Lowering Your Cholesterol Naturally

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Natural Cholesterol Guide Summary


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Cholesterol Reduction

Flavonoids are known to reduce cholesterol. A 30-day study of induced hyperlipidaemia in rats found that baicalein, quercetin, rutin and naringin reduced cholesterol, with baicalein being the most potent. Baicalein was also the most effective flavonoid in reducing triglyceride levels (De Oliveira et al 2002). In another in vivo study, rats were fed a cholesterol-laden diet and half were also given 5. baicalensis radix extract (Regulska-llow et al 2004). The treatment rats displayed a significant reduction in plasma triglycerides and total cholesterol as compared with control animals.

Monogenic hypercholesterolemias

Cetp Pcsk9

Important insights into CHD pathogenesis have come from the study of monogenic hypercholes-terolemias, and have led to the development of the most widely used class of lipid-lowering drugs, the HMG-CoA-reductase inhibitors (statins). Among the many known risk factors for atherosclerosis, very high low density lipoprotein (LDL) cholesterol levels are probably unique in their ability to lead to the development of premature atherosclerosis in humans in the absence of other additional risk factors. Table 24.2 summarizes the main characteristics of the known Mendelian disorders of severe hypercholesterolemia, all of which are associated with premature CHD. Autosomal dominant hypercholesterolemias Familial hypercholesterolemia (FH) was the first genetic disease of lipid metabolism to be clinically and genetically characterized and it represents the most common and most severe form of Mendelian hypercholesterolemia (Goldstein et al., 2001). The disease is caused by mutations in the LDL...

Familial hypercholesterolemia and statins

Perhaps the most dramatic example of monogenic diseases leading to treatments for common disease concerns familial hypercholesterolemia (FH) and the development of statins (Goldstein et al., 2001). FH is a relatively common dominant condition affecting 1 500 of the population. Individuals with FH have high levels of cholesterol at birth and will develop atherosclerosis and vascular disease in childhood. The risk of fatal heart disease before the age of 40 years is significantly higher than among the general population. Approximately one-third of patients with FH show no symptoms until sudden cardiac death. Through the pioneering work of Brown and Goldstein, we know that FH is caused by loss of function mutations in the LDL receptor gene (LDLR). The LDL receptor removes cholesterol from the blood stream. This piece of genetic detective work proved that high cholesterol is the cause of coronary disease in these patients. Extrapolating from this monogenic condition, these findings...

Hypercholesterolaemia And Hypertriglyceridaemia

Niacin has been used for the treatment of hypercholesterolemia and hypertriglyceridaemia since the 1950s. Large doses of niacin reduce total cholesterol, LDL-cholesterol, triglycerides and lipoprotein (a) levels and also markedly raise HDL-cholesterol C levels (lllingworth et al 1994). Considering these factors are also predictive of cardiovascular events, niacin is used to reduce overall risk of cardiovascular disease (Canner et al 1986). According to a recent meta-analysis effects on LDL- 2007 Elsevier Australia cholesterol and triglycerides appear to be more significant in females especially at doses 1 500 mg day (Goldberg 2004). Extended-release niacin (nicotinic acid) has been evaluated in at least four randomised, placebo-controlled trials, with the most efficacious results occurring at doses of 1 500-2000 mg day (Goldberg 1998, Grundy 2002, Guyton et al 2000, Morgan et al 2003). Results were dose- and time-dependent, with trials ranging in length from 4 to 16 weeks. At the 1500...

Hypertension And Cholesterol Lowering

CoQ10 has been studied both as stand-alone and adjunctive treatment in hypertension. According to a review of 8 studies, supplemental CoQ10 results in a mean decrease in systolic blood pressure of 16 mmHg and in diastolic blood pressure of 10 mmHg (Rosenfeldt et al 2003). The effect on blood pressure has been reported within 10 weeks of treatment at doses usually starting at 100 mg daily. One small 10-week open study of 26 subjects with essential hypertension study found that an oral dose of 50 mg taken twice daily also reduced total serum cholesterol levels with a modest increase in serum HDL-cholesterol (Digiesi et al 1994).

Reduces Serum Cholesterol Levels

A 2000 meta-analysis of 13 clinical trials concluded that garlic is superior to placebo in reducing total cholesterol levels, exerting a modest effect (Stevinson et al 2001). The mechanism of action involves inhibition of cholesterol synthesis by deactivating HMG-CoA reductase via enhanced phosphorylation, but not changing theamount of the enzyme, according to in vitro research (Liu & Yeh 2002). The compounds containing an allyl-d sulfide or a I lyl-su If hyd ryl group are most likely responsible for the inhibition of cholesterol synthesis by garlic and that this inhibition is likely to be mediated at sterol 4-alpha-methyl oxidase (Singh & Porter 2006). Clinical evidence also suggests it raises HDL levels and reduces triglyceride levels (Bordia et al 1998).

Ulcyte Or Questran

Lipex, Zocor) Cholestyramine (e.g. Questran lite, colestipol e.g. Colestid ) HMG-CoA reductase inhibitors (statins) HMG-CoA reductase inhibitors (statins) Cholestyramine (e.g. Questran lite, colestipol e.g. Colestid ) 1448 tions 1431 Cholestyramine (e.g. Questran lite, colestipol e.g. Colestid ) Cholestyramine (e.g. Questran lite, colestipol e.g. Colestid ) Willowbark

High Cholesterol

Probiotics modestly reduce cholesterol levels in healthy subjects and may have stronger effects in people with hyperlipidaemia. In another study, 32 subjects with serum total cholesterol ranging from 5.7 to 7.25 mg dl_ were randomly assigned to two treatments (1) Intake of a low-fat drinking yoghurt prepared with two ordinary yoghurt starters (Streptococcus thermophilus and Lactobacillus delbrueckii subsp. Bulgaricus placebo group) and (2) Intake of a low-fat drinking yoghurt prepared with the two yoghurt starters plus Bifidobacterium longum strain BL1 (problotlc group). After Intake for 4 weeks at 3 100 mL day, reduction of serum total cholesterol was observed In approximately half of the problotlc group subjects a particularly significant decrease In serum total cholesterol was found among subjects with moderate hypercholesterolemia (serum total cholesterol 6.2 mg dL). The serum lipid concentrations In the placebo group subjects were almost stable during the experimental periods...

Liver X and Farnesoid X Receptors

In addition, FXR activates expression of yet a fourth orphan receptor, SHP-1, which then dimerizes with the constitutively active LRH-1 and attenuates LRH LXR-mediated transcription of CYP7A, preventing further synthesis of bile acids from cholesterol.417 Despite its crucial role in gating bile acid biosynthesis and cholesterol clearance, LXRa is apparently not essential for survival as deletion of mouse LXRa yields phenotypically normal mice.418 However, when challenged with a high-cholesterol diet, these animals accumulate cholesterol in the liver due to failure to induce CYP7A activity, in spite of the presence of functional LXRj. Oxysterols apparently also upregulate expression of proteins involved in sterol lipid transport. For example, certain ABC transporters involved in lipid transport and cholesterol ester transfer proteins are activated through LXR signaling.419-421 An additional level of regulation may include transcriptional induction of...

Feedback Regulation Is Not Synonymous With Feedback Inhibition

In both mammalian and bacterial cells, end products feed back and control their own synthesis, in many instances by feedback inhibition of an early biosyn-thetic enzyme. We must, however, distinguish between feedback regulatio n, a phenomenologic term devoid of mechanistic implications, and feedback inhibition, a mechanism for regulation of enzyme activity. For example, while dietary cholesterol decreases hepatic synthesis of cholesterol, this feedback regulation does not involve feedback inhibition. HMG-CoA reductase, the rate-limiting enzyme of cholesterologenesis, is affected, but cholesterol does not feedback-inhibit its activity. Regulation in response to dietary cholesterol involves curtailment by cholesterol or a cholesterol metabolite of the expression of the gene that encodes HMG-CoA reductase (enzyme repression) (Chapter 26).

Pathogenesis of mitochondrial toxicity

An intact respiratory chain is the prerequisite for numerous metabolic pathways. The main task of the respiratory chain is to oxidatively synthesize ATP, our chemical currency of energy. In addition, the respiratory chain consumes NADH and FADH as end products of fatty acid oxidation. This fact explains the micro- or macrovesicular accumulation of intracellular triglycerides, which often accompanies mitochondrial toxicity. Last but not least, a normal respiratory function is also essential for the synthesis of DNA, because the de novo synthesis of pyrimidine nucleosides depends on an enzyme located in the inner mitochondrial membrane. This enzyme is called dihydroorotate dehydrogenase (DHODH) (Loffler 1997). The clinical implications of this fact are detailed below. The onset of mitochondrial toxicity follows certain principles (Walker 2002b)

Individual and Population Examples

As a general rule, individual-directed interventions bring about significant benefits to the individuals but have little impact on the population rates of disease or condition in question and vice versa for population-based interventions, which generally bring little benefit to each individual but have the potential to influence the prevalence or incidence of the condition (7). With obesity, this discrepancy is even more exaggerated (compared to, say, hypertension or hypercholesterolemia) because available individual interventions, apart from surgery, have modest long-term effects for the individuals under treatment (8,9). The efforts on population-based interventions related to obesity are much needed but are still in their infancy (1,10,11).

Using Hormonal Strategies To Improve Mammographic Density And Sensitivity Of Screening Mammograms

There may be women in whom reducing hormone levels will not result in reduced density. For such women and for women who due to medical (high cholesterol) or other reasons do not wish to reduce their hormone levels, alternative imaging techniques, currently being developed and tested, may be a good alternative.52

Body Size At Birth And Later Body Composition

Associated with body mass index and with the area of thigh muscle but not with subcutaneous fat on the thigh. The association between birth weight and body mass index may therefore have reflected an association with lean tissue rather than fat. Waist-hip ratio and truncal fat also have different metabolic associations. Waist-hip ratio is more strongly associated with serum triglyceride and HDL cholesterol concentrations than is the sub-scapular-triceps skinfold ratio (22). The associations between low birth weight and these two measures of body composition are likely to reflect influences in the intrauterine environment that are either different or act at different times.

Transduction of the Liver

Kim et al. (66) investigated correction of hypercholesterolemia in apolipoprotein E (apoE)-deficient mice by using either an FGAd-encoding mouse apoE cDNA (FG-Ad5-cE), an HDAd-encoding mouse apoE cDNA (HD-Ad5-cE), or an HDAd-bearing mouse genomic apoE locus (HD-Ad5-gE). Intravenous injection of ApoE-deficient mice with 5 X 1012 particles kg of FG-Ad5-cE resulted in an immediate fall in plasma cholesterol levels to within normal range (Fig. 6A). However, this effect was transient and plasma cholesterol levels increased after 28 days, returning to pretreatment levels by 112 days. Correlative with the plasma cholesterol levels, the levels of plasma apoE immediately increased shortly after injection but rapidly declined to pretreatment levels by day 28 (Fig. 6B). Similarly, intravenous injection of 7.5 X 1012 particles kg of HD-Ad5-cE produced a complete and immediate lowering of plasma cholesterol to normal levels, but in contrast to FG-Ad5-cE, the reduced levels lasted about 1 year...

Preventing Cardiovascular Disease

A double-blind, placebo-controlled study investigating the effects of a quercetin-containing supplement on plasma quercetin status, risk factors for heart disease and serum platelet fatty acid levels was conducted on 27 healthy men and women with cholesterol levels of 4.0-7.2 mmol L (Conquer et al 1998). The subjects consumed a quercetin-containing supplement (1 g quercetin day) or rice flour placebo for 28 days. Quercetin intakes were approximately 50-fold greater than dietary intakes previously associated with lower coronary heart disease mortality in epidemiologic studies. Plasma quercetin concentrations were approximately 23-fold greater in subjects consuming the quercetin capsules than in the placebo group. Quercetin supplementation did not alter serum total, LDL- or HDL-cholesterol or triglyceride levels, or other cardiovascular disease or thrombogenic risk factors such as platelet thromboxane B2 production, blood pressure or resting heart rate. This is in contrast to a previous...

Cardiovascular Effects

In a double blind, placebo-controlled, randomised trial of red clover-derived isoflavones (43.5 mg day), with 205 women aged between 49 and 65 years, active treatment had no significant effect on total cholesterol or HDL- and LDL-cholesterol levels or triglycerides (Atkinson et al 2004b). A single-blind, randomised crossover study of 21 healthy premenopausal women (aged 18-45 years) found that tablets containing 86 mg day isoflavones for two menstrual cycles did not significantly change total cholesterol, HDL- or LDL-cholesterol or triglyceride levels (Samman et al 1999). Another study of postmenopausal women with mild to moderate hypercholesterolemia also found red clover did not significantly affect plasma lipids (Howes et al 2000). A recent double-blind, randomised parallel study found that 86 mg day purified isoflavones derived from red clover also had no effect on cholesterol homeostasis or insulin resistance in 25 premenopausal women (Blakesmith et al 2003). However, there have...

Osteoporosis and Cardiovascular Disease in the Elderly

Osteoporosis and cardiovascular disease are common disorders that increase with aging. Accumulating evidence indicates that both disorders may share common pathophysiologic mechanisms as well as risk factors. Besides age and sedentary lifestyle, diabetes, hypertension, dyslipidemia, estrogen deficiency, and hyperhomo-cysteinemia are common risk factors for both disorders. Furthermore, therapeutic agents for osteoporosis have antiatherosclerotic properties and agents such as statins that are atheroprotective, and appear to increase bone mass and perhaps protect against fractures.

Cardiovascular Disease

There are many potential mechanisms by which soy may improve cardiovascular outcomes, including reduction in total cholesterol, LDL, HDL, triglycerides, lipoprotein a, blood pressure, C-reactive protein, homocysteine, endothelial function, systemic artery compliance, and oxidised LDL (Balk et al 2005). A review by the North American Menopause Society suggests that the most convincing health effects of soy can be attributed to the actions of isoflavones on lipids, with studies finding statistically significant reductions in LDL and triglycerides, as well as increases in HDL (Greenwood et al 2000). It is unclear how soy exerts its beneficial effects on lipid metabolism or Soy 1107

Monogenic genes as genetic risk factors in common disease

Mobogenic Sexy Video

Figure 10.1 Mortality from familial hypercholesterolemia according to sex and time. Mortality was estimated among 250 persons with 0.5 probability of carrying the V408M. Probands and the first 20 years of life were ignored. From Sijbrands et al., 2001. Figure 10.1 Mortality from familial hypercholesterolemia according to sex and time. Mortality was estimated among 250 persons with 0.5 probability of carrying the V408M. Probands and the first 20 years of life were ignored. From Sijbrands et al., 2001. Goldstein, J., Hobbs, H. and Brown, M. (2001). Familial hypercholesterolemia. In Scriver, C., Beaudet, A., Sly, W. and Valle, D., eds., The Metabolic and molecular bases of inherited disease. New York McGraw-Hill. pp. 2863-913. in Alzheimer's disease. Annu Rev Med, 47, 387-400. Rozmahel, R., Wilschanski, M., Matin, A. et al. (1996). Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nat Genet, 12, 280-87....

Atherosclerosis and Aging

There are two explanations for the increased prevalence of vascular disease in the elderly (1) the increased risk represents a longer duration of exposure to conditions that promote atherosclerosis (i.e., the time-dose product of the risk factors) and (2) atherosclerosis is a specific aging-associated process. It is important to note that these possibilities are not mutually exclusive and that from the perspective of a given elderly individual at risk for vascular disease, this distinction may not matter much. However, discrimination between these hypotheses has important implications for prevention of vascular disease, particularly at the population level. In the former case, preventive therapies should focus on early interventions on established risk factors such as hypercholesterolemia, hypertension, diabetes, obesity, and smoking in the latter case, specific therapies may be required to target the aging-associated mechanisms that accelerate atherosclerosis in the elderly.

Ginseng And Atherosclerosis

Atherosclerosis involves the irregular deposition of lipids such as cholesterol and triglycerides in yellowish plaques of atheroma in the subintimal layers of the inner walls of arteries and arterioles. Calcification may also occur with consequent hardening of the arteries. Atherosclerosis most commonly affects coronary arteries, cerebral arteries and peripheral arteries of the lower limbs. As a progressive condition it is particularly associatedm with old age. Ginseng was suggested as a medicament for the control of cholesterol levels and for the treatment of anaemia. Experimental evidence does shew that ginseng is capable of increasing the red blood cell count, of promoting serum protein synthesis and of stimulating RNA formation in the liver and DNA synthesis in bone marrow. Cholesterol, a steroid alcohol, occurs naturally in the body and is found particularly in the bile and gall bladder and in the lipoproteins of the blood plasma. Although endogenous cholesterol can be formed in...

Tools and Targets of Gene Therapy

Muscle Implants For Muscular Dystrophy

The liver is a very important focus of gene therapy because it controls many bodily functions and because it can regenerate. A gene therapy that corrects just 5 of the 10 trillion cells of the liver could produce an effect. For example, a liver gene therapy targets heart disease. Normal liver cells have low-density lipoprotein (LDL) receptors on their surfaces, which bind cholesterol in the bloodstream and bring it into the cell. When liver cells lack LDL receptors, cholesterol accumulates on artery interiors. Liver cells genetically altered to have more LDL receptors can relieve the cholesterol buildup. Such gene therapy could be lifesaving for children who have inherited familial hypercholesterolemia (see fig. 24.7). familial hypercholesterolemia

Fenugreek Seed And Leaf

In Indonesia, fenugreek is used to promote hair growth. In India, Southeast Asia, and Ethiopia, the seeds are soaked in water (the seeds swell because they are coated with mucilage) and are then drained and eaten to aid digestion, as a laxative, to treat bronchitis, and to cure sore throats. It is used to prevent sharp rises in blood sugar and to lower cholesterol.

Clinical Terms Related to the Cardiovascular System

A variety of inherited and environmental factors contribute to causing cardiovascular disease. Many cases are probably due to a fatty diet and sedentary lifestyle, against a backdrop of genetic predisposition. Disorders of the heart and blood vessels caused by single genes are very rare, but understanding how they arise can provide insights that are useful in developing treatments for more prevalent forms of disease. For example, widely-used cholesterol lowering drugs called statins were developed based on analyzing the molecular malfunction behind the one-in-a-million inherited condition familial hypercholesterolemia. Low-density lipoprotein (LDL) receptors on liver cells admit cholesterol into the cells, keeping the lipid from building up in the bloodstream and occluding arteries. When LDL receptors bind cholesterol, they activate a negative feedback system that temporarily halts the cell's production of cholesterol. In the severe form of familial hypercholesterolemia, a person...

Antiirritation By Refattening Agents

One of the effects of surfactants on skin is the alteration of its permeability barrier, which can be easily assessed by measuring the transepidermal water loss 17,18 . Using refat-tening ingredients or skin barrier repairing ingredients in the surfactant-based product can lead to a reduction of irritation if appropriately delivered to the skin surface. Such ingredients are often the basis for barrier cream effect when topically applied before or after contact with an irritant. Some of these ingredients can, however, be formulated into a surfactant system to act directly as anti-irritants in the mixture. The occlusive effect they bring at the surface of the skin delays the water loss and maintains the skin in a less dehydrated state. Furthermore, they can introduce a barrier that can protect the skin against surfactants when running repetitive applications. Several types of refattening ingredients are available and can be formulated in surfactant systems, such as ethoxylated mono-,...

Historical Perspectives

Many published accounts of the composition of lipids from human stratum corneum have been complicated by the almost inevitable presence of sebaceous lipids as well as exogenous contaminants. When stratum corneum samples are obtained from excised skin, there is almost always massive contamination with subcutaneous triglycerides as well as fatty acids derived from the subcutaneous fat. In addition, precautions must be taken to avoid contamination with environmental contaminants such as alkanes and cosmetic components. As a result of these complications, much work has been done with pig skin as a model 1-6 .

Apolipoprotein E APOE

Specifically, reduction in cellular cholesterol availability results in significant changes in APP trafficking and processing, with the resultant reduction in Ab formation (Runz et a ., 2002). In addition, patients who have taken statins for hypercholester-olemia appear to have a reduced incidence of Alzheimer's disease (Fassbender et a ., 2001 Jick et a ., 2000 Wolozin et a ., 2000).

Significant Interactions

X-v cholesterol-lowering medication Policosanol 941 Considering the mode of action of policosanol, it is likely to increase the cholesterol-lowering effects of statin drugs. However, a theoretical concern exists as to whether concurrent use will also increase the likelihood of adverse effects.

Soap Raw Materials Fats and Oils

The naturally occurring fats and oils used in soap making are glycerides with three fatty acid groups randomly esterified with glycerol (trihydroxy alcohol). The difference between fats and oils is merely one of their physical states fats are solids and oils are liquids. Fats and oils typically comprise both saturated and unsaturated fatty acid molecules containing between 7 and 21 carbons randomly distributed on the glycerol backbone. Overall, the reaction of caustic (lye) with triglycerides yields glycerin and soap in a reaction known as saponification. This is the most widely used soap making process. The second major soap making process is the neutralization of fatty acids with an alkali. Fats and oils are hydrolyzed (split) with high-pressure steam to yield crude fatty acids and glycerin. The fatty acids are then purified by distillation and neutralized with an alkali to produce soap and water (neat soap) 2-7 .

Clinical Classification

Liposarcoma Lump

Lipodystrophy is a loss of body fat in one or more regions of the body (19). It can have genetic causes or it can be acquired. Table 1 shows the various types of lipodystrophy. The clinical features include regional or general decrease in adipose tissue, severe insulin resistance, often with diabetes, markedly elevated triglycerides, and fatty liver. Acanthosis nigricans is also common. Animals with no body fat (20) show similarly marked insulin resistance that can be relieved when small amounts of fat are transplanted into the fat-deficient animals.

Increased Physical Activity

Increased physical activity improves cardiorespira-tory fitness, with or without weight loss. The latter improves the quality of life in overweight patients by improving mood, self-esteem, and physical function in daily activities. Physical activity reduces elevated levels of CVD risk factors, including blood pressure and triglycerides, increases HDL cholesterol, and improves glucose tolerance with or without weight loss. Furthermore, the more active an individual is, the lower the risk for CVD morbidity and mortality, and diabetes. Physical activity apparently has a favorable effect on distribution of body fat. Several studies showed an inverse association between energy expenditure through physical activity and several indicators of body fat distribution. Only a few randomized controlled trials that have tested the effect of physical activity on weight loss measured waist circumference. In some (but not all) studies, physical activity was found to produce only modest weight loss and...

Typical vs Atypical Ischemia

Once we consider it more likely than not that this patient had ischemic disease, the question of whether it was typical or atypical is somewhat more difficult to ascertain. First, it is necessary to define these two terms. Typical ischemic heart disease is generally considered secondary to coronary atherosclerosis, with atherosclerotic plaque (s) narrowing the lumen and causing damage to the coronary artery wall. The presence of atherosclerosis may increase the possibility of superimposed coronary artery lesions including acute plaque hemorrhage or rupture, luminal thrombosis, and or coronary artery spasm. The presence of atherosclerosis does not provide information concerning the pathogenesis of the plaque, whether it is idiopathic but associated with cigarette smoking, hypercholesterolemia, hypertension, or diabetes mellitus (or combinations of all of these), or whether it may be secondary to less common risk factors such as hyperhomocysteinemia, cocaine use, or radiotherapy (chest...

Monogenic disorders causing impaired reverse cholesterol transport

Low HDL cholesterol is a common finding in patients with premature CHD and usually precedes clinically apparent CHD (Goldbourt et al., 1997). Low HDL concentrations are most frequently associated with the components of the metabolic syndrome X and are rarely due to single-gene disorders (Durrington, 2003). The rare Tangier disease, characterized by very low or even Conversely, cholesterol ester transfer protein deficiency, which is a common cause for high HDL concentrations ( 2.5 mmol l) in Japan is thought to be a state of impaired reverse cholesterol transport, which may lead to premature CHD (Nagano et al., 2002). Thus, HDL cholesterol levels, efflux of cellular lipids as well as the kinetics of HDL metabolism are important determinants of the antiatherogenic effect of HDL (Tall, 1998 von Eckardstein, 2001).

Warfarin Resistance and Unstable INRS

It is less common for medicines to inhibit the action of warfarin than to potentiate it. Common drugs which inhibit warfarin action are barbiturates, rifampin, and nafcillin. Patients on these medications may require 20 mg of warfarin per day to maintain a therapeutic INR. Since most drug-warfarin interactions are mediated through induction of liver enzymes, it may take several days for the warfarin resistance to be noticed after starting the drug and several days for the effect to wear off after stopping the drug. Cholestyramine uniquely interferes with warfarin absorption.

Gh Treatment Of Patients With Abdominal Obesity

Hormone Transition Photoshot

We have learned that GH can improve several of the aberrations that occur both in GH deficiency and Syndrome X. Thus, in GH-deficient adults the lipolytic effects of GH results in a preferential reduction in visceral adipose tissue (66). Furthermore, GH reduces the diastolic blood pressure (103), reduces total cholesterol, LDL-cholesterol (57,104-106), and increases HDL-cholesterol concentrations (78,105,107). Furthermore, long-term GH treatment does not impair insulin sensitivity (82). With this background we have studied the effects of GH on the metabolic, circulatory, and anthropodometric aberrations associated with abdominal visceral obesity and Syndrome X (108).

Present Role Of Laboratory Animals

The atherosclerotic lesion mouse contributes to progress in the fight against atherosclerosis and related illnesses. Apo E3 transgenic mice express the human dysfunctional apo E variant of the apoli-poprotein. The Apo E3 transgenic mouse develops hyperlipidemia and atherosclerosis on a high fat high cholesterol diet. Plasma cholesterol levels in the apo E3 mice increase in 4 months, and they develop atherosclerotic lesions in their aortas. Because these lesions resemble those in human patients with atherosclerosis, the apo E3 mouse is a valuable animal model for studies on the genetics, development, and therapy of atherosclerosis.13

Mutations Affecting Membrane Proteins Cause Diseases

Amino acids, sugars, lipids, urate, anions, cations, water, and vitamins across the plasma membrane. Mutations in genes encoding proteins in other membranes can also have harmful consequences. For example, mutations in genes encoding mitochondrial membrane proteins involved in oxidative phosphorylation can cause neurologic and other problems (eg, Leber's hereditary optic neuropathy LHON). Membrane proteins can also be affected by conditions other than mutations. Formation of autoantibodies to the acetyl-choline receptor in skeletal muscle causes myasthenia gravis. Ischemia can quickly affect the integrity of various ion channels in membranes. Abnormalities of membrane constituents other than proteins can also be harmful. With regard to lipids, excess of cholesterol (eg, in familial hypercholesterolemia), of lysophospho-lipid (eg, after bites by certain snakes, whose venom contains phospholipases), or of glycosphingolipids (eg, in a sphingolipidosis) can all affect membrane function....

Oral contraceptives

Estrogens can cause nausea, breast tenderness and breast enlargement. Progestins can cause unfavorable changes in LDL and HDL cholesterol. Other adverse effects associated with oral contraceptives, such as weight gain or depression, are more difficult to attribute to one component or the other. Women smokers more than 35 years old who use combination oral contraceptives have an increased risk of cardiovascular disease.

Genetic and environmental contributions to CHD pathogenesis

Whilst environmental influences account for a significant part of individual and population susceptibility to CHD, the longevity of some individuals with multiple risk factors (e.g. smoking, hypercholesterolemia, hypertension), and the consistent and highly significant risk conferred by a positive family history of CHD, point to the importance of genetic factors in CHD pathogen-esis. Genes which control plasma lipids and lipoproteins are amongst the clearest examples of genetic risk factors for CHD (Table 24.1). Raised LDL cholesterol, triglycerides reduced HDL cholesterol

Children Of Centenarians

Offspring of centenarians have been found to have lipid profiles associated with lower risk for cardiovascular disease (Barzilai, Gabriely, Gabriely, Iankowitz, and Sorkin, 2001). Other findings show that middle-aged sons of long-lived parents had better systolic pressures, cholesterol levels, and decreased frequencies of the apoE fi-4 allele, compared to middle-aged sons of shorter-lived parents. Using a questionnaire-based cross-sectional study design, Terry and colleagues (2004) assessed the

Management of Side Effects

It must be stressed that the majority of patients are able to tolerate HAART well, even over years. Nevertheless, the monitoring of treatment by an HIV clinician, even in asymptomatic patients, is recommended in at least three-monthly intervals, and even more often at the beginning of a new HAART, when it should be weekly or fortnightly. Standard evaluations include a thorough history (allergies , other side effects ), physical examination and measurement of vital signs and body weight. Routine investigations include a full blood count, liver, pancreas and renal function tests, electrolytes (plus phosphate in patients on tenofovir) as well as fasting cholesterol, triglycerides and glucose levels.

Clinical manifestation

Frequently, complex metabolic alterations are associated with the described body shape alterations. These include peripheral and hepatic insulin resistance, impaired glucose tolerance, type 2 diabetes, hypertriglyceridemia, hypercholesterolemia, increased free fatty acids (FFA), and decreased high density lipoprotein (HDL). Often these metabolic abnormalities appear or deteriorate before the manifestation of fat redistribution. The prevalence of insulin resistance and glucose intolerance has been reported in the literature at 20 to 50 depending on the study design and measurement methods. Frank diabetes is less frequent with a prevalence of between 1 and 6 . Lipodystrophic patients present with the highest rates of metabolic disturbances. The therapy-induced dyslipidemias are characterized by increased low density lipo-proteins (LDL) and triglyceride-rich very low density lipoproteins (VLDL). Detailed characterization revealed an increase of apoplipoprotein B, CIII and E. Raised...

Hormone replacement therapy administration and regimens

In those women with a uterus, a progestin should be given continuously (2.5 mg of medroxyprogesterone per day) or in a sequential fashion 5-10 mg of medroxyprogesterone (Provera) for 1214 days each month . The most common HRT regimen consists of estrogen with or without progestin. The oral route of administration is preferable because of the hepatic effect on HDL cholesterol levels. modulator, FDA-labeled for prophylactic treatment of osteoporosis. This agent offers an alternative to traditional HRT. The modulator increases bone density (although only one-half as effectively as estrogen) and reduces total and LDL cholesterol levels.

Cholesterol Lowering Conjugates Designed to Function Through the Hepatic Lectin

In contrast to the approaches described above in which molecules designed to function within the liver are delivered through their interaction with the hepatic lectin, a strategy to use the hepatic lectin to eliminate unwanted species from serum has also been investigated. Specifically, Biessen et al. attempted to take advantage of hepatic lectin mediated endocytosis and subsequent ligand proteolysis to lower serum cholesterol levels 134 . It was anticipated that targeting the proteins responsible for serum cholesterol transport, high-density lipoprotein (HDL) and low-density lipo-protein (LDL), to hepatocytes via the hepatic lectin would lead to their degradation, thereby lowering serum cholesterol. Bifunctional ligand 29 was designed, in which cholesterol was linked to a trivalent galactose derivative (Fig. 20). When added to serum, compound 29 formed complexes with HDL and LDL. Intravenous injection of 29 into rats resulted in a decrease in detected serum cholesterol levels by 44 ....

Biomedical Demography

Demographers over the past half century have increasingly become involved with the design of surveys and the analysis of survey data, especially pertaining to fertility or morbidity and mortality. Recently, various kinds of physical measurements (height and weight), physiological measurements (of blood pressure and cholesterol levels), nutritional status (assessed by the analysis of blood or urine and other methods), physical performance (hand-grip strength or ability to pick a coin up from the floor), and genetic makeup (as determined by analysis of DNA) have been added to surveys, including those conducted by Christensen, Goldman, Weinstein, Zeng, and others. Such biological measurements can be used as covariates in demographic analyses in much the same way that social and economic information is used. These kinds of analyses are an important activity of biomedical demographers (Finch et al. 2000).

STI at the Patients Wish for Reduction of Toxicity

Interruption of therapy can have psychological advantages (Tuldra 2001). Quality of life improves (Moreno 2003), and many patients are relieved of the burden of continuous, lifelong therapy. Clinicians should take the wish for treatment interruption seriously. Presumably most patients expressing such a wish will interrupt sooner or later anyway so the interruption may as well be structured What about side effects Increased lipid levels (cholesterol, triglycerides) drop quite rapidly after stopping treatment (Hatano 2000, Jaeger 2002). However, the reduction of drug exposure during interruptions is unlikely to be so significant as to affect the cardiovascular risk profile.

Cardiovascular Protection

There are a number of ways in which beta-carotene may act to protect against cardiovascular disease. Free radical scavenging may prevent cellular transformations leading to atherosclerosis and protection of LDL oxidation may further act to protect against atheroma formation (Halliwell 1993). Other mechanisms proposed for the possible favourable effect of antioxidants include an increase of HDL cholesterol and the preservation of endothelial functions (Tavani & La Vecchia 1999). Patients with acute myocardial infarction (AMI) have also been shown to have reduced plasma antioxidant vitamins and enhanced lipid peroxidation upon thrombolysis, suggesting that antioxidants may reduce free radical generation processes in reperfusion injury in AMI (Levy et al 1998). In an animal study, atherosclerosis was inhibited in rabbits fed a high-cholesterol diet supplemented with all-trans beta-carotene. In that study all-trans beta-carotene 2007 Elsevier Australia

The Maternal UPD14 Syndrome

With the exception of one case of no apparent phenotype (Papenhausen et al., 1995), which was insufficiently documented at the molecular level (Robinson and Langlois, 1996), all other cases further illustrated this emerging syndrome (Coviello et al., 1996 Tomkins et al., 1996 Sirchia et al., 1994 Barton et al., 1996 Linck et al., 1996 Walgenbach et al., 1997 Splitt and Goodship, 1997 Robinson et al., 1994 Desilets et al., 1997 Miyoshi et al., 1998 Ralph et al., 1999 Harrison et al., 1998 Fokstuen et al., 1999 Martin et al., 1999). The birth is often premature and the birthweight low for gestational age. In about 30 of cases, the head grows rapidly in the postnatal period, owing to a hydrocephalic condition that, however, arrests spontaneously. A suggestive facies with prominent forehead (in association with arrested hydrocephalus) and supraorbital ridges, a short philtrum, and downturned mouth corners are present (Figure 2). There is hypotonia, hyperextensible joints, mild to moderate...

Relative frequency distributions

As Table 1-2 shows, a grouped frequency distribution can be transformed into a relative frequency distribution, which shows the percentage of all the elements that fall within each class interval. The relative frequency of elements in any given class interval is found by dividing , the frequency (or number of elements) in that class interval, by n (the sample size, which in this case is 200). By multiplying the result by 100, it is converted into a percentage. Thus, this distribution shows, for example, that 19 of this sample had serum cholesterol levels between 211 and 220 mg dl.

Frequency Distributions

A set of unorganized data is difficult to digest and understand. Consider a study of the serum cholesterol levels of a sample of 200 men a list of the 200 levels would be of little value in itself. A simple first way of organizing the data is to list all the possible values between the highest and the lowest in order, recording the frequency ( ) with which each score occurs. This forms a frequency distribution. If the highest serum cholesterol level were 260 mg dl, and the lowest were 161 mg dl, the frequency distribution might be as shown in Table 1-1

Specific interventions

Given the extensive indications that PIs are the culprits substantially contributing to the metabolic side effects, numerous attempts have tried to substitute the PI component of a regimen with nevirapine, efavirenz, or abacavir. Similarly, given the close association of stavudine-based therapy with lipoatrophy, replacement of this thymi-dine nucleoside analogue by, for example, abacavir or tenofovir has been evaluated in several studies. Indeed, these switch studies have demonstrated substantial improvement, although not normalization, of serum lipids (total and LDL cholesterol, triglycerides) and or insulin resistance in many patients. Protease inhibitor cessation has not been shown to improve lipoatrophy. However, stopping administration of the thymidine nucleoside analogue stavudine or zidovudine usually leads to a slow recovery (over months and years) measured by DEXA and moderate clinical increase in limb fat (Moyle 2005). Under restricted inclusion criteria and study...

Protease inhibitors PIs

All protease inhibitors can be used in combination with 2 NRTIs. PIs differ from each other in respect to their tolerability and side effects. As with adults, dyslipide-mia is associated with the use of protease inhibitors (Lainka 2002). It includes elevated total cholesterol, triglycerides (TG), and low density lipoprotein cholesterol (LDL-c) and decreases in high density lipoprotein cholesterol (HDL-c) In lipodys-trophy, there is a loss of subcutaneous fat (lipoatrophy) and or a deposition of fat tissue subcutaneously or in visceral stores (lipohypertrophy) including the presence of dorsocervical fat accumulation ( buffalo hump ) and increased waist-to-hip ratio. Lipoatrophy is marked by thinning of subcutaneous fat in the face, buttocks, and extremities associated with a prominent appearance of peripheral veins. The body habitus changes usually occur gradually over months to years. The exact prevalence of lipodystrophy in children is unknown and there are no clear diagnostic...

Etiology and Pathogenesis

The relationship between depression and cardiovascular disorders also provides insight into the mechanisms of depression. Abnormalities in neurotransmitters (including serotonin), platelet-activating factor, and nitric oxide, which are involved in atherosclerotic processes, have been implicated in the pathogenesis of depression (Plante, 2005). Moreover, vascular consequences of depression such as heart rate and pulse pressure variations may lead to endothelial dysfunction in critical microcirculation networks (cerebral, myocardial, and renal) and initiate physicochemical alterations in interstitial compartments adjacent to vital organs. Worsening depressive symptoms after a coronary event were associated with impaired autonomic control of the heart, and mortality was almost three times higher among the patients with MDD at the time of the initial event compared to those without depression (de Guevara et al., 2004). The finding of higher rates of relapse of depression among patients...

What Should Be Clarified Beforehand

Interactions are important in the choice of combination regimens. Whereas interactions between antiretroviral drugs are well known, interactions with other concomitant medications are often less well characterized. The urgent need for more research was recently demonstrated in a study investigating the interactions between HAART and statins. In healthy volunteers, the measurement of plasma levels showed that levels of simvastatin were elevated by 3,059 after concurrent dosing with ritonavir or saquinavir (Fichtenbaum 2002). One case of fatal rhabdomyolysis on simvastatin and nelfinavir has been described (Hare 2002). Many drugs should be avoided in combination with particular antiretroviral drugs, as incalculable interactions may occur. These include certain contraceptives. Even drugs that seem unproblematic at first glance can have unfavorable effects one study that received a lot of attention showed that plasma levels of saquinavir were

Relationship to Classical Indexes

It is important to analyze whether the previous analysis methodology for parameterizing the vessel behavior during the flow-mediated dilation test is linked to other clinical parameters and CVD risk factors traditionally used in the medical literature. Serum lipids, particularly cholesterol and the cholesterol fraction carried by low-density lipoproteins (LDL cholesterol) are recognized as a main causal factor of atherosclerosis 34 . In this disease lipids accumulate in the vessel wall, disturbing the vascular function of delivering sufficient blood flow to the affected territories, which ends with the manifestation of a vascular clinical event like heart attack or stroke. Moreover, knowing patients' lipid levels and modifying them with drugs and diet is the main preventive tool against cardiovascular diseases. From this point of view, cholesterol and LDL cholesterol are considered as risk factors, as higher levels identify individuals with higher risk whereas the cholesterol fraction...

Prevention Of Morbidity And Mortality Of Cardiovascular Disease

For over 25 years, fish and fish oils have been linked to cardiovascular health. This association was first recognised when significantly lower death rates from acute myocardial infarction (Ml) were found among Greenland's Inuit population, despite only moderate differences between the Inuits' blood cholesterol levels and those of other populations (Holub 2002). A high dietary omega-3 fatty acid intake in the form of marine mammals (seal, whale) and various fish were thought responsible for the protective effect (Bang et al 1980). In 1989, results from the first large, randomised, clinical trial investigating the effects of fatty fish consumption on survival and risk of secondary Ml confirmed a link to cardiovascular health (Burr et al 1989). The DART (Diet and Reinfarction study) found a modest intake of 2-3 portions weekly of fatty fish reduced mortality in men who had previously experienced a Ml and produced a relative reduction in total mortality of 29 during the 2-year follow-up,...

Dietary Sources and Metabolism of Vitamin A 321 Food Sources of Vitamin A

The two sources of retinol in the enterocyte (retinol that is absorbed directly by the enterocyte and retinol generated through cleavage of P-carotene and subsequent reduction of retinal to retinol) have the same metabolic pathway of esterification with long-chain fatty acids and release into the lymphatic circulation. In the enterocytes, lecithin-retinol acyltransferase (LRAT) and acyl-CoA-retinol acyltransferase (ARAT) are thought to be involved in the esterification of retinol, with retinyl esters formed by LRAT targeted for secretion in chylomicrons and retinyl esters formed by ARAT targeted for storage (148). The four main retinyl esters are produced in a proportion of about 8 4 2 1 for retinyl pal-mitate, retinyl stearate, retinyl oleate, and retinyl linoleate (170,171). The amount and type of fatty acids ingested with preformed vitamin A in the diet can modulate the pattern of retinyl esters that are secreted in chylomicrons (172). Chylomicrons are spherical lipoprotein...

Milk Composition and Purification of the Target Protein

It is important from a purification point of view that the fat is present in globular form in the size range of 0.1-10 (xm and with a density higher than the other constituents. The fat globule is enclosed in a membrane of polar lipids and proteins. Triglycerides make up 97 of the fat.

Endothelium Derived Vasoactive Substances

Endothelium-derived hyperpolarizing factors appear to play important roles, especially in the microvascula-ture (82). The chemical identity of EDHF has been related to several factors, such as epoxyeicosatrienoic acid (EET) (83), K+ (84), and anandamide (85). There is an emerging consensus that EDHF is unlikely to be a single factor and that considerable tissue and species differences exist for the nature and cellular targets of the hyperpolarizing factors. One of the potential targets is a KCa channel. Randall and Kendall (85) showed that anandamide, an endogenous cannabinoid derived from arachidonic acid, causes vasodilatation via opening of KCa channels. Hayabuchi et al. (86) demonstrated that EET also opens KCa channels via G-protein without changes in cAMP or cGMP. It is of interest that aging and hypercholesterolemia impair EDHF-mediated relaxation however, the mechanisms of impairment are not clear (82).

Transfer of Cholesterol to the Mitochondrion

Steroid-synthesizing cells have at least three metabolically active pools of cholesterol (1) a small, metabolically active pool of free cholesterol (2) a large storage pool in which cholesterol is stored as cholesterol esters of free fatty acids and (3) a fixed pool of membrane cholesterol, which is not available for steroid synthe-sis.9 The free cholesterol pool is formed from endogenous conversion of acetate to cholesterol via a complex series of reactions and by hydrolysis of cholesterol esters, including those that are part of the storage pool and those that are constituents of low-density lipoprotein (LDL) and high-density lipoprotein (HDL). After cellular uptake of these lipoproteins, LDL is processed through lysozymes, whereas HDL enters the cy-tosolic pool directly. Dietary cholesterol incorporated into LDL is most commonly used for steroid hormone biosynthesis. Although free cholesterol represents only a small fraction of the total cholesterol pool, this fraction can be...

Antilipemic and Hypoglycemic Effects

Because bilberry has traditionally been used to treat diabetes, which is associated with alteration of lipid metabolism, the effects of a bilberry leaf extract on plasma glucose and triglycerides were studied in various rat models (1). The study preparation was made by percolation of bilberry leaf powder with ethanol 40 (Indena, Milano, Italy). All statistical comparisons were done using unpaired i-tests. In Sprague-Dawley rats made diabetic with streptozocin, plasma glucose levels were 26 lower (p 0.05) 4 days after streptozocin administration, and 26.6 lower (p 0.01, unpaired i-test) 3 weeks after streptozocin administration in rats treated with bilberry extract at a dose of 3 g kg twice daily for five doses compared with untreated diabetic rats. Triglycerides were also 38.8 (p 0.05) lower in the treated rats. The extract did not affect glucose levels in control animals, and did not affect weight (1). In rats with diet-induced hyperlipidemia, triglycerides were lower in rats treated...

Change Due to Concern over Longterm Toxicity

L only better on NVP (triglycerides), LD unchanged Note In all studies (except Martinez 2003), randomization was against continuing PIs. All had an open-label design and all patients had been on PIs for several months at the time of the switch, with undetectable viral load. In all studies, quality of life improved in the switch arms (if it was evaluated). Studies in italics have only been available as conference abstracts. VLS viral load suppression in the switch arm versus the continuing arm. Wk weeks, LD lipodystrophy, LA lipoatrophy, L lipids, n.a. not available, n.s. not significant, TG triglycerides

Bacterial Cholesterol Metabolism

The intestinal tract has a major impact on cholesterol metabolism (34-36). A major source of intestinal cholesterol comes from the de novo synthesis of the sterol compound. Cholesterol also can enter the intestine from dietary sources. It has been estimated that 34-57 of dietary cholesterol is absorbed from the intestine (37). In humans cholesterol synthesized by the intestinal cells is introduced into the lumen by exfoliation of these cells. An additional source of intestinal cholesterol is via biliary excretion.

In Situ Profiling Of Transcription In The Gi Tract

Fucose and coordinates the decision to generate a signal for production of host fucosylated glycans when environmental fucose is limited or to induce expression of the bacteria's fucose utilization operon when fucose is abundant (68). Additional studies have evaluated the global intestinal response to colonization of gnotobiotic mice with B. thetaiotaomicron. This colonization dramatically affected the host's gene expression, including several important intestinal functions such as nutrient absorption, mucosal barrier fortification, and postnatal intestinal maturation (9). From the in situ global transcription profiles mentioned above and follow-up experiments it could be established that the production of a previously uncharacterized angiogenin is induced when gnotobiotic mice are colonized with B. thetaiotaomicron, revealing a mechanism whereby intestinal commensal bacteria influence GI-tract bacterial ecology and shape innate immunity (69). In addition, the cellular origin of the...

Lipids and surfactants

Simple lipids, or fatty acids, are n-alkyl carboxylic acids typically derived from the hydrolysis of the triglycerides of fats or of the phospholipids found in the cell wall. Many naturally occurring fatty acids contain one or more sites of unsaturation. Fatty acids are found in nature conjugated to such sugars as glycolipids or lipopolysaccharides, to amino acid residues of pep-tides and proteins, to glycerol to form the acylglycerols of fats, and to glyc-erophosphocholate and glycerophosphatidylethanolamine residues of phos-pholipids. Because of their amphipathic character, lipids have some tendency to form micelles, which chromatograph quite differently than the unaggre-gated compound. A class fractionation of plant-derived extracts into the component waxes (e.g., cetiolate), hydrocarbons, fatty acids (e.g., linoleic acid), fatty acid methyl esters (e.g., methylpalmitate), sterols (e.g., stigmas-terol), sterol esters (e.g., cholesteryl linoleate), glycerylethers (e.g., chimyl...

NRTI and lipodystrophy

The patterns of fat redistribution in patients who are exclusively receiving NRTIs are unlike those observed in patients during PI therapy. Peripheral fat loss is the major symptom observed in NRTI therapy (particularly using stavudine and di-danosine combinations), although a few clinical studies have described a minimal intra-abdominal fat increase in these patients, which is clearly less than under PIs. Given that, commonly, only a mild increase in triglycerides has been observed, exclusive NRTI therapy seems to be of minor impact on lipid metabolism. Postpran-dially elevated FFA in patients with lipodystrophy, together with in vitro experiments, have led to the hypothesis that NRTIs could impair fatty acid binding proteins (FABP) which are responsible for cellular fat uptake and intracellular fat transport. In contrast, addition of stavudine (Zerit ) to a dual PI regimen does not result in a further increase in the total cholesterol or triglyceride levels. It is well established...

Other Targets for AntiHDV Therapy

Because the production of mevalonate by the enzyme HMG-CoA reductase is a committed step in both the cholesterol and prenyl lipid biosynthetic pathways (Zhang and Casey 1996), it has been suggested that HMG-CoA reductase inhibitors-which are in widespread clinical use to treat hypercholesterolemia-might be used to inhibit prenylation. Prenylation can indeed be inhibited in vitro by an HMG-CoA reductase inhibitor, but the doses required are cy-totoxic (Sinensky et al. 1990). Because cellular needs for cholesterol can be exogenously supplied via the low density lipoproteins receptor system, synergy between HMG-CoA reductase inhibitors and FTIs can be considered. Similar potential synergistic effects might also be achieved by combining FTIs with other classes of drugs which inhibit additional steps in the pathway of prenyl protein synthesis. For example, most prenylated eukaryotic proteins are further processed by the sequential activity of the products of the Rce-1 (CXXX-box...

Evidence That Exosomes Play A Role In Stressinduced Hsp72 Release

Independently of the classical secretory pathway (based on the inability of Brefeldin A treatment to inhibit stress-induced HSP72 release), and that non-specific processes such as cell lysis could not account for stress-induced release of HSP72 (Lancaster and Febbraio, 2005). However, and in contrast to the results of Broquet and coworkers, we were unable to confirm a role for lipid rafts in stress-induced HSP72 release. Using methyl- -cyclodextrin (the cholesterol depleting agent) to disrupt lipid raft function, our results demonstrate that lipid rafts do not play a role in stress-induced HSP72 release from human peripheral blood mononuclear cells (PBMCs) (Lancaster and Febbraio, 2005). Importantly, our data demonstrate that methyl- -cyclodextrin highly effectively depleted intracellular cholesterol levels in a dose-dependent manner, confirming that our methyl- -cyclodextrin treatment regimen was efficacious.

Moving Into the Third Millennium After a Century of Screening

For many decades, the discovery of drugs has depended on screening. From the previous century until the 1960s, chemical compounds and natural products were tested in whole animal assays, and in the case of antibacterial and antitumor testing, the samples were tested in whole cell assays. Although screening was labor intensive and expensive, it was fruitful. A large number of successful drugs such as the cephalosporins, aminoglycosides, tetracyclines, macrolide antibiotics, doxyrubicin, etoposide, and other anticancer agents, steroids and drugs for use in the central nervous system and cardiovascular areas were discovered by screening 1,2 . In many cases, identification of the lead molecule, such as penicillin, cepha-losporin, macrolides, captopril, and mevacor, spawned a large number of analogs through chemistry programs 3-7 . A single lead molecule identified in one company has, in many cases, kept several hundred industrial chemists and biologists busy for several years.

Insights from rodent models

Early loss-of-function studies focused on molecules previously identified as potentially important modifiers of lipid handling. From these studies, apoE (Plump et al., 1992 Zhang et al., 1992) and the LDL receptor (Ishibashi et al., 1993) were confirmed as important modifiers of cholesterol levels. Mice lacking either apoE or the LDL receptor develop significant atherosclerotic lesions when fed a high fat diet. This observation paved the way for a deluge of studies looking at genetic influences on atherosclerosis lesion size in apoE and LDL receptor knockout mice (Glass and Witztum, 2001). Consequently, a solid body of new information has emerged on the mechanisms regulating plasma lipoprotein levels and controlling the initial stages of atherogenesis. The obvious advantage of studying the effect of a gene in mice predisposed to developing atherosclerosis is that anti-atherogenic effects of a gene may be more readily detected (Table 24.3). QTL studies of atherosclerosis with...

Evidence for the genetic basis of CHD

Family history of the disease is one of the strongest and most consistent risk factors for CHD. Relative risk estimates of between 1.5 and 5 have been derived from a range of family and population studies (Hawe et al., 2003 Lusis, 2003). At least a part of the risk of family history is conferred by the monogenic dyslipidaemias, including familial hypercholesterolemia (FH) (Goldstein et al., 1973), which carry a high penetrance of CHD. However, since the frequency of the FH heterozygous state, and of other monogenic dyslipidaemias, is only at

FMD Response Eigen Parameterization

As can be concluded from Table 5.7, a weak but significant correlation was found between AFMDc and LDL cholesterol in a damaging way and between AFMDc and HDL cholesterol in a protective way. This had been previously reported when studying dyslipidemic populations with a similar correlation magnitude, association that could be slightly attenuated in our population due to a narrower range of lipids variation. For instance, Kuvin et al. 38 found a correlation coefficient of HDL cholesterol and AFMDc of 0.3. The correlation between classical flow-mediated dilation and LDL cholesterol (r -0.40) had been previously reported by Aggoun et al. 39 in hypercholesterolemic patients. Other studies report one of these associations but rarely both or with stronger association coefficients 40 and never in natural large populations with normal lipid levels 41 . Triglycerides correlated significantly with baseline diameter, 0basal. The presence of wider vessels has been described for high-risk 38 and...

Oligopolygenic complex genetic hyperlipidemias

Combined hyperlipidemia, characterized by increased serum triglyceride and or cholesterol and decreased HDL cholesterol is the most common disorder of lipid metabolism affecting 1-2 of individuals in Western societies. The term familial combined hyperlipidemia (FCHL) was coined by Goldstein et al. to describe a pattern of lipid abnormalities (Goldstein et al., 1973) in survivors of myocardial infarction who had raised blood cholesterol and triglyceride levels. Originally, FCHL was described as a dominant disorder with a primary effect on blood triglyceride levels, a secondary effect on cholesterol levels, and with incomplete penetrance until the third decade (Goldstein et al., 1973). However subsequent segregation analyses (Austin, 1992

The Role Of Fibrinogen In Hemostasis

Fibrinogen is the principal substrate of the coagulation and fibrinolytic system. This clotting factor has the highest molecular weight of all of the clotting factors, and it is the substrate upon which the coagulation system is centered. This factor is heat labile but stable in storage. When fibrinogen is transformed to fibrin under the influence of thrombin, it is the onset of solid clot formation. The formation of fibrin occurs within minutes due in part to a positive feedback mechanism within the hemostasis system. Once clotting factors are activated, they accelerate the activity of the next factor, pushing the reaction to conclusion. Negative feedback occurs when the activity of the reaction is delayed. This is the role played by naturally occurring inhibitors within the hemostatic system. With the assistance of factor XIII and thrombin, the fibrinogen molecule is stabilized by cross-linked fibrin. Within hours, the fibrinolytic system swoops in to dissolve the clots that have...

Genetics of monogenic and complex dyslipidemias

Disorders of lipid metabolism, both monogenic and more genetically complex, are powerful risk factors for CHD. The major circulating lipids, cholesterol, phospholipids and triglycerides, are carried in the blood by several lipoprotein particles serving the physiological task of transporting dietary and endogenously produced lipids to peripheral tissues. The major pathways of lipoprotein metabolism in humans are illustrated in (Figure 24.1). Mutations in many of the lipoproteins, receptors and enzymes shown in the figure have been described in humans or engineered in rodents. Studies of these mutations have yielded the molecular basis of a wide range of dyslipidemias and in many cases elucidated the mechanism by which dysfunction of these proteins predispose to, or protect against, atherosclerosis and CHD.

Current applications of pharmacogenetics

The ability to individualize the use of currently used drugs will not only permit the identification of individuals vulnerable to drug side effects but, perhaps more importantly, will allow us to identify those patients who will or will not respond to a particular drug treatment. As discussed above, there are certain research areas where this is of vital importance, e.g. in the treatment of cancer, but also for other diseases such as the control of serum cholesterol with statins or the use of non-steroidal anti-inflammatory drugs, where a significant proportion of the population do not respond to these agents. For certain drugs there are already prescribing guidelines for example, in the treatment of childhood leukaemia with 6-mercaptopur-ine (Armstrong et al., 2004) and in the use of Glivec (Vastag, 2004) and Herceptin (Bell et al., 2004). There is, however, still an urgent need for new studies to identify genes which influence drug metabolism and efficacy, and to correlate...

Background And Relevant Pharmacokinetics

Lower serum concentrations of zeaxanthin have been associated with male gender, smoking, younger age, lower non-HDL cholesterol, greater ethanol consumption and higher BMI (Brady et al 1996). Lutein and zeaxanthin, together with other carotenoids, have also been found to be lower in people with chronic cholestatic liver disease, which can be attributed to malabsorption of fat-soluble vitamins, as well as other mechanisms of hepatic release (Floreani et al 2000). In an epidemiological study

Hiv And Tryptophan Depletion

An open, prospective trial has also concluded that extended-release niacin therapy is safe and effective for the treatment of dyslipidaemia associated with antiretroviral therapy 2000 mg day was given to 14 subjects for 14 weeks and resulted in significant reductions in serum levels of triglycerides, total cholesterol, and non-HDL-cholesterol (Gerber et al 2004).

Potential risks of PEP

The risks of PEP mainly concern the adverse effects of the antiretroviral substances. Most frequently this refers to gastrointestinal symptoms such as nausea, vomiting or diarrhea. Also possible are changes of hematology, transaminases or creatinine. There have been reports about elevated triglyceride and cholesterol levels and insulin resistance even in short term use of protease inhibitors.

Keep Your Heart Healthy

Cardiovascular disease (CVD) is the leading cause of death among New Yorkers, with 27,000 CVD-related deaths reported each year (New York City Department of Health and Mental Hygiene, 2004b). One quarter of New York City adults have been diagnosed with high blood pressure, and a similar number have been diagnosed with high cholesterol, with many more remaining undiagnosed. One-sixth of New York City adults are obese, and three-fourths of New Yorkers do not get at least 30 minutes of physical activity four or more days per week. More than 500,000 adult New Yorkers (9 ) have been diagnosed with diabetes, a 2 2-fold increase in the past decade. Another 250,000 New Yorkers may have diabetes and not know it, and close to a million more with pre-diabetes are likely to eventually develop diabetes. Blood pressure and cholesterol can be controlled with diet, exercise and medications. Control of blood pressure with medications significantly reduces the incidence of stroke, heart attack and...

Long Term Side Effects

Manifests as raised triglycerides and raised cholesterol. It is particularly seen with some protease inhibitors and is potentially important because it may lead to an increased risk of cardiovascular disease. In adult practice lipid lowering agents have been tried with some success but very few data exist for pediatric practice. Again, changing the medication should be considered.

Results and Discussion

Commensurate with the lower FAS protein expression, FAS RNAi resulted in a 4.0-fold decrease of FAS activity in LNCaP extracts, and reduced total lipogenesis as quantified by measuring the incorporation of 2- 14C -labeled acetate into cellular lipids of growing LNCaP cells (27). To investigate the impact of the decreased lipid synthesis by silencing the different lipid species, lipid extracts were analyzed by TLC for phospholipids and neutral lipids, respectively. The majority of 14C -label in control cells was incorporated into phospholipids (80 ), specifically in phospholipids partitioning into detergent-resistant membrane microdomains (28). FAS RNAi caused 2.0- to 3.0-fold decrease in the synthesis ofthese phospholipids, suggesting that FAS plays an important role in the control of membrane microdomain biology. Smaller amounts oflabel were found in triglycerides and free cholesterol (Figure 3). FAS RNAi caused a 7.0-fold decrease in the synthesis of triglycerides in LNCaP cells. In...

Laboratory Examination

Erectile dysfunction (ED) often occurs together with sexual disinterest and it may not be easy to establish which preceded the other. Under such circumstances, it is wise to investigate common causes of ED by ensuring that the patient does not have diabetes (obtaining a fasting blood sugar), or elevated lipids assessing his total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides , or abnormal thyroid function investigating his thyroid stimulating hormone (TSH) .

Common diseasecommon variant or not

At the time of writing, there are not enough data to be able to evaluate the extent to which the CD-CV hypothesis is true. There are a number of examples of common variants for complex diseases that are known (Lohmueller et al., 2003), and also clear examples of moderate allelic heterogeneity (at NOD2 CARD15, involved in Crohn's disease Hugot et al., 2001) and functional rare variants (associated with plasma levels of HDL cholesterol and LDL, and rates of sterol absorption Cohen

Answers To Patients Frequently Asked Questions

Astragalus appears to have numerous biological effects, such as digestive and immune system stimulation and heart muscle stimulation. Early research suggests that it may have a role in the treatment of asthma, memory deficits, elevated cholesterol levels and as an adjunct to chemotherapy treatment for cancer. When will it start working

Genetics of human coronary heart disease

Major Risk Factors For Heart Disease

The heritability of known risk factors that were included in this linkage study (including type 2 diabetes mellitus and hypertension) was high, suggesting that these intermediate phenotypes are genetically determined to a moderately high extent. However, whereas age, gender, diabetes and hypertension contributed significantly to the myocardial infarction phenotype, high cholesterol levels did not. Since many of the individuals in the study were on lipid-lowering therapy, this suggests that hypercholesterolemia now appears to be a less significant risk factor for myocardial infarction than diabetes and hypertension. The possibility that Cd36 deficiency in humans might be a cause of insulin resistance arose initially from rodent studies (Aitman et al., 1997b 1999 Pravenec et al., 2001). Cd36 is a multi-functional protein and belongs to the scavenger receptor family typified by SrB1 and mediates the specific uptake of long chain-free fatty acids by adipocytes and muscle cells. Cd36 is...

Elevated Triglyceride Levels

DHA and EPA supplementation significantly reduces triglyceride levels and is used as sole therapy in cases of elevation or as adjunctive therapy with cholesterol-lowering medication when indicated. According to Din et al, omega-3 fatty acids reduce triglyceride concentrations in a dose-dependent manner, with intakes of about 4 g day lowering serum triglycerides by 25-30 (Din et al 2004).

Public Health Aspects Of

Of major public health interest are the results of treatment trials of hypertension and use of statins in the elderly showing decreased incidence of dementia. Treatment of other risk factors for VaD is also indicated, including smoking, hyperfibrinogenemia, orthostatic hypotension, cardiac

Assessment of Risk Factors

Overall, the greatest danger of overweight obesity is the development of cardiovascular disease. Moreover, in the long term obesity predisposes to type 2 diabetes, which is itself a risk factor for cardiovascular disease. ATP III provides useful classifications for lipid and nonlipid risk factors. These classifications are shown in Tables 1 and 2, respectively. In ATP III, estimates are made of a person's absolute risk using Framingham risk scoring, which is available through the NHLBI (http htm). This scoring estimates the 10-year risk for developing myocardial infarction or coronary death. It is based on absolute levels of the following risk factors total cholesterol, HDL cholesterol, blood pressure, smoking history, and age. Framingham scoring can be carried out either by manual scoring or with a simple computer program, both of which are available on the NHLBI website. In addition, ATP III defines the metabolic syndrome for clinical practice according to five clinical features...

EGCG Modulation of Food Intake and Endocrine Systems

In male rats treated with EGCG for one week, the serum level of protein, fatty acids, and glycerol were not altered, but significant reductions in serum glucose (-32 ), lipids (-15 ), triglycerides (-46 ) and cholesterol (-20 ) were observed. Based on proximate composition analysis, there was no change in water and protein content, a moderate decrease in carbohydrate content, but a very large reduction in fat content, decreasing from 4.1 in control to 1.4 in EGCG-treated group. EGCG treatment also decreases subcutaneous fat by 40 to 70 , and abdominal fat by 20 to 35 in male rats (1, 26). Reduction of body fat may also influence the hormonal levels in animals and influence tumor growth.

Cholesterol Synthesis Is Controlled By Regulation Of HmgcoA Reductase

Regulation of cholesterol synthesis is exerted near the beginning of the pathway, at the HMG-CoA reductase step. The reduced synthesis of cholesterol in starving animals is accompanied by a decrease in the activity of the enzyme. However, it is only hepatic synthesis that is inhibited by dietary cholesterol. HMG-CoA reductase in liver is inhibited by mevalonate, the immediate product of the pathway, and by cholesterol, the main product. Cholesterol (or a metabolite, eg, oxygenated sterol) represses transcription of the HMG-CoA reductase gene and is also believed to influence translation. A diurnal variation occurs in both cholesterol synthesis and reductase activity. In addition to these mechanisms regulating the rate of protein synthesis, the enzyme activity is also modulated more rapidly by posttransla-tional modification (Figure 26-4). Insulin or thyroid hormone increases HMG-CoA reductase activity, whereas glucagon or glucocorticoids decrease it. Activity is reversibly modified by...

Chemical Components

A Iipid-rich extract, prepared by supercritical fluid (C02) extraction of freeze-dried stabilised NZ green-lipped mussel, is commercially available as Lyprinol. The main lipid classes in this preparation are sterol esters, triglycerides, free fatty acids (mainly EPA and DHA), sterols and phospholipids (Sinclair et al 2000).

Lipidlowering Activity

Although the mechanism of action is yet to be fully explained, studies show that chromium supplementation may decrease triglyceride levels, total and LDL-cholesterol and modestly increase HDL-cholesterol (Bahijri 2000, Lee & Reasner 1994, Press et al 1990, Preuss etal 2000).

Definition Of Obesity And Bmi Cutoff Points

Figure 5 Risk factors elevated serum cholesterol ( 6.2 mmol L), elevated total cholesterol HDL cholesterol ratio ( 4.4), elevated triglyceride ( 1.8 mmol L), elevated blood pressure ( 140 90mmHg), diabetes mellitus (OGGT 11.1 mmol L). Data are corrected for age, ethnicity, educational level, occupation, physical activity, smoking, and waist hip ratio. (From Ref. 20.) Figure 5 Risk factors elevated serum cholesterol ( 6.2 mmol L), elevated total cholesterol HDL cholesterol ratio ( 4.4), elevated triglyceride ( 1.8 mmol L), elevated blood pressure ( 140 90mmHg), diabetes mellitus (OGGT 11.1 mmol L). Data are corrected for age, ethnicity, educational level, occupation, physical activity, smoking, and waist hip ratio. (From Ref. 20.)


Although no clinical studies are available, three in vivo studies suggest that andrographis exerts significant dose-dependent hypoglycaemic activity comparable to that of metformin (Borhanuddin et al 1994, Zhang & Tan 2000a, b). A 49.8 reduction in fasting serum triglyceride levels was also achieved with andrographis treatment compared with 27.7 with metformin however, neither treatment affected cholesterol levels. A more recent animal trial also concluded that andrographolide (1.5 mg kg) lowers plasma glucose by enhancing glucose utilisation in diabetic rats (Yu et al 2003).

Kidney Failure

One open study of 80 patients with renal failure undergoing haemodialysis found that 1350 mg of chitosan taken three times daily effectively reduced total serum cholesterol levels (from 10.14 4.40 mmol Lto 5.82 2.19 mmol L)and increased serum haemoglobin levels (from 58.2 12.1 g L to 68 9.0 g L) (Jing et al 1997). After 4 weeks, significant reductions in serum urea and creatinine levels were observed. After 12 weeks, patients reported subjective improvements, such as feeling physically stronger, increased appetite and improved sleep, which were also significantly greater than the placebo group. Importantly, during the treatment period, no clinically problematic symptoms were observed.


Another double-blind, placebo-controlled randomised study of young, non-obese adults taking chromium nicotinate (equivalent to 220 g elemental chromium) for 90 days found no statistically significant differences in lipid levels (total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides) at this dose (Wilson & Gondy 1995). Similar results were found in older, non-obese subjects taking 1000 fjg chromium picolinate for 8 weeks (Amato et al 2000) suggesting that subjects without identified pre-existing hypercholesterolemia or other conditions predisposing them to hypercholesterolemia may not respond to treatment. However, a prospective, double-blind, placebo-controlled crossover study of mostly hispanic patients with type 2 diabetes also elicited disappointing results, finding that only triglyceride levels were significantly reduced (17.4 ) (Lee & Reasner 1994).

Atomic Level

The human body is composed of 11 elements that account for 99.5 of body weight (Fig. 3) (1). Three of these elements, carbon, hydrogen, and oxygen, are found in storage triglycerides or ''fat'' (Table 1). The average proportions of triglyceride as carbon, hydrogen, and oxygen are considered stable at 76.7 , 12.0 , and 11.3 , respectively. These stable elemental proportions allow the development of methods for deducing total body fat from total body carbon and other elements.

Molecular Level

Lipid is the main molecular-level component of interest in the study of human obesity. The term lipid refers to all chemical compounds that are insoluble or weakly soluble in water, but are soluble in organic solvents such as chloroform and diethyl ether (5). Lipids isolated from human tissues include triglycerides, sphyngomyelin, phospholipids, steroids, fatty acids, Table 1 Chemical Formulae and Elemental Stoichiometry of Representative Triglycerides Table 1 Chemical Formulae and Elemental Stoichiometry of Representative Triglycerides

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