Low density lipoprotein (ldl) cholesterol - Free Essay Example

Sample details Pages: 17 Words: 5131 Downloads: 5 Date added: 2017/06/26 Category Health Essay Type Narrative essay Did you like this example? Elevated cholesterol, particularly low density lipoprotein (LDL) cholesterol, is a well defined risk factor for the development of atherosclerosis (NCEP, 2002). Atherosclerotic lesions are thought to form in response to endothelial damage caused by excess LDL (Steinberg, 2005). Most cases of cardiovascular disease (CVD), the leading cause of mortality and disability in the developed countries, are ascribed to pathology of atherosclerosis. Don’t waste time! Our writers will create an original "Low density lipoprotein (ldl) cholesterol" essay for you Create order Strategies to lower plasma LDL cholesterol levels are therefore crucial in the prevention and treatment of CVD (OKeefe et al., 2009). Conversely to plasma LDL levels, elevated high density lipoproteins (HDL) are protective against the development of CVD. Low density lipoproteins are responsible for the transport of cholesterol and fatty acids from the liver to the various tissues of the body. In contrast HDL is responsible for the majority of reverse cholesterol transport (RCT), in which cholesterol from the peripheral cells are returned to the liver for excretion in the bile (Joy and Hegele, 2008). It is this major role that HDL plays in RCT that is attributed with HDLs anti-atherogenic effects. Therefore strategies which elevate HDL levels are also beneficial in the prevention and treatment of CVD. Plasma cholesterol can be synthesized by the body (hepatic or extra-hepatic sources) or absorbed from the intestines (dietary or biliary sources). Statins, which are a family of HMG-C OA reductase inhibitors, reduce cholesterol synthesis and are very effective and can achieve plasma cholesterol lowering of up to 55% and have been shown to reduce CVD risk by one-third (Stein, 2002). Statin therapy has also been shown to increase plasma HDL levels from 2-16%, it is not know if this increase is clinically significant to the efficacy of statin therapy as it is difficult to separate this small and variable increase from the benefit of the significant LDL lowering (Hou and Goldberg, 2009). Regardless of the statins efficacy of return LDL cholesterol levels to their desired range, a significant proportion of statin users continue to have adverse events (Alsheikh-Ali et al., 2007). Therapies which reduce intestinal cholesterol or bile acid absorption are also available. Plant sterol/stanols, dietary fibre, bile acid sequestrants have been shown to be effective, with LDL cholesterol reductions of 10-15%, 8.5-13% and 5-30% respectively (Hou and Goldberg, 2009). The drug Ez etimibe, which binds to Niemann-Pick C1 Like 1 (NPC1L1) protein a crucial mediator of cholesterol absorption (Chang and Chang, 2008), has also been demonstrated to lower LDL cholesterol levels by 16-19% (Pandor et al., 2009). The wide ranges of cholesterol lowering seen in each treatment are likely the product of genetic factors which vary the rates of cholesterol synthesis and absorption, as well as modulate the effectiveness of each intervention. Because of this genetic heterogeneity of cholesterol synthesis and absorption, being able to effectively measure these parameters and how they respond to different dietary, pharmaceutical or lifestyle interventions is paramount to understanding interventions effect on cholesterol metabolism. Methods to assess cholesterol absorption Direct Method A direct method of measuring cholesterol absorption refers to measuring cholesterol flux from the intestines to the lymph. It is a direct method because it does not use a faecal or plasma level of cholesterol to infer absorption (Gibson, 1984). The first direct method of measuring cholesterol absorption required a duodenal cannula for infusion and cannulisation of the mesenteric or thoracic lymph ducts to sample lymph (Pouteau et al., 2003a). This method has been successfully used to access cholesterol absorption in rats, dogs and rabbits. The use of radioactively labelled cholesterol in the duodenal infusion allows for the distinction between exogenous and billiary cholesterol and can be used to calculate the percent absorption of exogenous cholesterol. An alternative direct method for use in humans was introduced by Grundy and Mok (1977). The intestinal perfusion method (sometimes refered to as Method VII) requires intubation with a three-lumen tube. Liquid formula and ÃÆ'Ã… ¸-s itosterol (though to be a non-absorbable cholesterol degradation marker at the time) is infused into the duodenum at the Ampulla of Vater though the first tube, and intestinal content is aspirated from the 2nd and 3rd tube, 10 and 100 cm distal to the first, respectively. Analysis of the aspirate from allows for the calculation of net hourly cholesterol absorption across the 100 cm long segment of intestine. Discriminating between exogenous and endogenous sources of cholesterol can be done by infusing radioactive cholesterol. The use of ÃÆ'Ã… ¸-sitosterol as a non-absorbable marker in this method may not have been the most appropriate choice given what is known about plant sterols and inhibition of cholesterol absorption at even very low levels (Calpe-Berdiel et al., 2009; Ostlund et al., 2002a; Ostlund et al., 2002b). Plant sterols complete with cholesterol for absorption into gut enterocytes, but are then exported back into the intestines by ABCG5 and ABCG8 transporters. This inh ibition was seen by Grundy and Mok, who noticed that even small increases in ÃÆ'Ã… ¸-sitosterol concentration caused noticeable reductions in measured cholesterol absorption (Grundy and Mok, 1977). The use of an inhibitor of cholesterol absorption in a method to access cholesterol absorption obviously leads to underestimation of actual cholesterol absorption capacity, and this must be taken into account when comparing absorption values among different methods. Another downside to the direct measurements techniques is their invasiveness, however they are the only methods which yield direct measures of total, exogenous and endogenous cholesterol absorption across a section of the intestine (Gibson, 1984). Cholesterol balance methods Cholesterol balance methods use the differences between dietary cholesterol and faecal cholesterol, excluding cholesterol of endogenous origins, to estimate cholesterol absorption (Matthan and Lichtenstein, 2004). Radioactive labelled cholesterol is used to distinguish endogenous from exogenous cholesterol and faecal and plasma levels of cholesterol are measured. There are 4 main balance methods, following the nomenclatures from Grundy and Arhens (1969), they are Method I, II, III and V. Method I consists of a single dose of [14C] or [3H] radio-isotope labelled cholesterol administered intravenously (Grundy and Ahrens, 1969; Quintao et al., 1971). This radio-isotope labels endogenous cholesterol and its subsequent steroid products. Using the formula: daily exogenous absorbed cholesterol (mg/day) = daily cholesterol intake (mg/day) à ¢Ã¢â€š ¬Ã¢â‚¬Å" daily unabsorbed dietary cholesterol (mg/day), and daily unabsorbed cholesterol (mg/day) = faecal neutral steroids per day (mg/day) endogenous faecal neutral steroids per day (mg/day). Endogenous faecal neutral steroids are calculated by dividing the total radioactivity (dpm/day) in the total faecal neutral steroids by the specific activity (dpm/mg) of the plasma cholesterol 1-2 days prior (depending on gastrointestinal transit time). Method II requires continuous oral labelling with radioactive cholesterol (Grundy and Ahrens, 1969; Quintao et al., 1971). The radio-labelled cholesterol is generally incorporated into a liquid diet to insure a precise daily intake of radiosterol for many weeks. Cholesterol absorption is calculated using the formula Z = X + Y, and Z * SA(Z)= X *SA(X) + Y * SA(Y), where Z = total faecal neutral steroids (mg/day), SA(Z) = specific activity of total faecal neutral steroid (dpm/mg), X = faecal neutral steroids of endogenous origin (mg/day), SA(X) = specific activity of plasma cholesterol (dpm/mg), Y= daily unabsorbed dietary cholesterol (mg/day), and SA(Y) = specific activity of diet ary cholesterol (dpm/mg). The equations are solved for Y, and absorption measurements can be done at any time after 4 days of continuous radioisotope feeding, a isotopic steady state is not required. It has been shown that Method II provides more consistent data on cholesterol absorption than, and is therefore recommended over, Method I (Gibson, 1984; Matthan and Lichtenstein, 2004). Method III was introduced by Wilson and Lindsey (1965) and requires an isotopic steady state. Continuous feeding with radioisotope labelled cholesterol for greater than 100 days is required to reach an isotopic steady state. When an isotopic steady state is reached daily cholesterol turnover is calculated, and daily absorbed dietary cholesterol is calculated by the formula: Dietary cholesterol absorption (mg/day) = daily cholesterol turnover (mg/day) * (specific activity of plasma cholesterol/specific activity of dietary cholesterol). Failure to reach an isotopic steady state will yield an underestim ate of actual dietary cholesterol absorption (Gibson, 1984). The long period required to reach an isotopic steady state and difficulty determining when this state has been reached make Method III a difficult and unreliable method. Method III was shown to give lower values of cholesterol absorption than both Method I and II in direct comparison (Quintao et al., 1971). Method V (Grundy et al., 1971) is a combination of methods I and II. Subjects are continuously fed isotopically labelled cholesterol as in Method I and then given a single bolus of different isotopically labelled cholesterol as in Method II. The equations for Method II are used, with only the modification of the X *SA(X) term which is replaced by [(R)(SA(X oral)) / (SA(X intravenous))], where R= daily faecal neutral steroid excretion of intravenous cholesterol (mg/day), SA(X oral) = plasma specific activity of oral isotope taken 1 day before R (dpm/mg), SA(X intravenous) = plasma specific activity of intravenous isot ope taken 1 day before R. Method V was designed for situation when rates of cholesterol synthesis are unusually high (due to surgical or pharmacological interference with enterohepatic circulation), which can lead to endogenous cholesterol being secreted into the intestines prior to isotopic equilibration(Gibson, 1984). In this circumstance (very high synthesis) Method I would underestimate and Method II would overestimate cholesterol absorption. Methods I, II and V all require a marker for gastrointestinal transit time, and for cholesterol degradation in the gut. Chromic oxide is often used as a marker of gastrointestinal transit time. ÃÆ'Ã… ¸-sitosterol has been used as a control for cholesterol degradation, however it must again be mentioned that if ÃÆ'Ã… ¸-sitosterol is used as a marker then the cholesterol absorption values obtained are likely lower than the actual values. However, in these methods if the degradation of cholesterol in the gut is not accounted for, the calc ulated cholesterol absorption will be higher than the actual values (Quintao et al., 1971). Isotope ratio methods Isotope ratio methods measure only the percentage cholesterol absorption (Pouteau et al., 2003a), unlike balance methods, and require accurate record of dietary cholesterol intake to estimate the mass of exogenous cholesterol absorbed from the percentage (Matthan and Lichtenstein, 2004). Method IV (also called faecal isotope ratio method), first introduced by Borgstrom (1969) calculates cholesterol absorption as the percentage of a single oral dose of radio-labelled cholesterol not recovered in the faeces. A single 1 ÃŽÂ ¼Ci radio-labelled dose of both cholesterol and ÃÆ'Ã… ¸-sitosterol is administered orally and feces are collected for seven to eight days. The ratio of labelled cholesterol to labelled ÃÆ'Ã… ¸-sitosterol in a sample of the pooled faeces samples is compared to the ratio that was given orally and cholesterol absorption is calculated using the formula: Cholesterol Absorption (%) = 1 à ¢Ã¢â€š ¬Ã¢â‚¬Å"((Faecal Cholesterol (dpm) /Faecal ÃÆ'Ã… ¸-sitosterol (dpm) ) * (Oral Cholesterol (dpm)/Oral ÃÆ'Ã… ¸-sitosterol (dpm))) *100. This method has been modified to allow a single faecal sampling, Sodhi et al. (1974) administered a faecal flow marker, such as chromic oxide or carmine red, with the original test dose, and calculated the faecal isotopic ratio at the peak level of the marker in the faeces rather than a sample of the pooled faeces. This single faecal sampling modification of Method IV has been compared to the original Method IV and Method I in baboons and it yielded consistently higher absorption levels, suggesting that this modification may weaken the accuracy (Mott et al., 1980). Method IV, despite the long period of faecal collection required, uses a far smaller dose of radioactivity than the balance methods, and is relatively straightforward and simplistic in execution (Gibson, 1984). It does still require ÃÆ'Ã… ¸-sitosterol as a marker of cholesterol degradation in the gut, so it shares the drawbacks previously discussed. Th e plasma isotope ratio method (IRM or Method VI), was first introduced by Zilversmit (1972) in rats and then subsequently carried out in humans (Samuel et al., 1978). The IRM involves simultaneous oral and intravenous administration of C14 and H3 radio-labelled cholesterol and requires only a single blood sample 3-4 days afterwards. The methods principles are based on the measurement of drug absorption used in pharmacology. If the absorption of cholesterol was 100% than the specific activity curve of both radio labelled cholesterols would be the same, if absorption was zero, none of the orally administered cholesterol, and therefore zero radioactivity from the oral radioisotope would appear in the plasma. Since cholesterol absorption falls between zero and 100%, the ratio of the two plasma radioactivities, after normalization for dose, are used to calculate absorption using the formula: Cholesterol Absorption (%) = 100 * (% oral dose in plasma/ % IV dose in plasma), where % oral dos e and % IV dose in plasma are the percentage of IV and oral tracer in the plasma sample, respectively (Samuel et al., 1982). The ratio is calculated 3-4 days after radioisotope administration because the specific activity time curves of both radioisotopes must be parallel. This does not occur in human until 3-4 days due to a delay in the appearance of the oral radioisotope in the blood related to the mechanisms of cholesterol absorption (Gibson, 1984). The IRM advantages over previous methods include: 1)only a single blood sample is required, 2) a low dose of radioisotope is used, 3)it does not require faecal collection 4) it does not required markers, such as ÃÆ'Ã… ¸-sitosterol, to correct for faecal losses. The IRM lends its self to repeated use because of its short duration and low level of labelling, this allows for investigation of variations in cholesterol absorption under different experimental parameters in the same individual in a comparatively short time period. The IRM m ethod has been validated in human numerous times against method IV under different conditions yielding similar results(Samuel et al., 1978; Samuel et al., 1982). A third isotope ratio method, Method VIII was introduced by Crouse and Grundy (1978), it shares similarities to Method IV, average cholesterol absorption is calculated using the ratio administered cholesterol to ÃÆ'Ã… ¸-sitosterol measured in the faeces, but differs in the method of isotope administration. C14 Cholesterol and H3 ÃÆ'Ã… ¸-sitosterol are administered orally three times daily for 10 days, and faeces can be collected from day 4-10 (Gibson, 1984; Matthan and Lichtenstein, 2004). Following day 3 of isotope administration the ratio of isotopes in the faeces becomes essentially constant and cholesterol absorption is calculated by the formula: Absorption (%)= 100* ((Faecal cholesterol (dpm)/Faecal sitosterol (dpm))/1-dietary cholesterol (dpm)/ dietary sitosterol (dpm)) This method requires only the ratio o f radioactivity in a single faecal sample to be measured; faecal mass need not be calculated (Crouse and Grundy, 1978). Since ÃÆ'Ã… ¸-sitosterol is also administered with the labelled cholesterol it may underestimate actual cholesterol absorption. Plasma cholesterol specific radioactivity following the consumption of a test meal has also been investigated a measure of cholesterol absorption. Lin et al. (2005) measured cholesterol absorption in 11 individuals with Smith-Lemli-Opitz syndrome (SLOS), a cholesterol synthesis disorder, and compared plasma cholesterol apecific activity with cholesterol absorption measured by Method IV. They sampled blood 24, and 48 hours following radioisotope enriched tests meals, and calculated the specific radioactivity of the cholesterol in the plasma (dpm/mg cholesterol). These values correlated significantly with cholesterol absorption calculated by Method IV (r=0.594, p=0.009, and r=0.474, p=0.047 for 24 and 48 hours respectively). While this m ethod cannot calculate cholesterol mass or percent absorption, it could allow for investigation of relative changes in cholesterol absorption within an individual across different conditions. It requires only a single blood sample, no stool collection, and no use of a cholesterol degradation marker, such as ÃŽÂ ²-sitosterol. This method is very similar, to the single isotope tracer method that will be discussed in the stable isotope methods section (Wang et al., 2004). This relationship between plasma radioactivity at 24 hours and cholesterol absorption requires further validation, especially in healthy individuals. The use of radio-isotopes has been invaluable to the investigation of cholesterol absorption, however the advent of stable isotope laboratory techniques, especially developments in isotope ratio mass spectrometry has allowed radio-isotopes such as C14 and H3 tracers to be replaced with safer 13C, 2H and 18O stable isotope labelled tracers (Pouteau et al., 2003a). T his has reduced the difficulty related to containment, handling, disposal and overall safety associated with radioisotopes and allowed for investigation of cholesterol absorption in certain populations (children, pregnant and lactating mothers) which had previously been impossible do to the ethical considerations around radioisotope administration. Stable isotope methods for cholesterol absorption Cholesterol labelled with stable isotopes has been shown to have identical kinetics as radio-labelled cholesterol. This has led to the development of stable isotope techniques to investigate cholesterol absorption. Lutjohann et al. (1993) introduced a stable isotope version of Crouse and Grundy s (1978) Method VIII discussed above. Deuterated cholesterol and sitostanol were used in place of C14 cholesterol and H3 ÃÆ'Ã… ¸-sitosterol, and quantified using gas-liquid chromatography -selected ion monitoring. Cholesterol absorption was calculated as in Method VIII. The stable isotope method was twice compared to Method VIII, in six monkeys, yielding similar results. The stable isotope method produced and absorption range of 49-73% (mean of 60%), with coefficient of variation ranging from 3.9%-15.1% (mean 7.1%). The radioisotope produced a range of 51-69% (mean 61%) with coefficient of variation ranging from 1.9-13.6% (mean 5.1%) (Lutjohann et al., 1993). This stable isotope Method VIII was determined to be as effective as the radio-isotope Method VIII, without the risk of radioactive exposure to subjects and research staff. This method uses sitostanol, rather than ÃŽÂ ²-sitosterol, as a marker for faecal losses of cholesterol. This, however, does not remedy the problem other methods suffer from when using ÃŽÂ ²-sitosterol, as sitostanol is also an inhibitor of cholesterol absorption (Gylling et al., 1997; Miettinen et al., 1995). The plasma isotope ratio method (Method VI) (Samuel et al., 1982; Zilversmit, 1972) was also adapted to stable isotopes. Bosner et al. (1993) used 2H labelled oral and 13C labelled IV cholesterol to calculate the plasma stable isotope ratio and cholesterol absorption percentage. This method uses gas-chromatography à ¢Ã¢â€š ¬Ã¢â‚¬Å" mass spectrometry with select ion monitoring (GC/MS-SIM) or GS/MS- chemical ionization mode (CI) to determine isotopic enrichment. Bosner et al. (1999) further modified the Method VI to a single isot ope dual tracer method, using oral [2H]5 and IV [2H]6 cholesterol. Isotope detection in the plasma cholesterol is done by GC/MS- selected mass monitoring. Jones et al. (2000) were the first to use isotope ratio mass spectrometry to determine isotopic enrichment using the plasma isotope ratio method. Oral 13C and IV 3H cholesterol were administered to 15 hypercholesterolemic men, followed by blood sampling 2-3 days post administration. Free cholesterol from red blood cells was purified by thin layer chromatography and subsequently combusted to yield carbon dioxide and water. The CO2 was then measured for 13C enrichment against the international standard Pee Dee Belemetite (PDB) on an isotope ratio mass spectrometer (IRMS). The water was reduced to hydrogen gas via zinc reduction and 3H enrichment was measured against Standard Mean Ocean Water (SMOW) international standard by IRMS. The ratio of plasma enrichment of 13C to 3H cholesterol on day 3 after tracer administration was used to calculate cholesterol absorption. Recently, continuous flow gas chromatograph pyrolysis IRMS (GC/P/IRMS) systems and 18O or 3H cholesterol with gas chromatograph combustion IRMS (GC/C/IRMS) systems and 13C cholesterol have been used in calculating cholesterol absorption using IRM (Method VI)(Gremaud et al., 2001; Pouteau et al., 2003b). The use of IRMS vs GC/MS-SIM has vastly increased the precision of this method. The two single stable isotope methods for accessing cholesterol absorption were introduced by Ostlund et al. (1999) and Wang et al. (Wang et al., 2004). Ostlund et al. (1999) administered deuterated cholesterol to volunteers and measured the average oral cholesterol tracer in plasma ((mmol deuterated cholesterol/mol natural cholesterol) in blood samples taken 4 and 5 days post tracer administration using GC/MS. Wang et al. (2004) administered 13C cholesterol orally followed by blood sampling at 24, 48, 72 and 96 hours. 13C enrichment in plasma free cholesterol was mea sured using GC/C/IRMS. Average 13C enrichment from 24-96 hours and area under the curve (24-96 hours) of 13C enrichment were compared the cholesterol absorption percentage measured using the plasma dual stable isotope ratio method (Bosner et al., 1993) in 2 studies. The average and area under the curve of 13C enrichment in plasma free cholesterol correlated with cholesterol absorption percentage measured by stable isotope method VI (r values ranging from r=0.81, p=0.0001 to r=0.88, p=0.0001)(Wang et al., 2004). Both of these single isotope methods are used to compare treatment effects, such as pharmaceutical or dietary interventions and their effects relative to control, on cholesterol absorption. Absorption surrogate method The use of serum plant sterol levels to predict cholesterol absorption was first developed by Tilvis and Miettinen (1986). They showed that serum levels of ÃÆ'Ã… ¸-sitosterol and campesterol, when normalized for total serum cholesterol, correlated positively with cholesterol absorption as measured by Method VIII of Crouse and Grundy (1978). This measurement involves lipid extraction from a single blood sample followed by GC or HPLC to quantify serum plant sterol and cholesterol levels. The use of campesterol or ÃÆ'Ã… ¸-sitosterol to cholesterol ratio has since been used numerous times as a measure of cholesterol absorption (Gylling et al., 2007; Hallikainen et al., 2006; Matthan et al., 2009; Nissinen et al., 2008; Simonen et al., 2008). Nissinen et al. (2008) showed that ÃÆ'Ã… ¸-sitosterol to cholesterol ratio correlated better with cholesterol absorption than campesterol to cholesterol ratio, as measured by method VIII, across three diets varying in both cholesterol and fat le vels in 29 healthy male volunteers. It is important that when using serum plant sterol as surrogates for cholesterol absorption it is imperative that factors which are known to change serum plant sterol levels, such as the dietary intake of plant sterols (Chan et al., 2006), should be controlled for so as not to perceive a change in cholesterol absorption which may not exist (Vanstone and Jones, 2004). Serum plant sterol levels can be variable within and across different population (Chan et al., 2006), they can also be severely elevated in certain individuals due to genetic disorders (Berge et al., 2000; Lee et al., 2001). It is important that individuals with these genetic disorders are not included in studies using this method of estimating cholesterol absorption as serum plant sterol levels do not reflect cholesterol absorption in these individuals. Recently it has also been shown that serum plant sterol concentrations do not reflect cholesterol absorption in individuals with Smi th-Lemli-Opitz syndrome (Merkens et al., 2009), therefore the use of serum plant sterols as surrogates for cholesterol absorption should be verified prior to its use in a particular populations. The use of plant sterol surrogates does benefit from relative speed and simplicity compared to other previous discussed methods (Matthan and Lichtenstein, 2004; Pouteau et al., 2003a), it is the only estimate of cholesterol absorption which can be done in large scale studies. Methods to access cholesterol synthesis The primary pharmaceutical intervention used to lower elevated cholesterol levels are statins, which are inhibitors of HMG-CoA reductase, a key enzyme in cholesterol synthesis (Stein, 2002). Cholesterol synthesis contributes more to circulating cholesterol levels than cholesterol absorption (Dietschy, 1984; Pouteau et al., 2003a), and maintains cholesterol levels during fasting, therefore accurate assessment of cholesterol synthesis is essential to the field of cholesterol research. Balance Method Cholesterol synthesis can be estimated when intake of dietary cholesterol and excretion of total cholesterol is known during a metabolic steady state (Grundy and Ahrens, 1969). The criteria of this metabolic steady state are: constant plasma cholesterol and faecal cholesterol excretion levels during a period of constant weight. In this steady state, cholesterol synthesis is the difference between cholesterol excretion (faecal neutral sterols and bile acids) and intake. Dietary cholesterol intake must be accurately measured, and faeces must be collected, for a given period of time. Faecal flow must also me monitored to assure collection of faeces from the appropriate time period. Faecal neutral sterols and bile acids are measured in the faeces, typically by GC-MS, and cholesterol synthesis for a given period of time is calculated (Jones et al., 1998; Kempen et al., 1988). Although this method is the gold standard for calculating cholesterol synthesis, it is vulnerable to errors in t he estimation of both cholesterol intake and excretion which can potentially cause significant error. The balance method does determine the actual mass of cholesterol synthesized during a given period, it requires a metabolic steady state, accurate measurement of cholesterol intake and total faecal collection for the period of interest. Therefore this method is not suited for larger trials. Fractional conversion of squalene Daily cholesterol synthesis rate can be estimated by the fraction of infused radiolabelled melavonic acid converted to cholesterol (Liu et al., 1975; McNamara et al., 1977). [14C] mevalonic acid and [3H] cholesterol are administered intravenously, this infusion of labelled mevalonic acid rapidly labels the plasma squalene pool, reaching a maximum enrichment at ~100 minutes. Cholesterol synthesis is estimated by measuring squalene synthesis. Squalene synthesis is calculated by the percentage of melavonate dose converted to cholesterol, divided by the area under the curve of pasma squalene specific activity. This method assumes that plasma squalene synthesis is equivalent to cholesterol synthesis. The cholesterol synthesis rate estimated using this method has been shown to agree with cholesterol synthesis calculated by the balance method within 8% (Liu et al., 1975). The benefits of this method is it requires only 1 hour of a participants time, and can be repeated every 3 weeks (McNa mara et al., 1977), it does however require the administration of intavenous radioisotopes. Cholesterol synthesis precursors The concentrations of plasma precursors along the synthesis pathway of cholesterol have been used to as an indirect qualitative measure of cholesterol synthesis. Squalene (Miettinen, 1982), mevalonic acid (Parker et al., 1982), lanosterol, desmosterol and lathosterol have all been used a surrogates for cholesterol synthesis (Matthan et al., 2000; Miettinen et al., 1990). These precursors have has been shown to fluctuate with diurnal cholesterol synthesis patterns as well as in conditions in which cholesterol synthesis is elevated or reduced (Miettinen, 1982). These precursors correlate more closely with measured cholesterol synthesis when they are normalized for plasma cholesterol level, then as the absolute amount of precursor, and are normally expressed in mmol/mol cholesterol (Miettinen et al., 1990; Nissinen et al., 2008). When using cholesterol precursors as surrogates for cholesterol synthesis, dietary intakes of each precursor should be controlled for, this is particularly i mportant for squalene, which is abundant in olive oil and is at least partially absorbed into the blood (Ostlund et al., 2002b). The most consistent surrogate for cholesterol synthesis has been lathosterol (Kempen et al., 1988; Nissinen et al., 2008). Since cholesterol synthesis surrogates require only one blood sample they are ideal for estimating cholesterol synthesis in very large studies or epidemiological trials. Mass Isotopomer Distribution Analysis (MIDA) Mass isotopomer distribution analysis (MIDA) is a technique that can be used to measure the synthesis of biological polymers in vivo (Hellerstein and Neese, 1999). The technique uses the relative abundance (pattern or distribution) of polymer species which differ only in mass (mass isotopomers) produced during the administration of stable isotope labelled precursors. The distribution of the polymer species produced is compared to the theoretical distributions predicted by binomial and polynomial expansion. Using these theoretical distributions, parameters such a fractional synthesis rate can be calculated using combinatorial probability model. Since cholesterol is synthesized from subunits of acetyl-Coa, fractional synthesis of cholesterol can be calculated during the infusion of 13C labelled acetate (Neese et al., 1993). This method is very invasive, requiring a 24-hr intravenous infusion and serial blood sampling from a indwelling catheter (Di Buono et al., 2000). The cholesterol in the blood samples is measured by GC-MS to determine the distribution pattern of isotopomers from which the rate of synthesis is obtained. The data analysis relies on more complex mathematical modelling than other methods for estimating cholesterol synthesis. Deuterium Incorporation This method is based on the tritiated water uptake method by Dietchy and Spady (1984) used originally in animals. Deuterium incorporation method uses water as a tracer to determine the synthesis of free cholesterol (FC). The fractional synthesis rate (in pools/day) of free cholesterol is calculated from the rate of incorporation of deuterated water into de novo synthesized plasma or erythrocyte cholesterol. Orally administered deuterated water equilibrates with the bodys water and NADPH. Body water and NADPH account are the precursors for 22 of the 46 hydrogen in synthesized cholesterol (Jones, 1990). Deuterium enrichment of the precursor pool, plasma water, and in erythrocyte or plasma cholesterol are measured by IRMS. Fractional synthesis rate of free cholesterol (FSR-FC) is calculated using the following formula: FSR-FC (pools/day) = ( ÃŽÂ ´ cholesterol à ¢Ã¢â€š ¬Ã‚ °/ ÃŽÂ ´ plasma water à ¢Ã¢â€š ¬Ã‚ ° * 0.478) ÃŽÂ ´ refers to the change in deuterium enrichment over 24 hours and 0.478 is the ratio of cholesterol from body water and NADPH to total hydrogen in a cholesterol molecule, or the ratio of hydrogen which could be enriched by oral D2O administration (Jones et al., 1993). From the FSR-FC the ASR -FC (g/day) can be calculated by multiplying the FSR-FC by the M1 pool size (determined by Goodmans equation) and 0.33 the proportion of FC in total cholesterol. The ASR-FC is approximately the daily production of newly synthesized cholesterol. The three main assumptions required for deuterium incorporation are: 1)That the fraction of hydrogen derived from plasma water (22/46, or 0.478) is constant in denovo synthesized cholesterol. 2) That denovo synthesized free cholesterol rapidly exchanges between the site of synthesis and the major free cholesterol (plasma compartment) pool. Within this pool cholesterol migrates rapidly between cellular membranes and lipoproteins as well as between different classes of lipoproteins. 3) Deuterium uptake i nto the free cholesterol of the major (plasma) pool of cholesterol reflects synthesis in this pool and that synthesis of cholesterol in the major pool provides a reasonable measurement of total cholesterol synthesis as most sterol synthesis occurs in the intestines and liver which contribute to the plasma cholesterol pool. It must be acknowledged that the major (plasma) pool of cholesterol is at equilibrium with two other slow turnover pools outside the plasma, and that the slow inter-pool cholesterol exchange would cause insignificant entry of labelled free cholesterol into the central pool within a 24 hour time period (Dietschy and Spady, 1984; Jones, 1990). Although it has been shown that these assumptions are not perfect, the cholesterol synthesis estimates yielded by deuterium incorporation have been sensitive enough to show differences in cholesterol synthesis due to genetic factors, and dietary and pharmaceutical interventions. It has also been shown to correlate well with ch olesterol synthesis measured by the balance method (Jones et al., 1998), MIDA(Di Buono et al., 2000) and cholesterol synthesis surrogate levels (Matthan et al., 2000). Conclusion The methods used to quantify cholesterol absorption and synthesis reviewed in this article have yielded invaluable information, as well as provided effective means of measuring the experimental effects of various interventions, on cholesterol homeostasis. The methods have evolved substantially over the years, from radio-isotopes to stable isotopes, and from highly invasive to less invasive procedures. However, advancement in the quantification of cholesterol homeostasis must still be continued, with a goal of finding more accurate methods to measure cholesterol synthesis and absorption, perhaps simultaneously, something which until now is still unavailable. The advantages and drawbacks, as well as the type of information yielded by each method for measuring cholesterol absorption and synthesis must be weighed carefully when selecting an appropriate method. The cost and available technical expertise and facilities will limit which methods are available to each investigator. However, it is imperative that the assumptions and limitations of each method are checked to insure that its use is valid for each particular experimental question it is used to answer.

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Evidently, there are costs associated with developing a contingency plan which in the short-term may appear unnecessary; nevertheless as a response to the increasing number of disasters, contingency planning is essential to scheme to allow an organization to swiftly return to its operations while avoiding superfluous costs and minimizing casualties as a result of the increase in the overall effectiveness of response to an emergency or critical situation. The need for contingency planning primarily roots from the trend of exponential increase in the number of disasters. The World Disaster Report (2004) concluded that: Over the past decade, the number of natural andShow MoreRelatedBusiness Continuity Plans And The Disaster Recovery Plan1580 Words   |  7 Pages(BCP) and the Disaster Recovery Plan (DRP) are twin resources derived to preserve vital organization operations when facing an unsuspecting disaster. A disaster can be either natural or man-made. 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The Management Efficiency Unit Free Essays

I have been working in the Public Registry for the last 8 years.   The location of the offices is quite distant from my residence and sixteen other colleagues that work in the aforesaid department have the same problem.   Every morning we are required to travel a one hour ferry and nearly 2 hours drive to arrive at work. We will write a custom essay sample on The Management Efficiency Unit or any similar topic only for you Order Now The Management Efficiency Unit noted this issue and finally top management decide to take remedial action by requesting a transfer to another department, the Treasury Section, which mitigates such location problem. Unfortunately the scheme designed by executive management was not properly planned.   They also did not discuss this issue with operational managers who possess far greater knowledge on the day to day running of the office.   As a result the decision lacked practical issues and led to other problems, as will be further illustrated below. Everybody accepted the transfer and we were eventually informed that our training for the new job will take approximately two or three months and will take place in the head office of the Finance Department, which is also distant.   The new job was highly technical and involved a lot of accountancy issues, which the majority of us were not capable to comprehend that easily. The three months passed and we were still unable to work unsupervised from our tutors.   The impracticality of the decision was highlighted from the fact that our principal in charge, who was also taking training was still incapable to work on his own after three months. When these issues started to crop up, crises management arose.   A new assistant director was assigned to this division, who once realized of the vast serious problems arising from such decision, he immediately denied this new role. Demotivation arose in our section and staff is constantly complaining about the problems we are facing.   In addition no communication exists between us and executive management and we are alone with this new work, which we are not trained to do. The only reasonable solution that management was able to come up with is to extend the duration of the training to eight months.   However with this decision they have not yet solve the problem that the location of the office is far from home and are incurring additional costs to train us. If they planned carefully before deciding and discussed it with operational managers they would have definitely solved the problem more efficiently.   It is imperative that when managing change proper communication and planning exist. Reference: Johnson G.; Scholes K.; Whittington R. (2005). Exploring Corporate Strategy. Seventh Edition. England: Pearson Education Limited.    How to cite The Management Efficiency Unit, Essays

China Social Structure free essay sample

It will outline the different class’s that make up contemporary China’s social structure and give a detailed outlook and perspective on each class, and show what change they have undergone since the opening of China’s economy in the late 1970’s and introduction to a market based economy. The greatest outcome will see how the transfer of the class’s from a socialist dictated economy and society during the Mao era, rapidly changed and fused into the modern market based economy of today’s China. This essay should also indict who has benefited most from such a quick and bold move to a market economy, and those who have lost out and not been so lucky as others due to the open door policy of China which was introduced in 1978, by then Chinese Premier Deng Xiao Ping ( ). This essay will take each class individually and contrast them to other class’s, both those that existed during the Maoist era of pre-1978 and the class’s that have emerged as a result of the economic reforms pursued by China since the opening of its economy and internal reforms where introduced. We will write a custom essay sample on China Social Structure or any similar topic specifically for you Do Not WasteYour Time HIRE WRITER Only 13.90 / page Lastly it will look at if China’s communist party has steered away from the founding ethics of a socialist economy to that of a capitalist one due to social class division and what effect this can have on China in the near distant future. Firstly looking at the Peasant class, one of the three original social class’s during the Maoist period of 1949-1978, (the other two being the working class and the cadre class). The peasant class, along with the working class during Maoist China were dubbed the proletariat class, in comparison the relatively small but evident cadre class. The rural-urban divide has always been existent in Chinese society, largely based on economic and geographical contributions. However throughout the Maoist era, peasant’s standard of living; to a certain extent were raised. With the abolishment of savage landlords which persisted during the imperial and republican times and the introduction of many yet simple beneficiaries to rural areas of China, peasant’s standard of living from 1949-1976, actually rose significantly, ‘On the one hand, standards of living can be seen as improved due to the absence of warlords, bandits, landlord, and local tyrants. The government invested a lot in agriculture, especially water conservancy, irrigation works, chemical fertilizers, and agricultural machinery†¦. The life expectancy of peasants increased from less than forty years before 1949 to more than sixty years in the 1970s’[1] Simple improvements in education and health, the fundamentals of any society to prosper were drastically improved by the so called â€Å"barefoot† teachers and doctors. However, prosperity was limited due to collectivisation of all the land available for agriculture, restricting peasant’s income and also led to the disaster of the Great Leap Forward campaign, which saw many peasants suffer in comparison to their urban counterparts. Restrictive movements of people from rural to urban also led to a stagnated peasant society, with the introduction of the household registration system ( ) , ensuring that peasants and their families never had the chance to seek a more prosperous life in the cities or enjoy the benefits of those of urban household with hukou registration. The reforms of 1978 first and profoundly had an immediate effect on rural areas. This came with the abolishment of the commune system, establishment of free market practice in the countryside with agricultural products and the thriving success of the Town and Village Enterprises (TVE’s). By 1993, 145 million peasants had become members of the working class; however they would be referred to as peasant worker, and not urban worker due to the hukou registration system. (Li Yi, China Startifictaion, p. 105). Many rural inhabitants, after the reform era had taken jobs in cities, albeit as a floating population, due to the strictness of the hukou household registration system most rural registered workers in cities today don’t enjoy the benefits of their urban registered counterparts, of housing, health care and schooling for their children. Most rural areas are also responsible for development of their own areas, with little support from the government, taxes and fees remain high in proportion in the countryside, as is the cost and low opportunities of schooling and further education. Li Yi China Stratification p. 192)Peasants also missed out largely in China’s great economic boom during the 1990’s and early 2000’s, with China’s economic annual growth an average of 9% in recent years, peasant income has increased, but rather in some cases decreased (Li Yi China Stratification p. 219). Peasants are in a sense stuck within their boundaries due to the House hold Registration System, or hukou. This social â€Å"apartheid† has created a massive imbalance between the coastal urban areas and the mainly rural western half of China. Urban household registered hukou holders had much of the states benefits in housing, education healthcare and employment ( Fei Ling Wang, Chinese Society, Change, conflict and resistance, (New York, Routledge, 2000). But as with the opening reforms of the late 1970’s, not all urban households and workers have managed to benefit, with that creating class differences even within China’s urban populace. Throughout the Maoist era, most urban employment was contingent within State Owned Enterprises(SOE’s), with workers benefiting from the system dubbed the â€Å"iron rice bowl†. This system, commonly a factor of socialist geared economies and societies was the benefits urban state employees enjoyed throughout Mao’s reign. Benefits included housing, food rations, healthcare insurance and education of employee’s children. The â€Å"iron rice bowl† also supplied life long work and benefits to those who were employed with work units, danwei ( ) and simplified that throughout the socialist market era, little social conflicts and imbalanced occurred amongst the urban working class. As of 1978, as much of 78% of urban labour force were recipients of this â€Å"iron rice bowl† welfare. [2] Starting with the reforms initiated by Deng Xiao Ping, slowly the â€Å"iron rice bowl† was withdrawn and open competitiveness was encouraged. Seen as extremely costly to the state, SOE’s would now undergo huge transformation. â€Å"Grasp the big, release the small† was now in effect, with SOE’s that were making a loss to face closure, and the ones that remained facing intense competition from the more effectively run foreign enterprises and privately run sector. This in effect led to high levels of lay offs, never heard or seen of during the Mao regime, with estimates as high as 60 million, with an overall figure including those waiting on employment reaching 100million. [3] The huge amount of layoffs had never been experienced in China, and the sheer pressure on the state took hold, not all of employees who had lost their â€Å"iron rice bowl† could find work, due to the fact, they had worked in industries all their lives that largely included the same repetitive work, and had no grasp of competitiveness. Much of the lay offs were women, and above average age workers, the category that will find it hardest to find re employment. Much lacked a good education, having experienced the chaos of the cultural revolution of 1966-1976, which saw China’s education, especially upper levels deteriorate. This urban class, dubbed the xiagong, literally went from complete stableness in the â€Å"iron rice bowl† system to a complete foundation less society. Alongside the rural migrants of the â€Å"floating population†, who’s number in cities is rising, coincided with the now jobless former state urban workers. Competition for employment was extensive. With a poor social security service, or none at all, these former secure workers now faced a much tougher life to secure an income to support themselves and families, with wages below the average of urban household incomes, ‘it is not surprising that by early 2000, 73 per cent of China’s urban population had incomes below the national average, and just 27 per cent were above it,’[4] A real sense of anxiety surely crossed the minds of those who lost out, having gone from a society that provided everything to one now having to defend for themselves with the handicap of age, lack of education and skills that were needed to fill the positions now open to the market economy. Not only did they see there jobs and way of lives disappear, state benefits also dried up, or were not enough to help support this group of former state workers. The numbers who fell into poverty, which is classified depending on which city it is in China reached startling highs of almost 13 per ce nt of urban population, 40-50million, [5] in 2001. The unemployment figures, relating from state owned enterprises and cooperatives seems to have increased as of 2001, with China’s acceptance into the World Trade Organisation (WTO). The state-society model, developed throughout the Maoist years seems threaten, with the massive layoffs of these ordinary workers, however much of the managerial staff and cadre’s who where involved in the running of these SOE’s have benefited, becoming prime shareholders, re allocated to improved positions of employment and benefits that go with that, again dividing urban class standards, ‘People working in rich work units could easily get a comfortable spacious apartment, while those in poor work units remained in near-slum conditions. Work units ability to provide housing varied between state and collective sectors and with bureaucratic rank. While work unit housing was allocated to satisfy needs (large or multigenerational families were allocated first and got more living space) spacious and quality units were a work units resources and served as incentives to reward political and managerial authority, seniority , professional expertise, and social connections . ’[6] At the expense of the ordinary workers losing their occupations in the numbers, a new class of highly educated, well positioned (through connections like guanxi ( ) and entrepreneurial class has reaped the real rewards of the booming Chinese economy of the recent years. Have the government and the ruling Communist Party really shown nepotism away from its own founding base of the working class? What can the workers do t voice their concerns, in a country that restricts free speech and emotion? Any organisations of protests are met with harsh retaliations, and those accused of such activities are harshly dealt with. Taking the example of the Daqing petroleum protest of March 2002, in Daqing Heilongjiang province, the state must address and deal with these challenges sensitively, knowing that a lot rests on its outcome. In dealing with large scale outbreaks of protest like this the state has developed a ‘divide-and-rule strategy, encouraging employed workers to keep their distance from the protests, and intentionally causing the rank and file among the unemployed to believe that the protests are to blame for the cancellation of payments’[7]. This form of catch-22 policy has so far deemed successful in maintaining stability and control over any protest or arguments amongst the newly found unemployed â€Å"iron rice bowl† employees. This has allowed the government to keep on track with its promotion of the market based economy on a whole, as well formulating a large labour surplus into the workforce. The urban working class has definitely been the class that has lost most in the post-reform era of China, while a new class has benefited at their downfall. Reform era China has provided vast opportunities in newly emerging industries and privately owned, foreign invested or created from scratch enterprises have thrived. However demand for educated, well positioned workers, has left modern China with a development of a â€Å"middle class†. It is hard to say what exact characteristics make up this â€Å"middle class†, as in comparison to western middle class society, it is far from a following example, like the ownership of cars as common in western income families in the west is obviously not matched in China. In terms of income, an annual household income of 60,000-500,000 yuan is thought to qualify a household as middle strata levels. 8] This newly educated class, with social guanxi is the new driving force of China’s growth, with the closing of SOE’s and rising capitalist activity in the Chinese economy. Newly developed entrepreneurs, officially welcome into the Communist Party in 2001, by invite of the Thr ee Represents, have been behind much of China’s economic activity, able through connections, know how, and close connections to the party(Goodman, New Rich in China, p34-36) been able to secure funds to help develop their prestige. Professionals and managers have also been on ends of high salary turnovers, seen to the state as vital in its strategic to immense economic activity. Favours from the state also passed their way through to this new elite group, with property and housing given at lower rates, ‘the massive sale of public housing to employees throughout the 1990s occurred at highly subsidized prices for the existing housing stock, or alternatively employees were given the option of buying newly built houses while the work unit carried the lion’s share in construction or purchasing costs†¦buying extensively to cater for the needs of their professionals and other employees. ’ [9] These new homes ‘awarded’ to the newly emerging elites are often found close to the best schools and other community services, creating so called neighbourhood apartheid. An estimated 20-30 billion yuan was lost due to under value sales of land, ( www. internationalviewpoint. org/spip. php? article751) . So why has the state in turn favoured the class that had been, during the Maoist era received massive vocal attacks? Well in dealing with the massive under performing SOEs , the state could and did look to the emerging capitalists as a source of absorbing the loose employment that spilled out of the massive state owned unemployed. Capitalists are thought to have accounted for between 70-85% of China’s GDP ( Li Yi, China Stratification, p137), without this China may well have internally collapsed, unwilling to disband its loss making enterprises and not indulging into a market economy. This system, albeit seeming unfair, is following in Deng Xiao Ping’s approach of allowing some people to get rich first’. However this route, of eventually reaching a society where the middle class is prominent and thriving will take time and the correct policies and approach, with careful management.