) and enriched in SAA (up to + 10.2-fold, p < 0.05); such changes were most marked in the HDL3b subfraction. In vitro HDL enrichment in both lysophosphatidylcholine and phosphatidic acid exerted deleterious effects on HDL functionality. Conclusions In the early phase of STEMI, HDL particle subpopulations display marked, concomitant alterations in both lipidome and proteome which are implicated in impaired HDL functionality. Such modifications may act synergistically to confer novel deleterious biological activities to STEMI HDL. Significance Our present data highlight complex changes in the molecular composition and functionality of HDL particle subpopulations in the acute phase of STEMI, and for the first time, reveal that concomitant modifications in both the lipidome and proteome contribute to functional deficiencies in cholesterol efflux and antioxidative activities of HDL particles. These findings may provide new biomarkers and new insights in therapeutic strategy to reduce cardiovascular risk in this clinical setting where such net deficiency in HDL function, multiplied by low circulating HDL concentrations, can be expected to contribute to accelerated atherogenesis. [ABSTRACT FROM AUTHOR]

Cholesterol-laden monocyte-derived macrophages are phagocytic cells characteristic of early and advanced atherosclerotic lesions. Interleukin-6 (IL-6) is a macrophage secretory product that is abundantly expressed in atherosclerotic plaques but whose precise role in atherogenesis is unclear. The capacity of macrophages to clear apoptotic cells, through the efferocytosis mechanism, as well as to reduce cellular cholesterol accumulation contributes to prevent plaque progression and instability. By virtue of its capacity to promote cellular cholesterol efflux from phagocyte-macrophages, ABCA1 was reported to reduce atherosclerosis. We demonstrated that lipid loading in human macrophages was accompanied by a strong increase of IL-6 secretion. Interestingly, IL-6 markedly induced ABCA1 expression and enhanced ABCA1-mediated cholesterol efflux from human macrophages to apoAI. Stimulation of ABCA1-mediated cholesterol efflux by IL-6 was, however, abolished by selective inhibition of the Jak-2/Stat3 signaling pathway. In addition, we observed that the expression of molecules described to promote efferocytosis, i.e. c-mer proto-oncogene-tyrosine kinase, thrombospondin-1, and transglutaminase 2, was significantly induced in human macrophages upon treatment with IL-6. Consistent with these findings, IL-6 enhanced the capacity of human macrophages to phagocytose apoptotic cells; moreover, we observed that IL-6 stimulates the ABCA1-mediated efflux of cholesterol derived from the ingestion of free cholesterol-loaded apoptotic macrophages. Finally, the treatment of human macrophages with IL-6 led to the establishment of an anti-inflammatory cytokine profile, characterized by an increased secretion of IL-4 and IL-10 together with a decrease of that of IL-1β. Taken together, our results indicate that IL-6 favors the elimination of excess cholesterol in human macrophages and phagocytes by stimulation of ABCA1-mediated cellular free cholesterol efflux and attenuates the macrophage proinflammatory phenotype. Thus, high amounts of IL-6 secreted by lipid laden human macrophages may constitute a protective response from macrophages to prevent accumulation of cytotoxic-free cholesterol. Such a cellular recycling of free cholesterol may contribute to reduce both foam cell formation and the accumulation of apoptotic bodies as well as intraplaque inflammation in atherosclerotic lesions. [ABSTRACT FROM AUTHOR]