The assignment of numerical values to physical quantities underlies all quantitative statements in engineering and the physical sciences. This assignment is achieved by the process of measurement. The physical quantity being measured and the precision required in the numerical value determines the instrumentation to be used. The design of a measurement system therefore involves the analysis of the attribute to be measured, the means available for its detection and the verification that the measurement system performs as intended and can achieve the desired accuracy and precision. In this book Figliola and Beasley first discuss in general terms the basics of measurement, analogue and digital data acquisition systems and signal processing, the statistics of measurement and the analysis of error and uncertainty. In successive chapters they concentrate on the instruments and their physical basis in the areas of electricity, temperature, fluid flow, elastic strain and mechanics (displacement, motion, force and power). The coverage is directed towards measurements in various branches of engineering, with numerous worked examples and problems for students (approximately 30 to 40) at the end of each chapter. Since it is an American engineering text, the book uses both SI and English units. Unfortunately, the text is flawed by numerous errors. Some of the more egregious are that in chapter 1, `dimension' is used in place of `unit', the definitions given for the ampere and the ohm are in terms of `international' units that were abandoned in 1948 and derived units are expressed, for example, as `' in place of the standard forms (SI, ISO, ANSI) of `' or `'. There are furthermore numerous minor numerical errors and inconsistencies. One of the more serious flaws is the failure to distinguish between bias errors and uncertainty due to bias in the discussion of chapter 5. There is also a misuse of the student in the evaluation of uncertainty (although this error is not exclusively Figliola and Beasley's, since it occurs in ANSI documents on fluid flow measurement). Given the estimate for variance, with degrees of freedom, an uncertainty interval at confidence level p is properly , while the uncertainty for a combined quantity is where is evaluated from the Welch - Satterthwaite expression In spite of its shortcomings, the book collects a great deal of material in one place and, in the hands of a careful instructor who is aware of its flaws, could be useful as a supplementary text on measurement. E Richard Cohen

Abstract-An early component of atherogenesis is abnormal vascular smooth muscle cell (VSMC) proliferation. The presence of Chlamydia pneumoniae in many atherosclerotic lesions raises the possibility that this organism plays a causal role in atherogenesis. In this study, C pneumoniae elementary bodies (EBs) rapidly activated p44/p42 mitogen-activated protein kinases (MAPKs) and stimulated proliferation of VSMCs in vitro. Exposure of VSMCs derived from human saphenous vein to C pneumoniae EBs (3ϫ10 7 inclusion forming units/mL) enhanced bromodeoxyuridine (BrdU) incorporation 12Ϯ3-fold. UV-and heat-inactivated C pneumoniae EBs also stimulated VSMC proliferation, indicating a role of direct stimulation by chlamydial antigens. However, the mitogenic activity of C pneumoniae was heat-labile, thus excluding a role of lipopolysaccharide. Chlamydial hsp60 (25 g/mL) replicated the effect of C pneumoniae, stimulating BrdU incorporation 7Ϯ3-fold. Exposure to C pneumoniae or chlamydial hsp60 rapidly activated p44/p42 MAPK, within 5 to 10 minutes of exposure. In addition, PD98059 and U0126, which are two distinct inhibitors of upstream MAPK kinase 1/2 (MEK1/2), abolished the mitogenic effect of C pneumoniae and chlamydial hsp60. Toll-like receptors (TLRs) act as sensors for microbial antigens and can signal via the p44/p42 MAPK pathway. Human VSMCs were shown to express TLR4 mRNA and protein, and a TLR4 antagonist abolished chlamydial hsp60 -induced VSMC proliferation and attenuated C pneumoniae-induced MAPK activation and VSMC proliferation. Together these results indicate that C pneumoniae and chlamydial hsp60 are potent inducers of human VSMC proliferation and that these effects are mediated, at least in part, by rapid TLR4-mediated activation of p44/p42 MAPK. A therosclerosis is an inflammatory disease, with the earliest stages characterized by the invasion of the intima by mononuclear phagocytes and by intimal hyperplasia. 1 Accumulating evidence indicates that chronic infection with the ubiquitous respiratory pathogen Chlamydia pneumoniae, a Gram-negative obligate intracellular bacterium, may be an additional risk factor for atherosclerosis. Macrophages are thought to become infected with C pneumoniae in the respiratory tract and then enter the circulation and cross the endothelium at sites of preexisting vascular inflammation. The first report linking C pneumoniae to atherosclerosis identified the organism by electron microscopy in coronary atherosclerotic plaques and localized it to intimal smooth muscle cells (SMCs). 2 C pneumoniae has been found frequently in lesions of the aorta, iliac, carotid, and coronary arteries, 3-5 but is rarely found in normal arterial tissue. 6 In vitro evidence supports the notion that C pneumoniae can infect human arterial SMCs. 7-9 However, it is not clear whether C pneumoniae organisms that have been identified within SMCs of human atheromas are actively replicating or viable. Irrespective of whether C pneumoniae replicates within SMCs in vivo, its presence in atherosclerotic lesions r...

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The cytokine interleukin 1 (IL-1) inhibits contractile responses in rat aorta by causing endothelium-independent and prolonged activation of soluble guanylate cyclase. The present study tested whether IL-1 activates guanylate cyclase by inducing prolonged production of nitric oxide in cultured rat aortic vascular smooth muscle cells (VSMC). IL-I induced a marked timedependent increase in cyclic guanosine monophosphate (cGMP) in VSMC which was significant at 6 h, and increased progressively for up to 36 h. This effect of IL-1 was abolished when protein synthesis was inhibited with cycloheximide or actinomycin D, suggesting that the effect of IL-1 involves new protein synthesis. IL-1-induced cGMP accumulation was inhibited by the soluble guanylate cyclase inhibitors, methylene blue, LY83583, and hemoglobin and by the L-arginine analogue NGmonomethyl-L-arginine (L-NMMA). The inhibitory effect of L-NMMA was reversed by a 10-fold excess of L-arginine, but not by D-arginine. Nitrite, an oxidation product of nitric oxide, accumulated in the media of VSMC incubated with IL-1 for 24 h in the presence of L-arginine, whereas both IL-i-induced cGMP accumulation and nitrite production were attenuated in VSMC incubated in L-arginine-deficient medium. In L-arginine-depleted VSMC, IL-I-induced cGMP accumulation was restored to control levels by a 15-min incubation with L-arginine. These results demonstrate that IL-1 activates guanylate cyclase in rat VSMC by inducing production of nitric oxide via a pathway dependent on extracellular L-arginine. (J.

Hypoxia is thought to be a stimulus for the excessive proliferation of vascular smooth muscle cells (VSMC) that contributes to pulmonary hypertension, but the mechanisms involved are unknown. Here we tested whether hypoxia-inducible factor 1-alpha (HIF-1alpha), a master regulator of the transcriptional response to hypoxia, is involved in the enhanced mitogen-induced proliferative responses of hypoxic VSMC. Exposure to moderate hypoxia (5% O(2)) enhanced the proliferative responses of human pulmonary artery SMC (HPASMC) to mitogens including platelet-derived growth factor (PDGF), fibroblast growth factor 2 (FGF-2), and epidermal growth factor (EGF), compared with those in normoxia (20% O(2)). Moderate hypoxia elicited increased cellular HIF-1alpha levels, shown by Western blot analysis, and also enhanced PDGF-, FGF-2-, and EGF-induced expression of HIF-1alpha. Knockdown of HIF-1alpha or HIF-1beta levels in HPASMC with specific small interfering RNAs inhibited FGF-2-stimulated proliferation of HPASMC incubated in either 5% or 20% O(2) but failed to inhibit the comitogenic effect of hypoxia. Knockdown of HIF-1alpha similarly inhibited PDGF-stimulated proliferation, whereas HIF-2alpha knockdown had no effect on HPASMC proliferation. Knockdown of HIF-1alpha expression also inhibited growth factor-induced expression of cyclin A. We conclude that HIF-1alpha promotes proliferative responses of human VSMC to FGF-2, PDGF, and EGF by mechanisms that may involve HIF-1-dependent expression of cyclin A, but HIF is apparently not crucial to the enhancement of FGF-2-, PDGF-, and EGF-induced proliferation of VSMC that occurs during hypoxia.

Recent evidence supports a role of Toll-like receptor (TLR) signaling in the development of atherosclerotic lesions. In this study, we tested whether TLR4 signaling promotes a proinflammatory phenotype in human and mouse arterial smooth muscle cells (SMC), characterized by increased cytokine and chemokine synthesis and increased TLR expression. Human arterial SMC were found to express mRNA encoding TLR4 and the TLR4-associated molecules MD-2 and CD14 but not TLR2 mRNA. Mouse aortic SMC, on the other hand, expressed both TLR2 and TLR4 mRNA constitutively. Human SMC derived from the coronary artery, but not those from the pulmonary artery, were found to express cell surface-associated CD14. Low concentrations (ng/ml) of Escherichia coli LPS, the prototypical TLR4 agonist, markedly stimulated extracellular regulated kinase 1/2 (ERK1/2) activity, induced release of monocyte-chemoattractant protein-1 (MCP-1) and interleukin (IL)-6, and stimulated IL-1alpha expression in human aortic SMC, and exogenous CD14 enhanced these effects. Expression of a dominant negative form of TLR4 in human SMC attenuated LPS-induced ERK1/2 and MCP-1 release. LPS was a potent inducer of NF-kappaB activity, ERK1/2 phosphorylation, MCP-1 release, and TLR2 mRNA expression in wild-type mice but not in TLR4-signaling deficient mouse aortic SMC. These studies show that TLR4 signaling promotes a proinflammatory phenotype in vascular smooth muscle cells (VSMC) and suggest that VSMC may potentially play an active role in vascular inflammation via the release of chemokines, proinflammatory cytokines, and increased expression of TLR2.

Objective-Atherosclerosis encompasses a conspicuously maladaptive inflammatory response that might involve innate immunity. Here, we compared the role of Toll-like receptor 4 (TLR4) with that of TLR2 in intimal foam cell accumulation and inflammation in apolipoprotein E (ApoE) knockout (KO) mice in vivo and determined potential mechanisms of upstream activation and downstream action. Methods and Results-We measured lipid accumulation and gene expression in the lesion-prone lesser curvature of the aortic arch. TLR4 deficiency reduced intimal lipid by Ϸ75% in ApoE KO mice, despite unaltered total serum cholesterol and triglyceride levels, whereas TLR2 deficiency reduced it by Ϸ45%. TLR4 deficiency prevented the increased interleukin-1␣ (IL-1␣) and monocyte chemoattractant protein-1 mRNA levels seen within lesional tissue, and it also lowered serum IL-1␣ levels. Smooth muscle cells (SMC) were present within the intima of the lesser curvature of the aortic arch at this early lesion stage, and they enveloped and permeated nascent lesions, which consisted of focal clusters of foam cells. Cholesterol enrichment of SMC in vitro stimulated acyl-coenzyme A:cholesterol acyltransferase-1 mRNA expression, cytoplasmic cholesterol ester accumulation, and monocyte chemoattractant protein-1 mRNA and protein expression in a TLR4-dependent manner. A therogenesis involves a strikingly maladaptive inflammatory response, initially to retained and modified lipoproteins 1 and later to apoptotic or necrotic cell debris that accumulates within the arterial wall. 2 Toll-like receptors (TLR) elicit innate immune responses and inflammation when activated by either exogenous microbial products or endogenous molecules with similar structural features, and they are candidate mediators of atherogenic inflammation. TLR2 and TLR4 are expressed in arterial lesions of mice and humans, 3,4 and exogenous microbial TLR2 and TLR4 agonist ligands promote atherosclerosis in hypercholesterolemic mice, 5,6 implicating these receptors as candidate atherogenic mediators. In gene knockout (KO) mouse models, TLR2 deficiency reduced early atherogenic events and later aortic lesion development. 7,8 In contrast, deficiency of TLR4, the bacterial lipopolysaccharide (LPS) receptor, produced modest effects 9 or no effects 10 on aortic lesion burden in studies limited to advanced disease stages. However, prolonged and severe hypercholesterolemia may generate distinct modified lipids or proteins that promote inflammation and atherogenesis via distinct, TLR-independent pathways. Therefore, here we tested the hypothesis that TLR4 promotes atherogenesis during early-stage disease, using a mouse model of shorterterm and less severe hypercholesterolemia, and compared its influence to that of TLR2. Conclusion-TLR4TLR signaling strongly activates proinflammatory genes in multiple cell types found within early atherosclerotic lesions, but little is known about how this promotes atherogenesis. Such atherogenic TLR signaling may not be restricted to hematopoietic cells, beca...

Objective-Abdominal aortic aneurysm (AAA) is a life-threatening disease affecting almost 10% of the population over age 65. Generation of AAAs by infusion of angiotensin (Ang) II in apolipoprotein E-knockout (ApoE Ϫ/Ϫ ) mice is an animal model which supports an imbalance of the renin-angiotensin system in the pathogenesis of AAA. The effect of statins on AngII-mediated AAA formation and the associated neovascularization is not known. Here we determined the effect of simvastatin and the ERK inhibitor, CI1040, on AngII-stimulated AAA formation. Methods and Results-ApoEϪ/Ϫ mice infused for 28 days with AngII using osmotic minipumps were treated with placebo, 10 mg/kg/d simvastatin, or 100 mg/kg/d CI1040. 95% of AngII-treated mice developed AAA with neovascularization of the lesion, increased ERK phosphorylation, MCP-1 secretion, and MMP activity. These effects were markedly reversed by simvastatin and in part by CI1040. Furthermore, simvastatin and the ERK inhibitor U0126 reversed AngII-stimulated angiogenesis and MMP secretion by human umbilical vein endothelial cells. Key Words: angiotensin II Ⅲ abdominal aortic aneurysm Ⅲ statin Ⅲ ERK inhibition Ⅲ angiogenesis A bdominal aortic aneurysm (AAA) is a potentially lifethreatening degenerative vascular disease that affects 6% to 9% of men over the age of 65 years, claiming more than 15 000 lives annually. 1 Currently, surgical repair is the only effective method of AAA treatment. 2 Studies of the pathophysiology of AAA have demonstrated that human aneurysmal tissues are characterized by (1) chronic inflammation of the aortic wall with the accumulation of macrophages and MCP-1 secretion 3 ; (2) progressive degradation of extracellular matrix including elastin and collagen 4 ; (3) increased activity of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9 5 ; (4) reendothelialization of the dilated luminal surface of the vessel wall and pronounced neovascularization of the media and adventitia. 6,7 Several animal models of AAA have been developed in the mouse, including injury of the aortic wall with calcium chloride 8 or elastase. 9 Infusion of AngII via subcutaneous osmotic minipumps in ApoE Ϫ/Ϫ mice has also been shown to result in reproducible formation of suprarenal AAAs, which exhibit many characteristics of the human disease including secretion of MCP-1, 5 macrophage infiltration, secretion of MMPs, disruption of the media, rupture of the elastic layer, and neovascularization. 10 This is consistent with the finding that AngII not only plays a role in the control of cardiovascular and renal homeostasis but also affects vascular endothelial cell function, macrophage activation, 11 and the contraction, migration, and proliferation of vascular smooth muscle cells. 12 This model supports an imbalance of the renin-angiotensin system in the pathogenesis of AAA and is thus an important model for the study of mechanisms of AAA formation. Conclusions-TheseThe mitogen-activated protein (MAP) kinase family, including ERK, c-Jun N-terminal kinase (JNK), and p38 MAPK...