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W2012407931 abstract "Apolipoproteins AI and B are structural components of lipoprotein particles, and also determinants of the metabolic fate of the encapsulated lipid, cholesterol and triglyceride. Development of accurate assays for these apolipoproteins has opened the way for their use as predictors of coronary heart disease risk. Interpretation of AI and apo B levels is best undertaken with background knowledge of the metabolic status of an individual, especially the lipolytic capacity as reflected in the triglyceride concentration. Those with raised triglyceride, in general, not only have an elevated apo B/apo AI ratio, but also apo B-containing lipoproteins with a prolonged residence time and hence ample opportunity for modification and damage. Assessment of apolipoprotein levels is an aid to risk prediction and can be useful in tailoring treatment. Lipoproteins are nature's answer to the problem of transporting hydrophobic molecules in the aqueous milieu of blood plasma. These pseudomicellar structures comprise a coat of phospholipid and protein, and a core of cholesterol (in the form of cholesteryl ester) and triglyceride. They transfer lipids from sites of production to tissues where they are utilized for energy production, storage, membrane assembly or hormone synthesis. This lipid transport system is regulated by enzymes (such as lipases), cell surface receptors, and the key protein components of the lipoproteins, apolipoproteins. The last are essential for the correct assembly of lipoprotein particles, for the integrity of these particles during processing in the circulation, and for directing their metabolic fate, e.g. triglyceride to skeletal muscle or adipose tissue, cholesterol to the adrenal gland or liver. Pathological consequences follow when particles are directed to the wrong site, such as cholesterol to the artery wall. This is a result in some people of inherited metabolic abnormalities but in the majority is the response of a system, based on a ‘hunter-gatherer’ genome designed to cope with a paucity of calories, being exposed to continuous surfeit. Apolipoproteins (apo) AI and B are, respectively, structural proteins for high density lipoproteins (HDL), and the very low density-low density lipoprotein spectrum (VLDL-LDL). In general, apo B-containing lipoproteins carry lipid from liver and gut to the sites of utilization, whereas apo AI-containing particles mediate reverse cholesterol transport, returning excess cholesterol from peripheral tissues to the liver, the only organ capable of excreting it in significant quantities (in bile). Key pathways in lipoprotein metabolism are depicted in Fig. 1 [1, 2]. Briefly, chylomicrons rich in triglycerides are released from the intestine following absorption of dietary fat. These particles contain apo AI and a short form of apo B (B48, the N-terminal portion of full-length B100), and are metabolized rapidly to remnants which are removed by the liver. Triglycerides in chylomicrons are hydrolysed by lipoprotein lipase and the released fatty acids re-esterified in adipocyte fat stores. In fasting subjects the main triglyceride-rich lipoprotein is VLDL1 which is secreted by the liver. It is converted by lipoprotein lipase to smaller particles, VLDL2, and then to intermediate density lipoproteins (IDL). Hepatic lipase catalyses the final delipidation step to form LDL from IDL [1]. Plasma apo B levels, therefore, reflect the aggregate presence of all these lipoprotein species; the concentration of each is a function of its rates of production, interconversion and removal. Normal lipoprotein metabolism. This scheme depicts in a simplified form the main pathways of lipoprotein metabolism. Chylomicrons, released as a wave of particles from the intestine during fat absorption are lipolysed rapidly by lipoprotein lipase (LpL) to form remnants. The latter are cleared efficiently by the liver. In the postabsorptive state the liver secretes mainly triglyceride-rich VLDL1 but also VLDL2, IDL and LDL. VLDL1 is converted to VLDL2 and thence to IDL by removal of triglyceride via action of LpL. IDL conversion to LDL is mediated by hepatic lipase (HL). LDL is removed from the circulation by cell surface receptors present on all tissues (but mainly in the liver). Tissues that accumulate cholesterol transfer excess sterol to HDL via mechanisms that apparently favour donation to small, discoidal particles (via ABCA1) or large particles (via ABC G1). Free cholesterol taken up by HDL is sequested as cholesteryl ester following the action of lecithin cholesterol acyl transferase (LCAT). HDL C ester (CE) is then transferred to apo B-containing lipoproteins by CE transfer protein (CETP). Lp(a) has a separate route of synthesis in the liver, and of catabolism at unknown sites. Apo AI is the major protein of HDL. Its main functions are to act as a structural protein, to mediate transfer of cholesterol from cell surfaces to lipoprotein particles, and to activate the enzyme responsible for cholesterol esterification in the circulation, lecithin:cholesterol acyl transferase (LCAT). Cholesterol efflux from tissues occurs via receptors such as ABCA1 and ABCG1 [3-5]. The sterol acquired by HDL is then trapped by LCAT-mediated formation of cholesteryl ester, and in the process the structure of the lipoprotein changes from discoidal to spherical as the lipid becomes sequestered in the hydrophobic interior. Cholesteryl ester in HDL is then either passed by the action of cholesteryl ester transfer protein (CETP) to apo B-containing lipoproteins (VLDL and LDL) and so finds its way back to the liver, or is removed directly from the HDL by receptors such as SR-B1 on hepatocytes [4]. The standardization of lipid and lipoprotein measurements, including total cholesterol, LDL and HDL C, and triglyceride, was initiated in the early 1970s. At that time, there were only a few methodological approaches to measure apo AI and apo B. Measurements were primarily performed in research laboratories using in-house-developed radioimmunodiffusion and electroimmundiffusion techniques. These methods required incorporation of antibodies into gel matrix and were not automated. However, in the early 1980s commercially available automated methods became available for both proteins. These included immuno-nephelometric and immuno-turbidimetric assays with use of specific antibodies in the liquid phase. The first attempt at standardization of apo AI and apo B measurement was initiated in 1981 by the Centers for Disease Control (CDC) in collaboration with the International Union of Immunological Societies. A survey of over 100 research laboratories involved in apolipoprotein measurements found that coefficients of variation (CV) for apo AI and apo B methods were 15% and 24% respectively [6]. Major sources of variation were the use of different calibrators, lack of linearity and parallelism, matrix effect and inaccuracy of dilutions [6]. The International Federation of Clinical Chemistry (IFCC), recognizing the important clinical role of apo AI and apo B, in 1984 established a Committee on Apolipoprotein Standardization (chaired by Dr Santica Marcovina). Extensive evaluation of different methods, performed in the laboratories of Drs Santica Marcovina and Jean Charles Fruchart, confirmed the large amongst-method CVs and provided clear evidence that the primary problem in comparability amongst different methods was related to the difficulty of assigning values to assay calibrators. The various problems associated with the apolipoprotein measurements were presented at an IFCC meeting in Vienna, Austria, in 1988 [7]. Because of the considerable variability in apolipoprotein measurements, and consequently the lack of uniform clinical reference values and clinical decision points, it was concluded that a common standardization programme directly involving manufacturers of analytical systems for measuring apo AI and apo B should be implemented. This IFCC study was coordinated by the Northwest Lipid Research Laboratories (NWRL) at the University of Washington in Seattle, with support from the National Heart, Lung and Blood Institute, and participation of manufacturers and research laboratories involved in apolipoprotein measurements. The main objective of this standardization effort was to identify suitable reference materials to be used by the manufacturers to assign accuracy-based values to their assay calibrators. To achieve this objective, the study was conducted in three phases. In phase 1, candidate reference materials were evaluated in different test systems, and the most suitable candidate reference materials, one for apo AI and one for apo B, were identified [8]. The selected reference materials were further evaluated for their performance in phase 2 [9]. In phase 3, the selected reference materials were used to assign an accuracy-based value to the calibrators of the different test systems, and the data obtained on a set of 50 fresh-frozen patient samples by the different assays were compared. The amongst-laboratory CV for apo AI on each of the 50 samples ranged from 2.1% to 5.6%, and demonstrated that comparable apo AI values were obtained amongst laboratories using the common reference material SP1-01 as calibration material in different laboratories [10]. The amongst-laboratory CV for apo B on patient samples ranged from 3.1% to 6.7%, thus demonstrating the accuracy and comparability amongst a variety of immunochemical methods through the use of the common reference material SP3-07 [11]. Based on the documentation presented, these two reference materials were accepted by the World Health Organization (WHO) as the WHO/IFCC International Reference Materials for apo AI and apo B measurement. The availability of common reference materials for assigning values to the assay calibrators greatly improved agreement amongst laboratories in measureing apo AI and apo B. This fact was further demonstrated by comparing the apolipoprotein values in large population studies that used methods standardized by the WHO-IFCC reference materials. For example, apo AI and apo B measurements performed in two major population studies in US, NHANES III and Framingham Offspring studies [12-14], have shown that the distribution of apo AI and apo B values was nearly identical despite the use of different methodological approaches. In addition, in three population-based studies performed in Finland, Sweden and Italy [15-17], the percentile distribution of apo AI was nearly identical, whereas slightly higher apo B values were observed in the Swedish and Finnish compared with the American and Italian populations. The difference in apo B levels in Scandinavia was predicted based on the higher cholesterol levels in this population. Taken together, these findings establish that measurements of apo AI and apo B can be performed with high accuracy and precision. In contrast, the accuracy and comparability of the LDL and HDL C measurements (HDL C, LDL C) are more problematic, and unlike apo AI and apo B, there is no common reference material for HDL C and LDL C measurements. Moreover, it should be noted that the inaccuracies of the direct HDL C and direct LDL C measurement methods are not primarily the result of inaccuracy of the assay calibration, but the result of inherent problems in each of the assays. For the laboratory LDL C levels estimated by the Friedewald equation, the problems are multiple, as this approach utilizes values from three measurements – that of total cholesterol, HDL C and triglycerides – thus enhancing the probability of error. The accurate measurement of triglycerides has also been problematic because triglyceride measurement, as performed in general clinical chemistry laboratories, usually incorrectly includes measurements of monoglycerides and diglycerides, thus resulting in higher values. Additionally, the HDL C values obtained for the calculation of the LDL C often use direct HDL measurements that have inherent method-dependent inaccuracies. To evaluate the extent of misclassification of patients based on their LDL C levels, we compared LDL C values obtained by the Beta-Quantification procedure [18], which involves the separation of lipoproteins by ultracentrifugation, with those derived by the Friedewald equation. The comparison was made on 14 457 samples with triglycerides ≤400 mg dL−1, analysed at the NWRL in Seattle. Based on the LDL C values obtained by the Beta-Quantification procedure, samples were grouped into five ATPIII categories: (i) LDL C <100 mg dL−1 (n = 3813), (ii) LDL C 100–129 mg dL−1 (n =4828), (iii) LDL C 130–159 mg dL−1 (n = 3728), (iv) LDL C 160–189 mg dL−1 (n = 1547), and (v) LDL C >189 mg dL−1 (n = 541). Based on their LDL C values derived by the Friedewald equation, 259 subjects (6.8%) in group 1 were misclassified as false positive, 1034 (21.4%) were misclassified in group 2 (7% as false positive and 14.4% as false negative). In group 3, 958 subjects (25.7%) were misclassified (7.1% as false positive and 18.6% as false negative). In group 4, 482 subjects (31.2%) were misclassified (7% as false positive and 24.2% as false negative), whilst in group 5, 93 subjects (17.2%) were all misclassified as false negative. These data make it clear that estimation of LDL C by the Friedewald equation, even when determined by highly standardized lipid methods, results in a substantial level of misclassification, with serious impact on clinical decisions. In conclusion, standardization of apolipoproteins AI and B is easier to achieve because of the availability of suitable reference materials and uniformity of methodological approaches. Furthermore, unlike lipid and lipoprotein measurements, measurements of apolipoproteins can be performed in nonfasting samples. Furthermore, high triglyceride values can interfere with direct measures of HDL and LDL C, but do not appear to have a significant effect on the accuracy of apo AI and apo B measurements. A number of particles contribute to the circulating level of apo B in the same way that the full spectrum of lipoproteins is included in the measurement of plasma cholesterol. The observation that total cholesterol is related to risk of coronary heart disease (CHD) in a population is a reflection of the fact that most cholesterol is carried in apo B-containing lipoproteins and that all apo B-containing species appear to be atherogenic to a greater or lesser extent (Table 1). In normal subjects about 70% of cholesterol is found in LDL and the majority of plasma apo B is also in this density fraction. In some forms of dyslipidaemia known to be associated with increased risk of CHD, other lipoprotein species such as chylomicron remnants, VLDL remnants and IDL become predominant and contribute to the genesis of atheromatous lesions. To accommodate these in a single variable it was suggested recently that non-HDL C (i.e. total cholesterol minus HDL) be adopted as a measure of total atherogenic potential [19]. As all these lipoproteins contain apo B, measurement of this apolipoprotein provides a similar but not identical index, and apo B and non-HDL C are closely correlated [20]. The difference in these two measures lies in the fact that the cholesterol : apo B ratio varies, with denser lipoproteins having a higher protein (apo B) : lipid (cholesterol) ratio. Thus, plasma apo B primarily reflects LDL whereas a significant proportion of ‘non-HDL C’ is found in IDL and VLDL. Further, apo B gives a direct measure of particle number as there is one apo B peptide per lipoprotein, and if the number of particles rather than their cholesterol load is the more important attribute contributing to atherosclerosis, then measurement of the protein should give better prediction of risk. Recent clinical studies suggest, indeed, that apo B is superior to non-HDL C in identifying the risk of vascular events [20, 21], although this is not a universal finding [22]. The concentration and type of apo B-containing lipoprotein seen in the general population and in various states of dyslipidaemia is the net result of the processes which regulate lipoprotein production, interconversion and clearance. Typical rates for these metabolic pathways are shown in Fig. 2 (taken from [23]). In normal subjects, although VLDL1 is the main lipoprotein secreted by the liver, its rapid progress down the delipidation cascade means that the concentrations of VLDL1, VLDL2 and IDL in normals are kept low. LDL, on the other hand, is cleared relatively slowly from the circulation (residence time of 2.0–4.0 days; residence time is the reciprocal of fractional catabolic rate) and so it is this species that usually predominates. Lifestyle factors such as obesity promote VLDL synthesis which in turn leads to a rise in LDL and total apo B [24], whilst the rise in apo B with age is associated apparently with reduction in the activity of LDL receptors [25]. VLDL1 production is also influenced by insulin levels even in apparently healthy subjects [26]. In people with insulin resistance there is a failure to regulate properly VLDL production, and apo B levels rise in the VLDL, IDL and LDL density classes [24, 27]. Metabolic regulation of plasma and lipoprotein apo B levels. Depicted within each circle is the circulating pool (in mg) of apo B in VLDL1, VLDL2, IDL and LDL in normolipidaemic subjects. Rates of production by the liver for the four major classes are given in mg apo B per day. Fractional rates of conversion, e.g. from VLDL1 to VLDL2 (8.0 pools per day) or of catabolism (e.g. for LDL 0.4) pools per day are also provided. Individuals with significant hypercholesterolaemia (LDL C >4.5 mmol L−1) are likely to have raised levels of all apo B-containing lipoproteins as a result of reduced clearance of particles by receptors. The LDL receptor is a regulated cell membrane protein responsible for the internalization of lipoproteins by cells that require cholesterol. Decreased receptor number is the result of inherited abnormalities such as familial hypercholesterolaemia or is the metabolic response to sterol surfeit in tissues such as the liver [28]. Metabolic studies have shown the rate of VLDL2 direct production to be a further regulator of LDL concentration; this lipoprotein class is under separate metabolic control from VLDL1 and elevated synthesis rates are observed in hypercholesterolaemic individuals [29]. In individuals with hypertriglyceridaemia there is a combination of overproduction of VLDL (especially VLDL1) and inefficient lipolysis [1, 24]. Thus, apo B levels are elevated in both VLDL1 and VLDL2. Furthermore, a prolonged residence time in the circulation is seen for all apo B-containing lipoproteins (Table 2, adapted from [23]) which increases the opportunities for these particles to be modified by the processes of inter-particle exchange of lipid and protein components, and by lipolysis. For example, CETP transfers triglycerides from VLDL to LDL and HDL whilst cholesteryl ester moves from in the opposite direction (Fig. 1). Similarly, apolipoproteins CII, CIII and E are exchanged between particles, so that long-lived VLDL becomes depleted in apoC and enriched in apo E and cholesteryl ester. Such modified VLDL are resistant to further lipase action and are termed ‘remnants’ [30]. Elevation of apo B in VLDL is therefore associated not only with a higher number of particles but also with the fact that these lipoproteins have altered comparison. Remnant particles are particularly atherogenic as they can cause directly cholesterol deposition in macrophages [30]. Atherogenic lipoprotein phenotype (ALP) is the characteristic lipoprotein pattern seen in individuals with type 2 diabetes and metabolic syndrome. It is an at-risk dyslipidaemic state, associated with central obesity, in which VLDL is elevated, HDL is reduced, and LDL is smaller and denser than normal [31]. Plasma triglyceride is above average (i.e. >1.7 mmol L−1) but plasma and LDL C are usually ‘normal’. The condition is thought to arise from overproduction of VLDL1, due to hepatic insulin resistance, which leads, in turn, to raised circulating levels of this lipoprotein, and to the formation of remnants and slowly metabolized LDL. The latter has ample time to exchange core lipid with VLDL and chylomicrons to become triglyceride rich and hence susceptible to the action of hepatic lipase. The enzyme removes lipid from the particle and releases LDL that is smaller and denser than normal [1, 23, 31]. Thus, more LDL particles are present (higher apo B) but they are lipid depleted and so the LDL C is ‘normal’. Small, dense LDL is considered more atherogenic than its normal sized counterpart because it is more easily oxidized, penetrates the artery wall more freely and has higher affinity for proteoglycan [1, 27]. A similar lipid exchange and lipolysis process affects HDL and generates smaller sized particles. As small HDL undergo rapid catabolism, HDL C and apo AI levels fall [32] in ALP. Detection of an ALP is performed in specialist laboratories by analysis of LDL subfraction distribution using centrifugation, gradient gel electrophoresis or NMR spectroscopy [31]. These methods are expensive and not in routine use. In practice it is likely that a combination of moderately elevated triglyceride (>1.7 mmol L−1) and an increased apo B : apo AI ratio will identify most with this dyslipidaemic pattern, especially if this accompanied by measurement of waist size as an index of central obesity. Lipoprotein (a) is an apo B-containing lipoprotein of distinct properties and metabolism. It is produced by attachment of apo(a) (a polypeptide of highly variable length) to apo B on LDL via a disulphide linkage, probably immediately following secretion of apo(a) from hepatocytes [33]. Circulating Lp(a) does not participate in bulk lipid transport, and its metabolic fate appears separate from that of other apo B-containing lipoproteins. It is a risk factor for CHD, especially in subjects with elevated LDL [34], and it will contribute to the measured plasma apo B content but this is quantatively important only when Lp(a) levels are very high. HDL is highly heterogeneous, comprising a number of subfractions of potentially distinct metabolic properties. The lipoprotein is considered cardioprotective as indices of its content in plasma, HDL C or apo AI, are inversely related to risk of CHD [35]. However, there is considerable debate over which element of HDL most clearly reflects its role as an anti-atherogenic agent [35]. The cholesterol content of HDL may be a marker of the efficiency of reverse cholesterol transport. This would be true if, in general, cholesterol capture from cells by ABC A1/G1-mediated mechanisms [3, 4] is the rate-limiting step, i.e. HDL C clearance is relatively constant and the level of this lipid observed in the circulation is a function of cholesterol export from tissues. If the converse is true, i.e. higher HDL C is due to less effective clearance of this lipid fraction from the bloodstream, it is difficult to see how this could be an index of cardioprotection from atherosclerosis. Apo AI is considered to be the ‘active ingredient’ in HDL. It mediates cell–lipoprotein interactions, and is believed to be essential for cholesterol uptake into the lipoprotein and for deposition of the lipid in hepatocytes via the agency of SR-B1-like receptors [3, 4]. Evidence for this concept comes from studies in which apo AI administered in excess over a period of days was shown to promote fecal cholesterol excretion [36]. The protein also has anti-inflammatory and anti-oxidative properties and this may contribute to its cardioprotective role as inflammation and oxidation are believed to be key processes in atherosclerosis. It might be expected, therefore, that apo AI would exhibit a much stronger relationship to CHD risk than HDL C, but, in general, this is not the case [35] prompting speculation that it is the apo AI, in particular HDL sub-species, e.g. preβ HDL, that is of prime importance. HDL in plasma range from small discs containing apo AI and a few molecules of phospholipid to spherical entities near to the size of LDL (Fig. 3). Apo AI is the major protein present in all particles. In some it is complexed with apo A2, the second most abundant protein in HDL. Of note is that HDL undergoes constant remodelling with exchange of lipid and protein components between HDL subspecies and with other lipoproteins. The concentration of apo AI and of HDL subfractions observed in plasma is, therefore, a reflection of dynamic processes affecting the structure and function of this lipoprotein class. A major influence on HDL is the metabolic state of triglyceride-rich lipoproteins. Individuals with efficient lipolytic mechanisms clear VLDL and chylomicrons rapidly. Redundant surface phospholipids shed from these delipidated particles, and apo AI released from chylomicrons, is transferred to HDL, increasing the potential for particle formation. Likewise, the limited time for exchange of core lipid in people with healthy metabolism leads to a maintenance of high apo AI and cholesterol levels in large HDL particles [32]. The converse is true in those with reduced lipolysis rate with the net result that small, dense HDL are formed from which apo AI is likely to desorp and be catabolize rapidly [3, 4, 32]. Metabolic studies have shown a strong inverse relationship between HDL size and apo AI clearance rates, and a positive association between apo AI clearance and plasma triglyceride [32]. It follows that the apo AI plasma concentration can be understood best in the light of the prevailing plasma triglyceride level. HDL heterogeneity. HDL is highly heterogenous, and so apo AI in plasma resides in a variety of lipoprotein subfractions. The most abundant are larger, spherical HDL2 and HDL3. ApoA2 is present in HDL3, and to a lesser extent in HDL2. Smaller forms such as pre-β HDL can be identified on two-dimensional gel electrophoresis. They are present at low concentration but are considered highly active. In subjects with efficient lipolysis of triglyceride-rich lipoproteins there is a low level of exchange of HDL cholesteryl ester with VLDL and chylomicrons, and so HDL remain cholesterol rich and relatively large. Individuals with effective cell efflux mechanisms will also theoretically have increased tendency to form large HDL particles. The opposite is true in hypertriglyceridaemics (with raised levels of VLDL and chylomicrons) where HDL levels are low. The major goal in the use of plasma apolipoprotein measurements is to identify more accurately those at elevated risk and initiate appropriate interventions. A further objective is to understand for those on treatment, particularly drug therapy, the utility of subsequent assessment of apo AI and apo B. Findings from statin-based primary prevention trials such as WOSCOPS and AFCAPS/TEXCAPS [37, 38], and studies that used fibrates such as VA-HIT [39], reveal that the change in LDL or HDL C on drug is a relatively poor, or only partial predictor, of outcome. Likewise, attained levels of these lipid levels are variably informative; for example, in the Pravastatin Pooling Project, LDL C on therapy was positively but weakly related to risk of a coronary event [40]. Apolipoproteins have been measured in a number of large-scale outcome studies. In some, the results are similar to those found for cholesterol in LDL and HDL (e.g. in PROSPER [41]), whereas in others such as AFACPS/TexCAPS, the apo B : apo AI ratio was a powerful predictor of future risk in statin-treated subjects. Indeed, this was the only variable that gave a consistent association with incident coronary events across both the actively treated and placebo groups [38]. In the light of this observation it is important that the usefulness of apo B/apo AI to predict risk in treated subjects be tested in other trials. Measurement of apo AI and apo B plasma levels provides additional information to that obtained by assessing LDL and HDL C. The protein concentrations are linked to particle numbers in these major lipoprotein classes and are a reflection of metabolic status, especially if used in conjunction with plasma triglyceride. The assays for apo AI and apo B are accurate, reliable and widely available. Inclusion of these parameters in the standard lipid profile, first to aid in risk prediction, and then in refinement of lipid-lowering treatment, would be a useful addition to current CHD prevention strategies. No conflict of interest was declared. The excellent secretarial assistance of Ms Shelley Wilkie in the preparation of this manuscript is gratefully acknowledged." @default.
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W2012407931 title "Measurement and meaning of apolipoprotein AI and apolipoprotein B plasma levels" @default.
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