TO ARRANGE FOR YOUR STEM CELL CONSULTATION CALL TOLL FREE 1800-300-1063

2011

[Type the author name]

Dr. Steenblocks Alternative Therapies for Multiple Sclerosis

[Type the document subtitle]

2011

26381 Crown Valley Parkway, Suite 130 Mission Viejo, CA 92691, USA

 2011 by David A. Steenblock, D.O., Inc. All rights reserved.

DISCLAIMER: The use of stem cells or stem cell rich tissues as well as the mobilization of stem cells by any means, e.g., pharmaceutical, mechanical or herbal-nutrient is not FDA approved to combat aging or to prevent, treat, cure or mitigate any disease or medical condition mentioned, cited or described in any document or article on this website. This report and the information featured, showcased or otherwise appearing in it is not to be used as a substitute for medical advice, diagnosis or treatment of any health condition or problem. Those who read this report should not rely on information provided in it for their own health problems. Any questions regarding your own health should be addressed to your physician or other duly licensed healthcare provider. This report and its authors, owners and sponsors make no guarantees, warranties or express or implied representations whatsoever with regard to the accuracy, completeness, timeliness, comparative or controversial nature, or usefulness of any information contained or referenced in it. This report and its authors, owners and sponsors do not assume any risk whatsoever for your use of this document or the information posted herein. Health-related information and opinions change frequently and therefore information contained in this report may be outdated, incomplete or incorrect. All statements made about products, drugs and such in this report have not been evaluated by the Food and Drug Administration (FDA). Use of this Website does not create an expressed or implied professional relationship.

Page 2 of 34

Alternative Therapies for Multiple Sclerosis

By David Steenblock, M.S., D.O. and Lyn Darnell

This review is for educational purposes only and is not intended to be a substitute for your physician's advice. Multiple Sclerosis (MS) is an inflammatory, autoimmune, demyelinating disease of the central nervous system that destroys myelin, oligodendrocytes, and axons (14). Oligodendrocytes are white matter cells that produce myelin for the myelin sheath, a protective covering around nerve fibers that speeds neural transmission. Axons are nerve fibers that conduct nerve impulses away from a neuron. Between 250,000 - 350,000 people in the United States suffer from Multiple Sclerosis. The name relates to the multiple hardened (sclerotic) lesions and scars in the brain and spinal cord. Initial symptoms may include extreme fatigue, vertigo, optic neuritis, and numbness in the extremities. Most patients experience relapsingremitting episodes that over time can lead to progressive neurological deterioration. MS lesions are found in various stages in MS, from new, active lesions to old but inactive lesions. Lucchinetti and associates analyzed MS tissues from human biopsies and autopsies and found four distinct lesion patterns. Therefore, four distinct causes may be involved in MS. Pattern I showed autoimmune destruction mediated by T-cells and antibodies. Lesion edges were sharply demarcated and located around veins. Active demyelination was associated with inflammation but also present was remyelination and the preservation of oligodendrocytes. In the injured myelin sheaths, all myelin proteins were lost at the same rate. Pattern II lesions were the same as Pattern I but with the addition of IgG deposition and activated complement. Pattern III lesions were similar to viral or toxin-induced oligodendroycte dystrophy. Lesions were not around veins and lesion borders were diffuse and irregular. Lymphocytes and activated myeloid cells were detected but activated complements of IgG were not. The myelin sheaths showed a loss of Myelin Oligodendrocyte Glycoprotein (MOG). Oligodendrocyte death from apoptosis was prominent. Pattern IV lesions were similar to those of Pattern III, except oligodendrocyte death appeared necrotic. In the 83 cases analyzed, pattern II lesions were most common and characteristic of relapsing, remitting disease. Pattern IV lesions were found in patients with primary progressive disease and pattern III lesions were seen as "starter" lesions capable of converting to another pattern. Brain regions unaffected by inflammation and neurons with intact myelin sheaths also showed axonal damage (13). Page 3 of 34

In the central nervous system, microglia are tissue macrophages (immune cells) which have the ability to regulate and be regulated by immune cells (lymphocytes, macrophages, B cells) and stromal cells (neurons and glia). Microglia are found throughout the central nervous system and participate in the onset and progression of CNS inflammatory responses. Microglia, when activated, are highly damaging to CNS function through their production of neurotoxins, inflammatory cells (Inflammatory Protein-10, Macrophage Inflammatory Protein-1, Macrophage Inflammatory Protein-2, C-C Chemokine Ligand 19, Monocyte Chemoattractant Protein-1, Monocyte Chemoattractant Protein-2) and immune cells that produce antibodies. Microglia direct inflammatory responses can result in the brain and spinal cord being infiltrated with immune cells against foreign invaders as well as T-cells that destroy myelin proteins. They also limit inflammation by producing neuroprotectants and immunosuppressive factors. Whether activated microglia produce growth factors or neurotoxins such as nitric oxide and excess glutamate depends on the signals received from neurons, T cells, glia and macrophages (13). The destruction may be further enhanced by the presence of heavy metals, viruses and endotoxins. These factors contribute to a downward cycle of local inflammation, demyelination and axonal damage, which results in further inflammation, demyelination and axonal damage. Current therapies for MS are designed to delay disease progression by immuno-modulation or immunosuppression. Until recently, the persisting neurological damage has remained mostly irreversible. Today, there is increased optimism about slowing and perhaps reversing the disease with a comprehensive program that includes therapies that improve blood circulation, myelin regeneration, cell energy production, gut normalization, and dietary, anti-inflammatory, antimicrobial, immunemodulating and antioxidant factors.

Improved Blood Circulation

Reduced oxygen levels are found in MS patients and those patients with advanced cerebral atrophy have significantly reduced cerebral blood circulation and oxygen concentrations (114). Increased ischemia (lack of blood flow) and hypoxia (lack of oxygen) can contribute to a vulnerable blood-brain barrier, allowing the entry of pathogens and toxins. Hyperbaric (high pressure) oxygen improves the delivery of oxygen to damaged tissues in the brain and speeds their repair. Pressurized oxygen offers the following benefits: 1. Increases oxygen delivery to injured cells and tissues. 2. Reduces swelling and inflammation. 3. Increases the formation of new blood vessels to injured tissue. 4. Improves wound healing. 5. Improves the body's resistance to infections.

Page 4 of 34

6. Renews damaged neurons and their axons and dendrites. 7. Speeds the elimination of toxins. Most trials using hyperbaric oxygen for MS are for a month with higher pressures (1.75 - 2.5 ATA) but longer treatments at low pressures (1.2-1.5 ATA) may be more effective in reducing hypoxia and ischemia while reducing the risk of free radical generation caused by higher pressures. Long term HBOT within a comprehensive program that includes antioxidants may show more promise in promoting remission (46). With hyperbaric oxygen therapy, the patient is placed in a chamber and breathes 100% oxygen by mask while the pressure in the chamber is increased to 1.5 - 2.0 times the normal atmospheric pressure. This therapy provides a significant increase in oxygen delivery to the brain compared with that received by breathing air at normal pressure. Damaged brain tissue, either from immune attacks, infections, or toxins, is also hypoxic tissue (lacking oxygen). Hyperbaric oxygen pushes oxygen into the plasma (the liquid portion of the blood) and from the plasma, the oxygen diffuses into the white and grey matter of the brain, fights infection, reduces inflammation and speeds wound healing. Oxygen may also be beneficial for myelin production at low pressures of 1.5 ATA or 1.5 times the atmospheric pressure at sea level by supporting neural stem cell differentiation and the production of oligodendrocytes. We would like to see more research done in this area, especially in combination with ECP. External Counterpulsation (ECP) is a fairly new non-invasive alternative to heart surgery for some conditions of heart disease. ECP is FDA approved for the treatment of angina and congestive heart failure. The device pumps blood from the legs back to the heart. In the process, ECP also increases the blood supply (and therefore increased oxygen and nutrients and the removal of waste products) to other organs such as the brain, liver and kidneys. (112,115) It has been our experience that ECP, in combination with hyperbaric oxygen, improves brain function in patients with stroke and brain injuries and may also prove to be beneficial in MS cases as well. Stem cell therapies show great promise as a treatment for MS. However, the causes of myelin degeneration need to be addressed before the stem cells are given to maximize stem cell growth, migration, differentiation and renewed function.

Stem Cells and Multiple Sclerosis

CD34+ CD34 refers to an adhesion structure expressed on embryonic fibroblasts and nervous tissue. CD34+ stem cells are primitive, undifferentiated cells of the embryo, bone marrow, umbilical cord blood and adult tissue that have the capacity to differentiate into hematopoietic cells as well as a variety of other cells, including neurons and glial cells.

Page 5 of 34

The "First Cell" (fertilized egg) at the beginning of life is "totipotent," capable of generating every other cell of the body. When this First Cell divides into three embryonic layers (the ectoderm, mesoderm and endoderm), the daughter cells become "multipotent", able to transform into a variety of cell types, but unable to make an entire individual. CD34 (+) is a purified multipotent stem cell found in bone marrow and umbilical cord blood. These stem cells are capable of "homing" to an injured area where they move into the tissue and proliferate into the specific cells needed to repair the tissue. CD34(+) cells, and especially its CD133 subset, are capable of balancing the immune system as well as transforming into neuroprotective glia and myelin-producing oligodendrocytes and astrocytes. Such potency makes CD34+ stem cells a valuable treatment modality in immune disorders of the central nervous system such as Multiple Sclerosis.

Mesenchymal Stromal/Stem Cells

Mesenchymal stem cells are also multipotent cells, found in the bone marrow and umbilical cord blood. They are able to differentiate into adipocytes (fat cells), chondrocytes (cartilage making cells), osteocytes (bone producing cells) and neuronal/glial cells when specific growth factors are used. Mesenchymal stem cells help M.S. by releasing growth factors that protect the nerves and stimulate the growth of new neurons. Mesenchymal stem cells help support the matrix that supports neurons and they also reduce inflammation. Dr. Fernando Ramirez is treating patients with umbilical cord blood derived CD34+ and mesenchymal stem cells in Tijuana, Mexico. To date, these treatments twice a year have been able to slow the progression of M.S. and help people continue to work and be active.

Dr. Steenblock has done over 1,000 whole bone marrow treatments in which a person's own CD34+ and mesenchymal stem cells are used for brain repair. Bone marrow blood is extracted from the leg and then transfused into the arm and bloodstream. Numerous patients with M.S. have shown impressive responses following this procedure. It is, however, important that heavy metals, pesticides, viruses, etc. be eliminated before this treatment or any treatment to maximize the benefits of the circulating stem cells.

Any reader whod like to discuss whether an autologous (from self) stem cell-rich bone marrow treatment would help their particular medical issues can do so by calling 1-800300-1063 and setting up a phone consultation. Also: Dr. Steenblock www.stemgevity.com has developed an all natural stem cell mobilizer:

Page 6 of 34

Remyelination Studies
Since 1965, scientists have observed spontaneous myelin repair. However, the many factors involved in promoting a more profound repair than what occurs naturally and maintaining that repair are still being investigated. In the relapsing-remitting pattern, some remyelination is observed. Spontaneous remyelination is thought to be caused by previously quiescent oligodendrocyte progenitor cells rather than mature oligodendrocytes. Platelet-derived growth factor has been found to stimulate the multiplication and growth of these oligodendrocyte progenitor cells. In the progressive degeneration pattern, oligodendrocytes are destroyed. Implants of oligodendrocyte progenitor cells into MS patients have been successful. However, while Schwann cells also promote remyelination, their implants have a greater risk of fibroblast overgrowth that subsequently can destroy axonal pathways. Glial cell implants have had good results in creating oligodenrocytes (6). In an animal study, neural stem cells were transplanted into rats with experimental autoimmune encephalomyelitis (an animal model for MS). The cells migrated into the brain or spinal cord, exclusively into the inflamed white matter but not into adjacent gray matter regions. After two weeks, many transplanted cells had migrated into distant white matter tracts and acquired astroglial and oligodendroglial lineages. The authors conclude that the inflammatory process may attract the migration of transplanted precursor cells into the brain parenchyma (connective tissue network) (5). The effectiveness of stem cells in treating autoimmune disease was observed in patients who received hematopoietic stem cell transplants for leukemia and aplasia who also suffered from severe autoimmune disorders (lupus and rheumatoid arthritis). In 1998, Burt and coworkers treated 10 patients having autoimmune disease (6 patients with MS, 2 with Lupus, and 2 with rheumatoid arthritis) with autologous hematopoietic stem cells from bone marrow or mobilized from peripheral blood. CD 34+ stem cells were reinfused after either myelosuppressive conditioning with cyclophosphamide, methylprednisolone and antithymocyte globulin or myeloablative conditioning with total body irradiation, methylprednisolone and cyclophosphamide. Regimen-related nonhema-topoietic toxicity was minimal. All patients improved or had stabilization of disease for 5-17 months. The author concluded that T cell-depleted hematopoietic stem cell transplantation can be performed safely in patients with severe and debilitating autoimmune disease (10). Dr. Ouyang and associates of Nanjing University School of Medicine, China demonstrated positive results in a patient with progressive multiple sclerosis who received an autologous peripheral blood stem cell transplantation. The patient showed clinical remission and there was no relapse at the 6 month followup. The authors conclude that auto-Peripheral Blood Stem Cell Transplantation is effective and safe for progressive multiple sclerosis (73). An MRI study of MS patients who received hematopoietic stem cell transplantations showed disappearance of brain lesions 18 months after the transplant. These findings correlated with clinical stabilization in the patients (83). Page 7 of 34

In a multicenter Phase II study by Fassas and coworkers investigating autologous hematopoietic stem cell transplantation for multiple sclerosis, 85 patients with progressive MS (with a median Extended Disability Status Scale score of 6.5) were treated in 20 European centers. Neurological improvement was seen in 18 patients (21%). Confirmed progression-free survival was seen in 74% of the patients at 3 years. Disease progression was seen in 20%. The authors conclude that autologous HSCT early results are positive and feasible for the management of progressive MS (25). In a Phase II report by Fassas and associates, the authors used CD34+ cell transplantation in 15 Multiple Sclerosis patients. Patients were selected who had advanced secondary progressive or relapsingremitting MS or who showed worsening of the extended disability status scale despite interferon and other immunotherapies. They were treated with Cyclophosphamide, granulocyte colony stimulating factor, BCNU, Antithymocyte Globules, Methyl Prednisolone, MESNA, Cipor, Fluconoyol, and Acyclovir, Pentomidine, and Trimethoprim Sulfamethoxzaole Immunoglobins. There were a number of complications from this combination of powerful drugs. At 12 months, the Extended Disability Status Scale had improved in three patients, worsened in two and remained stable in nine. Despite withdrawal of all immunosuppressive therapy, only two patients had relapses. The authors conclude that CD34+ autologous stem cell transplantation using BCNU, Cylophosphamide and Antithymocyte Globules as conditioning regimen can be viewed as having an acceptable toxicity and effectiveness in reducing the progression of Multiple Sclerosis (12).

Umbilical Cord Derived Stem Cells

These results using peripheral blood stem cell mobilization techniques with powerful immune suppressants, antibiotics, antifungals and steroids had a number of side effects with only marginal effectiveness. One factor is that some of these medications actually inhibit stem cell growth and proliferation. When compared with the case studies to date of umbilical cord CD34+ stem cell transplantation given without additional medications, the umbilical cord stem cells show much greater success with virtually no side effects. Immune defenses in the blood of a fetus have to be compatible with the mother, so immune defenses are suppressed. Stem cells from umbilical cord blood have the advantage of having little or no antigens to cause immune reactions in the recipients and are therefore the safest stem cell for transplantation (if tested by American Association of Blood Banks standards). Steenblock Research Institute has followed several MS patients who were given umbilical cord stem cell treatments by Dr. Fernando Ramirez in Mexico. No side effects were reported. At first, the patients were given 1.5 million CD34+/CD133+ stem/progenitor cells. Improvements were seen in several patients but only for about four months and then another treatment was needed. Since then Dr. Ramirez has been using larger doses of cord stem cells and with additional combinations. New combinations have included mesenchymal cells from umbilical cord blood and cord stem cells with a fyn gene. The fyn gene increases the production of myelin base protein for the remyelination of axons. Better results have also been seen with catheter delivery of the cells more directly into the brain.

Page 8 of 34

Jim Haverlock has been struggling with multiple sclerosis for over twenty years. In 2003, his quest for more effective treatments led to cord stem cells. His story is available now in the book "Challenging the Dragon," available at Amazon.com.

A Comprehensive Stem Cell Program for MS

Stem cells seem to have the ability to greatly assist in regenerating the glial cells injured and destroyed in MS. Care must be taken for several months after stem cell administration to avoid products that inhibit stem cell growth and differentiation to neural progenitors. Such products include cortisone, alcohol, cigarettes, cocaine, air pollution, pesticides, and monosodium glutamate. Physical and emotional stress increase glutamate, which is toxic to neural stem cells and can damage neurons in the hippocampus, the area of learning and memory.

Depression and Stem Cell Therapy

One of the symptoms of Multiple Sclerosis is depression. A new model of depression is emerging that relates the consequences of stress to the inhibition of neural stem cell growth in the hippocampal dentate gyrus, an area of learning and memory as well as stem cell production in the brain (43). Factors such as stress-related adrenal hormones (glucocorticoids) that inhibit stem cell growth also seem to induce depression. The glucocorticoids stimulate corticosterone, an immune suppressant, that stimulates the production of glutamate which is toxic to neural progenitor cells. In animals studies corticosterone significantly reduces the proliferation of oligodendrocyte precursors throughout the white and gray matter regions of the brain (2). Since oligodendrocytes play a major role in remyelination, the use of immune-suppressive therapies may actually perpetuate depression as well as brain lesions. In contrast to the use of steroids for treating MS, stem cell therapies promote the proliferation of new oligodendrocytes, with the secondary benefit of alleviating depression. Generally, depression clears within 30 days after umbilical cord stem cell treatments.

Cell Energy Production

The mitochondria are the energy factories of the cell. Providing sufficient amounts of the precursors for ATP (adenosine 5'-triphosphate) will help the cell defend itself against toxic injury. Nutritional support for the mitochondria include acetyl-L-carnitine, lipoic acid, creatine, magnesium, coenzyme Q10, vitamin C, vitamin E succinate, biotin, thiamin (vitamin B1), riboflavin (B2), niacinamide (amide of B3) and pantothenic acid (B5). Spices that can reduce Complex I activity include cloves and cinnamon. Biochemical defects in Complex I may be a factor in multiple sclerosis. There are several pathways that can trigger programmed cell death. The first is the mitochondria being depleted of ATP and being overrun with free radicals. Free radical damage leads to increased glutamate which stimulates its NMDA receptors to open its channels to calcium influx. The calcium influx then Page 9 of 34

initiates programmed cell death, where proteases destroy the cell protein bonds, breaking up the cell in small enough pieces to be engulfed by immune cells called phagocytes. Antioxidants can help prevent free radical damage in the mitochondria. The second is injury to the extracellular matrix that supports the neurons. Elevated levels of MMP-2 and MMP-9 can reflect increases in matrix degradation and subsequent apoptosis or programmed cell death of the neurons. Nutrients that support the extracellular matrix include vitamin C, zinc metallothionine, alpha-ketoglutarate, glycine, proline and hydroxyproline. NMDA receptors on the myelin sheath can promote cell injury to axons and reducing free radical damage and glutamate toxicity can help reduce myelin damage. Garlic, magnesium, boron, DHA sulphate, lipoic acid, and n-acetyl-cysteine can help modulate glutamate-NMDA activity.

Methylation and Multiple Sclerosis

Folate and vitamin B12 deficiencies (methylcobalamin has greater neurological importance than cyanocobalamin) can cause neurologic and psychiatric disturbances, including depression, dementia, and demyelinating myelopathy (9). In most cases, folate and methylcobalamin injections improve MS symptoms and prevent relapses. Treatment with additional methyl donors such as Sadenosylmethionine, betaine, or methionine can also relieve depression and promote remyelination in patients with inborn errors of folate metabolism (8).

Autoimmune Disease and Patterns of Relapsing-Remitting Episodes

The first two patterns of lesions observed in Lucchinetti's research were most common and resembled the autoimmune destruction observed in T-cell mediated and antibody-augmented forms of experimental autoimmune encephalomyelitis (13).

The Myelin Sheath

Myelin sheaths are formed around axons by spiraling plasma membranes of Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system. Glycoproteins are prominent components of the plasma membranes and include protein zero and peripheral myelin protein-22 in peripheral nervous system myelin, myelin-associated glycoprotein located on the inside of sheaths in both the PNS and CNS and which functions in glia-axon interactions, and myelinoligodendrocyte glycoprotein (MOG) located on the outside of CNS myelin sheaths. MOG appears to be an important target antigen in multiple sclerosis (78). Autoimmune T-cell responses to myelin components are being investigated for their role in initiating and/or maintaining inflammatory responses resulting in myelin destruction. Myelin oligodendrocyte glycoprotein (MOG) is a myelin protein that can elicit greater anti-MOG B-cell responses in MS patients (42). In another study, MOG elicits similar T cell responses in MS patients and controls but with different cytokine activity. The MS samples elicited increased levels of Tumor Necrosis Factor-alpha (TNF-alpha) compared to the control samples (105). Tejada-Simon and associates found that MS patient MOG Page 10 of 34

samples elicited anti-MOG antibodies reacting predominantly to the extracellular 1-60 region while control samples elicited anti-MOG antibody reactions to the transmembrane/cytoplasmic domains (residues 154-218) (100). Autoimmune reactions have also been shown against cardiolipin (important in heart mitochondrial function) and DNA in MS patients (91).

Patterns resembling Virus and Toxin-induced Immune Responses

Pattern IV was found only in patients with primary progressive disease and patterns III and IV both resembled viral or toxin-induced oligodendrocyte dystrophy.

Mercury Toxicity
Mercuric chloride is toxic at low concentrations to oligodendroglial cells, resulting in cell death through apoptosis. (37). Symptoms of mercury toxicity include chronic fatigue, depression, poor memory and cognitive function, emotional instability, peripheral numbness or tingling, decreased sensations of touch, hearing or vision, hypersensitivity and allergies, persistent infections including chronic yeast overgrowth, compromised immune function and cardiovascular disease (79). Mercury levels are often elevated in MS patients, and may result from a variety of sources. 1. Dental Amalgams. Though research findings are contradictory, Huggins found a change in cerebrospinal fluid proteins following dental intervention, using CSF photolabeling. Changes were seen in ceruloplasmin, transferrin, IgG heavy and light chains, Apo E, transthyretin and other proteins. Additional markers that can be used to monitor MS include CSF, S100B and Glial-Fibrillary Acidic Protein (GFAP) (35). S100 B was found to be a good marker for relapsing MS and GFAP correlated with Disability Scales and may therefore be a marker for neurological damage (75). 2. Mercury contamination in fish and soil . Mercury is a major environmental concern, traditionally in freshwater fish and more recently because of the toxic effects on soil microorganisms. Those patients living near mercury emission sources are at greater risk of mercury contamination (66). Shark and Swordfish are reported to have the highest methyl mercury levels, and shrimp, scallops and salmon the lowest concentrations in ocean fish (33). Fish farms may not be safer than ocean fish. Fish farms may be producing fish with higher pesticide and mercury concentrations due to the use of contaminated feed sources (22). 3. Elevated insulin levels allow the cellular entry of heavy metals. Insulin is elevated by large meals, high sugar and refined carbohydrate diets, and oxidative stress. Antioxidants can help protect the cells from heavy metal toxicity. 4. Leaky Gut Syndrome can be caused by Candida endotoxins, alcohol, nutritional deficiencies,etc. which allows heavy metals and macromolecules to enter the bloodstream, causing immune and autoimmune responses, free radicals, and cell injury and death. An animal study by Keshavarzian and Page 11 of 34

associates demonstrated that supplementation with oats prevented gut leakiness and endotoxininduced liver damage (44). Chelating factors in various foods can prevent mercury absorption, including citric acid, tartaric acid, and cysteine, (24), selenium (31), garlic (52), chlorella (also an anti-inflammatory) (117), and cilantro (72). Methyl mercury can bind with L-cysteine and be transported across the blood brain barrier. L-leucine inhibits this transport. A balanced leucine/cysteine ratio is found in whey protein (79). Calcium and magnesium are also protective against mercury and methyl mercury toxicity (92). EDTA oral and i.v. chelation methods are currently being promoted for the removal of mercury and methylmercury as well as other heavy metals. Since heavy metals can inhibit stem cell growth, chelation is advised before stem cell therapy. Oral DMSA is a proven generally safe and effective method for removing mercury and lead.

Anti-virals

Multiple Sclerosis is associated with viral infections, including Herpesvirus 6, Epstein-Barr virus, herpes simplex, infectious mononucleosis, measles and mumps (especially after 15 years of age), Chlamydia, Mycoplasma pneumoniae, Varicella zoster, retroviruses, and nidoviruses (46).

Medicinal Plants
Ecinacea purpurea and Panax ginseng significantly enhanced Natural Killer activity and antibodydependent cellular immunity against human herpesvirus 6 infected cells (87).

Reticulosa
Reticulosa is a peptide-nucleic acid immunomodulator that boosts immune system activity in virallyinfected patients (51). It has broad-spectrum antiviral activity that includes the stimulation of gamma interferon, interleukin-1, interleukin-6 and Tissue Necrosis Factor-alpha (34). In general, it appears free of side effects, is reasonably priced and often effective.

Acyclovir
The antiviral drug acyclovir inhibits herpesvirus-6 infection and markedly reduces the frequency of disease exacerbations in patients with MS (46).

Sea Cucumber
Sea cucumber (Cucumaria japonica) (102) and coumarins from lemon peels (67) have been shown to have an inhibitory effect on Epstein-Barr virus.

Page 12 of 34

Palm Oil
Gamma- and delta-tocotrienols derived from palm oil exhibit a strong activity against Epstein-Barr virus expression (29) and may be of benefit to MS patients.

Factors that Promote Remyelination

The Ciliary Neurotrophic Family

CNTF, leukemia inhibitory factor, cardiotrophin-1, and oncostatin M have been shown to induce a strong promyelinating effect by promoting oligodendrocyte maturation, mediated through the 130 kDa glycoprotein receptor to the CNTF family (97).

Thyroid
T4 administration to experimental allergic encephalomyelitis animals resulted in an up-regulation of oligodendrocyte progenitors and mature oligodendrocytes in the spinal cord, ofactory bulb, and subventricular zone (11).

Thymus
Ikehara reports that the success rate of bone marrow transplants in patients over 45 years of age is low, due to the aging of the thymus. BMT plus embryonal thymus grafts can be used to treat late-onset autoimmune disease in mice and can be a valuable strategy for treating older patients with various intractable diseases, including autoimmune diseases. (36). NatCell Thymus, a thymus extract providing a broad spectrum of thymic peptides (www.atrium-bio.com) is being used successfully to restore immune balance in patients with autoimmune disease who are not on immune suppressants.

Adrenal Support
Krenn presents a case of Adrenoleukodystrophy that mimicks the symptoms of multiple sclerosis. Both conditions include lesions of the white matter which may be alleviated with adrenal support.(49). Adrenal insufficiency is present in 85% of the childhood cerebral forms and in about 70% of the adult forms of adrenoleukodystrophy (28) and may contribute to white matter lesions in multiple sclerosis as well. Since adrenal extracts may also promote corticosteroid-induced stem cell injury, products such the Atrium adrenal extracts should be used several weeks before stem cell therapy to strengthen the adrenal glands.

Page 13 of 34

Interleukin-1
Mason writes that interleukin-1 beta promotes remyelination and CNS repair through inducing astrocyte and microglia-macrophage-derived insulin-like growth factor-1 (63).

Interleukin-10
Interleukin-10 was found to protect against oligodendroglial death evoked by lipopolysaccharide and interferon-gamma. IL-10 downregulates the function of inflammatory cells and promotes survival of progenitors and differentiated oligodendrocytes. (68).

Interleukin-17
Interleukin-17 (Il-17) increases interferon-gamma that promotes nitric oxide synthesis that is toxic to neurons, especially in the presence of free radicals. Il-17 also stimulates the production of interleukin 1B and interleukin-6 and may play a role in inflammatory neurological diseases such as multiple sclerosis.

Interleukin-19
Interleukin-19 (Il-19) assists in the modulation of cytokines to preserve a balance in the system and prevent autoimmune disorders. Il-19 was shown to suppress inflammation in the development of experimental autoimmune encephalomyelitis in mice.

Immunoglobulin Therapy
High-dose intravenous immunoglobulin (IVIg) treatment is being used for inflammatory demyelinating disease. The treatment protects oligodendrocyte precursor cells and oligodendrocytes by inhibiting inflammatory mechanisms (96). Unfortunately, it has a high cost, needs to be given every three weeks and does not result in remissions.

Growth Factors
The more we learn about brain regeneration, the more complex it becomes. Certain growth factors can help stimulate oligodendrocyte cells and the production of myelin. However, oligodendrocytes and myelin also inhibit the growth of axons. It would seem that the system has a time for myelin production and a time for axonal growth. Therefore the alternate use of certain growth factors is suggested.

Glial Growth Factor

Glial growth factor 2 (GGF2) is a neuronal signal that promotes the proliferation and survival of oligodendrocytes. Mice with experimental autoimmune encephalomyelitis were treated with recombinant human GGF2 during both acute and relapsing phases leading to increased remyelination, decreased symptom severity and statistically significant reductions in relapse rate (59).

Page 14 of 34

Platelet-Derived Growth Factor

Platelet-Derived Growth Factor (PDGF) promotes oligodendrocyte progenitor cell proliferation and maturity (113).

Neurotrophin-3
Neurotrophin-3 (NT-3) promotes oligodendrocyte progenitor cell proliferation and maturity (113). Incorporating the gene of NT-3 in umbilical cord derived stem cells may help promote oligodendrocyte maturation in multiple sclerosis patients.

Leukemia Inhibitory Factor

Leukemia Inhibitory Factor (LIF) can be produced by myelin-reactive T cells in MS patients and is able to protect oligodendrocytes from tumor necrosis factor alpha-induced programmed cell death.

Insulin-like Growth Factor

Insulin-like Growth Factor promotes maturation in oligodendrocyte precursor cells (113).

Fibroblast Growth Factor 2

Fibroblast Growth Factor 2 (FGF2) inhibits oligodendrocytes and myelin production but stimulates axonal growth.

Brain Derived Neurotrophic Factor

Brain Derived Neurotrophic Factor (BDNF) stimulates neural stem cell growth and provides neuroprotection in the growth and differentiation of neural precursors.

Growth Hormone
Growth Hormone (GH) has been found to be deficient in the cerebrospinal fluid of multiple sclerosis patients. Growth hormone is neuroprotective, supports myelination, and regulates insulin growth factor-1, which helps the development of oligodendrocyte precursors.

Granulocyte Colony-Stimulating Factor

Granulocyte Colony-Stimulating Factor (G-CSF) has the ability to mobilize bone marrow stem cells. However, with multiple sclerosis, G-CSF can either promote inflammation and exacerbate the symptoms of MS, or it can act as an anti-inflammatory.

Phospholipids
Lipids, along with myelin protein assist in maintaining a normal myelin structure. Lipids include sphingomyelin, phosphatidylcholine and phosphatidylserine promote myelin stability. With Page 15 of 34

demyelination, there is an increase in lipid polyunsaturation and negatively charged phosphatidylserine and a decrease in sphigomyelin, phosphatidylcholine and sulfaides. This composition allows greater myelin fluidity, reductions in myelin adhesion, increases in membrane curvature and greater risk of demyelination.

Additional Factors Uric Acid

Uric acid suppresses the MS animal model experimental autoimmune encephalomyelitis. In a study involving humans, the MS patients were found to have lower average serum uric acid levels than the controls. (18). Scott and associates showed that uric acid selectively inhibits a highly neurotoxic combination of nitric oxide and hydrogen peroxide called peroxynitrite in multiple sclerosis and improves experimental autoimmune encephalomyelitis in mice (86). Inosine is a precursor of uric acid. High levels of inosine given to 11 MS patients stopped the progression of disease in all of the patients and improved clinical symptoms in 3 of the patients (94). Inosine should not be used in patients prone to gout and arthritis. Chen and associates found that the administration of inosine to rat models for experimental stroke resulted in significant axonal rewiring and improved motor function (16) and may therefore also improve axonal growth in MS patients. Further work concluded that the mode of inosine in experimental allergic encephalomyelitis was via its metabolism to uric acid (87). High copper levels induce low levels of uric acid while also having a pro-inflammatory effect. Thus a low copper diet may be indicated. Vitamin B2 is a cofactor for xanthine oxidase, and xanthine oxidase deficiency can also contribute to low uric acid levels (40).

Chlorella
This single cell fresh water detoxifying algae raises uric acid levels safely and consistently and should be considered by any person with MS.

Creatine
Phosphocreatine increases ATP regeneration which is important in supporting remyelination by oligodendrocytes (89).

Vitamin B12 Injections (Methylcobalamin rather than cyanocobalamin)

Cyanocobalamin activates glutamate receptors and promotes inflammation. Methylation is important in remyelination. Methyl donors include folate, betaine, methionne and S-adenosylmethionine. Vitamin

Page 16 of 34

B12 deficiencies are associated with demyelination and axonal degeneration (15). Methylcobalamin improves evoked potentials and nerve regeneration (48,50).

Ginseng
Ginseng increases Nerve Growth Factor which stimulates the growth of new oligodendrocytes (38).

Gingko biloba
Gingko biloba contains factors that stimulate Glial Cell Line-derived Neurotropic Factor in astrocytes. However, Gingko may also inhibit cytochrome P450 metabolism of other medications.

Vitamin A
Retinol levels for untreated relapsing-remitting (RR) MS patients was found to be lower than for patients with noninflammatory neurological disease (82). All-trans-retinoic acid (in cod liver oil) increases Ciliary Neurotrophic Factor, important in oligodendrocyte maturation and myelin production (111, 57). Retinoic acid also promotes myelin immune defense (57).

Taurine
Taurine is an amino acid that plays a role in cell membrane stability, bile salt formation, calcium homeostasis, growth modulation, cell osmosis, and modulating inflammation and immune response.

Moderate sunshine/vitamin D
Vitamin D is associated with alleviating autoimmune disorders. Vitamin D stimulates Brain Derived Neurotropic Factor which protects thymocyte precursors and regulatory feedback mechanisms involved in thymocyte differentation and immune function (60).

Spasticity Threonine
Hauser and associates used the amino acid L-threonine with 26 ambulatory MS patients with spasticity. Threonine at a daily dose of 7.5 g reduced signs of spasticity without the side effects of sedation and increased motor weakness found in anti-spasticity drugs used for MS. Threonine is a precursor for glycine biosynthesis and may enhance glycinergic postsynaptic inhibition of the motor reflex (32). Also see the section on magnesium below.

Page 17 of 34

Antioxidants
Free radicals, including peroxynitrite are induced in Multiple Sclerosis. Antioxidants can help protect the neural tissue from damage, induced by inflammatory cascades that result in free radical pathology and oxidative stress. Nordik investigated the clinical effects of providing dietary advice, vitamin supplementation and fish oil supplementation to newly diagnosed multiple sclerosis patients. At the end of a two year period, there was a significant reduction in the mean annual exacerbation rate and the mean Expanded Disability Status Scale (EDSS) as compared to pre-study values. Plasma total phospholipid n-3 fatty acids increased and n-6 fatty acids decreased significantly (70). The cod liver oil and fish oils used should be free of heavy metals.

Antioxidants and Tissue Necrosis Factor-alpha

TNFalpha, a pro-inflammatory cytokine, has been associated with demyelinating disorders, including Multiple Sclerosis. It reduces the gene expression (PPARdelta), responsible for oligodendrocyte survival and differentiation in oligodendrocyte progenitor cells. The reduction in PPARdelta gene expression results in reductions in myelin synthesis, maturation and turnover (17). TNFalpha is inhibited by green tea, curcumin, (85), quercetin (39) and resveratrol (109).

Antioxidants and Lipopolysaccharides

The "leaky gut" syndrome allows bacterial lipopolysaccarides to enter the blood stream. Lipopolysaccharides (LPS) are associated with extensive oligodendrocyte death (53). Several natural products have the ability to protect the microglia from lipopolysaccharide-induced neurotoxicity. LPS is a component of the bacterial wall of gram-negative bacteria and is one of the most potent activators of host inflammatory response and tissue injury. LPS treatment of microglial cells activates both p38 mitogen-activated protein kinase and nuclear factor-kappaB (NFkappaB), with consequent increases in interluekin-1 alpha, tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO) production (55). LPS also increases stress indicators, including plasma corticosterone and glucose concentrations; alterations in brain oxidative status, including elevated malondialdehyde levels (a lipid peroxidation index) and decreases in reduced glutathione; and brain metabolism disturbances including reductions in ATP/ADP ratios and increases in mitochondrial/cytosolic hexokinase ratios (45). 1) Silymarin from milk thistle can reduce LPS-induced superoxide generation and nuclear factor kappaB activation (110). 2) In in vitro studies, Vitamin E (alpha-tocopherol) activated microglial activity and silences an LPSactivated NF kappa B signaling cascade. The results suggest that alpha-tocopherol can induce quiescence to pathways associated with acute or chronic inflammatory conditions in the central nervous system (23).

Page 18 of 34

3) Melatonin functions as an antioxidant and has the ability to protect neurons from lipopolysaccharideinduced oxidative stress (80). Blue light (420-480 nm) has been found to increase serotonin, a precursor for melatonin. (see Dr. Payne's MS article at http://14ushop.com/wizard/)

4) N-acetylcysteine, a thiol antioxidant significantly reduces LPS-induced ROS production (superoxide anion), TNF alpha levels and NF-kappa B activity in macrophages from mice with lethal endotoxic shock. The levels approached those of macrophages from the control animals (105). 5) Estrogen and progesterone, at concentrations consistent with late pregnancy, inhibit LPS-induced nitric oxide and TNF-alpha production by activated microglia, and may contribute to the decreased severity of MS symptoms associated with pregnancy (21). Dr. Bansil and associates found a relationship between relapsing-remitting MS in 30 women and hormone fluctuations in the menstrual cycle. Those patients with a high estrogen to progesterone ratio had a significantly greater number of active MRI lesions than those with a low ratio (4). Progesterone is a known immune quieting agent.

Foods as Medicine
6) Green Tea, containing catechin and (-)-epigallocatechin-3-gallate (EGCG), has the ability to inhibit lipoplysaccharide and gamma-interferon-induced oxidative stress (3). Black tea has similar effects from inhibiting LPS-induced IkappaB kinase and NFkappaB activity (74). 7) Artichoke (118) has protective properties against inflammatory mediators, TNF alpha and LPS, in vitro. 8) Carnosol is a naturally occurring phytopolyphenol found in rosemary. Carnosol functions as an antioxidant and anticarcinogen. Carnosol significantly reduced LPS-induced nitric oxide and NF-kappa B production in a dose-dependent manner (56). 9) Quercetin (in onions and garlic) significantly inhibited LPS-induced nitric oxide production and suppressed the release of NF-kappaB (69). 10) The combination of Ginkgo biloba and quercetin were effective in inhibiting LPS-induced NF-kappa B as well as TNF-alpha activation (107). 11) Avocado contains antioxidants (persenone A and B) that can inhibit superoxide and nitric oxide generation induced by lipopolysaccharide and interferon-gamma in mouse macrophage cells (47). 12) Resveratrol in grape juice (red wine's alcoholic content can increase homocysteine levels-(7) has antioxidant and anti-inflammatory effects. Resversatrol strongly inhibits LPS-induced superoxide radical and hydrogen peroxide, arachidonic acid release, and cyclooxygenase-2 induction (62).

Page 19 of 34

13) Curcumin is the active ingredient in Indian curry. It has antitumor, antioxidant, and antiinflammatory properties. Curcumin inhibits two enzymes involved in inflammation, cyclooxygenase-2 (COX-2) and lipoxygenase (LOX).

Alpha-Lipoic Acid
Alpha lipoic acid was administered to mice with experimental autoimmune encephalomyelitis resulting in minimal inflammation and reductions in demyelination and axonal loss in the spinal cord. Alpha lipoic acid inhibited the activity of metalloproteinase-9 in a dose-dependent manner. The authors conclude that alpha lipoic acid is highly effective at suppressing and treating experimental autoimmune encephalomyelitis and does so by inhibiting T cell trafficking into the spinal cord, perhaps by acting as a metalloproteinase inhibitor (59).

Vitamin E Succinate and all-trans-retinoic acid

Vitamin E Succinate suppressed Epstein-Barr growth by 87% in vitro and all-trans-retinoic acid blocked Epstein-Barr activity by 58% in vitro, via transforming growth factor beta (103). Transforming Growth Factor Beta plays a role in neuronal survival and regeneration in Schwann Cell lesions (64). Vitamin E has direct neuroprotective antioxidant effects as well as anti-inflammatory indirect effects. Vitamin E inhibits microglial activation by suppressing the LPS-induced p38 MAPK and Nfkappa B signaling effects necessary for microglial activation (55).

Multiple Antioxidant Therapy

Odinak treated 14 patients with relapsing-remitting MS with a combination of antioxidants and neuroprotectors with various mechanisms of action (lipoic acid, nicotinamide, Acetyl cysteine, Betacarotine, alpha-tocopheryl acetate, ascorbic acid, selenium, pentoxifylline, cerebrolysin, and Amantadine hydrochloride for a duration of one month, twice a year. The treatment resulted in a significant reduction (2-3 times) of relapse frequencies in multiple sclerosis patients and a decrease of required corticosteroid medication. After antioxidant therapy the content of lipid peroxide products was significantly reduced and the author recommends antioxidant and neuroprotective program in relapsing-remitting multiple sclerosis (71).

Autoimmune Suppression Moderate Sunlight/Vitamin D

Dihydroxyvitamin D3 can prevent or markedly suppress experimental autoimmune encephalomyelitis, rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, and inflammatory bowel disease. The animals also needed to be on moderate to high calcium diets. Vitamin D hormone stimulates transforming growth factor and interleukin-4 production, which may suppress inflammatory T cell activity (20). In an animal study using the multiple sclerosis model of autoimmune encephalomyelitis, Page 20 of 34

the administration of 1,25-dihydroxyvitamin D3 demonstrated rapid clinical improvement in the rats, accompanied by an inhibition of CD4, MHC class II and type II nitric oxide synthase expression (27). 1,25dihydroxyvitamin D3 has also been reported to increase intracellular levels of glutathione, important in protecting neurons from oxidative stress-induced injury (90). In addition, photoimmunology studies have shown that ultraviolet B can specifically attenuate autoimmune disease processes, perhaps by increasing vitamin D levels (76). Cyclosporin A is widely used as an immunosuppressant by suppressing cytokine gene expression and inhibiting T lymphocytes. It may also protect against white matter lesions in stroke during hypoperfusion (108). However, the use of cyclophosphamide, either alone or in combination with Cyclosporin showed a significant reduction in oligodendrocyte-mediated remyelination in rat spinal cord demyelinated lesions (93).

Anti-inflammatory Diet Vegan Diets

Quasi-vegan diets are beneficial in the management of rheumatoid arthritis, MS, and SLE (65) In his Integrative Management approach to Multiple Sclerosis, Dr. Kidd suggests a diet low in saturated fats, three fish meals per week, and the elimination of allergenic foods and products. Small frequent meals are preferable to large three meals a day. Also avoid animal fats, fried foods, sugars and sweets, and processed and refined foods. Fresh, whole fruits, vegetables, grains, legumes, nuts and seeds include a synergy of bioavailable nutrients, enzymes, antioxidants and fiber that can retard and reverse age-related declines in cognitive and motor performance in rats (26) and can be an important component in a total lifestyle program for maximizing neuronal and cognitive function and reversing disease in humans. Nicotinamide is a potent inhibitor of inflammation. Nicotinamide is the amid form of niacin, (vitamin B3) and plays an important role in ATP synthesis (adenosine 5'-triphosphate) in the energy producing mitochondria of the cell. ATP is called molecular currency - a form of energy that can maintain the integrity of DNA and cell membranes against insults and inflammation. Foods containing niacin include brewer's yeast, chicken, fish, eggs, legumes, leafy vegetables, broccoli, tomatoes, carrots, carrots, dates, asparagus, and avocados.

Reduce Allergenic Foods

The avoidance of milk may benefit patients with MS. Peptides in milk can mimic antigens in myelin. CNS degeneration that resembles MS can be induced in mice with milk peptide injections (46).

Page 21 of 34

Fatty Acids
Dietary omega-3 fatty acids can be of great benefit to MS patients. Omega-3 fatty acids have been shown to alleviate pain in autoimmune disorders by inhibiting inflammatory mediators (eicosanoids and cytokines) in peripheral tissues as well as in glial cells Omega-3 fatty acids modulate voltage-gated calcium channels in heart and brain cells, preventing electrical hyperexcitability and a cascade of events leading to cell depolarization, oxidative stress, inflammation, cell injury and pain. Omega-3 fatty acids are safe as long as they supply less than 10% of the total energy intake and are given with sufficient amounts of vitamin E (88). Cod liver oil with its vitamin A and D content (1 tablespoon 2-3 times a day) is often of great benefit to MS patients.

Lecithin
Abnormal lipid metabolism in the brain is often seen in subjects with multiple sclerosis. Lecithin cholesterol acyltransferase from the cerebrospinal fluid was investigated in 16 subjects, half control subjects and half with active demyelinating disease. The levels of lecithin cholesterol acyltransferase in patients with active demyelinating disease or multiple sclerosis was only about half of that found in the control subjects (1).

Magnesium
Magnesium, zinc and calcium have been found to be deficient in central nervous system tissue in MS patients, especially in white matter tissue (116). Magnesium is important for the metabolism of thiamine, calcium, potassium, phosphorus, iron, sodium, hydrogen chloride, acetylcholine, nitric oxide, and for many enzymes, and for the elimination of lead and cadmium. Calcium and magnesium are also important in the development, structure and stability of myelin (30). A magnesium deficiency is associated with increased inflammation. The pathologies associated with magnesium deficiency range from cardiovascular disease to cancer and include peroxynitrite damage in multiple sclerosis (41). The effects of magnesium glycerophosphate oral therapy were studied in a woman with severe spastic paraplegia resulting from MS. There was significant improvement in the spasticity after only one week of treatment. No side effects were reported(81). Natural sources of magnesium include fresh green vegetables (chlorophyll), raw wheat germ, soybeans, low fat milk, whole grains, fish, figs, corn, apples, and almonds. Octacosanol contained in wheat germ and wheat germ oil increased endurance, total body reaction times, ECG, brachial pulse waves, pulse rate test, basal metabolism and oxygen intake tests in a physical training program with 894 subjects (19). Octacosanol is a constituent of Policosanol, now being used for cardiovascular health. Dr. Payne has created a diet with supplements suggested before and after meals at http://www.14ushop.com/wizard/DrPaynesMSsupportregimen32506.html .

Page 22 of 34

Digestion, Assimilation and Gut Flora

Patients with Inflammatory Bowel Disease have shown MS type lesions on the MRI, suggesting a link between gut dysbiosis and brain disorders (46).

Pancreatic enzymes
Pancreatic enzymes have been used to help reduce malabsorption and help disperse circulating immune complexes.

Anti-Candida Programs
Candida antibodies are often present in MS patients, suggesting an on-going chronic gastrointestinal yeast infection. This irritates the gut causing increased gut permeability and the subsequent absorption of glial toxic lipopolysaccharides. Transfer Factor, in conjunction with an aggressive anti-Candida program and probiotic recolonization should improve this condition.

In conclusion, there are a number of factors that can help restore myelin, axonal regrowth, cellular energy production, reduce viral infections and inflammation, promote antioxidant defenses against oxidative stress and balance the gut flora, if needed. Test results of specific nutritional deficiencies should be used to devise rotating diets for each MS patient.

Page 23 of 34

References
1) Albers JJ, Marcovina SM, Christenson RH. "Lecithin cholesterolacyltransferase in human cerebrospinal fluid: reduced level in patients with multiple sclerosis and evidence of direct synthesis in the brain." Int J Clin Lab Res, 1992; 22(3): 169-72. 2) Alonso, Gerard. "Prolonged corticosterone treatment of adulat rats inhibits the proliferation of oligodendrocyte progenitors present throughout white and gray matter regions of the brain." Glia, 2000, 31: 219-231. 3) Alvarez E, Leiro J, Orallo F. "Effect of (-)-epigallocatechin-3-gallate on respiratory burst of rat macrophages." Int Immunopharmacol, 2002, 2(6): 849-55. 4) Bansil S, Lee HJ, Jindal S, Holtz CR, Cook SD. "Correlation between sex hormones and magnetic resonance imaging lesions in multiple sclerosis." Acta Neruol Scand 1999, 99(2): 91-4. 5) Ben-Hur T, Einstein O, Mizrachi-Kol R, Ben-Menachem O, Reinhartz E, Karussis D, Abramsky O. "Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis." Glia 2003, 41(1): 73-80. 6) Benn T, Halfpenny C, Scolding N. "Glial Cells as targets for cytotoxic immune mediators." Glia, 2001; 36(2): 200-11. 7) Bleich S, Bleich K, Kropp S, Bittermann HG, Degner D, Sperling W, Ruther E, Kornhuber J. "Moderate alcohol consumption in social drinkers raises plasma homocysteine levels: a contradiction to the 'French Paradox'?" Alcohol & Alcoholism, 2001, 36(3): 189-92. 8) Bottiglieri T, Hyland K, Reynolds EH. "The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders." Drugs, 1994, 48(2): 137-52. 9) Bottiglieri T. "Folate, vitamin B12, and neuropsychiatric disorders." Nutr Rev, 1996; 54(12): 382-90. 10) Burt RK, Traynor AE, Pope R, Schroeder J, Cohen B, Karlin KH, Lobeck L, Goolsby C, Rowlings P, Davis FA, Stefoski D, Terry C, Keever-Taylor C, Rosen S, Vesole D, Fishman M, Brush M, Mujias S, Villa M, Burns WH. "Treatment of autoimmune disease by intense immunosuppressive conditioning and autologous hematopoietic stem cell transplantation." Blood 1998, 92(10): 3505-14. 11) Calza L, Fernandez M, Giuliani A, Aloe L, Giardino L. "Thyroid hormone activates oligodendrocyte precursors and increases a myelin-forming protein and NGF content in the spinal cord during experimental allergic encephalomyelitis." Proc Natl Acad Sci, USA 2002, 99(5): 3258-63. 12) Carreras E, saiz A, Marin P, Martinez C, Rovira M, Villamor N, Aymerich M, Lozano M, FernandezAviles F, Urbano-Izpizua A, Montserrat E, Graus F. "CD34+ selected autologous peripheral blood stem

Page 24 of 34

cell transplantation for multiple sclerosis: report of toxicity and treatment results at one year of followup in 15 patients." Haematologica 2003, 88(3): 306-14. 13) Carson, Monica. "Microglia as Liasisons between the Immune and Central Nervous Systems: Funcational Implications for Multiple Sclerosis." Glia, 2002; 40: 218-231. 14) Chang A, Tourtellotte WW, Rudick R, Trapp BD. "Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis." N Engl J Med, 2002, 346(3): 165-73. 15) Cheliout-Heraut F, Durand MC, Desterbecq E, Dizien O, de Lattre J. "Visual, auditory and somatosensory potentials in the diagnosis of vitamin B12 deficiency." Neurophysiol Clin, 1997; 27(1): 5965. 16) Chen P, Goldberg DE, Kolb B, Lanser M, Benowitz LI. "Inosine induces axonal rewiring and improves behavioral outcome after stroke." Proc Natl Acad Sci USA, 2002; 99(13): 9031-6. 17) Cimini A, Bernardo A, Cifone MG, Di Marzio L, Di Loreto S, Cifone G, Di Muzio L. "TNF alpha downregulates PPARdelta expression in olidogdenrocyte progenitor cells: implications for demyelinating diseases." Glia 2003, 41(1): 3-14. 18) Constantinescu CS, Freitag P, Kappos L. "Increase in serum levels of uric acid, an endogenous antioxidant, under treatment with glatiramer acetate for multiple sclerosis." Mult Scler, 2000, 696): 37881. 19) Cureton, Thomas. "The Physiological Effects of Wheat Germ Oil on Humans in Exercise- Forty-two physical training programs utilizing 894 humans." Charles C Thomas Publisher, Springfield, Illinois, 1972. 20) Deluca HF, Cantorna MT. "Vitamin D: its role and uses in immunology." FASEB J 2001; 15(14): 257985. 21) Drew PD, Chavis JA. "Female sex steroids: effects upon microglial cell activation." J Neuroimmunol, 2000, 111(1-2): 77-85. 22) Easton MD, Luszniak D, Von der GE. "Preliminary examination of contaminant loadings in farmed salmon, wild salmon and commercial salmon feed." Chemosphere, 2002; 46(7): 1053-74.

23) Egger T, Schuligoi R, Wintersperger A, Amann R, Malle E, Sattler W. "Vitamin E (alpha-tocopherol) attenuates cyclo-oxygenase 2 transcription and synthesis in immortalized murine BV-2 microglia." Biochem J, 2003, 370(Pt2): 459-67. 24) Endo T, Nakaya S, Kimura R. "Mechanisms of absorption of inorganic mercury from rat small intestine. IV: Effect of chelating agents and cysteine on absorption of mercuric chloride in situ and in vitro." Pharmacol Toxicol 1991, 68(3): 171-6.

Page 25 of 34

25) Fassas A, Passweg JR, Anagnostopoulos A, Kazis A, Kozak T, Havrdova E, Carreras E, Graus F, Kashyap A, Openshaw H, Schipperus M, Deconinck E, Mancardi G, Marmont A, Hansz J, Rabusin M, Zuazu Nagore FJ, Besalduch J, Dentamaro T, Fouillard L, Hertenstein B, La Nasa G, Musso M, Papineschi F, Rowe JM, Saccardi R, Steck A, Kappos L, Gratwohl A, Tyndall A, Samijn J, Samign J, Autoimmune Disease Working party of the EBMT (European Group for Blood and Marrow Transplantation). "Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study." J Neurol, 2002, 249(8): 108897. 26) Galli R., Shakitt-Hale B, Youdin K, and Joseph J. "Fruit Polyphenolics and Brain Aging." Annals of NY Acad Sci, 2002, 959: 128-132. 27) Garcion E, Sindji L, Nataf S, Brachet P, Darcy F, Montero-Menei CN. "Treatment of experimental autoimmune encephalomyelitis in rat by 1,25-dihydroxyvitamin D(3) leads to early effects within the central nervous system." Acta Neurpathol, 2003; 105(5): 438-48. 28) Girard S, Bruckert E, Turpin G. "Endocrine disease in adrenoleukodystrophy." Ann Med Intern (Paris), 2001; 152(1): 15-26. 29) Goh SH, Hew NF, Norhanom AW, Yadav M. "Inhibition of tumour promotion by various palm-oil tocotrienols." Int J Cancer, 1994, 57(4): 529-31. 30) Goldberg P, Fleming MC, Picard EH. "Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D." Medical Hypotheses, 1986; 21(2): 193-200. 31) Goyer RA. "Toxic and essential metal interactions." Annu Rev Nutr, 1997, 17: 37-50. 32) Hauser SL, Doolittle TH, Lopez-Bresnahan M, Shahani B, Schoenfeld D, Shih VE, Growdon J, Lehrich JR. "An antispasticity effect of threonine in multiple sclerosis." Arch Neurol, 1992, 49(9): 923-6. 33) Hightower JM, Moore D. "Mercury levels in high-end consumers of fish." Environ Health Perspect 2003, 111(4): 604-8. 34) Hirschman SZ, Chen CW. "Peptide nucleic acids stimulate gamma interferon and inhibit the replication of the human immunodeficiency virus." J Investig Med, 1996, 44(6): 347-51. 35) Huggins HA, Levy TE. "Cerebrospinal fluid protein changes in multiple sclerosis after dental amalgam removal." Altern Med Rev 1998, 3(4): 295-300. 36) Ikehara S. "Bone marrow transplantation for autoimmune diseases." Acta Haematol, 1998; 99(3): 116-32. 37) Issa Y, Watts DC, Duxbury AJ, Brunton PA, Watson MB, Waters CM. "Mercuric chloride: toxicity and apoptosis in a human oligodendroglial cell line MO3.13." Biomaterials, 2003, 24(6): 981-7. 38) Jiang F, DeSilva S, Turnbull J. "Beneficial effect of ginseng root in SOD-1 (G93A) transgenic mice." J Neurol Sci, 2000, 180(1-2): 52-4. Page 26 of 34

39) Jobin C, Bradham C et al. "Curcumin blocks cytokine-mediated NF-kappa-B actaivation and proinflammatory gene expression by inhibiting inhibiting factor I-kappa B kinase activity. J Immunol, 1999; 163: 3474-3483. 40) Johnson, S. "The possible role of gradual accumulation of copper, cadmium, lead and iron and gradual depletion of zinc, magnesium, selenium, vitamins B2, B6, D, and E and essential fatty acids in multiple sclerosis." Medical Hypotheses 2000, 55(3): 239-41. 41) Johnson, S. "The multifaceted and widespread pathology of magnesium deficiency." Medical Hypotheses, 2001, 56(2): 163-70. 42) Kennel De March A, De Bouwerie M, Kolopp-Sarda NM, Faure GC, Bene MC, Bernard CC. "Antimyelin oligodendrocyte glycoprotein B-cell responses in multiple sclerosis." J Neuroimmunol, 2003, 135(1-2): 117-25. 43) Kempermann G. "Regulation of adult hippocampal neurogenesis - implications for novel theories of major depression." Biopolar Disord, 2002, 4(1): 17-33. 44) Keshavarzian A, Choudhary S, Holmes EW, Yong S, Banan A, Jakate S, Fields JZ. "Preventing gut leakiness by oats supplementation ameliorates alcohol-induced liver damage in rats." J Pharmacol Exp Ther, 2001, 299(2): 442-8. 45) Kheir-Eldin AA, Motawi TK, Gad MZ, Abd-ElGawad HM. "Protective effect of vitamin E, beta-carotene and N-acetylcysteine from the brain oxidative stress induced in rats by lipopolysaccharide." Int J Biochem Cell Biol, 2001, 33(5): 475-82. 46) Kidd, Parris M. "Mutliple Sclerosis, An Autoimmune Inflammatory Disease: Prospects for its Integrative Management." Altern Med Rev, 2001; 6(6): 540-66. 47) Kim OK, Murakami A, Nakamura Y, Takeda N, Yoshizumi H, Ohigashi H. "Novel nitric oxide and superoxide generation inhibitors, persenone A and B, from avocado fruit." J Agric Food Chem, 2000, 48(5): 1557-63. 48) Kira J, Tobimatsu S, Goto I. "Vitamin B12 metabolism and massive-dose methyl vitamin B12 therapy in Japanese patients with multiple sclerosis." Inter Med, 1994, 33(2): 82-6.

49) Krenn M, Bonelli RM, Niederwieser G, Reisecker F, Koltringer P. "Adreno-leukodystrophy mimicking multiple sclerosis." Nervenarzt 2001, 72(10): 794-7. 50) Kuwabara S, Nakazawa R, Azuma N, Suzuki M, Miyajima K, Fukutake T, Hattori T. "Intravenous methylcobalamin treatment for uremic and diabetic neuropathy in chronic hemodialysis patients." Intern Med, 1999; 38(6): 472-5.

Page 27 of 34

51) Lazzarino DA, de Diego M, Hirschman SZ, Zhang KY, Shaikh S, Musi E, Liaw L, Alexander RJ. "IL-8 and MCP-1 secretion is enhanced by the peptide-nucleic acid immunomodulator, Product R, in U937 cells and primary human monocytes." Cytokine, 2001, 14(4): 234-9. 52) Lee JH, Kang HS, Roh J. "Protective effects of garlic juice against embryotoxicity of methylcercuric chloride administered to pregnant Fischer 344 rats." Yonsei Med J 1999, 4(5): 483-9. 53) Lehnardt S, Lachance C, Patrizi S, Lefebvre S, Follett PL, Jensen FE, Rosenberg PA, Volpe JJ, Vartanian T. "The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS." J Neurosci, 2002, 22(7): 2478-86. 54) Levine J, Reynolds R, Fawcett J. "The oligodendrocyte precursor cell in health and disease." Trends in Neurosciences, 2001, 24(1): 39-47. 55) Li, Y, Liu L, Barger SW, Mrak RE, Griffin WS. "Vitamin E suppression of microglial activation is neuroprotective." J Neurosci Res, 2001, 66(2): 163-70. 56) Lo AH, Liang YC, Lin-Shiau SY, Ho CT, Lin JK. "Carnosol, an antioxidant in rosemary, suppresses inducible nitric oxide synthease through down-regulating nuclear factor-kappaB in mouse macrophages." Carcinogenesis 2002, 23(6): 983-91. 57) Lovett-Racke AE, Racke MK. "Retinoic acid promotes the development of TH2-like human myelin basic protein-reactive T cells." Cell Immunol, 215(1): 54-60. 58) Mahon BC, Gordon SA, Cruz J, Cosman F, Cantorna MT. "Cytokine profile in patients with multiple sclerosis following vitamin D supplementation." J Neuroimmunol, 2003; 134(1-2): 128-32. 59) Marchionni MA, Cannella B, Hoban C, Gao YL, Garcia-Arenas R, Lawson D, Happel E, Noel F, Tofilon P, Gwynne D, Raine CS. "Neuregulin in neuron/glial interactions in the central nervous system. GGF2 diminishes autoimmune demyelination, promotes oligodendrocyte progenitor expansion, and enhances remyelination." Adv Exp Med Biol, 1000, 468: 283-95. 60) Maroder M, Bellavia D, Meco D, Napolitano M, Stigliano A, Alesse E, Vacca A, Giannini G, Frati L, Gulino A, Screpanti I. " Expression of trKB neurotrophin receptor during T cell development. Role of brain derived neurotrophic factor in immature thymocyte survival." J Immunol. 1996 Oct 1;157(7):286472.

61) Marracci GH, Jones RE, McKeon GP, Bourdette DN. "Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses experimental autoimmune encephalomyelitis." J Neuroimmunol, 2002; 131(1-2): 104-14. 62) Martinez J, Moreno JJ. "Effect of resveratrol, a natural polyphenolic compound, on reactive oxygen species and prostaglandin production." Biochem Pharmacol, 2000, 59(7): 865-70.

Page 28 of 34

63) Mason JL, Suzuki K, Chaplin DD, Matsushima GK. "Interleukin-1 beta promotes repair of the CNS." J Neurosci, 2001, 21(18): 7046-52. 64) Matsuoka I, Nakane A, Kurihara K. "Induction of LIF-mRNA by TGF-beta 1 in Schwann cells." Brain Res 1997; 776(1-2): 170-80. 65) McCarty MF. "Upregulation of lymphocyte apoptosis as a strategy for preventing and treating autoimmune disorders: a role for whole-food vegan diets, fish oil and dopamine." Med Hypotheses, 2001; 57(2): 258-75. 66) Meili M, Bishp K, Bringmark L, Johansson K, Munthe J, Sverdrup H, de Vries W. "Critical levels of atmospheric pollution: criteria and concepts for operational modeling of mercury in forest and lake ecosystems." Sci Total Environ, 2003; 403(1-3): 83-106. 67) Miyake Y, Murakami A, Sugiyama Y, Isobe M, Koshimizu K, Ohigash H. "Identification of coumarins from lemon fruit (Citrus limon) as inhibitors of tumor promotion and superoxide and nitric oxide generation." J Agric Food Chem, 1999, 47(8): 3151-7. 68) Molina-Holgado E, Vela JM, Arevalo-Martin A, Guaza C. "LPS/IFN-gamma cytotoxicity in oligodendroglial cells: role of nitric oxygen and protection by the anti-inflammatory cytokine IL-10." Eur J Neurosci, 2001, 13(3): 493-502. 69) Mu, MM, Chakravortty D, Sugiyama T, Koide N, Takahashi K, Mori I, Yoshida T, Yokochi T. "The inhibitory action of quercetin on lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophage cells." J Endotoxin Res, 2001; 7(6): 431-6. 70) Nordvik I, Myhr KM, Nyland H, Bjerve KS. "Effect of dietary advice and n-3 supplementation in newly diagnosed MS patients." Acta Neurol Scand, 2000, 102(3): 143-9. 71) Odinak MM, Bisaga GN, Zarubina IV. "New approaches to antioxidant therapy in multiple sclerosis." Zh Nevrol Psikhiatr Im S S Korsakova 2002; Suppl: 72-5. 72) Omura Y, Beckman SL. "Role of mercury (Hg) in resistant infections and effective treatment of Chlamydia trachomatis and Herpes family viral infections (and potential treatment for cancer) by removing localized Hg deposits with Chinese parsley and delivering effective antibiotics using various drug uptake enhancement methods." Acupunct Electrother Res, 1995, 20(3-4): 195-229.

73) Ouyang J, Ni X, Chen B. "A preliminary result of treatment of progressive multiple sclerosis with autologous peripheral blood stem cell transplantation in China. Zhonghua Nei Ke Za Zhi 2001, 40(8): 550-2. 74) Pan MH, Lin-Shiau SY, Ho CT, Lin JH, Lin JK. "Suppression of lipopo-lysaccharide-induced nuclear factor-kappaB activity by theaflavin-3, 3'-digallate from black tea and other polyphenols through downregulation of IkappaB kinase activity in macrophages." Biochem Pharmacol, 2000, 59(4): 357-67. Page 29 of 34

75) Petzold A., Eikelenboom MJ, Gveric D, Keir G, Chapman M, Lazeron RH, Cuzner ML, Polman CH, Uitdehaag BM, Thompson EJ, Giovannoni G. "Markers for Different Glial Cell Repsonses in Mutliple Sclerosis: Clinical and Pathological Correlations." Brain 2002, 125(Pt 7): 1462-73. 76) Ponsonby AL, McMichael A, van der Mei I. "Ultraviolet radiation and autoimmune disease: insights from epidemiological research." Toxicology, 2002, 181-182; 71-8. 77) Pozzilli C, Falaschi P, Mainero C, Martocchia A, D'Urso R, Proietti A, Frontoni M, Bastianello S, Filippi M. "MRI in multiple sclerosis during the menstrual cycle: relationship with sex hormone patterns." Neurology, 1999, 53(3): 622-4. 78) Quarles RH. "Myelin sheaths: glycoproteins involved in their formation, main-tenance and degeneration. Cell Mol Life Sci, 2002, 59(11): 1851-71. 79) Quig, David. "Cysteine Metabolism and Metal Toxicity." Alternative Medicine Review, 1998; 3(4): 262-270. 80) Reiter RJ, Tan DX, Allegra M. "Melatonin: reducing molecular pathology and dysfunction due to free radicals and associated reactants." Neuroendocrinol Lett, 2002, 23 Suppl 1: 3-8. 81) Rossier P, van Erven S, Wade DT. "The effect of magnesium oral therapy on spasticity in a patient with multiple sclerosis." Eur J Neurol, 2000, 7(6): 741-4. 82) Royal W 3rd, gartner S, Gajewski CD. "Retinol measurements and retinoid receptor gene expression in patients with multiple sclerosis." Mult Scler, 2002, 8(6): 452-8. 83) Saiz A, Carreras E, Berenguer J, Yague J, Martinez C, Marin P, Rovira M, Pujo T, Arbizu T, Graus F. "MRI and CSF oligoclonal bands after autologous hematopoietic stem cell transplantation in MS." Neurology 2001, 56(8): 1084-9. 84) Sandoval M, Okuhama NN, Zhang XJ, Condzo LA, Lao J, Angeles' FM, Musah RA, Bobrowski P, Miller MJ. "Anti-inflammatory and antioxidant activities of cat's claw (Uncaria tomentosa and Uncaria guianensis) are independent of their alkaloid content." Phytomedicine, 2002, 9(4): 325-37.

85) Sato M, Miyazaki T et al. "Quercetin, a bioflavonoid, inhibits the induction of interleukin 8 monocyte chemoattractant protein-1 expression by tumor necrosis factor alpha in cultured human synovial cells. J Rheumatol, 1997; 24:1680-1684. 86) Scott GS, Spitsin SV, Kean RB, Mikheeva T, Koprowski H, Hooper DC. "Therapeutic intervention in experimental allergic encephalomyelitis by administering uric acid precursors." Proc Natl Acad Sci USA, 2002; 99(25): 16303-8.

Page 30 of 34

87) See DM, Broumand N, sahl L, Tilles JG. "In vitro effects of Echinacea and ginseng on natural killer and antibody-dependent cell cytotoxicity in healthy subjects and chronic fatigue syndrome or acquired immunodeficiency syndrome patients." Immuno-pharmacology, 1997, 35(3): 229-35. 88) Shapiro, Haim. "Could n-3 polyunsaturated fatty acids reduce pathological pain by direct actions on the nervous system?" Prostaglandins, Leukotrienes and Essential Fatty Acids, 2003; 68: 219-224. 89) Shen W, Willis D, Zhang Y, Schlattner U, Wallimann T, Molloy GR. "Expression of creatine kinase isoenzyme genes during postnatal development of rat brain cerebellum: evidence for transcriptional regulation." Biochem J, 2002; 367(pt.2): 369-80. 90) Shinpo K, Kikuchi S, Sasaki H, Moriwaka F, Tashiro K. " Effect of 1,25-dihydroxyvitamin D(3) on cultured mesencephalic dopaminergic neurons to the combined toxicity caused by L-buthionine sulfoximine and 1-methyl-4-phenylpyridine." J Neurosci Res. 2000 Nov 1;62(3):374-82. 91) Shoenfeld Y, Ben-Yehuda O, Messinger Y, Bentwitch Z, Rauch J, Isenberg DI, Gadoth N. "Autoimmune diseases other than lupus share common anti-DNA idiotypes." Immunol Lett, 1988; 17(3): 285-91. 92) Singh CB, Singh SP. "Protective effects of Ca2+, Mg2+, Cu2+, and Ni2+ on mercury and methylmercury toxicity to a cyanobacterium." Ecotoxicol Environ Saf, 1992, 23(1): 1-10. 93) Smith PM, Franklin RJM. "The effect of immunosuppressive protocols on spontaneous CNS remyelination following toxin-induced demyelination." Journal of Neuro-immunology, 2001, 119(2): 261-268. 94) Spitsin S, Hooper DC, Leist T, Streletz LJ, Mikheeva T, Koprowskil H. "Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease." Mult Scler 2001, 7(5): 313-9. 95) Stangel M, Compston A, Scolding NJ. "Oligodendroglia are protected from antibody-mediated complement injury by normal immunoglobulins ("IVIg")." J Neuroimmunol, 2000, 103(2): 195-201. 96) Stangel M, Hartung HP. "Remyelinating strategies for the treatment of multiple sclerosis." Progress in Neruobiology, 2002; 68: 361-376.

97) Stankoff B, Aigrot MS, Noel F, Wattilliaux A, Zale B, Lubetzki C. "Ciliary neurotrophic factor (CNTF) enhances myelin formation: a novel role for CNTF and CNTF-related molecules." J Neurosci, 2002, 22(21): 9221-7. 98) Streit, Wolfgang. "Microglia as Neuroprotective, Immunocompetent Cells of the CNS." Glia, 2002; 40: 133-139.

Page 31 of 34

99) Szyper-Kravitz M, Uziel O, Shapiro H, Radnay J, Katz T, Rowe JM, Lishner M, Lahav M. "Granulocyte colony-stimulating factor administration upregulates telomerase activity in CD34+ haematopoietic cells and may prevent telomere attrition after chemotherapy." BR J Haematol, 2003, 120(2): 329-36. 100) Tejada-Simon MV, Hong J, Rivera VM, Zhang JZ. "Skewed autoantibody reactivity to the extracellular domain of myelin oligodendrocyte glycoprotein in multiple sclerosis." Immunology, 2002, 107(4): 403-10. 101) Tong, XW, Xue QM. "Alterations of serum phospholipids in patients with multiple sclerosis." Chin Med J, 1993; 106(9): 650-4. 102) Tsushima M, Fujiwara Y, Matsuno T. "Novel marine di-Z-carotenoids: cucumaria-xanthins A,B, and C from the sea cucumber, Cucumaria Japonica." J Nat Prod, 1996, 59(1): 30-4. 103) Turley JM, Funakoshi S, Ruscetti FW, Kasper J, Murphy WJ, Longo DL, Birchenall-Roberts MC. "Growth inhibition and apoptosis of RL human B lymphoma cells by vitamin E succinate and retinoic acid: role for transforming growth factor beta." Cell Growth Differ, 1995; 6(6): 655-63. 104) Van der Aa A, Hellings N, Bernard CC, Raus J, Stinissen P. "Functional properties of myelin oligodendrocyte glycoprotein-reactive T cells in multiple sclerosis patients and controls." J Neuroimmunol, 2003, 137(1-2): 164-76. 105) Victor, VM and De la Fuente M. "N-acetylcysteine improves in vitro the function of macrophages from mice with endothoxin-induced oxidative stress." Free Radical Res, 2002; 36(1): 33-45. 106) Vlieger AM, van den Hoogen FH, Brinkman DM, van Laar JM, Schipperus M, Kruize AA, Wulffraat NM. "Immunology in the medical practice. XXXII. Transplantation of autologous hematopoietic stem cells for treatment of refractory auto-immune diseases; preliminary favorable results with 35 patients." Ned Tijdschr Geneeskd 2000, 144(33): 1588-92. 107) Wadsworth TL, McDonald TL, Koop DR. "Effects of Ginkgo biloba extract (EGb761) and quercetin on lipopolysaccharide-induced signaling pathway involved in the release of tumor necrosis factor-alpha." Biochem Pharmacol, 2001; 62(7): 963-74. 108) Wakita H, Tominoto H and Akiguchi I. "Protective Effect of Cyclosporin A on Glial Activation and White matter alterations induced by chronic cerebral hypoperfusion." In Borlongan CV, Isacson O, Sanberg P.R. (ed) Immunosuppressant Analogs in Neuroprotection." Humana Press Inc. Totowa, NJ, 2003.

109) Wang MJ, Huang HM, Hsieh SJ, Jeng KC, Kuo JS. " Resveratrol inhibits interleukin-6 production in cortical mixed glial cells under hypoxia/hypoglycemia followed by reoxygenation." J Neuroimmunol 2001 Jan 1;112(1-2):28-34

Page 32 of 34

110) Wang, MJ, Lin WW, Chen HL, Chang YH, Ou HC, Kuo JS, Hong JS, Jeng KC. "Silymarin protects dopaminergic neurons against lipopolysaccharide-induced neurotoxicity by inhibiting microglia activation." Eur J Neurosci, 2002; 16(11): 2103-12. 111) Wang X, Halvorsen SW. "Retinoic acid up-regulates ciliary neurotrophic factor receptors in cultured chick neurons and cardiomyocytes." Neurosci Lett, 1998, 240(1): 9-12. 112) Werner, Dierk et al. "Pneumatic Exernal Counterpulsation: A New Noninvasive Method to Improve Organ Perfusion." American Journal of Cardiology 1999; October 15, 84: 950-952. 113) Wilson HC, Onischke C, Raine CS. Human Oligodendrocyte Precursor Cells in Vitro: Phenotypic Analysis of Differential Response to Growth Factors. Glia, 2003; 44: 153-165. 114) Wuerfel J, Bellmann-Strobl J, Brunecker P, Aktas O, McFarland H, Villringer A, Zipp F. Changes in cerebral perfusion precede plaque formation in multiple sclerosis: a longitudinal perfusion MRI study. Brain 2004, 127(Pt 1): 111-9. 115) Xu, Yu-yun and Zhen-sheng Zheng. "External Counterpulsation", Chinese Medical Journal 1990; 103(9): 768-771 116) Yasui M, Ota K. "Experimental and clinical studies on dysregulation of magnesium metabolism and the aetiopathogenesis of multiple sclerosis." Magnes Res, 1992, 5(4): 295-302. 117) Yasukawa K, Akihisa T, Kanno H, Kaminaga T, Izumida M, Sakoh T, Tamura T, Takido M. "Inhibitory effects of sterols isolated from Chlorella vulgaris on 12-0-tetradecanoylphorbol-13-acetate-induced inflammation and tumor promotion in mouse skin." Biol Pharm Bull, 1996, 19(4): 573-6. 118) Zapolska-Downar D, Zapolski-Downar A, Naruszewicz M, Siennicka A, Krasnodebska B, Koldziej B. "Protective properties of artichoke (Cynara scolymus) against oxidative stress induced in cultured endothelial cells and monocytes." Life Sci, 2002, 71(24): 2897-08. 119) Zheng SX, Zhou LJ, Chen ZL, Yin ML, Zhu XZ. "Bilobalide promotes expression of glial cell linederived neurotrophic factor and vascular endothelial growth factor in rat astrocytes." Acta Pharmacol Sin, 2000, 21(2): 151-5.

Page 33 of 34

For information on Dr. Steenblocks treatment program for MS please call us toll free at 1-800-300-1063
For more information on Multiple Sclerosis as well as video testimonials featuring patients who have successfully undergone stem cell therapy at Dr. Steenblocks clinic please go to our website at WWW.STEMCELLMD.ORG

TO ARRANGE FOR A STEM CELL CONSULTATION CALL: 1-800-300-1063 www.strokedoctor.com www.stemcellmd.org www.stemgevity.com www.davidsteenblock.com 26381 Crown Valley Parkway, Suite 130 Mission Viejo, CA. 92691

Office: 1-949-367-8870

Toll Free:

Page 34 of 34