• The President's Desk  — Health Freedom, Tax-Exempt Vitamins

• Immune-Boosting Strategies During a Critical Time of Year  — 

• Are AGEs Implicated in Atherosclerosis?  — 

• Colon Health  — A Proactive Plan

• Paying Tribute to Shari Lieberman, PhD, CNS, FACN  — 

• Pet Corner  — Urinary Tract Health in Dogs

• Multivitamins Reformulated Based on Compelling Research  — 

• Brain Regeneration  — Key Nutrients Support The Growth of Brain Cell Neurites and Dendrites

• Melatonin Improves Age-Related Changes  — Breaking News
• Celiac Disease Becoming Increasingly Common, Research Indicates  — Breaking News
• Magnesium Supports Healthy Blood Pressure  — Breaking News
• Nutrient Supports Weight Management  — Breaking News
• Nutrient Helps Maintain Eye Health  — Breaking News
• Herbal Constituent May Strengthen the Arteries  — Breaking News
• Natural Sugar Substitute Supports Oral Health  — Breaking News
• New Research Supports Multivitamin Use  — Breaking News

• Xylitol & Osteoporosis
• Irregular Cardiac Rhythm
• BioDIM® to Balance Estrogen
• Relapsing Polychondritis
• Ear Health
• Lung Health
• Hyperactive Mania in Child
• Migraines in Child
• Liver Health, High MCV
• Vitiligo

Due to the government’s heavy hand, we’re often prohibited from reporting upon scientific studies that can empower you to learn about health. Now, Congressman Ron Paul has introduced three bills that would restore constitutional government and end FDA and FTC censorship of health information. In addition, another bill introduced by House of Representatives members Earl Blumenauer and Ginny Brown-Waite would make certain nutritional supplements tax deductible. These bills are some of the most crucial health-related legislation to appear before Congress.

Under the Health Freedom Act (HR 3395), FDA may not prohibit statements concerning a nutrient affecting a disease (including treatment effects) from being made in the market and may only act against a statement if the agency possesses clear and convincing evidence of the statement’s falsity.

Freedom of Health Speech Act (HR 3394) prevents the Federal Trade Commission from acting against any advertiser that communicates a health benefit for a product unless the FTC first establishes based on clear and convincing evidence that the statement made is false and that its communication causes public harm.

Congressional Responsibility Act (HR 3396) prohibits regulations from regulatory agencies from going into effect unless passed into law by Congress in the way in which the Constitution designates.

We urge you to write your Congressional Representatives and Senators to support each of these bills. On our website (www.vrp.com) you’ll find suggested wording for a letter that you can modify with your appropriate politicians’ names prior to emailing, mailing or faxing the communication.

At the same time, you may want to make your voice heard about the Tax Equity for Meal Replacements and Supplements Act of 2009 (HR 3406), which seeks to exempt the purchase of certain supplements from gross personal incomes. The legislation would allow consumers to deduct dietary supplements with health claims (such as calcium, vitamin D, etc.) from their Flexible Spending Accounts.

Together, we can make a difference in an issue crucially important to both our fundamental rights as U.S. citizens and our individual health.

The cold and flu season we are facing this year will likely be unlike any other we have experienced in this lifetime. As September begins and children return to school and university classes, the threat of contracting a virus increases.

Children bring home from school more than just homework, since schools act as “amplifying sites” for the spread of infectious diseases, outbreaks, and pandemics.¹ In one trial conducted between November 1, 2001 and April 30, 2002, researchers studied 3,771 children less than 14 years of age with no chronic medical conditions who presented with respiratory tract infections.² Nasopharyngeal swabs were collected for the isolation of influenza viruses and viral RNA detection. Information was also collected concerning respiratory illnesses and related morbidities among the study children and their household contacts. Influenza virus was demonstrated in 352 cases. One of the findings of the study was that in comparison with the influenza negative children, those who were influenza positive were more often attending day care centers or schools. Furthermore, their parents and siblings had more respiratory illnesses, received more antipyretics and antibiotics, needed more medical visits, missed more work or school days, and needed help at home to care for the ill children for a longer period of time.

Immune-Support Strategies

When children return to school it is an ideal time to begin a proactive immune support program. This will lay the foundation for optimal wellness throughout the winter months. The following natural strategies are often used in clinical practice to support immune health at this time of year, in preparation for when our immune systems are particularly challenged.

Mushrooms and Immunity

A special formula (known as ImmuneAssist^® 24/7) combines six mushrooms hybridized to bring out the most potent aspects of their immune enhancement properties. This allows the mushrooms to possess greater potential than any other mushrooms grown elsewhere today, including wild crafted varieties. This new formula has emerged as one of the most important ways to support immunity.

The mushrooms contained in the formula possess a high degree of immune-modulating activity thanks to polysaccharides known as 1-3 beta glucans. It is these 1-3 beta glucans that are mandatory for proper immune system function.

The mushrooms Agaricus blazei, Cordyceps sinensis, Grifola frondosa, Ganoderma lucidum, Coriolus versicolor and Lentinula edodes enhance nonspecific immunity, improve the secretion of IGA, and increase the function of monocytes-macrophages and the activity of natural killer cells. These mushrooms also are able to increase immunological balance and stability and increase the ratio of the Th/Ts immune cells.³

Researchers have investigated the role that mushrooms can play in modulating immunity. In one in vitro study of Grifola frondosa (maitake mushroom) extract, researchers stimulated a macrophage cell line from mice with extracts from Grifola frondosa then noted the effects on the growth of influenza A virus in canine kidney cells. The results indicated that Grifola frondosa reduced virus yields and increased the production of TNF-alpha, an antiviral cytokine. The researchers concluded that components of Grifola frondosa might induce the production of certain factors, including TNF-alpha, which are responsible for the inhibition of viral growth in vitro.⁴ Grifola frondosa also has been found to regulate the immune system in humans.⁵

Other studies have looked at the antiviral activity of Cordyceps sinensis, one of the most valued Chinese medicinal mushrooms. In 25 patients with chronic hepatitis B, 3 months of using Cordyceps resulted in an improvement in immunity as indicated by the fact that CD4 and CD4/CD8 ratio increased significantly compared with the controls.⁶

Animal studies also have shown that Cordyceps can regulate cellular immunity, enhance production of spleen lymphocytes and increase production of IL-2 from splenocytes. IL-2 (interleukin-2) is a cytokine, a protein released by white blood cells, which plays an important role in immunity by enhancing natural killer cell function and the production of T cells.⁷

Ganoderma lucidum extract, known as Reishi mushroom, was found to increase the immune responses of patients with advanced stage cancer and to significantly increase the mean natural killer cell activity compared to baseline along with improving other aspects of immunity.⁸

Another mushroom, Coriolus versicolor, restored immune responses to normal levels in tumor-bearing animals with suppressed or enhanced immune responses. In these animals, the killer T cell activity was augmented by intraperitoneal or oral administration of Coriolus versicolor.⁹

Lentinula edodes (Shitake), another well-documented immune modulator, has been found to stimulate immunomodulating cytokines in vitro¹⁰ and to enhance the ability of macrophages to phagocytize (or “eat”) foreign invaders in rodents.¹¹

Purified EGCG

Combining the mushrooms mentioned above with EGCG, the polyphenol compound found in green tea, is potentially the most important aspect of the ImmuneAssist 24/7 formula.^12-13 A number of studies have investigated EGCG’s activity against various strains of the flu. In one published report, two catechins from green tea, EGCG and ECG, were found to be potent inhibitors of influenza virus replication in cells and this effect was observed in all influenza virus subtypes tested, including A/H1N1, A/H3N2 and B virus. EGCG and ECG also suppressed viral RNA synthesis in the cells.¹⁴

An earlier in vitro study tested EGCG in cells infected with adenovirus, which is responsible for 5–10 percent of upper respiratory infections in children, as well as many infections in adults. Adding EGCG to the medium of infected cells reduced virus yield by two orders of magnitude.¹⁵

According to the researchers, “We conclude that the anti-adenoviral activity of EGCG manifests itself through several mechanisms, both outside and inside the cell, but at effective drug concentrations well above that reported in the serum of green tea drinkers.”

A purified form of EGCG is used within the formula ImmuneAssist 24/7. The EGCG is suspended in a time-released matrix so that it doesn’t break down in stomach acid, allowing much more of this virus-blocking compound into the blood stream than can be obtained by drinking green tea.

Silver Liquid

Mild Silver Protein (MSP) has been used since the 19th century as an anti-microbial agent, with a wide range of bactericidal, fungicidal and virucidal properties. Silver has been used to speed wound healing, purify water and preserve beverages.¹⁶ Silver was one of the mainstays of medical practice in Europe and America during the period from 1900 until the beginning of the modern antibiotic era, which began in the 1940s.

Historically, various forms of silver were used in literally hundreds of ailments, including pneumonia, tuberculosis and pleurisy,¹⁷ gonorrhea and syphilis,18 wounds, leg ulcers, pustular eczema, impetigo and boils.¹⁸ It has been used in acute meningitis and epidemic cerebro-spinal meningitis,¹⁷ Mediterranean fever, erysipelas, cystitis, typhus, typhoid fever, and tonsillitis,¹⁷ dacryocystitis, corneal ulcers, conjunctivitis and blepharitis,¹⁹ and various forms of septicemia, including puerperal fever, peritonitis and post-abortion septicemia.^{17, 20}

Silver is unique among antimicrobial agents in its broad spectrum of action. It has been claimed to kill some 650 different disease organisms²¹ including 95 percent of 72 strains of herpes virus.²² Recently, it has been reported that intravenous mild silver protein caused a dramatic reduction in viral load of three patients with human immunodeficiency virus (HIV+).²³

Silver can be used by adults to keep their defenses strong and to establish a proactive shield against viral attacks.

Vitamin D3

The activated form of vitamin D, 1,25(OH)2D, a steroid hormone, has been shown to have profound effects on human immunity. Vitamin D acts as an immune system modulator, preventing excessive expression of inflammatory cytokines and enhancing the activity of macrophages as they destroy viral invaders. In addition, vitamin D dramatically stimulates the expression of potent antimicrobial peptides that exist in natural killer cells, and in cells lining the respiratory tract where they play a major role in protecting the lung from infection. Vitamin D also reduces the incidence of respiratory infections in children.²⁴

In addition to 5,000 and 1,000 IU vitamin D3 capsules, a liquid form of Vitamin D3, an ideal option for children, is available here.

EpiCor^® and EpiCor^® Junior

The yeast fermentation product known as EpiCor is an immune modulator and powerful antioxidant that causes an increase in the activity of natural killer cells, which play an important part in immune health. EpiCor was found to enhance the immune system and significantly reduce cold and flu symptoms.

In a randomized, double-blind, placebo-controlled clinical trial, researchers studied 116 people recently vaccinated against the flu. Subjects received either daily supplements of EpiCor (500 mg) or a placebo. The scientists collected data on the subjects at the study’s start and after six and 12 weeks.

The researchers found that the subjects given EpiCor experienced significantly fewer cold and flu symptoms and significantly shorter duration of symptoms, compared to subjects taking the placebo. Among the 116 study participants, those who did have symptoms experienced a reduction in the duration of symptoms by 14 percent after taking EpiCor. The overall occurrence of cold and flu symptoms was reduced by 21 percent in the EpiCor group.²⁵

The above study and a large body of evidence that shows EpiCor can enhance immunity, indicates EpiCor for adults and EpiCor Junior for children are viable options to enhance health.

Fast Response

Despite our best efforts to fend off a viral attack, our defenses sometimes are weakened and illness results. Specific plant-derived compounds have been used in traditional Chinese medicine for two thousand years to enhance immune health and are meant to be taken by adults at the first onset of illness. Concentrated extracts of Forsythia suspense fruit, Lonicera japonicus flower, Platycodon grandiflorum root, Mentha arvensis, Lophatherum gracile stem and leaf, Glycyrrhizae uralensis root, Schizonepeta tennifolia herb, Glycine max seed, Arctium lappa fruit and Phragmites communis rhizome (found in Fast Response formula) all have properties that can profoundly maximize immune health.

In immunized mice, Glycyrrhizae uralensis increased the production of splenocytes, white blood cells found within the spleen that are important in immunity, and increased antibody production.²⁶ Platycodon grandiflorum, another immune stimulating herb, activates macrophages, which engulf and digest viruses and other pathogens, a process known as phagocytosis. However, unlike many other immune stimulating botanicals, platycodon activates B cells rather than T cells.²⁷

Phragmites communis, in animal studies, reduces atrophy of the thymus and spleen both of which are critical to the body’s immune system.²⁸ A new compound isolated from Forsythia in 2002 was shown to inhibit the respiratory syncytial virus (RSV), the most commonly identified cause of lower respiratory tract infections in young children. In the elderly, the virus can mimic a long and severe common cold.²⁹

Platycodon grandiflorum, Arctigenin (a component of Arctium lappa) and Mentha arvensis have equally important effects on the respiratory tract. Platycodon grandiflorum is known to clear the lungs and reduce phlegm production.³⁰ Arctigenin markedly improved lung health in mice with pneumonia caused by influenza virus infection. Arctigenin also prolonged the survival time of mice infected with flu virus.³¹ Mentha arvensis, an extract derived from mint, inhibits histamine release from mast cells in vitro.³²

Fast Response also includes vitamin A and zinc, two nutrients important in building immunity.

Conclusion

When children return to school, immunity enhancement should return to the top of everyone’s priority list. Bolstering the immune system now can set the stage for a healthier winter. ImmuneAssist 24/7, Silver Liquid, Vitamin D3, EpiCor and EpiCor Junior are all excellent ways to strengthen the immune system while Fast Response should be kept on hand for immediate action if the immune system fails.

References

1. Stebbins S, Downs JS, Vukotich CJ Jr. Using nonpharmaceutical interventions to prevent influenza transmission in elementary school children: parent and teacher perspectives. J Public Health Manag Pract. 2009 Mar-Apr;15(2):112-7.

2. Principi N, Esposito S, Marchisio P, Gasparini R, Crovari P. Socioeconomic impact of influenza on healthy children and their families. Pediatr Infect Dis J. 2003 Oct;22(10 Suppl):S207-10.

3. Ruwei W, Yiyuan X, Peijun J, Xing W, Holliday JC. Immune-Assist brand Dietary Supplement as an Adjunct for Chemo and Radiation Therapy in Cancer Treatment. Unpublished Study.

4. Obi N, Hayashi K, Miyahara T, Shimada Y, Terasawa K, Watanabe M, Takeyama M, Obi R, Ochiai H. Inhibitory Effect of TNF-alpha Produced by Macrophages Stimulated with Grifola frondosa Extract (ME) on the Growth of Influenza A/Aichi/2/68 Virus in MDCK Cells. Am J Chin Med. 2008;36(6):1171-83.

5. Deng G, Lin H, Seidman A, Fornier M, D’Andrea G, Wesa K, Yeung S, Cunningham-Rundles S, Vickers AJ, Cassileth B. A phase I/II trial of a polysaccharide extract from Grifola frondosa (Maitake mushroom) in breast cancer patients: immunological effects. J Cancer Res Clin Oncol. 2009 Mar 1. Published Online Ahead of Print.

6. Gong HY, Wang KQ, Tang SG. [Effects of cordyceps sinensis on T lymphocyte subsets and hepatofibrosis in patients with chronic hepatitis B]. [Article in Chinese] Hunan Yi Ke Da Xue Xue Bao. 2000 Jun 28;25(3):248-50.

7. Cheng Q. [Effect of cordyceps sinensis on cellular immunity in rats with chronic renal insufficiency]. [Article in Chinese] Zhonghua Yi Xue Za Zhi. 1992 Jan;72(1):27-9, 63.

8. Gao Y, Zhou S, Jiang W, Huang M, Dai X. Effects of ganopoly (a Ganoderma lucidum polysaccharide extract) on the immune functions in advanced-stage cancer patients. Immunol Invest. 2003 Aug;32(3):201-15.

9. Tsukagoshi S, Hashimoto Y, Fujii G, Kobayashi H, Nomoto K, Orita K. Krestin (PSK). Cancer Treat Rev. 1984 Jun;11(2):131-55.

10. Liu M, Li J, Kong F, Lin J, Gao Y. Induction of immunomodulating cytokines by a new polysaccharide-peptide complex from culture mycelia of Lentinus edodes. Immunopharmacology. 1998 Nov;40(3):187-98.

11. Zheng R, Jie S, Hanchuan D, Moucheng W. Characterization and immunomodulating activities of polysaccharide from Lentinus edodes. Int Immunopharmacol. 2005 May;5(5):811-20.

12. Nance CL, Siwak EB, Shearer WT. Preclinical development of the green tea catechin, epigallocatechin gallate, as an HIV-1 therapy. J Allergy Clin Immunol. 2009 Feb;123(2):459-65.

13. Xu J, Wang J, Deng F, Hu Z, Wang H. Green tea extract and its major component epigallocatechin gallate inhibits hepatitis B virus in vitro. Antiviral Res. 2008 Jun;78(3):242-9.

14. Song JM, Lee KH, Seong BL. Antiviral effect of catechins in green tea on influenza virus. Antiviral Res. 2005 Nov;68(2):66-74.

15. Weber JM, Ruzindana-Umunyana A, Imbeault L, Sircar S. Inhibition of adenovirus infection and adenain by green tea catechins. Antiviral Res. 2003 Apr;58(2):167-73.

16. Bechhold H. Colloids in Biology and Medicine, New York. D. van Nostrand, 1919, pp. 364-76.

17. Duhamel B Electric Metal Colloids and Their Therapeutical Applications Lancet 1912; 29-30.

18. Searle A. The Use of Colloids in Health and Disease, London: Constable & Co., 1920, pp 67-111.

19. Legge Roe A. Collosol Argentum and its Opthalmic Uses. Br. Med. J. Jan.16, 1915. 104.

20. Brown G. Colloidal Silver in Sepsis. Am. J. Obstetrics. 1916, Jan-June, 136-141.

21. Powell J. Our Mightiest Germ Fighter, Sci Digest. 1978, Mar., 57-60.

22. Chang TW, Weinstein L. Prevention of Herpes Keratoconjunctivitis in Rabbits by Silver Sulfadiazine, Antimicrob. Agents Chemother, 1975;8: 677-78.

23. Dean W, Mitchell M, Whizar Lugo V, South J. Reduction of Viral Load in AIDS Patients with Intravenous Mild Silver Protein--Three Case Reports. Clinical Practice of Alternative Medicine. Spring, 2001.

24. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E. Epidemic influenza and vitamin D. Epidemiol Infect. 2006 Sep 7;1-12 [Epub ahead of print].

25. Moyad MA, Robinson LE, Zawada ET, Jr, Kittelsrud JM, Chen DG, Reeves SG, Weaver SE. Effects of a Modified Yeast Supplement on Cold/Flu Symptoms. Urologic Nursing. February 2008;28(1): 50-55.

26. Sun HX, Pan HJ. Immunological adjuvant effect of Glycyrrhiza uralensis saponins on the immune responses to ovalbumin in mice. Vaccine. 2006 Mar 10;24(11):1914-20.

27. Han SB, Park SH, Lee KH, Lee CW, Lee SH, Kim HC, Kim YS, Lee HS, Kim HM. Polysaccharide isolated from the radix of Platycodon grandiflorum selectively activates B cells and macrophages but not T cells. Int Immunopharmacol. 2001 Oct;1(11):1969-78.

28. Miao MS, Gu LY, Fang XY, Miao YY. [Effect of Phragmites communis polysaccharide on the aged-model mice]. [Article in Chinese] Zhongguo Zhong Yao Za Zhi. 2004 Jul;29(7):673-5.

29. Zhang GG, Song SJ, Ren J, Xu SX. A new compound from Forsythia (Thunb.) Vahl with antiviral effect on RSV. J Herb Pharmacother. 2002;2(3):35-40.

30. Guo L, Zhang C, Li L, Xiao YQ. [Advances in studies on Platycodon grandiflorum] [Article in Chinese]. Zhongguo Zhong Yao Za Zhi. 2007 Feb;32(3):181-6.

31. Yang Z, Liu N, Huang B, Wang Y, Hu Y, Zhu Y. [Effect of anti-influenza virus of Arctigenin in vivo] [Article in Chinese]. Zhong Yao Cai. 2005 Nov;28(11):1012-4.

32. Shin TY. Inhibition of immunologic and nonimmunologic stimulation-mediated anaphylactic reactions by the aqueous extract of Mentha arvensis. Immunopharmacol Immunotoxicol. 2003 May;25(2):273-83.

Arterial stiffening occurs as early atherosclerosis is developing and is associated with increased risk of cardiovascular events, dementia, and death. Atherosclerosis is an inflammatory disease in which fatty substances, cholesterol, platelets, cellular waste products, and calcium accumulate on the inner lining (endothelium) of arteries. These plaques grow in size and may occlude the artery causing diminished blood flow and oxygen transport or may rupture and induce heart attacks or strokes. In the United States, it is estimated that atherosclerosis affects one in four Americans, causing approximately 42 percent of all deaths. Approximately half of these deaths are due to atherosclerotic coronary heart disease (CHD).¹

Heart-Harming Compounds

Although it is common to focus on many aspects of arterial stiffening, one potential factor involved in this damaging process is often overlooked. That potential cause is known as Advanced glycosylation end products, or AGEs for short. AGEs are formed by the attachment of sugars (glycosylation) onto biological proteins or lipids. This reaction is irreversible causing glycated proteins and lipids to accumulate over time. AGE formation and accumulation is greatly accelerated with high levels of circulating sugars and oxidative stress.² Hyperglycemia (elevated blood sugar) increases reactive oxygen species and carbonyl intermediates, such as glyoxal and methylglyoxal, which increases glycosylation.³ AGEs react with molecules such as proteins and lipids creating cross-linkages, causing them to become less elastic and less degradable by enzymes. Glycosylated hemoglobin (HbA1c) is an example of AGEs and is measured to evaluate blood sugar control in diabetics.

AGEs interact with specific cell receptors such as RAGE. RAGE activation may lead to an increase in inflammatory responses and cellular injury.⁴ The interaction between AGEs and RAGE modulate numerous physiological functions, such as gene expression, intracellular signaling, and the release of pro-inflammatory molecules and free radicals that contribute towards the pathology of numerous diseases.⁵

In this article, I will discuss the role that AGEs play in the health of the cardiovascular system.

Cross-linking and the Heart

AGE accumulation is associated with cardiovascular dysfunction including atherosclerotic plaque formation, decreased vascular and myocardial (heart muscle) elasticity, endothelial dysfunction, and hypertension.⁶

Arterial stiffness is caused by inflammatory molecules, endothelial cell dysfunction, and reactive oxygen species.⁷ In addition, AGEs alter structural proteins causing cross-linking of collagen and elastin in the myocardium and arterial wall leading to age-related increase in cardiovascular stiffness. Researchers have also shown that plasma levels of AGEs are significantly higher in hypertensive patients compared to subjects with normal blood pressure. Additionally, they found that plasma AGE levels correlate to aortic stiffness independent of age and blood pressure.⁸ Even among healthy adults, AGE levels are associated with increased arterial stiffness.⁹

In blood vessels, cross-linkages trap other proteins, such as LDL cholesterol, leading to a cascade of events that result in accelerated atherosclerotic formation. Data suggests that AGEs act through receptor-independent and dependent mechanisms increasing vascular damage, fibrosis, and inflammation associated with accelerated atherogenesis.¹⁰ In addition, AGE accumulation is associated with atherosclerotic plaque formation independent of hyperglycemia.¹¹ AGEs act directly, as well as through receptors, to alter the function of many proteins including antioxidant and metabolic enzymes, calcium channels, lipoproteins, and transcriptional and structural proteins. This results in endothelial dysfunction, inflammation, and oxidative stress, which are characteristic of hypertension and atherosclerosis. Also, researchers have found that AGEs quench nitric oxide (NO), which is an endothelium-derived relaxing factor in smooth muscle. Decreasing levels of NO by AGEs results in impaired relaxation which is associated with hypertension, atherosclerosis, and diabetes.¹²

RAGES and Blood Vessels

The AGE receptors are also important in the development of atherosclerosis. By engaging the RAGEs, AGEs induce the expression of pro-inflammatory mediators in various vascular cell types and are involved in a variety of microvascular and macrovascular complications. Studies indicate that low levels of circulating endogenous secretory RAGE (esRAGE) and total soluble RAGE (sRAGE) induce the progression of carotid intima-media thickness, a marker of atherosclerosis, independently of conventional cardiovascular risk factors.¹³ Researchers have found that fasting insulin, the pro-inflammatory cytokine interleukin-6, glucose levels, and insulin resistance are major factors determining circulating esRAGE levels. Pulse wave velocity, another measure of arterial stiffness, was found to be associated with esRAGE levels, indicating that low esRAGE levels correlate with inflammation and arterial stiffness and may play an important role on RAGE interaction-induced atherosclerosis.¹⁴

In one study, investigators examined the relationship between the levels sRAGE and endothelial dysfunction in non-diabetic subjects with suspected coronary artery disease. Plasma levels of sRAGE were evaluated and endothelial function was measured by endothelium-dependent flow-mediated vasodilation (FMD) of the brachial artery. The subjects were followed for 48 months to assess the occurrence of major cardiovascular events. The results showed that plasma sRAGE level was an independent predictor of endothelium-dependent FMD, and decreased levels of sRAGE were associated with significantly higher number of adverse cardiovascular events. The study authors concluded that this data suggests that sRAGE plays a pivotal role in atherothrombosis (rupture of atherosclerotic plaque).¹⁵

Pharmaceutical agents that prevent AGE formation, break cross-links, or block AGE receptors reduce vascular and myocardial stiffness, inhibit atherosclerotic plaque formation, and improve endothelial function. They have also been shown to improve arterial compliance in elderly patients with vascular stiffening thus improving cardiac function and blood pressure.^16-17 This suggests that therapeutics that positively affect AGE formation and activity, such as some natural options, may greatly impact the progression of cardiovascular diseases.

Natural AGE-Reduction Strategies

Numerous nutrients and botanicals (found in the formula AGEBlock^®) are effective inhibitors of AGE formation. B vitamins have been shown to inhibit both AGE formation and associated free radical damage. Several studies have found that pyridoxal-5-phosphate (the active form of vitamin B6) significantly inhibits AGE formation. In fact, one study showed that P5P inhibited platelet aggregation (the clumping together of platelets) in rats injected with AGEs.¹⁸

Additional research indicates that pyridoxal-5-phosphate, thiamine, and thiamine pyrophosphate can protect DNA from damage by inhibiting production of hydroxyl and superoxide radicals due to methylglyoxal-induced AGE formation.¹⁹ Studies also show that benfotiamine, the lipid-soluble derivative of thiamine, inhibits AGE formation and pro-inflammatory nuclear factor (NF)kb activation, as well decreases diabetic complications.²⁰

Given the link between glycation and oxidation, it is not surprising that several antioxidants have been shown to inhibit AGE formation. Carnosine is a dipeptide (beta-alanyl-L-histidine) normally present in many vital tissues.²¹ Carnosine exhibits antioxidant properties as well as the ability to prevent the formation of AGEs, cross-linking reactions, glycation, and protein carbonyl group formation.^22-23 Carnosine has been shown to scavenge aldehyde byproducts from lipid peroxidation preventing DNA-protein and protein-protein cross-linking reactions²⁴ and inhibits protein modification induced by methylgloxal, a puruvate aldehyde metabolite implicated in AGE formation.²⁵ Methylglyoxal (MG) (pyruvaldehyde) is an endogenous metabolite which is present in increased concentrations in diabetics and implicated in formation of advanced glycosylation end-products (AGEs) and secondary diabetic complications. In addition, research shows that carnosine decreases oxidative stress and formation of reactive oxygen species and reactive nitrogen species, protects membranes from free radical damage, regulates macrophage function, and chelates reactive metals. Muscle carnosine levels decrease significantly with age, as one study found a 63 percent decrease from age 10 to age 70.²⁶

The antioxidants N-acetyl cysteine and lipoic acid have been shown to decrease cell death induced by AGEs.²⁷ In addition, numerous studies indicate that alpha-lipoic acid reduces oxidative stress and prevents the formation AGEs.^28-29 One study found that the combination of benfotiamine plus alpha-lipoic acid completely normalized increased AGE formation and reduced increased monocyte hexosamine-modified proteins by 40 percent in type 1 diabetic subjects.³⁰ The hexosamine pathway has been implicated in the pathogenesis of diabetic complications. Elevated blood sugars increase hexosamine synthesis and contribute to the pathogenesis of diabetic complications.

The antioxidant botanicals Psidium guajava L. (Guava) and Ilex paraguariensis (Yerba Maté) also inhibit glycation. Studies have shown that Psidium guajava L. aqueous extract significantly inhibits low density lipoprotein (LDL) glycation in a dose-dependent manner suggesting that this herb has potential therapeutic uses in the prevention of cardiovascular and neurodegenerative diseases associated with glycation.³¹ Ilex paraguariensis, rich in polyphenols, has been shown to exert significant dose-dependent inhibition of AGE formation comparable to the standard antiglycation agent aminoguanidine.³² Research indicates that the active constituents chlorogenic acid and caffeic acid are the main substances responsible for the antiglycation effect of this herb.³³ In addition, Ilex paraguariensis extract has been shown to inhibit the progression of atherosclerosis in animal models.³⁴

Conclusion

AGE formation has detrimental effects on the cardiovascular system including the induction of arterial stiffening and atherosclerosis. A number of natural substances, all found in AGEBlock, are effective AGE inhibitors and may help decrease the accumulation and damaging effects of AGEs, possibly slowing the progression of atherosclerosis and cardiovascular disease.

References

1. Centers for Disease Control and Prevention. Potential Infectious Etiologies of Atherosclerosis: A Multifactorial Perspective. Available at: http://www.cdc.gov/ncidod/eid/vol7no5/oconnor.htm#1. Accessed on: 8-10-09.

2. Forbes JM, Soldatos G, Thomas MC. Below the radar: advanced glycation end products that detour “around the side”. Is HbA1c not an accurate enough predictor of long term progression and glycaemic control in diabetes? Clin Biochem Rev. 2005 Nov;26(4):123-34.

3. Tan D, Wang Y, Lo CY, et al. Methylglyoxal: its presence and potential scavengers. Asia Pac J Clin Nutr. 2008;17 Suppl 1:261-4.

4. Wendt TM, Tanji N, Guo J, et al. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol. 2003 Apr;162(4):1123-37.

5. Ahmed N. Advanced glycation endproducts--role in pathology of diabetic complications. Diabetes Res Clin Pract. 2005 Jan;67(1):3-21.

6. Zieman SJ, Kass DA. Advanced glycation endproduct crosslinking in the cardiovascular system: potential therapeutic target for cardiovascular disease. Drugs. 2004;64(5):459-70.

7. Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005 May;25(5):932-43.

8. McNulty M, Mahmud A, Feely J. Advanced glycation end-products and arterial stiffness in hypertension. Am J Hypertens. 2007 Mar;20(3):242-7.

9. Semba RD, Najjar SS, Sun K, et al. Serum carboxymethyl-lysine, an advanced glycation end product, is associated with increased aortic pulse wave velocity in adults. Am J Hypertens. 2009 Jan;22(1):74-9.

10. Jandeleit-Dahm K, Cooper ME. The role of AGEs in cardiovascular disease. Curr Pharm Des. 2008;14(10):979-86.

11. Vlassara H, Fuh H, Donnelly T, et al. Advanced glycation endproducts promote adhesion molecule (VCAM-1, ICAM-1) expression and atheroma formation in normal rabbits. Mol Med. 1995 May;1(4):447-56.

12. Bucala R, Tracey KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest. 1991 Feb;87(2):432-8.

13. Katakami N, Matsuhisa M, Kaneto H, et al. Serum endogenous secretory RAGE level is an independent risk factor for the progression of carotid atherosclerosis in type 1 diabetes. Atherosclerosis. 2009 May;204(1):288-92.

14. Choi KM, Yoo HJ, Kim HY, et al. Association between endogenous secretory RAGE, inflammatory markers and arterial stiffness. Int J Cardiol. 2009 Feb 6;132(1):96-101.

15. Chiang KH, Huang PH, Huang SS, et al. Plasma levels of soluble receptor for advanced glycation end products are associated with endothelial function and predict cardiovascular events in nondiabetic patients. Coron Artery Dis. 2009 Jun;20(4):267-73.

16. Bakris GL, Bank AJ, Kass DA, et al. Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process. Am J Hypertens. 2004 Dec;17(12 Pt 2):23S-30S.

17. Geronikaki A, Gavalas A, Dislian V, et al. Inhibition of renin-angiotensin system and advanced glycation end products formation: a promising therapeutic approach targeting on cardiovascular diseases. Cardiovasc Hematol Agents Med Chem. 2007 Oct;5(4):249-64.

18. Yamagishi S, Matsui T, Takenaka K, Nakamura K, Takeuchi M, Inoue H. Pigment epithelium-derived factor (PEDF) prevents platelet activation and aggregation in diabetic rats by blocking deleterious effects of advanced glycation end products (AGEs). Diabetes Metab Res Rev. 2009 Mar;25(3):266-71.

19. Suji G, Sivakami S. DNA damage during glycation of lysine by methylglyoxal: assessment of vitamins in preventing damage. Amino Acids. 2007 Nov;33(4):615-21.

20. Hammes HP, Du X, Edelstein D, et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med. 2003 Mar;9(3):294-9.

21. Jackson MC, Lenney JF. The distribution of carnosine and related dipeptides in rat and human tissues. Inflamm Res. 1996 Mar;45(3):132-5.

22. Hipkiss AR. Would carnosine or a carnivorous diet help suppress aging and associated pathologies? Ann N Y Acad Sci. 2006 May;1067:369-74.

23. Reddy VP, Garrett MR, Perry G, et al. Carnosine: a versatile antioxidant and antiglycating agent. Sci Aging Knowledge Environ. 2005 May 4;2005(18):pe12.

24. Guiotto A, Calderan A, Ruzza P, et al. Carnosine and carnosine-related antioxidants: a review. Curr Med Chem. 2005;12(20):2293-315.

25.  Hipkiss AR, Chana H. Carnosine protects proteins against methylglyoxal-mediated modifications. Biochem Biophys Res Commun. 1998 Jul 9;248(1):28-32.

26. Stuerenburg HJ. The roles of carnosine in aging of skeletal muscle and in neuromuscular diseases. Biochemistry (Mosc). 2000 Jul;65(7):862-5.

27. Loske C, Neumann A, Cunningham AM, et al. Cytotoxicity of advanced glycation endproducts is mediated by oxidative stress. J Neural Transm. 1998;105(8-9):1005-15.

28. Thirunavukkarasu V, Anitha Nandhini AT, Anuradha CV. Lipoic acid improves glucose utilisation and prevents protein glycation and AGE formation. Pharmazie. 2005 Oct;60(10):772-5.

29. Kunt T, Forst T, Wilhelm A, et al. Alpha-lipoic acid reduces expression of vascular cell adhesion molecule-1 and endothelial adhesion of human monocytes after stimulation with advanced glycation end products. Clin Sci (Lond). 1999 Jan;96(1):75-82.

30. Du X, Edelstein D, Brownlee M. Oral benfotiamine plus alpha-lipoic acid normalises complication-causing pathways in type 1 diabetes. Diabetologia. 2008 Oct;51(10):1930-2.

31. Hsieh CL, Yang MH, Chyau CC, et al. Kinetic analysis on the sensitivity of glucose- or glyoxal-induced LDL glycation to the inhibitory effect of Psidium guajava extract in a physiomimic system. Biosystems. 2007 Mar;88(1-2):92-100.

32. Lunceford N, Gugliucci A. Ilex paraguariensis extracts inhibit AGE formation more efficiently than green tea. Fitoterapia. 2005 Jul;76(5):419-27.

33. Gugliucci A, Bastos DH, Schulze J, et al. Caffeic and chlorogenic acids in Ilex paraguariensis extracts are the main inhibitors of AGE generation by methylglyoxal in model proteins. Fitoterapia. 2009 Sep;80(6):339-44.

34. Mosimann AL, Wilhelm-Filho D, da Silva EL. Aqueous extract of Ilex paraguariensis attenuates the progression of atherosclerosis in cholesterol-fed rabbits. Biofactors. 2006;26(1):59-70.

With the recent death of Farrah Fawcett, colorectal cancer has had a prominent place in the news. Colorectal cancer is one of the most common cancers. In 2008, an estimated 148,810 people were diagnosed with colorectal cancer and approximately 49,960 people died of the disease, according to the American Cancer Society. Colorectal cancer is the third most commonly diagnosed cancer and the third leading cause of cancer death in both men and women in the US.¹

Early colorectal cancer is particularly insidious since it often has no symptoms. However, most colorectal cancer has its origins as a polyp, a small growth that forms in the colon wall and that can over time grow and become malignant. The growth of these polyps can result in bleeding or blocking the intestine. At this stage, common warning signs of colorectal cancer include:

• Bleeding from the rectum
• Blood in the stool or in the toilet after having a bowel movement
• A change in the shape of the stool
• Cramping pain in the lower stomach
• A feeling of discomfort or an urge to have a bowel movement when there is no need to have one
• New onset of constipation
• Abnormal weight loss

Colorectal cancer screening through colonoscopies is essential to detecting the disease and should be an essential part of any over-50 health care regimen. In addition, the risk of developing colon cancer as well as the risk of dying from colon cancer is reduced through regular physical activity, maintaining a healthy body weight and eating a healthy diet low in sugary foods and high in fiber. Furthermore, a number of other natural strategies can be employed to protect colon health.

Protecting the Colon

Short chain fatty acids (SCFA) are extremely important to the functioning of the colon. The fermentation of dietary carbohydrates, particularly degradation-resistant starches and dietary fiber, results in the colonic production of SCFAs, primarily acetate, propionate, and butyrate. Insufficient SCFAs can contribute to a significantly less healthy colon, yet levels of SCFAs in the intestines vary markedly with diet.² Epidemiologic studies have shown that there is an association between diet and the incidence of colorectal cancer and that butyrate is a potential anticarcinogenic compound.³

The SCFAs have numerous functions in the intestines. SCFAs are readily absorbed by the intestinal mucosa, or the innermost lining of the colon, and have been shown to stimulate intestinal mucosal growth. Butyrate, the major energy source for the cells that line the colon, has been shown to induce enzymes promoting mucosal cell restoration. SCFAs also stimulate sodium and water absorption in the colon.⁴ In addition, SCFAs enhance the motility of the intestinal tract by stimulating contractions and shorten emptying of the ileum (the last section of the small intestine), which may protect ileal mucosa against the potentially harmful effects of the reflux of colonic contents.⁵ Also, the secretion of mucus, an important part of the intestinal mucosal barrier, has been shown to be stimulated by SCFAs, especially butyrate, in the colon.⁶

Butyrate, acetate and propionate have been shown to be effective anti-inflammatory and immune-modulating agents in human colon cancer cell lines and mouse models.⁷ Butyrate, propionate and acetate inhibited the proliferation and migration and increased the differentiation of a human colon cancer cell line in studies.⁸ Particularly, butyrate has been investigated for its inhibition of pro-inflammatory markers and the role this plays in prevention of inflammatory bowel disease (IBD) and cancer.⁹ Butyrate has also been studied in the prevention of colon cancer, through its ability to promote cell differentiation, cell-cycle arrest and apoptosis (programmed cell death) of transformed colon cells. Butyrate’s ability to increase cell differentiation is important because cancer cells are poorly differentiated; a low-grade cancer is therefore “well-differentiated.”

Butyrate has been shown to decrease experimentally induced DNA damage in human colon cells and colon cancer cell lines by approximately 50 percent.¹⁰ Some researchers believe that a diet low in resistant starch and fiber and the resulting low production of SCFAs in the colon may explain the high occurrence of colon disorders seen in Western civilizations.¹¹

Instigator of Colonic Damage

While butyrate and other short chain fatty acids protect the colon, ammonia can act as a destructive agent. Ammonia is produced as a by-product in the colon by bacterial fermentation of protein and other nitrogen-containing substances. As protein intake increases, levels of ammonia in the colon also increase. Elevated levels of colonic ammonia may have adverse health effects. Research indicates that ammonia levels as low as 5 mmol/L can have detrimental effects on epithelial cells that line the colon. The toxicity of ammonia toward colonic epithelial cells can lead to cell destruction and increased turnover of these cells.¹² In addition, increased production of ammonia from eating a high-protein diet was shown to increase the incidence of colon cancer in animal models.¹³ Levels of ammonia found in the colon after consumption of the typical Western diet are associated with increased viral infections, promotion of growth of cancer cells, cell toxicity, altered nucleic acid synthesis, and increased mass of the intestinal mucosal cells.¹⁴

It is therefore extremely important to the health of the colon to implement strategies to reduce ammonia while also increasing levels of butyrate.

Larch Arabinogalactan

Larch arabinogalactan (Larch AG), a highly branched polysaccharide (a large sugar molecule resistant to degradation) derived from the bark of the larch tree (Larix species), is known for its ability to increase the production of short-chain fatty acids, particularly butyrate and propionate. It has also been shown to decrease the generation and absorption of ammonia in the colon.¹⁵

Arabinogalactan (AG) is a non-digestible soluble dietary fiber that resists breakdown by enzymes and enters the large bowel intact where it is fermented by colonic bacteria. Arabinogalactan is approved by the FDA as a dietary fiber source.

Research has demonstrated that ingestion of Larch AG has a significant effect on enhancing beneficial gut microflora, specifically increasing anaerobes such as Lactobacillus while reducing levels of ammonia.¹⁶

Larch arabinogalactan also has immune modulating activity that is important for several intestinal disorders. Larch arabinogalactan has been shown to stimulate natural killer (NK) cell cytotoxicity, which has been shown to be abnormal in conditions such as IBS and IBD. There is evidence Larch also may inhibit the metastasis of tumor cells to the liver, making it a worthwhile consideration for cancer protocols.¹⁷

Vitamin D3

Studies have shown that butyrate and vitamin D3 can work in unison to inhibit colon cancer cells. Evidence indicates that the cell cycle arrest that butyrate induces in colon cancer cells is influenced by the up-regulation of the vitamin D receptor. Furthermore, butyrate-induced cell differentiation in colon cancer cells is mediated by the vitamin D receptor. Vitamin D when added with butyrate to colon cancer cells worked with the butyrate to increase the cell differentiation.^18-19

Probiotics

While increasing butyrate levels and reducing ammonia levels is crucial to optimal colon health, there is a third component that must be addressed. Pathogenic bacteria in the colon produce bacterial enzymes such as beta-glucosidase, beta-glucuronidase, and urease, all of which may contribute to the development of colon cancer by generating carcinogens. It is therefore advantageous to build healthy levels of beneficial intestinal bacteria such as Lactobacillius Rhamnosus GG (LGG).  LGG has been found to exert antiproliferative activity on human gastric cancer cells and human colonic cancer cells.²⁰

Conclusion

Optimal colon health involves increasing levels of butyrate, lowering levels of ammonia and making the intestines a hospitable environment for beneficial bacteria. Pairing Larch AG with Vitamin D3 and Lactobacillus Rhamnosus GG (found in Culturelle^®) can therefore be an effective strategy for enhancing colon health.

References

1. American Cancer Society website, www.cancer.org, accessed August 17, 2009.

2. Sanderson IR. Short chain fatty acid regulation of signaling genes expressed by the intestinal epithelium. J Nutr. 2004 Sep;134(9):2450S-2454S.

3. Roy MJ, Dionne S, Marx G, Qureshi I, Sarma D, Levy E, Seidman EG. In vitro studies on the inhibition of colon cancer by butyrate and carnitine. Nutrition. 2009 Jul 18. Published Online Ahead of Print.

4. D’Argenio G, Mazzacca G. Short-chain fatty acid in the human colon. Relation to inflammatory bowel diseases and colon cancer. Adv Exp Med Biol. 1999;472:149-58.

5. Cherbut C, Aubé AC, Blottière HM, Galmiche JP. Effects of short-chain fatty acids on gastrointestinal motility. Scand J Gastroenterol Suppl. 1997;222:58-61.

6. Shimotoyodome A, Meguro S, Hase T, Tokimitsu I, Sakata T. Short chain fatty acids but not lactate or succinate stimulate mucus release in the rat colon. Comp Biochem Physiol A Mol Integr Physiol. 2000 Apr;125(4):525-31.

7. Tedelind S, Westberg F, Kjerrulf M, Vidal A. Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: a study with relevance to inflammatory bowel disease. World J Gastroenterol. 2007 May 28;13(20):2826-32.

8. Fu H, Shi YQ, Mo SJ. Effect of short-chain fatty acids on the proliferation and differentiation of the human colonic adenocarcinoma cell line Caco-2. Chin J Dig Dis. 2004;5(3):115-7.

9. Andoh A, Tsujikawa T, Fujiyama Y. Role of dietary fiber and short-chain fatty acids in the colon. Curr Pharm Des. 2003;9(4):347-58.

10. Rosignoli P, Fabiani R, De Bartolomeo A, Spinozzi F, Agea E, Pelli MA, Morozzi G. Protective activity of butyrate on hydrogen peroxide-induced DNA damage in isolated human colonocytes and HT29 tumour cells. Carcinogenesis. 2001 Oct;22(10):1675-80.

11. Scheppach W. Effects of short chain fatty acids on gut morphology and function. Gut. 1994 Jan;35(1 Suppl):S35-8.

12. Robinson RR, Feirtag J, Slavin JL. Effects of dietary arabinogalactan on gastrointestinal and blood parameters in healthy human subjects. J Am Coll Nutr. 2001 Aug;20(4):279-85.

13. Bartram HP, Scheppach W, Schmid H, Hofmann A, Dusel G, Richter F, Richter A, Kasper H. Proliferation of human colonic mucosa as an intermediate biomarker of carcinogenesis: effects of butyrate, deoxycholate, calcium, ammonia, and pH. Cancer Res. 1993 Jul 15;53(14):3283-8.

14. Visek WJ. Diet and cell growth modulation by ammonia. Am J Clin Nutr. 1978 Oct;31(10 Suppl):S216-S220.

15. Kelly GS. Larch arabinogalactan: clinical relevance of a novel immune-enhancing polysaccharide. Altern Med Rev. 1999 Apr;4(2):96-103.

16. Robinson RR, Feirtag J, Slavin JL. Effects of dietary arabinogalactan on gastrointestinal and blood parameters in healthy human subjects. J Am Coll Nutr. 2001 Aug;20(4):279-85.

17. Kelly GS. Larch arabinogalactan: clinical relevance of a novel immune-enhancing polysaccharide. Altern Med Rev. 1999 Apr;4(2):96-103.

18. Gaschott T, Stein J. Short-chain fatty acids and colon cancer cells: the vitamin D receptor--butyrate connection. Recent Results Cancer Res. 2003;164:247-57.

19. Gaschott T, Werz O, Steinmeyer A, Steinhilber D, Stein J. Butyrate-induced differentiation of Caco-2 cells is mediated by vitamin D receptor. Biochem Biophys Res Commun. 2001 Nov 2;288(3):690-6.

20. Orlando A, Messa C, Linsalata M, Cavallini A, Russo F. Effects of Lactobacillus rhamnosus GG on proliferation and polyamine metabolism in HGC-27 human gastric and DLD-1 colonic cancer cell lines. Immunopharmacol Immunotoxicol. 2009;31(1):108-16.

We are deeply saddened by the loss of a dear friend and respected colleague, Shari Lieberman, PhD, CNS, FACN, who recently passed away. Dr. Lieberman has been a frequent contributor to Vitamin Research News and we have produced a number of her formulas. Most recently, she was very much involved in the development of Nutracidin^™, a formula providing powerful immune support for those with viral, fungal or bacterial concerns.

Dr. Lieberman’s contributions to the nutritional supplement field have been extensive. She spent countless hours using her immense knowledge to help thousands of people improve their own health. She was a Certified Nutrition Specialist, a Fellow of the American College of Nutrition and a member of the New York Academy of Science. The author of numerous books, she has been in private practice in New York City as a clinical nutritionist for more than 20 years.

Dr. Lieberman’s knowledge and passion for nutritional science will be missed by everyone here who knew her.

Urinary incontinence is a problem that is not unusual in an older dog, especially the spayed female dog. This is noted by urine pooling where a dog has been lying. While it is commonly a consistent problem, it can be intermittent.

Anytime a dog starts to show this problem, it needs to be worked up to be sure there is no problem with bladder or urethral infections. Depending on the age of the dog, a minimum of a sterile urinalysis is needed before any treatment is started. In the older dog, it may be very worthwhile to get a full blood panel run along with the urinalysis. This allows your dog’s doctor to evaluate for any other problem that may be present.

If something is out of line on the urinalysis report but it does not indicate an infection, then cancer should be ruled out along with multiple openings through the bladder sphincter. This particular problem is rarely attributed to cancer and will usually show up in the quite young dog if it is a physical problem.

Treatment is typically a product called phenylpropanolamine and was very inexpensive. The problem that occurred a few years ago is some foolish people were buying the product in huge quantities and using it in the production of methamphetamine.

Because of these less than desirable folks, we now have to use a chewable product (Proin^®) that is not so cheap.

The other treatment we used a lot 15 years ago and earlier was estradiol. There used to be a long-acting form that was quite effective. Problem was, if just a little too much was used, a spayed female dog would be brought into a false heat. While she did not have ovaries or a uterus, she would swell and bleed just like she was in heat. In addition, she would attract intact male dogs. It definitely was not fun if the dose was a little high or she was more sensitive than usual.

If you would like to try something different once you know there is no infection, consider trying Saw Palmetto Extract. I started using this over 15 years ago and it has worked in 70 to 80 percent of the cases. It has a tonic effect. A tonic is a substance that balances the biochemical and physiological events that comprise body systems. The body is able to select and utilize what it needs from a tonic herb. When I first started using the herb, it was thought there were phytoestrogens in the herb and that still may be a part of its effect.

The biggest problem is the dose as it is much higher than the human dose. I usually start small dogs up to about 40 pounds on 500 mg three times per day, medium sized dogs up to 100 pounds on 1,000 mg three times per day and giant breed dogs on 1,500 mg three times per day. The dose can be lowered to twice per day once a good effect has been achieved and some dogs can eventually get along on once per day. If it doesn’t help, definitely try the Proin.

We pride ourselves on our ability to keep up with the latest nutritional research and will consistently offer new products and update older products to keep up with new science. Consequently, we have reformulated our multivitamins to correspond to the most up-to-date research available.

Among other changes to our multivitamins, you will find:

•   We have replaced folic acid with MTHF (5-methyltetrahydrofolate), the “active” form of folate that has recently become available as a supplement. MTHF is the most biologically active form of folate and is the molecule to which folic acid must be converted in the body to be utilized.¹ For many years, well ahead of other multivitamins in the marketplace, we have also used a superior form of vitamin B12 (methylcobalamin) in our multivitamins.

•   Increased dosage of Vitamin D3. Over the last five years, an increasing amount of evidence indicates the levels of vitamin D3 needed for optimal health are far above the RDA. Vitamin D3 has been shown to be important in virtually every aspect of health including immunity, bone and heart health.^2-3

•   Green Tea has been added to many of the multinutrient formulas due to an abundance of new research showing green tea’s wide-reaching role in health. This phytonutrient has been shown to have a number of interesting properties, including antiviral and antibacterial effects,⁴ the ability to reverse vascular dysfunction in patients with coronary artery disease,⁵ inhibit solar-induced skin tumor development in mice,⁶ promote weight loss,⁷ and improve breast and prostate health.^8-9

•   Selenium is now present in our multi formulas as methylselenocysteine. MSC is a naturally occurring form of selenium that is readily absorbed and that enhances the body’s production of detoxifying compounds such as glutathione peroxidase. This form of selenium is one of the most well-studied in its ability to promote colon, prostate and breast health.^10-12

•   Researchers have recently taken a strong interest in trans-resveratrol due to its possible role as a longevity enhancer, its ability to improve heart health, and possible antimutagenic actions as demonstrated in a number of in vitro studies using cancer cells from the breast, cervix, esophagus, prostate, lung, melanoma (a highly virulent form of skin cancer), and leukemia.^13-14 It’s antimutagenic potential also has been explored in animal studies.¹⁵ Due to a wide array of compelling research that has continued to be published, trans-resveratrol has now been added to many of our multivitamin formulas.

•   Flower pollen extract, which helps to neutralize free radicals, has been shown to possess potent anti-inflammatory activity,¹⁶ to promote liver health, improve lipid profiles and decrease atherosclerotic plaque formation.^17-18 In patients with rheumatoid arthritis flower pollen improved gastrointestinal and liver health and reduced the clinical manifestations and course of RA.¹⁹ Graminex G-60^™ flower pollen extract, which does not trigger seasonal allergy reactions, has been added to Women’s Essentials along with pomegranate extract and astaxanthin known for their ability to protect the skin from damage. Women’s Essentials also now has increased levels of iron bis-glycinate.

•   HMR Lignan^® is another important ingredient added to Women’s Essentials and Extend Ultra. Isolated from the knots of spruce, HMR Lignan possesses strong antioxidant activity and is important for breast, prostate and uterine health.^20-22

•   Many of VRP’s multis now include two powerful forms of vitamin K2 (MK-4 and MK-7). MK-7 has been associated with reductions in the incidence of coronary heart disease and with positively affecting bone health.^23-24

Other important changes to many of the formulas include the addition of a digestive enzyme blend to ensure the most effective nutrient uptake, increased levels of N-acetyl cysteine in Extend Core and Extend Plus, reduced levels of beta carotene in all the formulas and the addition of benfotiamine, known for its AGE-blocking effects, to Optimum D, Extend Plus, and Extend Ultra.

References

1. Meletis CD. Active Folate: New More Bioavailable Form Addresses A Common Nutrient Deficiency. Vitamin Research News. Available at www.vrp.com.

2. Gorham ED, Garland CF, Garland FC, Grant WB, Mohr SB, Lipkin M, Newmark HL, Giovannucci E, Wei M, Holick MF. Optimal Vitamin D status for colorectal cancer prevention: a quantitative meta analysis. Am J Prev Med. 2007 Mar;32(3):210-6.

3. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for Vitamin D. Am J Clin Nutr. 2007 Jan;85(1):6-18.

4. Kassem MA, Fanaki NH, Fawzi MA, Dabbous FSE. Influence of green tea on the antimicrobial activity of some antibiotics against multiresistant clinical isolates. Presented at the Society for General Microbiology”s 162nd meeting, March 31, 2008, Edinburgh, Scotland.

5. Widlansky ME, Hamburg NM, Anter E, Holbrook M, Kahn DF, Elliott JG, Keaney JF Jr, Vita JA. Acute EGCG Supplementation Reverses Endothelial Dysfunction in Patients with Coronary Artery Disease. J Am Coll Nutr. 2007 Apr 26 (2):95-102.

6. Suchitra Kativar, Craig A Elmets, Santosh K Katiyar. Green tea and skin cancer: photoimmunology, angiogenesis and DNA repair. The Journal of Nutritional Biochemistry. 2007 May 18 (5):287-296.

7. Zheng G, Sayama K, Okubo T, Juneja LR, Oguni I. Anti-obesity effects of three major components of green tea, catechins, caffeine and theanine, in mice. In Vivo. 2004 Jan-Feb;18(1):55-62.

8. Gu JW, Young E, Covington J, Johnson JW, Tan W. Oral Administration of EGCG, an Antioxidant Found in Green Tea, Inhibits Tumor Angiogenesis and Growth of Breast Cancer in Female Mice. Presented at the 121st Annual Meeting of the American Physiological Society, part of the Experimental Biology 2008 scientific conference, San Diego, April 2008.

9. Harper CE, Patel BB, Wang J, Eltoum IA, Lamartiniere CA. Epigallocatechin-3-Gallate suppresses early stage, but not late stage prostate cancer in TRAMP mice: mechanisms of action. Prostate. 2007 Oct 1;67(14):1576-89.

10. Bhattacharya A, Tóth K, Sen A, Seshadri M, Cao S, Durrani FA, Faber E, Repasky EA, Rustum YM. Inhibition of colon cancer growth by methylselenocysteine-induced angiogenic chemomodulation is influenced by histologic characteristics of the tumor. Clin Colorectal Cancer. 2009 Jul;8(3):155-62.

11. Wang L, Bonorden MJ, Li GX, Lee HJ, Hu H, Zhang Y, Liao JD, Cleary MP, Lü J. Methyl-selenium compounds inhibit prostate carcinogenesis in the transgenic adenocarcinoma of mouse prostate model with survival benefit. Cancer Prev Res (Phila Pa). 2009 May;2(5):484-95.

12. Zhang X, Zarbl H. Chemopreventive doses of methylselenocysteine alter circadian rhythm in rat mammary tissue. Cancer Prev Res (Phila Pa). 2008 Jul;1(2):119-27.

13. Dean W. Resveratrol: Clinical and Anti-Aging Benefits. Anti-Aging Nutrient Review and Update Part 6. Vitamin Research News. Available at www.vrp.com.

14. VRP Staff. Resveratrol: Remarkable Longevity Enhancer and Heart Protector. Vitamin Research News. Available at www.vrp.com.

15. Sengottuvelan M, Deeptha K, Nalini N. Resveratrol ameliorates DNA damage, prooxidant and antioxidant imbalance in 1,2-dimethylhydrazine induced rat colon carcinogenesis. Chem Biol Interact. 2009 Jun 10. Published Online Ahead of Print.

16. Loschen G, Ebeling L. [Inhibition of arachidonic acid cascade by extract of rye pollen] Arzneimittelforschung 1991 Feb;41(2):162-7.

17. Wójcicki J, Samochowiec L, Bartłomowicz B, Hinek A, Jaworska M, Gawrońska-Szklarz B. Effect of pollen extract on the development of experimental atherosclerosis in rabbits. Atherosclerosis. 1986 Oct;62(1):39-45.

18. Wójcicki J, Samochowiec L, Hinek A. The effect of Cernitins on galactosamine-induced hepatic injury in rat. Arch Immunol Ther Exp (Warsz). 1985;33(2):361-70.

19. Voloshyn OI, Pishak OV, Seniuk BP, Cherniavs’ka NB. [The efficacy of flower pollen in patients with rheumatoid arthritis and concomitant diseases of the gastroduodenal and hepatobiliary systems] [Article in Ukrainian]. Lik Sprava. 1998 Jun;(4):151-4.

20. Boccardo F, Lunardi GL, Petti AR, Rubagotti A. Enterolactone in breast cyst fluid: correlation with EGF and breast cancer risk. Breast Cancer Res Treat. 2003 May;79(1):17-23.

21. Bylund A, Saarinen N,  Zhang JX, Bergh A, Widmark A, Johansson A, Lundin E, Adlercreutz H, Hallmans G, Stattin P, Makela S. Anticancer Effects of a plant lignan 7- hydroxymatairesinol on a prostate cancer model in vivo. Exp Biol Med (Maywood). 2005 Mar;230(3):217-23.

22. Katsuda S, Yoshida M, Saarinen N, Smeds A, Nakae D, Santti R, Maekawa A. Chemopreventive effects of hydroxymatairesinol on uterine carcinogenesis in Donryu rats. Exp Biol Med (Maywood). 2004 May;229(5):417-24.

23. Gast GC, de Roos NM, Sluijs I, Bots ML, Beulens JW, Geleijnse JM, Witteman JC, Grobbee DE, Peeters PH, van der Schouw YT. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis. 2009 Sep;19(7):504-10.

24. Katsuyama H, Saijoh K, Otsuki T, Tomita M, Fukunaga M, Sunami S. Menaquinone-7 regulates gene expression in osteoblastic MC3T3E1 cells. Int J Mol Med. 2007 Feb;19(2):279-84.

25. van Summeren MJ, Braam LA, Lilien MR, Schurgers LJ, Kuis W, Vermeer C. The effect of menaquinone-7 (vitamin K2) supplementation on osteocalcin carboxylation in healthy prepubertal children. Br J Nutr. 2009 May 19:1-8. Published online ahead of print.

There are two basic cell populations in the human body—the dividing (or mitotic) cell populations and the non-dividing (or post-mitotic) cell types. Brain cells, or neurons, for a long time were considered non-dividing post-mitotic cells that formed during embryogenesis and never replaced themselves.

We now know that brain cells can, under certain conditions, replace themselves and regrow their neural communications networks. What is especially true is that neurites and dendrites, the long filament or root-like terminal branches that are extensions of the brain cells themselves, can regrow and elongate when given the proper nutrients. Neurites and dendrites comprise the wiring communications network that allows brain cells to communicate with each other. Loss of brain cells with age is a normal process, but the loss of neurites and dendrites disrupts the neural communications network severely, preventing brain cell “cross-talk” and is a far more serious matter. Senescence of the central nervous system is characterized by a loss of neurons, neurites and dendrites and results in physiological and behavioral impairments. It is believed that reductions in the levels of growth factors, like nerve growth factor and other trophic growth factors leads to major declines in brain cell performance and degenerative diseases.¹ The good news is that certain supplements act as growth factors or stimulate the brain to produce growth factors to maintain and rebuild the neural communications network.

In 1991, it was discovered that the presence of acetyl carnitine increased the effects of nerve growth factor on the outgrowth of neurites from brain cells 100 times greater than when just nerve growth factor itself was present. This was an interesting observation at the time but nerve growth factor is an internally produced protein in the brain and it was not really known how to stimulate or regulate its production.²

In 1995 it was discovered that the supplement acetyl carnitine arginate mimicked the effect of nerve growth factor and caused neurite outgrowth of PC12 cells “in a manner similar to that elicited to by nerve growth factor (itself).”³ Synergy between acetyl carnitine arginate and acetyl carnitine had earlier been demonstrated when both were tested separately and together on brain cells and found to be highly synergistic in the production of the neurotransmitters GABA, glutamate, somatostatin and other brain peptides.⁴

Synergistic Action on Brain Cell Regrowth

The reason the two carnitines work synergistically on brain cell regrowth came from the observation that acetyl carnitine creates nerve growth factor receptors for nerve growth factor or its mimic acetyl carnitine arginate to act on.² So, the one carnitine grew the receptors that NGF acted on, thereby regrowing neurites, and the other compound mimicked the effects of nerve growth factor itself. The two pieces of the puzzle were finally put into place.^2-3

Acetyl carnitine and acetyl carnitine arginate are two synergists that regrow brain cell neurites and dendrites so powerfully that the average length of neurites produced by the mixture of the two resulted in a 19.5 percent increase in neurite outgrowth with the mixture compared to neurite outgrowth of 5.6 percent using acetyl carnitine alone in brain cell cultures.³

In addition, acetyl carnitine arginate protects neurons against the toxicity caused by the presence of beta amyloid plaque found in old brain cells.⁵ Beta amyloid production is strongly implicated in the development of Alzheimer’s disease and is found in great abundance in Alzheimer’s brains. When beta amyloid was added to healthy human brain cell cultures, neurotoxicity took place in 5 days and cell death occurred within 8 days. Acetyl carnitine arginate added at the same time completely prevented or “reverted” beta amyloid toxicity by preventing its disrupting effect on the normal brain cell’s calcium balance, or homeostasis.⁵

Since 1988, it was known that the buildup of lipofuscin, another oxidized protein found in all older cells, was reduced in brain cells when acetyl carnitine was fed to rats as they aged.^6-7 Acetyl carnitine also prevented emotional changes that occur in older rats, like increased rearing behavior and decreased locomotor activity and even in advanced age kept this behavior to the levels seen in younger rats.⁸

Other studies have demonstrated that acetyl carnitine prevents a variety of structural changes to the aging brain from the hippocampus, prevents decreases in receptor site sensitivity, and prevents loss of receptors in various areas over the brain. Within seven days, treatment with acetyl carnitine increases serotonin and dopamine output in rat brains. Acetyl carnitine also protects rats against the emotional effects of a chronic stress reaction called escape behavior.⁹

In several human trials, acetyl carnitine improved pain, nerve regeneration and sensory perceptions in patients with diabetic neuropathy.¹⁰ A meta-analysis, or a summary of all the studies to date using acetyl carnitine in mild cognitive impairment and mild Alzheimer’s disease showed significant improvements in these conditions.¹¹ Acetyl carnitine in randomized studies was successfully used for chronic fatigue syndrome¹² and fatigue in multiple sclerosis.¹³ It also was used successfully in depressed patients, for cognitive defects in alcoholism, and in patients with organic brain syndrome and cerebrovascular insufficiency.^14-17

In many early studies, acetyl carnitine has been proposed to prevent brain aging,^{8, 18} and given its successful clinical history in the brain since these proposals, it is a shining star in the field of prevention of the progression of already-existing brain diseases in intervention studies. It also has proven itself in brain regeneration in animal and human brain cell studies. Together with the proven synergy between acetyl carnitine arginate and acetyl carnitine in regrowing neurites and dendrites, it is a vitally important dietary supplement for the brain.

Other Brain-Regenerating Nutrients

Uridine

Uridine, or its most common salt, uridine-5-monophosphate, UMP, is a building block of RNA and DNA and, like acetyl carnitine arginate and acetyl carnitine, it is important to brain health. Uridine-5-monophosphate is the usual dietary source of uridine, found in the milk of mammals. Recent research is increasingly showing that uridine is essential for growth and development throughout life.¹⁹ It was once thought that only infants needed uridine during early developmental stages since mature mammals are capable of synthesizing their own uridine. Uridine monophosphate is still routinely added to all infant and most parenteral formulas. Uridine monophosphate has the phosphate group removed in the body by the phosphatases and when uridine is transported into the brain, the body again adds the phosphate group to cross the blood-brain barrier.²⁰

In the 1960s, it was discovered that uridine is an essential ingredient for adult brain functioning. In 1968, one researcher found that uridine is the real dietary source of cytidine, a building block of the cell membrane component and signaling agent, phosphatidylcholine, which is necessary for memory and is a major component of cell membranes.²¹ Phosphatidylcholine levels decline with age in all mammals and these declining levels appear to play a major role in memory loss.

A great deal of brain research, especially when it comes to memory and cognition, is conducted with gerbils and rats because they have close similarities to human brain structure. Gerbils, in particular, lose cognition in a manner strikingly similar to humans.²²

Research into the 1970s showed that rats that watched visual stimuli and then were required to perform training tasks took up more uridine into their brains than rats not required to perform tasks. It was also shown that rats that were exposed to visual stimuli had increased uptake of uridine into the visual areas of the brain and needed uridine for memory in responding to the visual stimuli. It was becoming apparent that uridine plays an important role in memory retention.²³

In 2000 it was shown that human brain cells when exposed to uridine for 4 days had increased neurite outgrowth and neurofilament expression. A variety of chemicals that prevented incorporation of nucleotides into brain cells all prevented the neurite outgrowth in the brain cells caused by uridine, showing that uridine was responsible for the neural regeneration.²⁴

In 2005, a study confirmed that uridine added to brain cell cultures stimulated neurite outgrowth branching and increased the number of new neurites per cell. The researchers found that uridine stimulated neurite outgrowth and branching by two different pathways—it enhanced phosphatidylcholine synthesis, as was previously shown in the earlier studies, but it also blocked receptors that stopped neurites from growing.²⁵

In the same year, a study showed that orally administered uridine-5-monophosphate given to aged rats increased the release of dopamine in the right striatum of their brains to a level of 341 compared to a control group level of 221, a 35 percent increase. Biomarkers of neurite outgrowth, neurofilament-70 and neurofilament-M protein levels increased to 182 percent and 221 percent higher than in the control rats. The study demonstrated that even in old rats, oral uridine intake increases neurotransmitter release and neurite outgrowth in vivo.²⁶

Gotu kola (Centella asiatica)

Gotu kola is a perennial plant native to India and has been used in Ayurvedic traditional medicine for thousands of years. It is mentioned in the ancient Chinese Shennong Herbal during the Tang dynasty 2,000 years ago. Gotu kola and its extracts have been incorporated into the Indian pharmacopeia in the early 1800s and officially registered as a drug in France in the 1880s.

Traditionally, Gotu kola has been used for nervous disorders such as senility and epilepsy and a brain tonic to improve memory. It has been called a “brain food” and has been recommended for overstressed people, depression, to improve reflexes and to prevent nervous breakdown. Gotu kola has also been well-known for improving circulation in patients with phlebitis and peripheral neuropathy.²⁷

Scientific research into Gotu kola extracts and its effects on the brain really only began in earnest in the past decade. In 2002, Gotu kola water extracts were administered to rats where it improved their cognitive function in terms of learning and memory in a standard shuttle box avoidance and step through test. Brain levels of malondialdehyde (MDA), the most prominent final breakdown product of cell membrane damage was reduced and brain levels of the endogenous antioxidant glutathione were increased.²⁸

In 2003, the same researchers again showed improved cognitive function in rats in two well-accepted tests for improved intelligence. They confirmed the reduced MDA brain levels and increased brain glutathione levels.²⁹

A breakthrough year occurred in 2005 regarding the number of studies published using Gotu kola extracts on brain function and structural changes. In one study, where Gotu kola was given to mice during postnatal development stage “(the) extract caused brain cell dendrite outgrowth and branching of dendrites in the hippocampal area of the brain.” This showed the extract “can influence the neuronal morphology and promote the higher brain function of juvenile and young adult mice.” In other words, permanent structural out branching of the neural network of the brain was observed and this resulted in higher brain functioning.^30-31

In the same year, Gotu kola alcohol extract stimulated a marked increase in neurite outgrowth in human brain cells. It was shown than many different fractions of Gotu kola extracts produced neurite branching and outgrowth from the human cells, proving that there are several active principles in Gotu kola causing this growth. These active principals were identified as asiaticosides and asiatic acid. When the alcohol extract was added to the drinking water of old rats “(they) demonstrated more functional recovery and increased axonal regeneration (of neurites and dendrites), larger calibers of axons and greater numbers of myelinated (sheath-covered) axons.” The authors concluded “taken together, our findings indicate that components in Centella ethanolic [Gotu kola] extract may be useful for accelerating repair of damaged neurons.”³²

The most desirable Gotu kola extract to use is a hydro-alcoholic extract standardized to a much higher percentage of active asiaticoside principles than the vast majority of Gotu kola extracts.

Conclusion

Acetyl carnitine increases the effects of nerve growth factor 100 times when in NGF’s presence. It increases the expression of nerve growth factor receptor sites, which nerve growth factor acts on to regrow neurites and dendrites. Acetyl carnitine arginate mimics the effects of nerve growth factor itself. The two supplements act synergistically.

Uridine is another supplement that has been shown to regrow neurites and dendrites during growth and development stages in vivo orally. It has been shown to stimulate neurite-dendrite outgrowth in older animals, too, while improving their mental abilities.

Gotu kola improves cognition in older animals while stimulating neurite-dendrite growth and out branching in key areas of the brain because of the presence of several active principals called asiaticosides. It improves cognition and outgrowth in both older animals and also during the growth and development stages of younger animals.

Combining these four brain-regeneration nutrients can have a dramatic effect on cognitive health.

References

1. Sarter, M, Bruno, JP. Developmental origins of the age-related decline in cortical cholinergic function and associated cognitive abilities. Neurobiol Aging. 2004 Oct;25(9):1127-39.

2. Tagliatatela G, Angelucci L, Ramacci MT, Werrbach-Perez K, et al. Acetyl-L-carnitine enhances the response of PC-12 cells to nerve growth factor. Brain Res Dev Brain Res. 1991 Apr 24;59(2):221-30.

3. Taglialatela, G, Navarra D, Olivi A, Ramacci MT, Werrbach-Perez K, et al. Neurite outgrowth in PC12 cells stimulated by acetyl-L- carnitine arginine amide. Neurochem Res. 1995 Jan;20(1):1-9.

4. Westlund KN, Lu Y, Werrbach-Perez K, Hulsebosch CE, Mrgan B, et al. Effects of nerve growth factor and acetyl-L-carnitine arginyl amide on the human neuronal line HCN-1A. Int J Dev Neurosci. 1992 Oct;10(5):361-73.

5. Scorziello A, Meucci O, Calvani M, Schettini G. Acetyl-L-carnitine arginine amide prevents beta 25-35-induced neurotoxicity in cerebellar granule cells. Neurochem Res. 1997 Mar;22(3);257-65.

6. Amenta, F, Ferrante F, Lucreziotti R, Ricci A, Ramacci MT. Reduced lipofuchsin accumulation in senescent rat brain by long term acetyl-L-carnitine treatment. Arch. Gerontol Geriatr. 1989 Sep-Oct;9(2):147-53.

7. Ramacci, MT, De Rossi M, Lucreziotti, MR, Mione MC, Amenta F. Effect of long-term treatment with acetyl-L-carnitine on structural changes of ageing rat brain. Drugs Exp Clin Res. 1988;14(9):593-601.

8. Kohjimoto Y, Ogawa T, Matsumoto M, Shirakawa K, Kuwaki T, Yasuda H, et al. Effects of acetyl-L-carnitine on the brain lipofuchsin content and emotional behavior in aged rats. Jpn J Pharmacol. 1988 Nov;48(30:365-71.

9. Tolu P, Masi F, Leggio B, Schleggl S, Tagliamonte A, de Montia MG. Effects of long-term acetyl-L-carnitine in rats: I. Increased dopamine output in mesocorticolimbic areas and protection toward acute stress exposure. Neuropsychopharmacology. 2002 Sep;27(3):410-20.

10. Sima AA, Calvani M, Mehta M, Amato A. Acetyl-L-carnitine Study Group. Acetyl-l-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care. 2005 Jan;28(1):89-94.

11. Montgomery SA, Thal LJ, Amrein R. Meta-analysis of double-blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol. 2003 Mar;18(2): 61-71.

12. Vermeulen RC, Scholte HR. Exploratory open label, randomized study of acetyl and propionylcarnitine in chronic fatigue syndrome. Psychosom Med. 2004 Nar-Apr;66(2):276-82.

13. Tomassini V, Pozzilli C, Onesti E, Pasqualetti P, Marinelli F, Pisani A, et al. Comparison of the effects of acetyl-L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomized, double-blind, crossover trial. J. Neurol Sci. 2004 Mar 15;218(1-2):103-8.

14. Garzya G, Corallo D, Fiore A, Lecciso G, Petrelli G, Zotti C. Evaluation of the effects of L-acetylcarnitine on senile patients suffering from depression. Drugs Exp Clin Res. 1990;16(2):101-6.

15. Tempesta E, Troncon R, Janiri L, Colusso L, Riscica P, Saraceni G, et al. Role of acetyl-L-carnitine in the treatment of cognitive deficit in chronic alcoholism. Int J Clin Pharmacol Res. 1990;10(1-2):101-7.

16. Herrmann WM, Dietrich R, Hiersemenzel R. Pharmaco-electroencephalographic and clinical effects of the cholinergic substance-acetyl-L-carnitine-in patients with organic brain syndrome. Int J Clin Pharmacol Res. 1990;10(1-20:81-4.

17. Arrigo A, Casale R, Buonocore M, Ciano C. Effects of acetyl-L-carnitine on reaction times in patients with cerebrovascular insufficiency. Int J Clin Pharmacol res. 1990;10(1-2):133-7.

18. Fiora L, Rampello L. L-acetylcarnitine attenuates the age-dependent decrease of NMDA-sensitive glutamate receptors in rat hippocampus. Acta Neurol (Napoli) 1989 Oct;11(5):346-50.

19. Wang, L, Pooler AM, Albrecht MA, Wurtman, RJ. Dietary uridine-5’-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats. J Mol Neurosci. 2005;27(1):137-45.

20. Wang L, Albrecht MA, Wurtman RJ. Dietary uridine-5’-monophosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat. Brain Res. 2007 Feb 16;1133(1):42-8.

21. Dawson DM. Enzymatic conversion of uridine nucleotide to cytidine nucleotide by rat brain. J Neurochem. 1968 Jan;15(1):31-4.

22. Delbarre G, Delbarre B, Casset-Senon D. The use of the Mongolian gerbil as a model for cerebrovascular involvement. Paroi Arterielle. 1980;6(3):161-5.

23. Smith JR. Distribution of 3H-uridine-5 in rat brain areas after exposure to various training tasks-an autoradiographic analysis. Pharmacol Biochem Behav. 1975 May-Jun:3(3):463-70.

24. Silei V, Politi V, Lauro GM. Uridine induces differentiation in human neuroblastoma cells via protein kinase C epsilon. J Neurosci Res. 2000 Jul 15;61(2):206-11.

25. Pooler AM, Guez DH, Benedictus R, Wurtman RJ. Uridine enhances neurite outgrowth in nerve growth factor-differentiated PC 12 (corrected). Neuroscience. 2005;134(1):207-14.

26. Wang L, Pooler AM, Albrecht MA, Wurtman RJ. Dietary uridine -5-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats. J Mol neurosci. 2005;27(1):137-45.

27. Pointel JP, Boccalon H, Cloarec M, Ledevehat C, Joubert M. Titrated extract of Centella asiatica (TECA) in the treatment of venous insufficiency of the lower limbs. Angiology. 1987 Jan;38(1 Pt 1): 46-50.

28. Veerendra Kumar MH, Gupta YK. Effect of different extracts of Centella asiatica on cognition and markers of oxidative stress in rats. J. Ethnopharmacol. 2002 Feb;79(2):253-60.

29. Veerendra Kumar MH, Gupta YK. Effect of Centella asiatica on cognition and oxidative stress in an intracerebroventricular streptozotocin model of Alzheimer’s disease in rats. Clin Exp Pharmacol Physiol. 2003 May-Jun;30(5-6):336-42.

30. Rao SB, Chetana M, Uma Devi P. Centella asiatica treatment during postnatal period enhances learning and memory in mice. Physiol Behav. 2005 Nov 15;86(4):449-57.

31. Soumyanath A, Zhong YP, Gold SA, Yu X, Koop DR, Bourdette D, Gold BG. Centella asiatica accelerates nerve regeneration upon oral administration and contains multiple fractions increasing neurite elongation in-vitro. J Pharm Pharmacol. 2005 Sept;57(9):1221-9.

32. Garcia-Alloza M, Dodwell SA, Meyer-Luehmann M, Hyman BT, Bacskai BJ. Plaque-derived oxidative stress mediates distorted neurite trajectories in the Alzheimer mouse model. J Neuropathol Exp Neurol. 2006 Nov;65(11):1082-9.