FIVE COMMON DIETARY FACTORS CONTRIBUTING TO HIGH CHOLESTEROL LEVEL

Most of the cholesterol in the body is synthesized by the liver. Cholesterol synthesis is affected by various factors such as excessive fat & cholesterol intake, fat structure & composition, lack of dietary fiber, postprandial glucose levels, etc. Consumption of eggs was also positively associated with elevated cholesterol in the past. However, American Heart Association (2000) suggests that contrary to the popular belief, 1 or 2 eggs per day, as part of a balanced diet, do not contribute to high cholesterol levels. This was echoed by a small study conducted by Njike et al (2010) who also concluded that daily consumption of eggs did  not affect serum cholesterol or other lipid profiles in a negative way.

Five common dietary factors contributing to high cholesterol:-

1.    Refined carbohydrates

As refined carbohydrates are rapidly digested to glucose, this provokes a high insulin response, which in turn, activates the synthesis and activity of an enzyme HMGCoA Reductase, involved in cholesterol synthesis (Ness & Chambers 2000 Benyon et al 2007).

2.    Lack of fibre

Fibre-rich foods such as beans, lentils, vegetables, seeds, nuts, etc. are a good source of plant sterols & stanols, also known as phytosterols, which are plant cell membranes compounds with chemical structures similar to cholesterol. Consumption of plant sterols inhibit the intestinal absorption of cholesterol and can decrease LDL cholesterol (Malinowski & Gehret 2010).  

3.    Lack of oily fish in the diet

Oily fish (salmon, trout, sardines, mackerel, herring, anchovy, etc.) are rich in Omega 3 fatty acids, which help to lower LDL cholesterol by inhibiting triglycerides (TGCs) production (Holub 2009). Increased triglycerides are associated with greater formation of LDL cholesterol, as TGCs provide higher availability of Acetyl-CoA, a substrate for cholesterol synthesis (Bradley-Hillgartner et al 1995). 

4.    High saturated fats

Animal studies show that diets high in saturated fats (e.g. red meat & dairy products) also activate the liver enzyme HMG-CoA Reductase (Bradley-Hillgartner et al 1995), thus contributing to high cholesterol levels.

5.    Trans fats   

Trans fats (e.g. in processed foods such as crisps, cakes, biscuits, pastries, etc.) increase the synthesis of LDL cholesterol and lower HDL cholesterol  twice as much as saturated fats (Clifton et al 2004). This makes trans fats particularly hazardous. A 2% increase in energy intake from trans fat has been associated with a 23% increase in cardiovascular risk (Remig et al 2010). 

References:

American Heart Association (2000) An eating plan for healthy adults The new 2000 guidelines Our American Heart Association Diet Dallas TX

Benyon S Roach JO Lim MY (2007) Metabolism and Nutrition (3^rd edition) Mosby

Bradley-Hillgartner F Salati LM Goodridge G (1995) Physiological and molecular mechanisms involved in nutritional regulation of fatty acid synthesis Physiological Reviews 75 47 -76

Clifton PM Keogh JB Noakes M (2004) Trans fatty acids in adipose tissue and the food supply are associated with myocardial infarction The Journal of Nutrition 134 7 1848

Holub BJ (2009) Docosahexaenoic acid (DHA) and cardiovascular disease risk factors Prostaglandins, Leukotrienes and Essential Fatty Acids 81 2-3 199-204

Malinowski JM Gehret MM (2010) Phytosterols for dyslipidemia American Journal of Hospital Pharmacy 67 14 1165-73

Ness GC Chambers CM (2000) Feedback and hormonal regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase: the concept of cholesterol buffering capacity  Proceedings of the Society for Experimental Biology and Medicine 224 1 8-19

Njike V Faridi Z Dutta S Gonzalez-Simon AL Katz DL (2010) Daily egg consumption in hyperlipidemic adults-effects on endothelial function and cardiovascular risk Nutrition Journal Jul 2 9:28

Remig V Franklin B Margolis S Kostas G Nece T Street JC (2010) Trans fats in America: a review of their use, consumption, health implications, and regulation Journal of the American Dietetic Association 110 4 585-92

Three reasons for vitamin D supplementation

As days are getting shorter and darker and the sunlight is in short supply, vitamin supplementation may be beneficial.

Vitamin D has many therapeutic values to mention just a few:-

1.   Resistance to infections - vitamin D has immuno-regulatory properties. Vitamin D stimulates the maturation of Natural Killer (NK) cells (Fernandes de Abreu et al 2009) and vitamin D receptors are found in significant concentrations in T lymphocytes and  macrophages (Deluca & Cantoma 2001).

2.   Inflammation - Vitamin D supplementation has been shown to inhibit the influx of inflammatory cytokines in the lung, while increasing the secretion of anti-inflammatory interleukin 10 by T-regulatory cells (Sandhu & Casale 2010). Vitamin D has been shown to exert beneficial effects on Th1 cell mediated inflammatory conditions (Ikeda et al 2010).  As reported by Timms et al (2002), lack of vitamin D is also associated with increased levels of MMP9 (matrix metalloproteinase), enzymes involved in degradation of extracellular proteins & inflammation.

References:

Deluca FH and Cantorna MT (2001) Vitamin D: its role and uses in immunology The FASEB Journal 15:2579-2585

Fernandes de Abreu DA Eyles D Féron F (2009) Vitamin D a neuro-immunomodulator: Implications for neurodegenerative and autoimmune disease Psychoneuroendocrinology 34 Suppl 1 S265-77

Homa ST (1995) Calcium and meiotic maturation of the mammalian oocyte  Molecular Reproduction and Development  40 1 122-34

Ikeda U Wakita D Ohkuri T Chamoto K Kitamura H Iwakura Y Nishimura T (2010) 1alpha,25-Dihydroxyvitamin D(3) and all-trans retinoic acid synergistically inhibit the differentiation and expansion of Th17 cells  Immunology Letters (online) last accessed 30.08.2010 at  http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T75-50KWFSH-1&_user=4315376&_coverDate=11%2F30%2F2010&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=4315376&md5=0db7205a5e444b36b920db657faf0f40&searchtype=a

Timms PM Mannan N Hitman GA Noonan K Mills PG Syndercombe-Court D Aganna E Price CP  Boucher BJ (2002) Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM 95 12 787-96

Thys-Jacobs S Donovan D Papadopoulos A Sarrel P Bilezikian JP (1999) Vitamin D and calcium dysregulation in the polycystic ovarian syndrome Steroids 64 6 430-5

Sandhu MS Casale TB (2010) The role of vitamin D in asthma Annals of Allergy, Asthma and Immunology 105 3 191-9

B vitamins and Alzheimer's Disease

It is encouraging to hear something positive about vitamins in the media, for a change. However, research in relation to B vitamins and homocysteine metabolism and Alzheimer’s Disease (AD) is not new. High homocysteine can contribute to AD by vascular damage and direct neurotoxicity (Aisen et al 2008). Kado et al (2005) also confirmed that low levels of B6, B12 and folate were predictors of cognitive function and decline in older adults.

However, we must not forget other contributing factors to AD such as heavy drinking; alcohol depletes folic acid, contributing to memory loss (A Harvard Medical School Special Health Report 2008:28).

High refined carbohydrates and sugars have also been implicated, as they result in prolonged excessive insulin secretion, which leads to elevated blood levels of beta amyloid (A Harvard Medical School Special Health Report 2008:21) and accelerated cellular damage in cerebral neurons (Henderson 2004).

Farooqui et al (2007) suggested that n3 eicosanoids derived from EPA and DHA retard neuro-inflammation, oxidative stress, and apoptotic cell death in the brain tissue. They also found that ingredients of fish oil inhibit generation of beta-amyloid.

Fascinatingly, research in mice shows that moderate coffee drinking may have protective effect on AD as it lowers beta-amyloid (Abeta) levels (Arendash et al 2006).

References:

Arendash GW Schleif W Rezai-Zadeh K Jackson EK Zacharia LC Cracchiolo JR Shippy D Tan J (2006) Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production Neuroscience 142 4 941-52

Aisen PS Schneider LS Sano M Diaz-Arrastia R van Dyck CH Weiner MF Bottiglieri T Jin S Stokes KT Thomas RG Thal LJ Alzheimer Disease Cooperative Study (2008) High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial The Journal of the American Medical Association 300 15 1774-83

Farooqui AA Ong WY Horrocks LA Chen P Farooqui T (2007) Comparison of biochemical effects of statins and fish oil in brain: the battle of the titans Brain Research Reviews 56 2 443-71

Harvard Medical School (2008) Improving Memory Understanding age-related memory loss Harvard Health Publications

Henderson ST (2004) High carbohydrate diets and Alzheimer's disease Medical Hypothesis 62 5 689-700

Kado DM Karlamangla AS Huang MH Troen A Rowe JW Selhub J Seeman TE (2005) Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging The American Journal of Medicine 118 2 161-7

Macronutrients, Balancing Blood Glucose & Insulin Resistance

Blood glucose regulation

The resting body uses about 10 grams of glucose per hour (2 teaspoons) for energy and all body functions. Blood glucose is regulated by 2 opposing hormones - insulin (an anabolic hormone and glucagon - a catabolic hormone (Roach & Benyon 2003). After a meal insulin secretion is activated and glucagon secretion is minimized. When there is a fall in blood glucose (under about 4 mmol/l) it leads to a pronounced decrease in insulin secretion and increase in glucagon secretion. Glucagon increases blood glucose levels by releasing glucose stored as glycogen in the liver.

Other hormones involved in blood glucose regulation are adrenaline, noradrenaline, growth hormone, cortisol and gastric hormones GIP and GLP-1 (see later). Adrenaline nor-adernaline and cortisol increase blood glucose via glycogenolysis and gluconeogenesis. Adrenal hormones are therefore critical in maintaining normal blood sugar levels, especially during stress (Wilson 2004).

Insulin is secreted by β cells of the pancreas in response to increased circulating levels of glucose and amino acids after a meal (Pessin & Saltiel 2000). High glycaemic index (GI) foods such as sugars and refined carbohydrates which are rapidly converted to glucose provoke exaggerated insulin response. Insulin facilitates glucose transport into the cells via specific glucose transporters. Insulin binding on cell membrane receptors increases the number of glucose transporters (Lord & Bralley 2008:556). There are four glucose transporters - GLUT-1, GLUT-2, GLUT-3 & GLUT- 4. Each of them has different tissue distribution (Roach & Benyon 2003:7).

Insulin primarily increases the rate of glucose uptake into striated muscle and adipose tissue by shuttling GLUT-4 proteins to the membrane (Cloe 2010). Skeletal muscles account for approximately 75% of insulin-stimulated glucose uptake (Shulman et al 1990). The ability of insulin to stimulate glucose uptake by muscles and adipose tissue is key to blood glucose homeostasis (Leney & Tavare 2009) as the skeletal muscle is the main determinant of insulin sensitivity (Vessby 2000).

Post-prandial phase

If body cells require energy, glucose is immediately metabolized for energy production. However, excess glucose, not utilised for energy is either used for amino acid synthesis by cells throughout the body or stored as glycogen in the liver and muscle cells. Glycogen stored in the liver maintains blood glucose concentrations between the meals or during a fast. Its stores last about 12 – 24 hours (Roach & Benyon 2003:30). Although muscle is much larger than liver and we store twice as much glycogen in the muscle, glycogen stored in the muscles provides fuel for muscle contraction only, and does not help to maintain blood glucose levels. Muscle lacks the enzyme glucose-6-phosphatase, which in the liver converts glucose-6-phosphate to glucose (Roach & Benyon 2003:30).

When glycogen stores are full, insulin, an anabolic hormone, increases lipid synthesis from extra glucose in liver and fat cells. These are exported as lipoproteins (eg LDL cholesterol) to other tissues, including adipose tissue, which uses fatty acids to synthesize triglycerides (Tortora & Derrickson 2006:953).

Insulin inhibits fatty acid release from triglycerides stored in adipose and muscle tissue as it inhibits the activity of hormone sensitive lipase (Lafontan & Langin 2009), which is the key enzyme in the mobilization of FAs from adipose tissue (lipolysis). Insulin also inhibits gluconeogenesis and glycogenolysis.

Insulin resistance (IR)

Metabolic insulin resistance is a highly complex condition, defined as higher than normal concentrations of insulin required to maintain normal blood glucose level - euglycaemia. On a cellular level IR is a defect in signal transduction via the insulin receptors (Adochio et al 2009). As suggested by Pessin & Saltiel (2000), this complex phenomenon may be a combination of genetic defects combined with environmental stressors, such as obesity or infections, or there may be reduced key molecular functions within the cell, resulting in insufficient signal transduction to generate the full response of glucose uptake.

According to Hyman (2008:359), common signs and symptoms of IR are central obesity, PCOS or infertility, fatigue, post-prandial fatigue after carbohydrate meals, sugar craving, hypoglycaemia night sweats, irritability, palpitation, dizziness and fatigue relieved by eating), hypertension, chronic fungal infection and family history of diabetes, hypoglycaemia or alcoholism. IR, if not managed can further progress to type 2 diabetes mellitus (T2DM) (Corcoran et al 2007).

Macronutrients and insulin resistance (IR)

Studying macronutrients in isolation does not give a complete picture, as we normally eat a mixture of macro- & micro-nutrients (Frayn 2001). It is well known that addition of fat to a carbohydrate meal slows gastric emptying and reduces the glycaemic response (Jenkins et al 1981). Normand et al (2001) demonstrated that addition of moderate amount of fat (17g) to a meal delayed absorption of carbohydrates and reduced glucose concentration up to 3 hours after meal ingestion. However, a large amount of fat (42g) leads to two-phase increased glucose concentration; first immediately after a meal and a second peak approx. 3 hours after the meal ingestion, concurrently with elevated plasma insulin and non-esterified fatty acids (NEFAs) concentrations, which as reported by Frayn et al (1996) may be associated with IR. Adochio et al (2009) also noted that high-fat (HF) overfeeding resulted in significant insulin resistance in skeletal muscles.

IR and FA composition in phospholipid cell membrane

Research regarding the FA composition in phospholipid membrane and IR is under intensive investigation; however, the results are inconclusive as no method of measuring dietary fat intake is entirely reliable. Most studies suggest that some FA promote IR while others protect against it. For example, high dietary MUFA abundant in olive oil are largely associated with improved insulin sensitivity, while saturated fatty acids (SFAs) promote it (Soriguer et al 2004 Marshall et al 1997). Vessby et al (2001), Perez-Jimenez et al (2001) noted that replacement of saturated fats with either mono or polyunsaturated fats (PUFAs) improve insulin sensitivity. FAs incorporated into phospholipid membrane influence membrane rigidity and ‘fluidity’, which is vital for signalling and recruitment of GLUT proteins to the cell membrane. Since insulin signalling and transport of GLUT-4 to the cell membrane are greatly membrane related events, membrane fluidity is essential to insulin sensitivity (Frayn et al 2010). As observed by Vessby (2000), obese patients and those with T2DM have a higher concentration of saturated FAs and a lower concentration on n6 FAs in the cell membrane, both associated with IR.

Giaco et al (2007) observed that in healthy individuals, moderate fish oil supplementation (3.6 g of n3 containing 2.1 g of EPA & 1.5g DHA) did not affect  cell function, insulin secretion or insulin sensitivity. They also noted that a higher n6 / n3 phospholipids ratio, had a significant reduction in insulin sensitivity. However, fish oil supplementation worsened their glucose tolerance. They concluded that those individuals should not be supplemented with n3, instead their n6 intake should be reduced. However, they agreed that there is an inverse relationship between n3 and T2D, which they suggested may be due to the anti-inflammatory properties of fish oils or other properties.
Adochio et al (2009) also observed macronutrient composition influence on insulin signalling. They found that high-calorie high carbohydrate diet (HC) increased insulin signalling in skeletal muscles. They attributed it to modest hyperinsulinemia which is characteristic of high carbohydrate overfeeding.

Similar to intake of saturated fats, dietary intake of trans fatty acids (TFA) is equally associated with detrimental effects on insulin sensitivity (Corcoran 2007). Stender and Dyerberg (2004) suggest that TFA may affect cell membrane function via their effect on ion channels and transport proteins such as GLUT-4. Studies on rats by Saravanan et al (2005) showed that TFAs and SFAs altered the expression of different genes associated with insulin sensitivity in rat adipose tissue. This was confirmed by Mozaffarian (2006) who proposed that TFA incorporated into the cell membranes directly affect transcription factors and signalling pathway for genes involved in inflammation. Shoelson et al (2007) in their review attributed IR to proinflammatory cytokines such as TNF-α, which as reported by Mozaffarian (2009) are produced by TFAs, as well as IL-6 and other markers of inflammation.

IR and intramyocellular lipid metabolism

Coen et al (2010) Pan et al (1997) and Lee et al (2006) observed that some IR phenotypes are associated with accumulation of fatty acids in skeletal muscle. Ceremide and diacyglycerol (DAG) levels are increased following high saturated fat intake. Both ceramide and diacyglycerol (DAG) are signalling molecules which have been shown to interfere with insulin sensitivity (Chavez et al 2003 Montell et al 2001). Ceramides may also be also responsible for reduced GLUT-4 translocation to the plasma membrane and diminished glycogen synthase activity (Corcoran et al 2007), consequently increasing lipogenesis.

The benefits of n6 PUFA on IR are inconsistent. Marotta et al (2004) observed substantial increase of triaglycerol (TGA) concentrations in muscle cells of rats fed high calorie diet rich in sunflower oil. However, when these lipids were substituted for SFAs or MUFAs there was no change in the lipid composition. Studies in rats by Taouis et al (2002) showed that n6 PUFA reduced GLUT-4 content in muscle cells, while diets rich in n3 and n6 PUFAs maintained insulin sensitivity. Contrary Lee et al (2006) noted that rats fed diet high in n6 FAs increased TAG formation rather than other metabolites and actually improved insulin sensitivity.

GIP & GLP-1 functions and secretion

Two gastric hormones involved in enhanced postprandial insulin secretion are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Their actions are called the ‘incretin effect’. As observed by Yoder et al (2009), in rats, secretion of both hormones is induced by the release of carbohydrates, fats, protein or mixed meals. Although the mechanisms are not clear, they suggest that GIP secretion depends on nutrient absorption, while GLP-1 is secreted in the presence of nutrients in the lumen. This was previously expressed in a review by Drucker (2006) who noted that in humans GIP is secreted by entero-endocrine K cells in duodenum and proximal jejunum and GLP-1 is secreted by intestinal L cells mainly in the distal ileum and colon, in response to a range of nutrients, and within minutes of food ingestion. Ahren (2004) reports that GLP-1 receptors have been found in various organs in the body including stomach, duodenum, heart, lungs, hypothalamus and other tissues.
Some scientists believe that secretion of GLP-1 and GIP depends on the caloric value of the meal. Yoder et al (2009) noted increased GLP-1 and GIP output in rats fed high fat diet, (high calorie density), and that secretion is dose-dependent. Baggio & Drucker (2007) in their review also observed that GLP-1 secretion is dependent on the caloric value of the ingested meal.

Meier et al (2003) observed therapeutic value of GLP-1 - exogenous administration of the hormone normalised blood glucose levels in type 2 diabetics by slowing gastric emptying and transit of nutrients from the stomach to small intestine. This confirms the role of GLIP-1 in the ileal brake reflex, which slows small bowel transit in presence of fat.

GIP & GLP-1 and insulin secretion

Wang et al (1996) noted that GIP increases the postprandial insulin secretion by upregulating  cells insulin gene transcription and synthesis. This was confirmed by Baggio and Drucker (2007) who observed that GIP stimulates  cells proliferation and reduces their apoptosis. They also noted that GIP increases fatty acids synthesis and their inclusion into triglycerides, while down regulating lypolysis (same functions as insulin).

GLP-1 functions are similar to GIP; it stimulates insulin secretion by stimulating  cells proliferation and reducing their apoptosis (Yoder et al 2009). However, Nauck et al (1997 & 2002) and Maljaars et al (2008) noted that GLP-1 improves glycaemic control by inhibiting gastric emptying, decreasing GI motility and reducing delivery of absorbed nutrients. Nauck et al (2002) also noted that GLP-1 effect on  cells is dose-dependent; the higher the blood glucose level, the greater its effect on insulin secretion.

Heller et al (1997) and Drucker (2006) noted that in α cells of the pancreas GLP-1 inhibits glucagon secretion when blood glucose is high (same as insulin). However, as GLP-1 secretion is glucose dependent, it is unlikely that it will impair glucagon secretion in response to hypoglycaemia (Nauck et al 2002). Also, as observed by Drucker & Nauck (2006) GLP-1 is rapidly degraded - circulating half life of 2 minutes.

Beysen et al (2002) reported increased plasma GLP-1 concentration following MUFA and PUFA ingestion and a delayed increase with saturated fatty acids ingestion, which slow down intestinal absorption.

Reactive Postprandial Hypoglycaemia (RPH) and incretin secretion (GLP-1 & GIP)

The cause of RPH is still being debated. Symptoms occur within 4 hours of eating (NIDDK 2008). Shortage of other hormones involved in blood glucose regulation – eg glucagon, cortisol, growth hormone and adrenaline ca also contribute to RPH. However, the main cause appears to be exaggerated insulin response (Brun et al 2000).

Tamburrano et al (1989) suggested that PRH is due to idiopathic reactive hypoglycaemia (IRH) due to increased insulin sensitivity and inadequate glucagon secretion. Miholic et al (1991) and Owada et al (1995) suggested that PRH may be due to exaggerated response to GLP-1 (as observed after gastric surgery). Leonetti et al (1989) observed increased insulin sensitivity and a reduced glucagon response, which led to an increase of glycogen synthase activity and increased glycogen synthesis in the muscle, while at the same time inhibiting glycogenolysis in the liver, causing RPH. Saha (2006) who observed RHP in healthy individuals during routine screening attributed it to exaggerated insulin and GLP-1 response and defects in counterregulation raising plasma glucose levels. Saha (2006) suggested that a mixed meal containing complex carbohydrates, fats and protein would provoke a more natural stimulus and ensure slower entry of glucose into intestine and therefore slower absorption. This was echoed by Ells et al (2005) who observed in a small double-blind randomized crossover design including ten healthy female volunteers that rapidly digested starches increased both glucose and insulin concentration more rapidly and to higher peaks than slowly digestible starch. This could be due to increased GLP-1 secretion, which as noted by Nauck et al (2002) is dose-dependent - the higher the blood glucose level, the greater GLP-1 & insulin secretion.

Blood glucose and brain function

Mental functions and the feeling of well-being are dependent on a steady supply of fuel to the brain as the brain is normally entirely dependent on glucose for energy. The brain cannot synthesize glucose or store substantial amounts as glycogen in astrocytes (Cryer 2007). When blood glucose level is high, the glucose transport into the brain exceeds the rate of brain glucose metabolism (Blomqvist 1991). However, when the blood glucose falls, the brain glucose metabolism is reduced and the brain is starved of its primary fuel resulting in hypoglycemia and symptoms such as anxiety, irritability, aggression, panic attacks, depression, poor concentration, etc. (Thomas & Bishop 2007:554).

Nocturnal hypoglycemia

If blood glucose drops too low at night, it can lead to nocturnal hypoglycaemia, which causes the release of glucose regulatory ‘stress hormones’, such as adrenaline, noradrenaline and cortisol, which breakdown glucose stored as glycogen (Wilson 2004).

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Written by Breda Gajsek, Principal BCNH

SEROTONIN - THE 'HAPPY' NEUROTRANSMITTER

Serotonion plays a part in numerous functions in the human body including modulation of appetite, sleep, mood and emotion (Schloss & Williams 1998). It also plays a role in memory and learning (Sarkisyan & Hedlund 2009) and temperature regulation (Hodges et al 2008).

In addition, a high comorbidity exists between depression and CVD (Halaris 2009). It is well established that serotonin plays an important part in the pathogenesis of CVD via platelet aggregation and regulation of smooth muscle in the CV system (Nigmatullina et al 2009, Jonnakuty & Gragnoli 2008).

Serotonin receptors are also widespread in the gastro-intestinal tract (found on neurones, smooth muscle cells and epithelial cells) where it plays a vital role in intestinal secretion, sensation and peristalsis (Jonnakuty & Gragnoli 2008). It is thought that altered serotonin signaling may contribute to GI conditions such as irritable bowel syndrome (Sikander et al 2009, Camilleri 2009).

Serotonin is synthesised from an amino acid tryptophan via two steps:-

1. Tryptophan to 5-HTP
2. 5-HTP to serotonin

5-HTP is an intermediate in the metabolism of tryptophan to serotonin. It may be more beneficial than tryptophan, as tryptophan can also be metabolized along different pathways (e.g. to niacin), whereas 5-HTP is a direct precursor to serotonin. In addition, 5-HTP easily crosses the blood-brain barrier (BBB) without the need for a transport protein (and therefore does not compete with other amino acids) (Jonnakuty & Gragnoli 2008).

1. Conversion of tryptophan to 5-HTP (5-hydroxytryptophan) is via rate-limiting enzyme tryptophan hydroxylase (Stipanuk & Watford 2000:406), a non-heme iron-dependent enzyme (Windahl et al 2008). Other essential cofactors include folic acid (Bland & Jones 2005:641), vitamin C (Stone & Townsley 1973), calcium (Kuhn et al 1997) and magnesium (Lysz et al 1982). SAMe also functions as a methyl donating co-factor in this rate-limiting step (Mischoulon & Fava 2002)

Indirectly, adequate vitamin B3 levels are also required (if inadequate niacin is present, tryptophan will be preferentially converted to niacin) and low levels of other B vitamins can also have a negative effect on production (Osiecki 2006 :494)

2. Conversion of 5HTP to serotonin by 5-hydroxytryptophan decarboxylase a pyridoxal phosphate (active form of vitamin B6 dependent enzyme (Stipanuk & Watford 2000:406). Zinc is required for the conversion of B6 to its active form (Ebadi et al 1984). Magnesium is also essential for this conversion (Jonnakuty & Gragnoli 2008)

Methyl donors, e.g. TMG and SAMe, must be present for the serotonin pathways to function correctly (Miller 2008).

If you take 5-HTP as a supplement, you must take it with a carbohydrate-rich snack, which triggers the release of insulin. Insulin decreases plasma levels of certain amino acids that compete with tryptophan for transport across the BBB (Takeda et al 2004). This allows more tryptophan into the brain, which is then synthesized into serotonin.

Conventional treatment

Low levels of serotonin have been linked to depression and the main conventional treatment for depression is through the use of SSRIs (selective serotonin reuptake inhibitors), which slow down the process of serotonin reuptake (neurones normally recycle serotonin by absorbing it into the pre-synaptic terminal once it has elicited the desired effect on the post-synaptic neurone). This leads to the chemical remaining in the vicinity of the receptors for longer, making it more likely that enough will build up to trigger an impulse in the next neurone. SSRIs work by allowing the body to make the best use of the reduced amounts of serotonin that it has at the time.

Side effects of SSRIs are an important issue - approximately 15% of patients cannot tolerate certain side effects and may discontinue SSRIs (Khawam et al 2006)

Common side effects include:-

• Sleep disturbances and insomnia
• Sexual dysfunction
• Weight gain
• Nausea and vomiting

Less common symptoms include:-

• Drowsiness
• Headache
• Loss of appetite
• Diarrhoea

It has also been claimed that antidepressants, especially SSRIs, may lead to an increased risk of suicide, particularly among children and adolescents. Although the evidence is inconclusive, the US FDA has warned clinicians of the risk and recommends close monitoring of patients at the start of treatment (Khawam et al 2006)

Refrences:
available on the request

Please email your views, comments, research, etc. to admin@bcnh.co.uk

AMALGAM DEBATE MAY BECOME OBSOLETE IN A NOT TOO DISTANT FUTURE

Amalgam fillings may become obsolete. Stem cell researchers hope that stem cells could be used to repair and replace damaged human tissue, including our teeth.

Here is some fascinating reading from the StemSave website:- http://www.stemsave.com/stemcellteeth.aspx

Stem Cells in Teeth

The tooth is nature's 'safe' for your family's unique stem cells

Baby teeth, wisdom teeth and permanent teeth with healthy pulp (fractured teeth and healthy teeth extracted for orthodontic indications) are all candidates for stem cell recovery and cryopreservation.

The tooth is nature's "safe" for these valuable stem cells, and there is an abundance of these cells in baby teeth, wisdom teeth and permanent teeth - Tooth Eligibility Criteria. The stem cells contained within teeth are capable of replicating themselves and can be readily recovered at the time of a planned dental procedure.

Living stem cells found within extracted teeth were routinely discarded every day, but now, with the knowledge from recent medical research, StemSave gives you the opportunity to save these cells for future use in developing medical treatments for your family.

Aside from being the most convenient stem cells to access, dental stem cells have significant medical benefits in the development of new medical therapies. Using one's own stem cells for medical treatment means a much lower risk of rejection by the body and decreases the need for powerful drugs that weaken the immune system, both of which are negative but typical realities that come into play when tissues or cells from a donor are used to treat patients.

Further, the stem cells from teeth have been observed in research studies to be among the most powerful stem cells in the human body. Stem cells from teeth replicate at a faster rate and for a longer period of time than do stem cells harvested from other tissues of the body.

Stem cells in the human body age over time and their regenerative abilities slow down later in life. The earlier in life that your family's stem cells are secured, the more valuable they will be when they are needed most.

Stem cell-based therapies are being investigated for the treatment of many conditions, including neurodegenerative conditions such as Parkinson’s Disease and Multiple Sclerosis, liver disease, diabetes, cardiovascular disease, autoimmune diseases, musculoskeletal disorders and for nerve regeneration following brain or spinal cord injury...

MERCURY - BEAUTIFUL POISON: are amalgam fillings safe?

Controversy about the safety of amalgam fillings continues. Research is conflicting, although there is general consensus that Hg, as a metal is toxic. A group of BCNH tutors, students, graduates and scientists will review and analyse evidence and report on their findings over the next few weeks.

The article below is published on the World Health Organisation site (online) accessed on 20.11.2008 at

http://www.euro.who.int/chemsafety/mercury/20071221_3?PrinterFriendly=1&

Mercury

Mercury and its compounds are highly toxic to humans, ecosystems and wildlife. Even relatively low doses can have serious neurotoxic effects on adults and children. Initially considered as an acute and local problem, they are now understood to be a global challenge with chronic effects. Some studies also show renal and cardiovascular effects. New epidemiological findings indicate that toxic effects may occur at lower exposure levels then previously considered. Methylmercury can cross the placenta, entering the fetus and accumulating in its brain and other tissues. Hence, exposure of women of childbearing age and children is of the greatest concern.

Owing to the transport of mercury through the environment and its bioaccumulation, the principle source of exposure to methylmercury in the general population is diet, in particular fish consumption. Dental amalgams are the main source of mercury exposure for most people in developed countries. Other sources include cosmetics, thiomersal in vaccinnes, thermometers and other medical devices.

Specific concerns are the potential exposures of population living near contaminated sites, waste and dumping sites, and plants producing mercury-containing products. Identifying such sites, assessing health risks from exposure and developing risk management programmes may have immediate positive health effects on the exposed population, and help to prevent the risk of future exposure.

© 2008 World Health Organization

Here are some interesting abstracts downloaded from PubMed. BCNH students can access research papers from BCNH website.

J Expo Sci Environ Epidemiol. 2008 May;18(3):326-31. Epub 2007 Sep 12

Maternal amalgam dental fillings as the source of mercury exposure in developing fetus and newborn.

Palkovicova L, Ursinyova M, Masanova V, Yu Z, Hertz-Picciotto I.

Department of Environmental Medicine, Slovak Medical University, Bratislava, Slovakia.

Dental amalgam is a mercury-based filling containing approximately 50% of metallic mercury (Hg(0)). Human placenta does not represent a real barrier to the transport of Hg(0); hence, fetal exposure occurs as a result of maternal exposure to Hg, with possible subsequent neurodevelopmental disabilities in infants. This study represents a substudy of the international NIH-funded project "Early Childhood Development and polychlorinated biphenyls Exposure in Slovakia". The main aim of this analysis was to assess the relationship between maternal dental amalgam fillings and exposure of the developing fetus to Hg. The study subjects were mother-child pairs (N=99). Questionnaires were administered after delivery, and chemical analyses of Hg were performed in the samples of maternal and cord blood using atomic absorption spectrometry with amalgamation technique. The median values of Hg concentrations were 0.63 microg/l (range 0.14-2.9 microg/l) and 0.80 microg/l (range 0.15-2.54 microg/l) for maternal and cord blood, respectively. None of the cord blood Hg concentrations reached the level considered to be hazardous for neurodevelopmental effects in children exposed to Hg in utero (EPA reference dose for Hg of 5.8 microg/l in cord blood). A strong positive correlation between maternal and cord blood Hg levels was found (rho=0.79; P<0.001). rho="0.46," rho="-0.37,">

Biol Trace Elem Res. 2008 Aug 22. [Epub ahead of print]

Thyroid Hormones and Methylmercury Toxicity

Soldin OP, O'Mara DM, Aschner M.

Departments of Medicine, Oncology and Physiology, Center for Sex Differences, Lombardi Comprehensive Cancer Center, LL, S-166, Georgetown University Medical Center, 3800 Reservoir Road, N.W., Washington, DC, 20057, USA, os35@georgetown.edu.

Thyroid hormones are essential for cellular metabolism, growth, and development. In particular, an adequate supply of thyroid hormones is critical for fetal neurodevelopment. Thyroid hormone tissue activation and inactivation in brain, liver, and other tissues is controlled by the deiodinases through the removal of iodine atoms. Selenium, an essential element critical for deiodinase activity, is sensitive to mercury and, therefore, when its availability is reduced, brain development might be altered. This review addresses the possibility that high exposures to the organometal, methylmercury (MeHg), may perturb neurodevelopmental processes by selectively affecting thyroid hormone homeostasis and function.

Arch Toxicol. 2007 Nov;81(11):759-67. Epub 2007 May 4

Mercuric dichloride induces DNA damage in human salivary gland tissue cells and lymphocytes

Schmid K, Sassen A, Staudenmaier R, Kroemer S, Reichl FX, Harréus U, Hagen R, Kleinsasser N.

University of Regensburg, Regensburg, Germany.

Amalgam is still one of the most frequently used dental filling materials. However, the possible adverse effects especially that of the mercuric component have led to continued controversy. Considering that mercury may be released from amalgam fillings into the oral cavity and also reach the circulating blood after absorption and resorption, it eventually may contribute to tumorigenesis in a variety of target cells. The present investigation focuses on genotoxic effects below a cytotoxic dose level of mercuric dichloride (HgCl(2)) in human samples of salivary glands and lymphocytes to elucidate a possible role in tumor initiation. DNA migration due to single strand breaks, alkali labile sites and incomplete excision repair was quantified with the aid of the single cell microgel electrophoresis (Comet) assay. The concepts of Olive Tail Moment, percentage of DNA in the Tail and Tail Length were used as measures of DNA damage. To control for cytotoxic effects, the trypan blue exclusion test was applied. Human samples of the parotid salivary gland and lymphocytes of ten donors were exposed to HgCl(2)concentrations from 1 to 50 microM. N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and dimethyl sulfoxide (DMSO) served as controls. Increasing dose-dependent DNA migration could be demonstrated after exposure to HgCl(2) in cells of the salivary glands and lymphocytes. In both cell types a significant increase in DNA migration could be shown starting from HgCl(2)concentrations of 5 microM in comparison to the negative control. The viability of the cell systems was not affected except at the highest concentration (50 microM) tested. These data indicate genotoxic effects of mercuric dichloride in human salivary glands and lymphocytes at concentrations not leading to cytotoxic effects or cell death. Consequently, a contributory role in oral salivary gland tumor initiation warrants further investigation.

J Environ Pathol Toxicol Oncol. 2007;26(4):305-22

Need for informed consent for dentists who use mercury amalgam restorative material as well as technical considerations in removal of dental amalgam restorations

Edlich RF, Greene JA, Cochran AA, Kelley AR, Gubler KD, Olson BM, Hudson MA, Woode DR, Long WB 3rd, McGregor W, Yoder C, Hopkins DB, Saepoff JP.

Biomechanical Engineering and Emergency Medicine, DeCamp Burn and Wound Healing Center, University of Virginia Health System, Charlottesville, VA, USA. richardedlichmd@gmail.com

Amalgam restorative material generally contains 50% mercury (Hg) in a complex mixture of copper, tin, silver, and zinc. It has been well documented that this mixture continually emits mercury vapor, which is dramatically increased by chewing, eating, brushing, and drinking hot liquids. Mercury has been demonstrated to have damaging effects on the kidney, central nervous system, and cardiovascular system, and has been implicated in gingival tattoos. While mercury amalgams may result in detrimental exposure to the patient, they can also be a danger in dental practices. In Europe, the federal governments of Norway, Finland, Denmark, and Sweden have enacted legislation requiring that dental patients receive informed consent information about the dental restorative material that will be used. In the United States, a few state governments have enacted informed consent legislation for dental patients receiving dental restorations. These state legislations were enacted by Maine, California, Connecticut, and Vermont. It is a sad tragedy that mercury is causing such health damage to many people. The American Dental Association has said for the past 150 years that the mercury in amalgam is safe and does not leak; however, no clinical studies were ever done and the Food and Drug Administration approved amalgam under a grandfather clause. Subsequent studies have shown this claim of safety not to be true. Over ten years ago, the Federation of American Societies for Experimental Biology Journal published a comprehensive article calling mercury restorative material a major source of mercury exposure to the U.S. population. The authors of this paper recommend that federal and state legislation be passed throughout our country to ensure that consent forms are given to patients receiving silver-mercury amalgam restorative material.

J Long Term Eff Med Implants. 2005;15(6):709-21

Dental amalgam restorations: daily mercury dose and biocompatibility

Mitchell RJ, Osborne PB, Haubenreich JE.

Department of Oral Health Practice, Division of Restorative Dentistry, College of Dentistry, University of Kentucky, Lexington, Kentucky 40536-0027, USA. rjm1@uky.edu

Over the past 150 years, silver-tin-copper amalgam has been the most frequently used dental restorative material. Amalgam may be the single most frequently used implant material. In the early 1980s, researchers discovered that amalgam restorations release mercury vapor during chewing. This review describes the research that has led to an estimate of the daily dose of mercury that will be absorbed by a subject with a large number of amalgam restorations. Along the way, the history and chemistry of dental amalgam are outlined. The routes of absorption of liquid mercury, ionic mercury, organic mercury, and mercury vapor are also briefly described. The daily dose is found to be 14% of the threshold above which observable adverse neurological symptoms are expected. The review concludes with a summary of the research on the adverse effects of dental amalgam. As expected from the low daily dose, few adverse neurological symptoms have been reported. There is also little evidence of an association of amalgam restorations with neurodegenerative diseases, altered renal function, adverse pregnancy outcomes, or autoimmune diseases. There is a lack of data on neurobiological and neurodevelopmental effects on children who may be exposed to mercury from maternal amalgam restorations during gestation. Additional data on the role of amalgam, if any, in Alzheimers disease and multiple sclerosis are needed.

J Nephrol. 2002 Mar-Apr;15(2):171-6

Mercury in dental restoration: is there a risk of nephrotoxicity?

Mortada WL, Sobh MA, El-Defrawy MM, Farahat SE.

Urology and Nephrology Center, Mansoura University, Faculty of Science, Egypt.

BACKGROUND: Concern has been voiced about exposure to mercury (Hg) from dental amalgam fillings, and there is a need to assess whether this leads to signs of nephrotoxicity. METHODS: A total of 101 healthy adults (80 males and 21 females) were included in this study. The population as grouped into those having amalgam fillings (39 males and 10 females) and those without (41 males and 11 females). Hg was determined in blood, urine, hair and nails to assess exposure. Urinary excretion of beta2-microglobulin (beta2M), N-acetyl-beta-D-glucosaminidase (NAG), gamma-glutamyltransferase (gammaGT) and alkaline phosphatase (ALP) were determined as markers of tubular damage. Albuminuria was assayed as an early indicator of glomerular dysfunction. Serum creatinine, beta2M and blood urea nitrogen (BUN) were determined to assess glomerular filtration. RESULTS: Hg levels in blood and urine were significantly higher in persons with dental amalgam than those without; in the dental amalgam group, blood and urine levels of Hg significantly correlated with the number of amalgams. Urinary excretion of NAG, gammaGT and albumin was significantly higher in persons with dental amalgam than those without. In the amalgam group, urinary excretion of NAG and albumin significantly correlated with the number of fillings. Albuminuria significantly correlated with blood and urine Hg. CONCLUSION: From the nephrotoxicity point of view, dental amalgam is an unsuitable filling material, as it may give rise to Hg toxicity. Hg levels in blood and urine are good markers of such toxicity. In these exposure conditions, renal damage is possible and may be assessed by urinary excretions of albumin, NAG, and gamma-GT.

In August 2008 WHO published a 170 page document 'Guidance for Identifying Populations at Risk from Mercury Exposure'. We will objectively review this document and other research and report back our finding. It should be interesting.