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2012, 13(11), 15447-15463; https://doi.org/10.3390/ijms131115447
Dietary Docosahexaenoic Acid (22:6) Incorporates into Cardiolipin at the Expense of Linoleic Acid (18:2): Analysis and Potential Implications
Metabolic Research Centre (in IHMRI), School of Health Sciences, University of Wollongong, Wollongong, NSW 2522, Australia
Author to whom correspondence should be addressed.
Received: 18 October 2012; in revised form: 14 November 2012 / Accepted: 20 November 2012 / Published: 21 November 2012
Cardiolipin is a signature phospholipid of major functional significance in mitochondria. In heart mitochondria the fatty acid composition of cardiolipin is commonly viewed as highly regulated due to its high levels of linoleic acid (18:2n − 6) and the dominant presence of a 4×18:2 molecular species. However, analysis of data from a comprehensive compilation of studies reporting changes in fatty acid composition of cardiolipin in heart and liver mitochondria in response to dietary fat shows that, in heart the accrual of 18:2 into cardiolipin conforms strongly to its dietary availability at up to 20% of total dietary fatty acid and thereafter is regulated. In liver, no dietary conformer trend is apparent for 18:2 with regulated lower levels across the dietary range for 18:2. When 18:2 and docosahexaenoic acid (22:6n − 3) are present in the same diet, 22:6 is incorporated into cardiolipin of heart and liver at the expense of 18:2 when 22:6 is up to ~20% and 10% of total dietary fatty acid respectively. Changes in fatty acid composition in response to dietary fat are also compared for the two other main mitochondrial phospholipids, phosphatidylcholine and phosphatidylethanolamine, and the potential consequences of replacement of 18:2 with 22:6 in cardiolipin are discussed.
Keywords:phospholipids; fatty acids; mitochondria; peroxidation; apoptosis; cancer; tumor
1. Introduction
Cardiolipin (CL) is the only prevalent di-phospholipid present in mammalian membranes [1–4] and is primarily found in the inner leaflet of the inner mitochondrial membrane where it is synthesized [1]. As a consequence of its structure CL possesses four rather than the usual two fatty acids and may be viewed either as two phosphatidic acid molecules joined together by glycerol, or as a phosphatidic acid joined to a phosphatidylglycerol molecule, or even as two phosphatidylglycerol molecules sharing the same glycerol molecule. As CL is found almost exclusively in mitochondria it has been called the signature phospholipid of mitochondria [2]. CL has important roles in oxidative phosphorylation and in triggering mitochondrial-induced apoptosis [2,3,5]. These roles in turn are linked to CLs ability to bind mitochondrial proteins required for ATP production [4,6] and to peroxidise in interactions with cytochrome c [7].
Phospholipids vary extensively in their acyl composition containing a mixture of saturated (SFA), monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids [8], yet most phospholipids (>99%) in mammalian membranes avoid multiple PUFAs on the same phospholipid molecule [8,9]. This seems not to apply to CL that in cardiac mitochondria has a high PUFA content with a tetra-linoleic acid (4×18:2n − 6) molecular species being its most prevalent molecule. This tetra linoleic acid species of CL has been found to associate with the mitochondrial ADP/ATP carrier more close than a tetra-palmitoyl (4×16:0) species [10] and to have a higher affinity for cytochrome c in comparison to CL molecules with high levels of oleic (18:1), stearic (18:0) and palmitic acid (16:0) respectively [11]. High levels of the 4×18:2 species of CL in cardiac mitochondria and high levels of 18:2 generally are described in mitochondria isolated from other mammalian tissues. For example, Schlame et al. [12] reported that 4×18:2 CL comprises 80% of all CL in human heart, 70%–77% in dog heart, 41%–77% in rat heart and 50% in cow heart, while Han et al. [13] reported that this same species of CL comprises 42% of CL in rat heart and 52% in rat liver. Other groups have reported the 18:2 content of CL in liver and brain as lower than 60%, meaning that the 4×18:2 molecular form of CL may not be as common in some of these tissues [14–16].
Although high 18:2 content is seemingly preferred in CLs interactions with proteins [10], this high PUFA content coupled with CLs potential exposure to free radical oxygen species (ROS) produced in the mitochondria put this phospholipid at high risk of oxidative damage [2]. Peroxidation at bis-allylic carbons (i.e., –CH=CH-CH2-CH=CH–) present in PUFAs is the primary form of oxidative damage that occurs in phospholipids. The reason for this is that hydrogen atoms bound to bis-allylic carbons have weaker bond energies due to the presence of the surrounding double bonds, making them more prone to abstraction by free radicals [17]. Therefore, the more bis-allylic carbons, the higher the number of weaker bound hydrogen atoms the more peroxidisable the fatty acid [18]. Although 18:2 is the least unsaturated of the PUFAs, the fact that there are up to four of these fatty acids packed together on the same molecule makes CL highly likely to peroxidise in comparison to other mitochondrial phospholipid classes. Peroxidation of CLs PUFAs is likely to decrease its affinity for protein binding, disrupt the structure of the inner mitochondrial membrane and produce a number of cytotoxic products, with CL peroxidation identified as an early event in the apoptotic cascade [11,19–22]. Therefore, changes in CLs PUFA content could be expected to affect both its interaction with proteins and susceptibility to peroxidation, modifying its function in mitochondria. Such changes are thought to be unusual as one of the widely held beliefs about mammalian CL fatty acid composition is that it is highly regulated, primarily due to its high levels of 18:2 and the prevalence of a 4×18:2 molecular species in cardiac mitochondria and an apparent resistant to dietary manipulation [12]. Here we review the evidence that, contrary to popular belief, CLs PUFA composition is amenable to change dependent upon the fat composition of the diet, particularly the presence of docosahexaenoic acid (22:6n − 3) that will readily replace 18:2 when present in the diet at up to 20% of total fatty acid.
2. Cardiolipin Response to Dietary Fat Composition
2.1. Dietary Trials Investigating Cardiolipin in Animal Models
It has been known for some time that dietary fats affect phospholipid composition [23] and CL seems to be no exception. The fatty acid composition of CL has been reported in numerous studies examining the effects of various dietary fatty acids on the phospholipid composition of heart and liver mitochondria. Most (~75%) of these studies have used rats [15,16,23–38] and most others, mice [39–43]. These studies supply the raw data used in the present study for an analysis of the 18:1, 18:2 and 22:6 content of CL in heart and liver against changes in dietary fat.
The primary focus of many of these studies has been PUFA, that cannot be produced in mammals unlike SFA and MUFA that can be formed de novo from basic carbon sources [44]. The sources of dietary SFA, MUFA and PUFA used in these studies have been in the form of oils commonly eaten by humans including fish, linseed, corn, olive, rapeseed and soybean, although one study used crocodile oil [41] (see Table 1). The majority of the studies predate the use of mass spectrometry, instead using combinations of thin layer chromatography or high-pressure liquid chromatography together with gas chromatography. One limitation of these techniques (versus a lipidomics approach) is that they cannot readily determine the abundance of specific phospholipid molecular species within each phospholipid class. However, these studies do provide the total fatty acid composition of the various CL molecular species.
2.2. Regulator-Conformer Paradigm
In order to better understand the relationship between CL composition and the fatty acid composition of the diet we analysed all available data in accordance with the conformer-regulator paradigm (often used in comparative physiology), plotting the level of a fatty acid in the diet (i.e., 18:1, 18:2, 22:6) against its level or that of another fatty acid (e.g., 22:6) in CL. If the fatty acid composition of CL conformed perfectly to its dietary composition (i.e., is a conformer) a slope of 1 is produced (when the proportion of a fatty acid in the diet is plotted against its level in CL) but if fatty acid composition is perfectly regulated (i.e., not influenced by diet) the slope is zero [46]. In this model, slopes not significantly different from zero would indicate regulation whereas those significantly greater than zero but below 1 would indicate weak to strong dietary conformity, and slopes of 1 or more would indicate very strong, active dietary conformity. Previous work using this model has shown that total SFA, MUFA and PUFA content are likely to show a regulator pattern, but within PUFAs, the omega-6 (n-6) and omega-3 (n-3) fats such as 18:2 and 22:6 respectively, tend to show varying levels of dietary conformity, particularly at low dietary levels where presumably their essential dietary nature is displayed [47,48].
As the primary aim of this study was to examine CL remodeling in relationship to dietary fat consumption in healthy animals, a small number of exclusion criteria needed to be applied: 18:2 is the most readily consumed PUFA in the human diet (~42% of fatty acids consumed [49]) and an essential fatty acid in mammals. Therefore our analysis excluded any diets containing less than 2% of 18:2 as a proportion of total dietary fatty acid. Based on the work of Owen et al.[50], in order to allow adequate time for phospholipid remodeling to occur, any dietary interventions of two weeks or less were excluded. Where dietary levels of eicosapentaenoic acid (20:5n − 3 or EPA) were greater than 10%, or in the case comparing 18:2 versus 22:6 in the same diet (Figure 2) where 20:5 levels exceeded those of 22:6, these diets were excluded due to the confounding effect of 20:5 conversion through to 22:6. In the entire analysis the only study excluded as a gross outlier was that of Berger et al., 1992 [42] whereas all other studies, including another Berger [40] study were included. Although many studies reported SFA in low levels in CL, presumably due to the presence of immature CL (see discussion in section 3), SFA content was not examined, as not all studies reported SFA's shorter than 18:0. In the case of the omega-3 fatty acid linolenic acid (18:3), although it is consumed at moderate levels in the diet [49], little if any appears in most phospholipids [8] including CL [12], presumably due to its conversion through to longer chained omega-3 fats. The omega-6 fatty acid arachidonic acid (20:4) was not included in the present analysis but has been reported in CL at levels ranging from 0–12% [23,26,40]. Where different feeding periods were used in the same study the period closest to four months was chosen since it represented an average common feeding period across the studies. Diets with unspecified 22:6 from maternal sources or high proportions of trans-fats where excluded from the analysis.
Line fit and slopes in all figures were determined using segmental linear regression with an unconstrained line intercept available in GraphPad Prism® Version 6 (Graphpad Software: La Jolla, CA, USA, 2012). All statistical analyses were performed using the same software package and slope values are reported as slope ±95% confidence interval.
2.3. Unsaturated Fatty Acid Composition of Cardiac Cardiolipin Against Dietary Levels
Oleic (18:1), linoleic (18:2), and docosahexaenoic (22:6) acids are the three most commonly reported unsaturated fatty acids present in CL [15,16,24,26–30,32,33,39–41,43,45]. Figure 1 shows the percentage of 18:1 and 18:2 in CL against their percentage in the diet in heart and liver. The incorporation of 18:2 into cardiac CL shows a distinctive biphasic pattern with a rapid rise in CL 18:2 levels from 2%–20% of dietary fat indicating a conformer pattern as indicated by a slope of 1.17 ± 1.10 (p = 0.038). At these lower levels of dietary 18:2 intake, CL seems to be actively accruing 18:2 into its structure, as would be predicted from the high 18:2 content generally reported for CL. At dietary levels where 18:2 is above 20% (range 21%–68%) of dietary fat, the incorporation of this fatty acid reduces to a regulated pattern with a slope of 0.036 ± 0.524, leveling off with ~70% of CL fatty acid being 18:2 (or ~65% when rat and mouse values are combined), supporting the common belief that 18:2 levels in CL is largely a regulated phenomenon. In the case of 18:1, no significant trend was apparent with a slope of 0.036 ± 0.094 (p = 0.886) across a wide dietary range (0–78%), indicating a regulated pattern with 18:1 comprising around ~10% of cardiac CL fatty acid content.
Analysis of 22:6 levels in heart CL (Figure 2) shows that when 22:6 is absent in the diet a small amount of 22:6 (2%–8%) is still present in CL, demonstrating conversion such as that of 18:3 by the liver (the primary 22:6 synthesizing organ in mammals [53]) and its incorporation into heart CL. When 22:6 is present in the diet at levels of up to 20% of total fatty acid it is readily incorporated into CL, indicating a strong active conformer pattern (as found for 18:2) with a slope of 1.43 ± 0.58 (p < 0.0001). Although 22:6 was examined over a more attenuated range (0–37%) than 18:2, once the dietary levels of 22:6 were >20% of total dietary fatty acid, the pattern is suggestive of a regulated level as indicated by the plateauing of 22:6 levels at ~20% of fatty acid CL content. Therefore 18:2 and 22:6 seem to be readily incorporated into heart CL when their levels in the diet are up to 20% of total dietary fatty acid, indicating a strong active conformer pattern, but at higher dietary levels a regulated pattern is suggested, whereas 18:1 shows a regulated pattern throughout a wide range of dietary availability.
2.4. Unsaturated Fatty Acid Composition of Hepatic Cardiolipin against Dietary Levels
Fewer studies have examined CL acyl remodeling in liver compared to heart, but what is available [24,31,33,40,41] is shown in Figure 1 for 18:1 and 18:2 and in Figure 2 for 22:6 (both figures use combined species data). In general, the level of 18:1 in liver is higher (at ~20%), and 18:2 and 22:6 levels are lower than those in heart. Presumably 18:1 is acting as an alternative for some of the 18:2 and 22:6 fatty acids in liver, with some studies reporting 18:1 levels as high as 55% in liver CL [24,31,35]. There was no clear trend for 18:1 incorporation into liver CL other than towards a very mild, but not significant accrual (with a slope of 0.237 ± 0.266; p = 0.076) throughout the dietary range examined (2%–70%) with overall 18:1 levels seemingly regulated. Similarly, 18:2 showed little indication of any strong trend to incorporate into liver CL at either low or high dietary 18:2 intakes (Figure 1) with a slope of 0.164 ± 0.352; (p = 0.33) across a broad dietary range, again indicating an essentially regulated phenomenon. Although there is little data for 22:6 in liver CL (Figure 2), what is available suggests a conformer pattern when 22:6 levels are below 10% of total dietary fatty acid with a slope of 1.04 ± 0.85 (p = 0.02).
2.5. The Effect of Dietary 22:6 on the Incorporation of 18:2 into Heart and Liver CL
Heart CL clearly accrues both 18:2 and 22:6, and liver CL accrues 22:6 at low dietary levels, but how do dietary levels of 22:6 influence levels of 18:2 in CL? Here we examine all studies that incorporated both 22:6 and 18:2 into the same diet and measured heart [15,23,28,33,37,39,41,43,45] and liver [15,31,33,41,42] CL fatty acid composition. The results of this analysis are shown in Figure 2. When 22:6 was between 0–20% of dietary fat, the 18:2 content of CL ranged from 1%–58% with an average of 21% and no statistical relationship found between the dietary levels of these two fatty acids. For example, in heart when 22:6 was at its highest level in the diet (37%) the level of 18:2 was also one of the highest of any of the diets (56%) indicating that changes in 18:2 levels in CL are not simply due to 22:6 displacing 18:2 in the diet.
Owing to the more limited number of studies available that included both 22:6 and 18:2 in the same diet, the analysis includes data for both rat and mouse tissues. Figure 2 clearly shows the deposing influence of 22:6 on 18:2 levels in cardiac CL at 22:6 levels of up to 20% of total dietary fatty acid. At dietary levels where 22:6 is less than 20% of total fatty acids, 22:6 incorporates into cardiac CL (slope 1.43 ± 0.58; p = 0.0001) whilst at the same time in the same cardiac tissue the levels of 18:2 in CL decreases (slope −2.14 ± 1.24; p = 0.002). At higher 22:6 levels (above 20% of fatty acids), 18:2 appears to plateau at just under 40% of total fatty acids in heart CL which is below its "normal level" of ~70% (as shown in Figure 1), whereas 22:6 plateaus at just above ~20% of total fatty acid making up most of the difference (Figure 2). Although somewhat less convincing, due to the smaller amount of data available, liver CL also appears to accrue 22:6 at the expense of 18:2 (slope 1.041 ± 0.846; p = 0.022), when it is available at low levels in the diet (Figure 2). Furthermore, although based on a single study [33], the current evidence suggests that liver CL does not accrue more 22:6 once its levels are above 10% of total fatty acid in the diet. At this point 18:2 plateaus at slightly over ~20% of CL fatty acid content, down on the normal ~30%–60% (see Figure 1), with 22:6 at ~13% of CL fatty acid making up a large proportion of the difference. Therefore CL in heart and liver maintain 18:2 levels at ~70% and 50% respectively, and in the case of heart will readily accrue 18:2 from the diet when this fatty acid is at lower levels (<20%). However, when 22:6 is available in the diet it is incorporated at the expense of 18:2 until 22:6 makes up ~20% of CL fatty acid content in heart and ~13% in liver, after which both 18:2 and 22:6 levels seem to remain relatively constant i.e., regulated.
2.6. A Comparison of 22:6 Incorporation into Mitochondrial Phospholipids
Although functionally important, CL is not the major phospholipid class in mitochondria, comprising ~15% of mitochondrial phospholipids. The two major mammalian mitochondrial (and cell) phospholipids are phosphatidylcholine (PC) and phosphatidylethanolamine (PE), which makeup ~45% and ~35% of total mitochondrial phospholipid respectively [54]. Since some of the studies [11,21,22,25,26,28,29,31,32,34–41,48] examined here included data for these two major phospholipids we have included a brief analysis of 18:1, 18:2 and 22:6 incorporation into these two major phospholipids in heart and liver mitochondria. This analysis is also useful as most studies report tissue responses rather than mitochondrial responses to variations in dietary fat. The results of this analysis are shown in Figures 3.
The incorporation of 18:1 and 18:2 into PC and 18:1 into PE of cardiac mitochondria, as shown in Figure 3, indicates that there are no significant trends in the incorporation of these fatty acids into these two phospholipids across a broad range of dietary supplementation (2%–78%), indicating a regulated pattern in heart. The incorporation of 18:2 into cardiac PE shows a weak but significant conformer trend with increasing levels across the same dietary range with a slope of 0.056 ± 0.051 (p = 0.034). In contrast, 22:6 in both PC and PE in heart mitochondria display a strong conformer trend with slopes of 0.93 ± 0.45 (p = 0.0003) for PC and 0.89 ± 0.58 (p = 0.005) for PE when 22:6 levels were up to 38% of dietary fatty acid.
In liver mitochondria the same pattern is present, namely the incorporation of 18:1, 18:2 into PC and 18:1 into PE showing no significant trends in their incorporation into these two phospholipids across a broad dietary range. Liver mitochondrial PE shows a weak conformer uptake for 18:2 (slope 0.045 ± 0.038; p = 0.024) but both liver PC and PE both show a strong dietary conformer pattern for 22:6 uptake with slopes of 0.95 ± 0.32 (p < 0.0001) for PC and 1.33 ± 0.79 (p = 0.0025) for PE across a dietary range of 22:6 of up to 20%.
Therefore the general pattern in liver and heart PC and PE was for 18:1 to be regulated in both classes of both tissues, for 18:2 to be regulated in PC heart and liver but a mild conformer effect in PE, and for 22:6 to be a strong conformer to dietary levels in both classes and tissues. As mitochondria membranes represent a significant portion of cell phospholipids and CL, PC and PE are the most common mitochondrial phospholipids, increases in their 22:6 content presumably accounts for a portion of the well-known [50] dietary induced increase in 22:6 levels in total membrane phospholipids.
3. Consequences of Cardiolipin Composition
The present analysis of a comprehensive compilation of studies reporting changes in CL fatty acid composition in response to dietary fats shows that the accrual of 18:2 into cardiac CL occurs readily. The analysis indicates a strong conformer pattern when dietary levels of 18:2 are between 2%–20% of total dietary fatty acid, with higher dietary availability of 18:2 showing regulated levels. In liver, no trend was evident for 18:2 incorporation into CL across a broad range of dietary 18:2 intakes, indicating a regulated level of 18:2 into CL of liver mitochondria. When 22:6 and 18:2 are present in the same diet, and 22:6 is between 0–20% of total dietary fatty acids, the data indicates that CL preferentially incorporates 22:6 into its structure at the expense of 18:2. This preferred incorporation of 22:6 over 18:2 seems to be present in both heart and liver. This ability of 22:6 to displace 18:2 has previously been noted in phospholipids of heart. For example, in a dose response study of dietary 22:6 (0–32%) examining myocardial phospholipids, Owen et al.[50] found that 22:6 replaced 18:2, and to a lesser extent 18:1. Other studies comparing diets low and high in 22:6 have noted similar trends in cardiac phospholipids [39,41] and CL specifically [15,24,34,41].
The present analysis found that not only will 22:6 replace 18:2 in CL, but also that this replacement will occur only at dietray 22:6 levels of up to ~10% and 20% in liver and heart respectively and against high dietary background levels of 18:2 (of up to 56%). The strength and veracity of these relationships is highlighted when considered against the highly varied dietary backgrounds used in the studies that produced the results. Exclusions were limited to only diets deficient in 18:2, took place for no longer than two weeks or had high 20:5 backgrounds when examining 22:6. Based on our analysis, we have shown that CL is a molecule with a preference for 18:2 but an even greater fondness for 22:6 (when 22:6 is available in the diet at up to 10% or 20% of total fatty acid for liver and heart respectively). Dependent upon its availability in the diet, cardiac CL will accrue 22:6 up to a maximum of approximately 20% and liver CL up to 13% of its total fatty acid content.
The selectivity of 22:6 over 18:2 in CL and the preferential incorporation of these two fatty acids over others is likely due to the complex nature of CL synthesis and remodeling. CL is synthesized from the condensation of a PG molecule with cytidine diphosphate diacylglycerol resulting in what is commonly referred to as immature CL that has a mixed acyl content and is then remodeled to produce mature CL [2]. The selected incorporation of fatty acids during remodeling was recently investigated by Kiebish et al.[55], who reported that only 1-5% of the fatty acids incorporated into CL during the remodeling process come from PC and PE, with this process having low acyl selectivity [55]. By far the majority of fatty acids are drawn from the pool of acyl CoA fatty acids and this incorporation is highly selective [55]. Interestingly, heart acyltransferases were reported to have 1.3 times the specificity for 22:6 over 18:2, which in turn had specificity many times higher than that of any other fatty acid. In contrast, liver acyltransferases had a far higher specificity for 18:2 over 22:6 or any other fatty acid [55]. The specificities of these acyltransferases, and tissue differences are likely to explain the underlying mechanism by which 22:6 replaces 18:2 in heart CL but does not explain the response in liver. This remodeling of CL is similar to that of PC and PE in that all three classes are dependent upon the activity and specificities of various acyltransferases [56].
Based on the roles CL performs in the mitochondria, the functional consequences of accruing 22:6 into the structure of CL are likely to be significant. Three studies have examined the effect of 22:6 incorporation into CL on mitochondrial oxidative phosphorylation. These studies reported either no change [39] or a decrease in activity [15,38]. More recent work in this area has shown a similar trend of dietary 22:6 either decreasing or not affecting mitochondrial respiration [57,58]. It is possible that 22:6 in CL might increase inner mitochondrial membrane fluidity and permeability to protons, decreasing the efficiency of oxidative phosphorylation suggesting that 18:2 is a preferred fatty acid for CL-protein interactions [10]. The incorporation of 22:6 over 18:2 into CL will increase its susceptibility to oxidative damage (peroxidation), which is an important mechanism in both cell health and diseases [59–61]. The peroxidisability of 22:6 is about 5 times that of 18:2 [62]. So the incorporation of 22:6 at the expense of 18:2 at up to ~20% of CLs acyl content will more than double CLs likelihood of undergoing oxidative damage. CL has been shown to be more susceptible to peroxidation than other phospholipid classes both in vitro[63] and in vivo[20] due to its high level of 18:2 and proximity to ROS production and the presence of 22:6 will accentuate this susceptibility. The remodeling of CL with increased 22:6 via the presence of a lyso CL acyltransferease (ALCAT1) has also been implicated in pathological remodeling reminiscent of type-2-diabetes, although numerous other changes were also associated due to the presence of this particular acyltransferase [64].
The natural peroxidation of CL is likely coupled to its binding to the haem-containing cytochrome c[7,65,66] and may be related to the transfer of CL from the inner to the outer mitochondrial membrane during apoptosis [67]. Cardiolipin peroxidation is thought to be an early event in mitochondrial-induced apoptosis related to cytochrome c release, production of cytotoxic products and disruption of the inner and outer mitochondrial membranes [11,19,20]. Therefore, the replacement of 18:2 by 22:6 would be expected to increase mitochondrial susceptibility to oxidative damage and apoptosis [68]. In addition, the products formed during peroxidation of omega-3 PUFA such as 22:6 are proposed to be more reactive, and potentially disruptive, than those produced from omega-6 PUFA such as 18:2 [69]. However, the fact that CL accrues 22:6 in place of 18:2 increasing its peroxidative potential clearly indicates that under normal dietary circumstances this is not a problem as peroxidation of mitochondrial phospholipids would seem to offer a selective property if it was disadvantageous. The increased presence of 22:6 in the cardiac and skeletal muscle membrane has been linked with improved oxygen efficiency of muscular contractions and fatigue resistance [70]. Yet these changes are likely underpinned by interactions occurring between phospholipids and proteins at the molecular level within the membrane. This is where the acyl composition of phospholipids can influence membrane proteins by changing factors such as; membrane fluidity, intramembrane pressure gradients and dipole potentials [71]. The accrual of 22:6 into phospholipids in a conformer fashion probably reflects the essential dietary nature of omega-3 generally and the readiness of tissues to use the preformed fatty acid if available. Yet the precise benefits are again likely to be found in fundamental properties that we do not fully understand and are particular to different membranes operating in a variety of different tissues.
One highly speculative area where changes in CL acyl composition might be of some potential therapeutic benefit is in the case of breast cancer treatment. The presence of 22:6 in the diet appears to sensitize this tissue to apoptosis when given alone or alongside conventional cancer treatments [72–75]. The incorporation of 22:6 into the phospholipids of mammary tumors in rats seems to occur readily and shows a conformer pattern (comparing plasma to tumor phospholipid 22:6 levels [76]) similar to cardiac CL at low 22:6 levels. This ready incorporation of 22:6 into tumor phospholipids is likely due to tumor growth, and where examined, CL seems as effective at incorporating 22:6 compared to other phospholipids [68]. The composition of CL in normal tumor tissue compared to parent tissue often shows a profile that is abnormally elevated in SFA consistent with immature CL before 18:2 remodeling [77,78]. Interestingly, lymphocytes with CL containing more saturated fatty acids (16:0) have also been found to proliferate more rapidly [79]. The high SFA in CL is likely related to common disturbances in cancer mitochondria that see's these cells utilize aerobic glycolysis in a phenomenon commonly referred to as the Warburg effect [80]. Cancer cells also show a decreased sensitivity to apoptosis [81] and based on the potential importance of CL peroxidation in apoptosis, it has been suggested that the low PUFA content of cancer cells inhibits the peroxidation-related mechanism of apoptosis [22]. Tentatively, it might suggested that diets that facilitate 22:6 incorporation into CL (and other phospholipids) of cancer cell mitochondria might make these tumors more susceptible to apoptosis and radiation targeted tissue destruction.
4. Conclusions
The best-known CL molecular species is the tetra-linoleic (4×18:2) species that dominates in mammalian heart mitochondria. Familiarity with this molecule, the high level of 18:2 associated with CL and the results of a few early dietary studies produced a view that the acyl composition of CL is largely regulated and less amenable to change based on variation in dietary fat composition compared to other phospholipids [12]. However, our analysis of data from many different studies indicates that CL is amenable to change in dietary fat composition and that 18:2 accrual into cardiac CL occurs primarily at up to 20% of dietary fatty acid and thereafter levels are regulated at ~70% of CL fatty acid content. Whereas in liver there is no indication of accrual at lower 18:2 dietary levels and overall levels of 18:2 in liver CL are lower. The analysis clearly indicates that when 18:2 and 22:6 are present in the diet together, that the biochemistry of the cell favors the incorporation of 22:6 over 18:2 when 22:6 is present in the diet at levels of up to 20% in heart and also possibly in liver mitochondria (at up to 10%). The incorporation of 22:6 into mitochondrial CL, PC and PE most likely accounts for a large portion of the well-known capacity of the diet to increase the 22:6 content in total cellular membrane phospholipids. Finally, based on the importance of CL in cellular respiration and in mitochondrial-mediated apoptosis, the replacement of 18:2 with the more peroxidisable 22:6 may result in changes in the properties of CL and therefore mitochondria.
We declare that there are no conflicts of interest associated with this manuscript. We would like to thank Tony Hulbert for reading an earlier version of the manuscript and providing useful feed-back that resulted in us rewriting the whole manuscript - Thanks Tony. This paper was supported by a major grant from the Illawarra Health and Medical Research Institute (IHMRI) and was written as part of the PhD dissertation of Colin Cortie.
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Figure 1. The relative content of 18:1 and 18:2 of cardiolipin in heart and liver against their dietary levels. Values for heart are for rat (●) and those for liver are for rat and mice (○). For heart, a biphasic pattern of incorporation of 18:2 into CL was apparent (also present with mice values added) with a rapid initial conformer uptake between 2%–20% of dietary 18:2 and thereafter a relatively constant, regulated level. No biphasic trend was apparent for 18:1 in heart or 18:1 and 18:2 in liver. Data for heart came from the following studies [15,16,23,24,26–29,33,35–38,45,51] and that for liver from [15,24,33,35,40,41,52]. Diets with greater than 3% 22:6 or greater than 10% EPA were excluded from the analysis due to effects on 18:2 (see Figure 2) and conversion of 20:5 through to 22:6.
Figure 2. The relationship between the dietary availability of 22:6 and 18:2 and cardiolipin content of the same fatty acids in heart and liver of rat (●) and mice (○). Data for both organs indicate a biphasic relationship with CL 22:6 content increasing, and 18:2 content decreasing at dietary 22:6 levels between 0–20% and thereafter stabilizing. Data used included: control diet [36], sunflower oil and tuna oil [23], diet 1 and 4 [39], 4 month time point [45], high 18-3 diet, long chain n-3 diet [43], control, high 22:6 [33], soy oil and crocodile oil [41], sardine oil, corn oil [15], 18:2 and long chain n-3 [28].
Figure 3. The relative content of 18:1, 18:2 and 22:6 in phosphatidylcholine (PC) and phosphatidylethanolamine (PE) of heart and liver mitochondria against their respective level in the diet. Each figure includes both rat (●) and mouse (○) data. The incorporation of 18:2 into PE of both heart and liver show slight dietary conformity whereas 22:6 in both PC and PE of both heart and liver demonstrate strong dietary conformity throughout the dietary range examined. All other fatty acids in PC and PE of liver and heart demonstrated a relatively regulated content across the broad dietary range of fatty acids examined. Data used for heart PC was from [15,23,24,27,28,30,33,34,36–41,43], for heart PE from [24,25,39,40], for liver PC from [15,24,26,31,33,40,41] and for liver PE from [15,24,26,31,33,40,41]. Data excluded from the analysis included diets that contained higher 20:5 than 22:6.
Table 1. Details of species, sources of fat, measurement method and feeding period of studies examined.
|Source of fat
|Measurement method
|Dietary fat (w/w)
|Feeding period (weeks)
|Yamaoka et al., 1988 [15]
|Corn oil, sardine oil
|McGee et al., 1996 [16]
|Not stated
|Charnock et al., 1986 [23]
|Sunflower oil, tuna, vegetable oil
|4% or 16%
|Astorg et al., 1991 [24]
|Sunflower seed oil, linseed oil
|Ikeda et al., 1996 [26]
|Safflower oil, perilla oil, palm oil, ethyl 20:4
|Innis and Clandinin, 1981 [27]
|Soya-bean, rapeseed
|Jahouvey et al., 1990 [28]
|Palm oil, olive oil, sunflower oil, linseed oil, menhaden oil
|Kramer, 1980 [29]
|Corn oil, zephyr oil
|Novak et al., 2006 [30]
|Standard chow diet
|Power et al., 1994 [31]
|Coconut oil, olive oil, safflower oil, menhaden oil
|2% or 20%
|Taniguchi et al., 1993 [33]
|20:5 and 22:6 methylesters
|Yamaoka et al., 1990 [34]
|Corn oil, sardine oil
|Hoy and Holmer, 1990 [35]
|Marine oil, olive oil, sunflower seed oil
|Charnock et al., 1984 [36]
|Sunflower seed oil, sheep kidney fat
|4%, 12%
|Charnock et al., 1991 [37]
|Sunflower, fish oil
|Robblee and Clandinin, 1984 [38]
|Beef tallow, soybean oil
|7%, 7.5%, 21% or 23%
|Lee et al., 2006 [45]
|Soybean oil, fish meal, soybean meal, alfalfa meal, corn meal
|Croset and Kinsella, 1989 [39]
|Ethyl esters of 18:2, 22:6
|Berger and German, 1990 [40]
|Safflower oil, free fatty acids of 18:2, 20:5
|Watkins et al., 2001 [41]
|Crocodile oil, soybean oil
|Hussein et al., 2009 [43]
|Coconut oil, safflower oil, flaxseed oil
TLC: thin layer chromatography; GC: gas chromatography; HPLC: high pressure liquid chromatography; MS: mass spectrometry.
© 2012 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).


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Shenanigan - Milkyway EP
Swedish artist Shenanigan, has us very excited at Maharetta hq. His unique and elegant style demonstrates his clear understanding and appreciation for all elements of the modern psychedelic spectrum.
Presented In two tracks, Marco articulates his diverse ability to shape shift between both light and dark styles.

subset: commoncrawl


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Mixed Media Artwork
Contact Doria for info or purchase.
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SALISBURY, Md. – The Salisbury University volleyball team will be hosting its "Dig Pink" match on Saturday, October 26 when it hosts Frostburg State University, with the match set to begin at 12 p.m.
The Sea Gulls will be working with the Side-Out Foundation to help raise money for the promotion of breast cancer awareness and education. The Side-Out Foundation has been committed to the unification of volleyball and its alliance with the breast cancer movement, while being involved with middle and high school, club and professional volleyball players and coaches.
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My brother, Marky, agreed to drive me to college. I travelled light and only had one box of stuff in the back of his car. During the journey, we chatted and caught up with what I'd been up to in America. When we arrived in Oxford hours later, he parked and I asked directions to the accommodation office. There was a big queue of students so we got in line for the keys to my room, which took about an hour. When the paperwork was complete, there was yet another queue for directions to the various halls of residence. Marky was neither student-friendly nor the most patient person in the world. As we joined the back of another queue, he wasn't happy.
"Fuck this" he snapped and, in his indomitable way, barged past the passive students. He got to the front desk, grabbed a folded map of Oxford and walked out of the accommodation office. I followed his lead, smiling. We probably made it to Heyford Hill House before we'd have got to the front of that queue. I unloaded my stuff and we said our goodbyes. He wasn't fucking about. In less than a minute, he was off, the long drive North ahead.
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I have encouraged staff (unsucessfully in most cases) to share their stories of what they do and why they do it. And I thought you might be interested in mine.
I arrived in work at 8am and had a bleep from Avon 1. A patient was poorly, his relatives were anxious, he was in a side room and had requested communion. I spent 30 minutes or so with this lovely man and agreed to take him communion in the afternoon.
Just as I was leaving the bleep went for another ward. A staff members mother had deteriorated. I had met them the day before. She was a wonderful lady of 95 and she made me laugh as she told me what's what. I shared some support with her family and then went on my way.
A volunteer came in to see me to talk about whether she could give some time to the hospital, and whilst she was here, I met some people in the most tragic of circumstances. One by one the family members came to see me and there was a huge amount of tears shed. I can't say what the circumstances are for fear of breaching confidentiality. Let me just say that none of us would want to swap places with them.
And then, just as I was catching my breath, a bleep came. The lady I had seen earlier had passed away peacefully. I went to give some support and prayers as they requested. Again the grief was palpable and tears flowed.
In between, I did some mundane stuff, had numerous laughs and jokes, teased some people; was teased by others. I fired off some emails, published some good stuff on the blog about Avon 1. And went home knackered.
It might not seem much. I didn't save anyone's life. I was just there at some extreme times in peoples lives.
Why do I do it? Well, it's what I do. And I hope it brings some humanity and comfort to those I meet.
Is it important? I don't know, but it can be to those individuals.
Is it easy? Not really. It's hard to be in the presence of such raw human emotion and for it not to stick to you.
It was a busy day, but not unusual.
And now you know. Keep reading the blog and passing it on to your friends. David


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Metroshuttles are free buses linking the main rail stations, car parks, shopping areas and businesses.
Metroshuttle services operate in Manchester city centre, Bolton and Stockport.
Click here to see Metroshuttle routes.
Piccadilly Station – Portland Street – Charlotte Street (Chinatown) – Cross Street – St Mary's Gate - Deansgate – (Spinningfields, peak times only) – Deansgate (John Rylands Library peak times only) – John Dalton Street – Cross Street – King Street – New York Street (Chinatown) – Chorlton Street (Central Coach Station) – Piccadilly Station


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Low-Fat Apple Spice Walnut Muffins
It's Fall! The summer humidity has been whisked away on a crisp autumn breeze. Temperatures have plummeted. The days are getting shorter. The leaves are tinted with reds, oranges and yellows.
Ahhh, Fall. My favorite season. Half of what I love about Fall are the changes taking place outside, but the other half is the food. Apples, pumpkins, soups and chilis, cranberries, cinnamon, and a great excuse to eat all the comfort foods I love.
As the weather turned cooler last week, I was craving something warm and cozy with apples in it. I immediately thought of the hearty and comforting Low-Fat Oatmeal Blueberry Applesauce Muffins I made in the Spring. I thought the whole grains, oatmeal and cinnamon would be a perfect compliment to Fall's first apples. I made a few more changes and additions, and in no time I had warm, delicious, perfectly Fall-ish low-fat apple spice walnut muffins.
Like their inspiration, these muffins have a hearty texture. No light fluff here. They're moist and bursting with apple flavor. To make them a little more decadent, I topped them with a maple glaze. What? I said they were low-fat, not low-calorie!
Low-Fat Apple Spice Walnut Muffins
Inspired by Joy the Baker
Makes about 12 muffins
Any oats will work, but use old fashioned or steel cut oats for a heartier texture. Depending on how sweet your apple butter is, you may need to adjust the amount of sugar in the recipe. My apple butter had no added sugar, so it wasn't overly sweet. For an even lower-fat and healthier muffin, you can omit the walnuts and the maple glaze. Either way, they're a delicious taste of Fall.
Ingredients for the Muffins
1 ¼ cups whole wheat flour
1 ¼ cups oats
1 tsp baking powder
½ tsp baking soda
¼ tsp salt
½ tsp cinnamon
3/4 cup unsweetened applesauce
1/4 cup apple butter
½ cup low-fat or non-fat buttermilk
scant (a little less than) ½ cup firmly packed brown sugar
2 tbsp canola oil
1 large egg, lightly beaten
1/4 cup chopped walnuts
1 medium apple, peeled and diced (I used Fuji because they're my favorite)
Ingredients for the Maple Glaze
2-3 tablespoons of maple syrup
1/3 cup of powdered sugar
1/4 tsp of vanilla extract
Preheat oven to 375°F.
Line a 12 cup muffin tin with paper liners or spray with nonstick cooking spray. If you plan on eating them straight out of the oven, give the liners a spritz of cooking spray so the muffins won't stick.
Whisk together flour, oats, baking powder, baking soda, salt and cinnamon in a large bowl. Combine applesauce, apple butter, buttermilk, sugar, oil and the egg in a medium bowl. Make a well in dry ingredients and add applesauce mixture, stirring until just moist. (Don't over mix them! The batter will be thicker than your average muffin batter.) Carefully fold in diced apple and walnuts.
Divide evenly among 12 muffin cups. Bake at 375°F for 16-18 minutes, or until a toothpick comes out clean. Cool on a wire rack.
Combine the maple syrup, sugar, and vanilla in a small bowl until thick but pourable. Drizzle on cool muffins and allow to harden at room temperature.
October 1, 2009 6:17 pm
These look incredible and I love how healthy they are!
October 2, 2009 12:45 am
YUM! the picture looks amazing, and the recipe sounds even better. look forward to giving these a try. :)
Comments are closed.


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National Tree Day is this weekend!
Date: 30-Jun-17
Author: Debbie Agnew
The 22nd National Tree Day is this weekend!
In the lead up please join us in celebrating Australia's breathtaking natural environment with award-winning photographer and National Tree Day Ambassador, Steve Parish as he presents his 50-year love affair with trees in a stunning online photo collection, It's In Our Nature.
This online exhibition takes you on a journey across our great country, from the heart of our Red Centre, to our lush rainforests. Steve captures the beauty, diversity and true nature of Australia and its people. His photography instills a sense of awe, beauty, hope and reverence for our natural environment. Steve's striking imagery and narrative reflect the power and potential of nature to inspire us and is a tribute to the living giving force within each and everyone of us. It teaches us that connecting with nature helps grow qualities like creativity, collaboration, resilience, vitality and empathy - qualities we all strive for! These findings have been the subject of Planet Ark and Toyota's research over the past couple of years.
Toyota is celebrating their 18th year as the Major Sponsor of Planet Ark's National Tree Day. We'd like to thank Toyota for making National Tree Day possible. Toyota mobilises its entire business network of dealers, staff and brand ambassadors to support Tree Day and assist local schools, councils and groups to take an active part in caring for their local environment.
This year the official National Tree Day site will be in Sydney's geographical centre with Parramatta City Council at Third Settlement Reserve, Edison Road Winston Hills.
For those in Victoria, please join us with the City of Hobsons Bay and help us green Kororoit Creek, Blackshawa Road, Altona North.
We would love for you to join us at either of these events - if you do, please come and say hi!
If you can't make either of those sites, there are hundreds of community sites taking place across the country. To find a site near you visit the Tree Day website and search via your suburb and postcode. And if you are organising a Tree Day event for your business, please do let us know!
Hear from our very own Debbie Agnew, National Tree Day Manager about the lessons she's learned from trees and the inspiration behind Australia's largest community tree planting and nature-care event.
- Schools Tree Day, Friday 28 July 2017
- National Tree Day, Sunday 30 July 2017
We welcome any support businesses can offer to the many amazing volunteers who make the event possible. For more information visit the Tree Day website.
Happy planting!!
Debbie was Planet Ark's Tree Day Manager from 2012-2017 and had a major impact on the success and direction of Australia's largest nature care event.
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Berlin-based Instagram competitor EyeEm is gearing up for the third edition of its Photo Hack Day, which they boast is "Europe's largest image-centric hackathon."
Held at an as yet unconfirmed location in Berlin on the weekend of June 1-2, the hackathon will go for 24 hours – the aim is to "rapidly prototype new photo applications that revolutionise the way we take, see and interact with pictures". Last year, winners enjoyed a weekend trip to London where they held a pitch at the AKQA offices.
The photo hackathons have drawn big names in the past such as Facebook, Nokia and Getty Images. Ideas workshopped during the hackathon include Helmut, an app that scans analogue film, and Tourist Eraser, a nifty app for frustrated travellers sick of tourists taking over their totally awesome pictures of attractions.
Keep your eyes on their website for announcements on what's in it for the winners and exact event details and schedules.
For related posts, check out
Berlin photo sharing app EyeEm wins in Instagram scandal
Photo Hack Day with EyeEm, SoundCloud, Tumblr, AKQA…
EyeEm, Wooga, Scolibri win for host city Berlin at The Europas


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Patricia Thank you so much, we are thrilled with the pictures. we all had such fun and you so very quickly put us all at ease. The results are stunning.
Becky and family
Thank you so much, best photography ever! I was not looking forward to having a photographer in my home during my daughters bridal prep, however it felt like we had known you for ever, you fitted in so well and thank you for those very special images.
Thank you, we have watched the DVD so many times, each time having a cry. You so made our day, you were everywhere, yet never in the way, capturing scenes which we just did not notice.
You were amazing, you so added to Sam and Bonnies wedding day.
We could not be more pleased with the way Patricia and her associate handled our wedding. Professional yet easy going, an ideal combination for a wedding. Understanding our wishes, and capturing the spirit of the day. We liked the way our wedding photography was managed, never dominating the day, but reassuringly always present. We are so very happy with the results.
Thank you for stepping in at such incredibly short notice. Cannot believe the beautiful results. My granddaughters images are stunning, thank you for sending them to us, they are now framed and hold pride of place in our living room.
Thank you for the image of my son, you have a great talent.
You so captured the real character of my daughter, would love extra copies awesome!
Pat, Brilliant photography, thank you so much for the beautiful memories you have given us with the images of our grandchildren.
Pat, thank you so much for taking the amazing photos for my web site, love them, am so very pleased. Would like to book you for the market photography in December.
Pat, thank you for capturing the real spirit of the Rugby Academies, look forward to your being with us in 2014.
Pat has a special knack for putting young people at ease in front of the camera. She involves them in making the picture special. We are very pleased with the portraits of our grandchildren, and so are all our relatives to whom we gave them as presents.
Just wanted to tell you how delighted we were with the photo shoot you did for us with our new grandson. The pictures are amazing, both in their clarity and their informal approach. We have a set of memories to keep that truly reflect our happy little grandson with his adoring family.
I've known Pat for four years and have had many photo sessions in that time. Having had no experience of sitting for photos, I found that Pat was encouraging and put me at ease. She is outgoing and easy to work with.
We are so grateful for the portfolio of photographs that you have taken of Xenia, which she will use for promoting herself as a budding young actress. You have really taken some beautiful photographs of her. Xenia always feels so at ease in your studio, so that she is not self-conscious and this has enabled you to create a range of interesting images from the quirky to the glamorous.


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All black sturdy Birkenstocks.. or strappy elegant Asos heels? Not a question you have to ask yourself every day, but these 2 can fight it out with eachother in a few days since they're both on their way to my doorstep. Yep, this just happened!
Let me know, are you a fan of the Birks? Or glad if the whole thing is passed? I am most definitely a fan, I ordered the black patent Arizona over 4 years ago and since then they've been on holidays, citytrips and last year they mostly served as gardening/outdoor DIY'ing shoes (I'm sorry for putting you through that sweet slippers, don't be mad!) Therefore I knew it was a good investment to buy the all-black-Monterey and treat 'em well this time :)


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Business Management Course Level 4
Business Management Assignment Based Course Endorsed by ABC Awards - Special Offer
CPD Courses
- Exam(s) / assessment(s) is included in price
- Tutor is available to students
Add to basket or enquire
Business Management Course Level 4
Endorsed Business Management Level 4 Certificate of achievement. This high-quality, advanced-level Business Management Level 4 course has been designed for ambitious newcomers and existing professionals alike. Discover what it takes to begin or advance a rewarding lifelong career in Business Management - Course at the highest level. Whether interested in climbing the career ladder with an established organization or starting your own business from scratch, a world-class Business Management - Course qualification could make all the difference.
Developing a deep and comprehensive understanding of key Business Management issues and concepts can improve and enhance career prospects across most contemporary sectors. On a global basis, employers consistently favour professionally-qualified administrative specialists over entry-level admin workers. Across both private and public sectors alike, flawless administrative competencies are required to facilitate key operations and activities. Regardless of the size, nature or purpose of the organization, quality administration lies at the heart of every successful business. Even in an era where automation is playing an increasingly important role in business operations, qualified professionals are still required to plan, implement, oversee and manage every essential process.
From advanced time-management to business etiquette to advanced HR and office management, this exclusive business administration diploma provides candidates with an essential practical and theoretical foundation. With the dedicated support of the CPD Courses team from start to finish, the career you've always dreamed of could be right at your fingertips.
Business Management Course Level 4
Business Management Benefits
When studying for an advanced Business Management with CPD Courses, every learner benefits from:
- All required course materials and supporting documentation included as standard within the initial course fee.
- The freedom to study in your own time and at your own pace with no deadlines or time restrictions to worry about.
- 24/7 access to our exclusive digital learning platform from any location worldwide with an Internet connection for complete flexibility and convenience.
- Comprehensive support provided by qualified and professional tutors with extensive industry experience and expertise.
- The opportunity to earn an internationally-recognized qualification from an accredited awarding organization.
Business Administration Diploma Learning Objectives
Our highest-level diploma in business administration was designed for anyone looking to climb the career ladder to the highest possible levels in a business or office setting. We focus on the kind of practical and valuable course content that can be immediately transferred to a professional working environment. Both for existing professionals in pursuit of career advancement and newcomers looking to secure their first professional positions, an internationally-recognized Business Administration qualification could make all the difference.
Stand out as a candidate of proven commitment and refined capabilities, while developing the confidence it takes to succeed in a position of leadership.
Each learner is provided with their own dedicated tutor for comprehensive support and guidance from start to finish. Every tutor within the CPD Courses team has been hand-selected in accordance with relevant industry experience, proven capabilities and commitment to success. We take enormous pride in nurturing every learner to discover and reach their full potential, providing all the support required to kick-start inspiring success stories. Undergoing constant improvements for guaranteed relevance, our business courses could be just the ticket to fast-track your career advancement.
Study in your own time and at your own pace for a recognized qualification that could transform your career prospects for life.
Upon successful completion of this course, you will be able to:
- Confidently work in a leadership position in any business environment
- Understand a variety of business types and management positions
- Perform a variety of key HR management functions and duties
- Extract maximum value from performance appraisals and interviews
- Carry out the most important business administration tasks
- Understand the objectives and functions of financial management
- Fulfil a variety of resource management responsibilities
- Produce professional reports and business communications
- Create and implement an effective marketing plan
- Delegate duties and build an efficient workforce
- Supervise teams and work forces of various sizes and types
- Build and maintain invaluable long-term customer relations
- Understand the process of starting and running your own business
Business Administration Course Outline
Our exclusive diploma in business administration is delivered across 10 intensive yet accessible modules. In order to successfully complete the course, the modules must be completed in order, along with an assessment at the end of each module.
Module 1 – The Business Environment
Module 2 – Fundamentals of Administrative Management
Module 3 – HR Management
Module 4 – Performance Management
Module 5 – Managing Finance
Module 6 – Managing Resources
Module 7 – Effective Marketing
Module 8 – Business Communications and Report Writing
Module 9 – Time, Stress and Crisis Management
Module 10 – Assess, Manage and Monitor Risks
Who is this course for?
Business Management Course Level 4
Our highest-level Business Management was created for anyone looking to reach the very top of the ladder in any business or office environment. Newcomers to the job market can improve their initial employment prospects enormously with a recognised qualification, as can existing professionals in pursuit of promotion. Entrepreneurs and small business owners may also find their capabilities, confidence and performance benefit significantly from targeted studies.
Providing learners with the opportunity to study in their own time and at their own pace, our courses are ideal for those with insufficient time to commit to traditional training or career development. With no deadlines or time restrictions to worry about, you are free to study as and when you choose. Access your course materials via our exclusive digital learning platform from any location and at any time for total flexibility and convenience.
For anyone who is serious about building a rewarding career for life in business management, our exclusive Business Administration Diploma comes highly recommended.
Business Management Course Level 4
We work hard to keep all of our courses as accessible as possible for all learners.
Endorsed Certificate of achievement
At the end of the course, learner can claim an endorsed certificate by paying £95 accreditation fee.There are £9 postal charges for the UK students and £15 for the non UK students.
Certificate of Completion from CPD
Certificate of Completion from CPD (soft copy) can be claimed for £10. If you need hard copy of this certificate you will pay £25 + postal charges (£9 for UK students, £15 for outside UK)
Career path
Business Management Course Level 4
Upon successful completion of Business Management, candidates may choose careers including:
- Administrative Assistant
- Administrative Coordinator
- Administrative Manager
- Bookkeeper
- Contract Administrator
- Executive Assistant
- Facility Manager
- File Clerk
- Financial Clerk
- General Office Clerk
- Program Administrator
- Program Manager
- Receptionist
Questions and answers
No questions or answers found containing ''.
Danica asked:
How do you gain the qualification? Exams or assessments, or both? Thanks Danica
Dear Danica, The Business Management course is assignment based. You will complete an assignment after each unit. There is no formal exam at the end of the course.This was helpful. Thank you for your feedback.
Jess asked:
Hi, How many words are each assignment? and are there learning resources available (ebooks, journals, eat) to use included in the price? Thank you :)
Yes, all the learning resources are included in the price mentioned for this Business management course. There is no specific word count for the assignments.This was helpful. Thank you for your feedback.
Husainah asked:
How are the assessments completed and what form do they take? Is it essay based? Also, is there a timeframe in which this course must be completed?
Dear Husainah, Our courses are assignment based, after each course unit you will complete an assignment which you will submit to your tutor for marking and you will move on to your next unit and assignment. This way you will complete this business management course. In the end, all your submitted work is assessed by the Awarding body and they issue the certificate. There is no formal exam to take at the end. You can complete the course in 6–12 months' time.This was helpful. Thank you for your feedback.
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Legal information
This course is advertised on reed.co.uk by the Course Provider, whose terms and conditions apply. Purchases are made directly from the Course Provider, and as such, content and materials are supplied by the Course Provider directly. Reed is acting as agent and not reseller in relation to this course. Reed's only responsibility is to facilitate your payment for the course. It is your responsibility to review and agree to the Course Provider's terms and conditions and satisfy yourself as to the suitability of the course you intend to purchase. Reed will not have any responsibility for the content of the course and/or associated materials.


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Kate Bryan, a 32-year-old Catholic who writes for conservative and anti-abortion organizations, has claimed in an Op-Ed for The Washington Post that her celibacy allows her to pursue "the feminist dream."
Bryan is abstaining from all types of sexual affection, including kissing, until marriage. She explains in her essay that she subscribes to a notion of chastity put forth by Saint John Paul II — namely "that every human being is a sexual being, but that we're also rational — which means we don't have to be mastered by our physical desires."
Because no one ever accomplished anything while also maintaining an active sex life, Bryan believes that her commitment to "sexual integrity" has left her with enough free time to pursue all her goals and interests, like sculling on the Potomac River. And that, apparently, is feminism.
"I spend all day, every day doing the things that I want to do, because I'm not wasting my time worrying about waking up next to a stranger, contracting a sexually transmitted infection or missing a period," she writes.
You do you, Kate. But here's a thought: someone who actively opposes women's reproductive rights may not the best person to ruminate on the principles of feminism.
Read the full Op-Ed at The Washington Post


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Richie Cicardo owes his life to a hunt for headphones.
The 24-year-old left his mother Susan Trivino's apartment to find a pair Wednesday afternoon — and returned minutes later to discover her and his sister shot to death in a Bronx bloodbath.
Cicardo "had left to go downstairs to get a pair of headphones," said NYPD Chief of Detectives Robert Boyce. "At which time when he came back, he found both (women) had been shot."
Susan Trivino, 54, and her daughter Suchari Guzman, 29, were gunned down by the mom's jilted boyfriend Jorge Vega, who botched a suicide try after executing the two women.
"Right now, he's still alive," said Boyce of the killer. "We don't think he's going to make it. He shot himself in the head."
Vega, 52, is a former Metropolitan Transportation Authority bus driver who recently left his job and was dumped by Trivino one day before the killing, said Boyce.
A weeping Cicardo, after finding his mom and sister shot to death, carried his 1-year-old niece Abbygail to safety in a nearby apartment and then called 911.
The infant was inside the apartment when Vega opened fire on her mother and grandmother.
The television in the murder apartment was turned up so loudly that no neighbors heard any of the gunshots from Vega's licensed .9-mm Ruger handgun, said Boyce.
Most Read
Cops finally turned down the volume after arriving at the murder scene.
Police were investigating reports that Vega was recently dismissed from his $70,000-a-year job by the MTA, although the shooter's family insisted the hard-drinking bus driver had resigned.
Boyce said the couple had a tumultuous relationship prior to the breakup, with a domestic incident report filed in September.
"There was harassment," said Boyce. "There was an argument ... No one had any prior arrest for anything."
Vega, a former police officer in his native Puerto Rico, was hospitalized in critical condition. He and Trivino had dated for some time, and only recently moved into the Soundview apartment.


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In general, infertility is seen as no pregnancy after 12 months of trying, or the inability to carry a pregnancy to term. But, if you are over 35 years, or if you have reason to believe that there may be a fertility problem, you should not wait for one year of trying before seeing me.
Patient Information Booklets
Merck Serono have provided a set of information publications, which many patients find very useful. Please note that the information contained in the Merck Serono publications is general information only and does not constitute medical advice by me.
Patient Information Booklets
Triple J Radio
Simone has featured on Triple J's 'Hack' current affairs program on a number of occasions. Her excerpts from the program are below.
The Body Clock
Listen: Misconceptions of the body clock
Listen: What is a body clock
Listen: Beat your body clock
Listen: What causes endometriosis pain


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A coal factsheet for the future
The International Energy Agency (IEA) is a Paris-based intergovernmental organization formed in the wake of the 1973 oil crisis. The IEA acts a policy adviser to its 28 member states. It also works with non-members such as Russia, India and China, in efforts to promote alternatives to fossil fuels.
Recently the IEA came out with a report claiming that, "coal's share of the global energy mix continues to rise, and by 2017 coal will come close to surpassing oil as the world's top energy source"
Here are some of the other startling highlights from the IEA's Medium-Term Coal Market Report 2012 Factsheet:
- Coal demand is growing everywhere but in the United States: The trend of the last decade continued in 2011, with coal supplying nearly half of the incremental primary energy supply. Chinese demand grew by 233 mt. The only region where coal demand declined was in the US.
- The world will burn around 1.2 billion more tonnes of coal per year by 2017: That's more than the current annual coal consumption of the United States and Russia combined.
- China has become the largest coal importer in the world: It wasn't until 2009 that China became a net importer of coal, two years later it surpassed Japan for the top spot.
- India will increase its influence in coal markets: With massive coal reserves, and a population of over 1.2 billion coupled with electricity shortages, the country is on the verge of becoming a major coal consumer.
- Australia will recover its throne as the biggest coal exporter: While Indonesia currently holds the top spot with exports past the 300 mt line, Australia is expected to reach 356 mt by 2017.
- The coal renaissance in Europe is only temporary: High gas prices and oversupply from the US have made coal a prime fuel choice for the gas age. But the IEA is quick to point out that increases in renewable energy and the retirement of coal plants will decrease coal consumption across Europe.


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Important Areas of Application of Multimedia Design
It could specifically useful for business makes use of. Fresh and older electronic mass media exploited simply by commercial performers is media. Performers create inspiring presentations to hold the eye of consumers. Additionally, it may useful for enterprise to enterprise communications and also interoffice marketing and sales communications. Imaginative services make advanced stage presentations to promote concepts or rejuvenate exercising. Authorities services and also nonprofit providers also seek the services of commercial media developer to style sales pitches.
Imaginative Sectors
It truly is extensively applicable inside creative sectors. Inside creative sectors it truly is useful for different purposes like great disciplines, enjoyment, business disciplines, literature, mass media and application. Media designers are incredibly imaginative and possess simple technical and also analytical expertise.
Enjoyment and Great Disciplines
Media is deeply found in enjoyment industries to produce special effects and also animations inside videos. Media games can be obtained web CD-ROMs software packages are also available. A number of it is features are sometimes also used inside game titles. Specialist have the ability to incorporate various strategies of various mass media in a fashion that permits viewer to be able to get involved. It might be found in theatre with ie all the things form of electronic digital mass media. It can be found in standard through great arts and are viewed in public. One particular big advantage regarding multimedia is the fact anybody can duplicate perfect replicates of virtually any presentation whenever.
Education and learning
It might be traditionally used inside education and learning. It is accustomed to generate computer centered online classes and also reference publication just like encyclopedia and also almanacs. An ideal personal computer based classes users knowledge several sales pitches, text message and related illustrations inside diverse details platforms.


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