39th Orthomolecular Medicine Today Conference

International Society for Orthomolecular Medicine

April 30, 2010 Dear OMT Delegates, Welcome to our 39th Annual International Orthomolecular Medicine Today conference.

We hope these next three days will provide fresh insight and clinical evidence for the advancement of your work and practice in this important field.

At the completion of last year’s conference, we faced the loss of Dr Abram Hoffer, the father of Orthomolecular Medicine. For over 40 years, Dr Hoffer’s vision and leadership provided the impetus for the continued growth of Orthomolecular Medicine worldwide, particularly the annual Orthomolecular Medicine Today conference you are attending today and for the Journal of Orthomolecular Medicine.

One year later, we are pleased to report that during this time of transition, we have experienced many areas of opportunity and growth, both in our educational efforts for the public and for health professionals. We invite you to join us at the ISOM and CSOM Meeting on Friday, April 30, to hear updates from Canada and around the world.

We thank you for your dedication to Orthomolecular Medicine and wish you a great conference.

Sincerely,

Thanks to Our Generous Sponsors Steven Carter Director International Society for Orthomolecular Medicine

ISOM and CSOM Meeting Friday, April 30 5:30 pm – 6:30 pm Pacific Ballroom Please join us after Dr Burke’s presentation to hear the update from CSOM, the Canadian Society for Orthomolecular Medicine. A brief report will be given on our activities in education, communications and advocacy.

In addition, members from some of the 13 countries in attendance will also provide an update of their activities.

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ince 1970, this quarterly Journal for health professionals has published the best of nutritional research and clinical trials. New articles describing the orthomolecular approach to health management and treatment of disease are accompanied by lively editorials, case reports, book reviews, and correspondence. The Journal of Orthomolecular Medicine has led the way in presenting, far in advance of other medical journals, new health concerns and treatments.

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Table of Contents Exhibitor Floor Plan.............................................................................................................................. 4 Our Exhibitors....................................................................................................................................... 5 Speaker Biographies............................................................................................................................... 6 Conference Schedule............................................................................................................................. 7 Presentation Notes Nigel Plummer, PhD The Developmental Origins of Modern Disease: Are We Programmed to Develop Disease In the Womb?.......................................................................................................11 Aileen Burford-Mason, PhD Nutrition in Pregnancy: An Orthomolecular Approach.......................................................................25 Bruce Ames, PhD A Diet for Health and Longevity: How Do We Get There?.................................................................36 David Brownstein, MD Iodine: The Synergistic Importance of an Underutilized Nutrient.......................................................43 Hal Gunn, MD Integrative Cancer Care: The InspireHealth Experience and Site Specific Immunotherapy..................60 Dan Burke, PhD Secondary Plant Metabolites and Cytochome P450 Enzymes in Cellular Regulation...........................70 Dag Poleszynski, PhD Optimal Nutrition from an Evolutionary Perspective..........................................................................80 William Grant, PhD The Health Benefits of Vitamin D and Estimates of Reductions in Mortality Rates.............................88 for Canada and the United States Adrian Gombart, PhD Antimicrobial Effects of Vitamin D.....................................................................................................97 John Hoffer, MD, PhD Orthomolecular Psychiatry: Past, Present and Future........................................................................107 William Shaw, PhD Toxic Chemicals, Mitochondria and Mental Health..........................................................................108 Jonathan Prousky, ND, MSc Vitamin B12 and Psychiatry...............................................................................................................119 Jonathan Prousky, ND, MSc Chronic Fatigue Syndrome: A Disorder of Microcirculation..............................................................131 Elson Haas, MD Orthomolecular Detoxification for Inflammatory Conditions...........................................................141 Ron Hunninghake, MD Orthomolecular Stress Management..................................................................................................150

3 Badge colour code: Red=Speaker; Blue=Full Delegate; Yellow=Sessional Delegate; Green=Exhibitor

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39th Orthomolecular Medicine Today Conference Exhibitor Floor Plan Convention Floor Pacific Ballroom

Break Station

Registration

Entrance

Literature

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EXHIBITORS (by booth number)

1. York Downs Pharmacy 2. Acquired Intelligence, Inc. 3. Advanced Orthomolecular Research 4. Bioclinic Naturals 5. Vita Aid Professional Nutrition Products 6. Rocky Mountain Analytical 7. Nutritional Fundamentals for Health (NFH) 8. Integrative Therapeutics Canada 9. BDR INT Inc. 10. Finlandia Natural Pharmacy 11. Seroyal International, Inc.

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12. Douglas Laboratories of Canada/Pure Encapsulations 13. Vibrant Health/GUNA Canada 14. Doctor’s Data, Inc. 15. Homeocan, Inc. 16. Foster Health, Inc. 17. Nutri-Chem Pharmacy Ltd. 18. Protocol for Life Balance 19. The Great Plains Laboratory, Inc. 20. Metagenics Canada, Inc. 21. Boucher Institute of Naturopathic Medicine 22. Canadian Association of Naturopathic Doctors

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39th Orthomolecular Medicine Today Conference Please Visit Our Exhibitors Acquired Intelligence, Inc. #205-1095 McKenzie Avenue Victoria, BC, V8P 2L5, Canada 250 483 3640 sales@salvestrol.ca www.salvestrol.ca Advanced Orthomolecular Research 3900 - 12th Street NE Calgary, AB, T2E 8H9 Canada 1 800 387 0177 jill@aor.ca www.aor.ca

Finlandia Natural Pharmacy 1111 West Broadway Vancouver, BC V6H 1G1 604 733 5323 www.finlandiapharmacy.com

BDR INT, Inc. 4245 Number 4 Side Road, RR#6, Milton, ON L9T 2Y1 Canada 1 866 634 8075 / 905 336 8075 bdrint@gmail.com www.nanovitaminc.ca

Foster Health, Inc. 21-21 Dallas Road, Victoria, BC V8V 4Z9 250 381 9133 info@fosterhealth.ca www.fosterhealth.ca

Bioclinic Naturals 1550 United Boulevard Coquitlam, BC, V3K 6Y2 Canada 877 433 9860 lcasavant@bioclinicnaturals.com yfenton@bioclinicnaturals.com www.bioclinicnaturals.com

The Great Plains Laboratory, Inc. 11813 W. 77th Street Lenexa, KS 66214 USA 800 288 0383/ 913-341-8949 cgram@GPL4U.com www.greatplainslaboratory.com

Boucher Institute of Naturopathic Medicine 435 Columbia Street, Ste 110, New Westminster, BC V3L 5N8 Canada 604 777 9981 www.binm.org Canadian Association of Naturopathic Doctors 20 Holly Street, Suite 200, Toronto, ON M4S 3B1 Canada 800 551 4381/ 416 496 8633 info@cand.ca www.cand.ca Doctor’s Data, Inc. 3755 Illinois Avenue St. Charles, IL 60174, USA 800 323 2784 inquiries@doctorsdata.com www.doctorsdata.com

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Douglas Laboratories of Canada/ Pure Encapsulations 552 Newbold Street London, ON, N6E 2S5, Canada 866 856 9954 info@douglaslabs.ca www.douglaslabs.ca

Homeocan, Inc. 3025 boul. de L’Assomption, Montreal, PQ, H1N 2H2 800 556 0824 homeocan@homeocan.ca www.homeocan.ca Integrative Therapeutics Canada 2696 Nookta Street, Vancouver, BC, V5M 3M5 Canada 800 665 3414 johnny@enzymaticcanada.com www.integrativeinc.com Metagenics Canada, Inc. 851 Rangeview Road Mississauga, ON L5E 1H1 800 268 6200 www.metagenics.com

Nutritional Fundamentals for Health (NFH) 3405 F.X. Tessier Vaudreuil-Dorion, PQ, J7V 5V5 Canada 866 510 3123 info@nfh.ca www.nfh.ca Protocol for Life Balance 7018 Wellington Road, #124, Guelph, ON, N1H 6J4 Canada 877 776 8610 www.protocolforlife.com Rocky Mountain Analytical Unit A, 253147 Bearspaw Road NW, Calgary, AB T3L 2P5 Canada 866 370 5227 info@rmalab.com www.rmalab.com Seroyal International Inc. 490 Elgin Mills Road East Richmond Hill, ON, L4C 0L8 Canada 800 263 5861 sales@seroyal.com www.seroyal.com Vibrant Health/GUNA Canada 600 Wilfrid Laurier Mt. St. Hillaire, PQ J3H 4X6 Canada 450 536 1295/1 877 486 2226 info@GunaCanada.com or info@VibrantHealth.com www.GunaCanada.com Vita Aid Professional Nutrition Products #302-20285 Maple Ridge, BC V2X 8G1 Canada Phone: 1 604 465 1688 info@vitaaid.com www.vitaaid.com York Downs Pharmacy 3910 Bathurst Street, Room 304 Toronto, ON M3H 2N8 416 633 2244 info@yorkdownsrx.com www.yorkdownsrx.com

Nutri-Chem Pharmacy Ltd. #205 - 1305 Richmond Road, Ottawa, ON K2B 7Y4 613 820 4200 info@nutrichem.com www.nutrichem.com

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Speaker Biographies Elson M. Haas, MD, has been an Integrated medicine family practitioner since 1973, and founder and director of Preventive Medical Center of Marin in San Rafael CA for 25 years. He is also the author of eight books in the areas of health, nutrition and detoxification, including Staying Healthy with Nutrition, The New Detox Diet, and Staying Healthy with the Seasons. Dr. Haas works with Dr Kunin as advisor to San Francisco’s Orthomolecular Health Medicine organization. Elson does regular magazine and radio interviews and speaks at many venues around the world.

Bruce Ames, PhD, is a Professor of Biochemistry and Molecular Biology, Emeritus, University of California, Berkeley, and a Senior Scientist at Children’s Hospital Oakland Research Institute. A member of the National Academy of Sciences, his numerous awards include the Gold Medal Award of the American Institute of Chemists (1991), the Glenn Foundation Award of the Gerontological Society of America (1992), the Honda Foundation Prize, Japan (1996), the Medal of the City of Paris (1998), the U.S. National Medal of Science (1998), the Linus Pauling Institute Prize for Health Research (2001), and the American Society for Microbiology Lifetime Achievement Award (2001). Dr. Ames’ 540plus publications have resulted in his being among the few hundred most-cited scientists in all fields. www.bruceames.org

John Hoffer, MD, PhD, is a professor of medicine at McGill University where he conducts research at the Lady Davis Institute for Medical Research.

He earned his medical degree from McGill and his doctorate in Human and Clinical Nutrition from M.I.T. Dr Hoffer is also a senior physician in the divisions of Internal Medicine and Endocrinology in Montreal’s Jewish General Hospital. His research interests are in protein-energy malnutrition and vitamin therapy for chronic disease. Dr. Hoffer has served for many years on the Nutrition and Metabolism Committee of the Canadian Institutes for Health Research.

David Brownstein, MD, is a graduate of the University of Michigan and Wayne State University School of Medicine. He is Board-Certified by The American Academy of Family Practice and a member of the American Academy of Family Physicians and the American College for the Advancement in Medicine. Dr. Brownstein is the Medical Director of the Center for Holistic Medicine in West Bloomfield, MI, and has authored nine books including Drugs that Don’t Work and Natural Therapies That Do; The Miracle of Natural Hormones; Overcoming Thyroid Disorders; Iodine: Why You Need It, Why You Can’t Live Without It; The Guide to a Gluten-Free Diet; and The Guide to a Dairy-Free Diet.

Ron Hunninghake, MD, is the Chief Medical Officer of the Olive White Garvey Center for Healing Arts, the clinical division of The Center for the Improvement of Human Functioning, International. He is a 1976 graduate of the University of Kansas. Dr. Hunninghake was associated with the Family Practice Group in Minneapolis, Kansas, from 1978 to 1980, and Salina Family Physicians, KS, from 1982 to 1989. In addition to his full-time practice at The Center, Ron is a regular presenter at medical conferences, and at The Center’s “Lunch & Lecture” series on timely, health-related topics. Dr. Hunninghake has published three books on health and wellness: The User’s Guide to Inflammation, Arthritis, and Aging (2005); The User’s Guide to Energy-Boosting Supplements (2006); Stop Prediabetes Now (2007).

Aileen Burford-Mason, PhD, is an Immunologist, Cell Biologist and Nutritionist with a deep interest in the evidence base for orthomolecular health. She graduated in biochemistry from University College, Dublin, and received a PhD in immunology from the University of Hertfordshire. Her scientific papers cover many fields including gastroenterology, pathology, cancer and infectious diseases.

She has published articles on gastrointestinal colonization with Candida and its relationship to health. She was Assistant Professor in the Dept. of Pathology in the Faculty of Medicine, University of Toronto. In 2004, Dr. Burford-Mason cofounded and currently serves as Board President of the Holistic Health Research Foundation of Canada.

Nigel Plummer, PhD, has his doctorate in microbial physiology from the University of Surrey (London) and has worked at Pfizer in antibiotic research and development. His research on the use of normal flora in the prevention and treatment of genito-urinary candidiasis has won him numerous awards.

Dr. Plummer continues his solid commitment to research throughout his career in collaboration with research institutes and universities within the UK and Europe, developing an extensive knowledge specializing in probiotics, natural antimicrobials and fish oils. Dr. Plummer’s research involves the role of probiotics in the modulation of the gastrointestinal microbiota and the prevention of antibiotic resistance post antibiotic.

Dan Burke, PhD, Emeritus Professor of Pharmaceutical Metabolism, is Head of Research for Salvestrol Natural Products Ltd, in Syston, Leicester, UK. With a PhD in Drug Metabolism from the University of Surrey, an international university career spanning 35 years and over 200 published research articles, Professor Burke is an expert on the metabolism, toxicity and interactions of drugs, environmental chemicals and natural compounds. His specialty is the Cytochrome P450 system, which he has researched in species as diverse as humans and citrus fruits. Cancer - its causation, detection, prevention and treatment - has formed a consistent thread throughout his research and teaching, which includes nearly 20 years on the science faculty of Aberdeen University medical school.

Dag Viljen Poleszynski, PhD, studied at University of Wisconsin, Madison (MS 1971, MBA 1972); Faculty of Science, University of Oslo (MSc 1987), Institute of Sociology, University of Tromsø (PhD 1999). In 1974, he became a research assistant in political economy at the International Peace Research Institute in Oslo (PRIO) and later worked on energy, ecology and health. In 1999 he received a PhD for an historical analysis of complementary medicine. In 2002 he became the science editor of a popular science magazine (www.matoghelse.no). He has published more than 850 articles and co-authored/edited 44 books.

Adrian F. Gombart, PhD, is a Principal Investigator in the Linus Pauling Institute, and Associate Professor in the Department of Biochemistry and Biophysics at Oregon State University. He received both his undergraduate and Master’s degree in Biology and Genetics, respectively, at Oregon State University. He has a doctoral degree in Microbiology from the University of Washington. With over 57 scientific publications, Dr. Gombart was recognized for his contributions to the field of vitamin D and immunity with a Young Investigator Award from the Vitamin D Workshop held at the NIH in 2005. His research is supported by the NIH. William Grant, PhD, has a doctorate in Physics and a 30-year career in atmospheric sciences. He turned to epidemiological studies in 1996, first investigating the role of diet in the risk of Alzheimer’s disease, then the role of sugar in the etiology of coronary heart disease and animal products in the risk of several types of cancer. In 2000 he realized that solar ultraviolet-B affected the risk of many types of cancer in the United States. He retired from NASA in 2004 to pursue health studies full time, establishing Sunlight, Nutrition, and Health Research Center (SUNARC) in San Francisco. His current projects include investigating the role of vitamin D in reducing the risk of various types of disease.

Jonathan Prousky, ND, MSc, graduated from Bastyr University (Kenmore, WA) with a Doctorate in Naturopathic Medicine. He is the Chief Naturopathic Medical Officer at the Canadian College of Naturopathic Medicine and he also supervises in the Robert Schad Naturopathic Clinic. In 2008 he obtained a Master of Science degree in International Primary Health Care from the University of London. His private practice focus is on optimizing mental and neurological health with nutrition and botanical medicines. Dr. Prousky is the author of Anxiety: Orthomolecular Diagnosis and Treatment; Naturopathic Nutrition; and Principles & Practices of Naturopathic Clinical Nutrition. Dr. Prousky recently was selected to serve as the Editor in Chief of the Journal of Orthomolecular Medicine.

Hal Gunn, PhD, is a graduate of the University of British Columbia. He is CoFounder and CEO of InspireHealth, an integrated cancer care centre in Vancouver, Canada, which has become a national model for integrated cancer care. He is respected nationally by both his conventional and integrative medicine colleagues for his interest in bridging the worlds of complementary and conventional medicine. Dr. Gunn has a clinical appointment with the UBC School of Medicine and teaches at the Boucher Institute for Naturopathic Medicine. Dr. Gunn is also founder and CEO of Qu Biologics, a biotechnology company founded to develop and test Site Specific Immunotherapy, a novel approach to stimulate the body’s innate immune response to cancer.

William Shaw, PhD, received his doctorate in biochemistry and human physiology from the Medical University of South Carolina. He is board certified in the fields of clinical chemistry and toxicology by the American Board of Clinical Chemistry. Dr Shaw has supervised large endocrinology, nutritional biochemistry, toxicology and immunology departments in positions at the Center for Disease Control (CDC) and Smith Kline Laboratories in Atlanta, GA. As the Director of The Great Plains Laboratory Inc. for Health, Nutrition and Metabolism in Lenexa, Kansas, he specializes in providing diagnostic tools that aid in the diagnosis and treatment of mental health disorders, mitochondrial disorders, neurological diseases, chronic health issues and immune diseases.

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PROGRAM FRIDAY, APRIL 30

Session Three • Vitamin D

8:00 am Registration 8:30 am Exhibit Area Opens

10:30 am

Session One • Perinatal to Longevity 9:00 am

Nigel Plummer, PhD The Developmental Origins of Modern Disease – Are We Programmed to Develop Disease In the Womb?

11:30 am Adrian Gombart, PhD Antimicrobial Effects of Vitamin D 12:30 pm Lunch – Visit Exhibitors Linus Pauling institute Update

10:00 am Break – Visit Exhibitors 10:30 am Aileen Burford–Mason, PhD Nutrition in Pregnancy: An Orthomolecular Approach

Session Four • Orthomolecular Psychiatry

2:00 pm John Hoffer, MD, PhD Orthomolecular Psychiatry: Past, Present and Future

11:30 am Bruce Ames, PhD A Diet for Health and Longevity: How Do We Get There?

3:00 pm William Shaw, PhD Toxic Chemicals, Mitochondria and Mental Health

12:30 pm Lunch – Visit Exhibitors Award Presentation: 2010 Orthomolecular Doctor of the Year

4:00 pm Break – Visit Exhibitors

Session Two • Orthomolecular Oncology

4:30 pm Inaugural Abram Hoffer Memorial Lecture Jonathan Prousky, ND Vitamin B12 and Psychiatry

2:00 pm David Brownstein, MD Iodine: The Synergistic Importance of an Underutilized Nutrient

5:30 pm Exhibit Area Closes

3:00 pm Hal Gunn, MD Integrative Cancer Care: The InspireHealth Experience and Site Specific Immunotherapy

2010 Orthomolecular Medicine Hall of Fame Reception, Dinner and Induction Program 7:00 – 9:00 pm

4:00 pm Break – Visit Exhibitors 4:30 pm

SUNDAY, MAY 2

Dan Burke, PhD Secondary Plant Metabolites and Cytochome P450 Enzymes in Cellular Regulation

8:30 am Exhibit Area Opens

Session Five • Orthomolecular Medicine 9:00 am Jonathan Prousky, ND, MSc Chronic Fatigue Syndrome: A Disorder of Microcirculation

10:00 am Break – Visit Exhibitors

5:30 pm Exhibit Area Closes

Feed Your Head A New ISF Documentary Film 7:00 pm – 8:00 pm

10:30 am Elson Haas, MD Orthomolecular Detoxification for Inflammatory Conditions

SATURDAY, MAY 1

11:30 am Ron Hunninghake, MD Orthomolecular Stress Management

8:30 am Exhibit Area Opens

1:00 pm Exhibit Area Closes

Session Three • Vitamin D

Public Workshop

9:00 am Dag Poleszynski, PhD Optimal Nutrition from an Evolutionary Perspective 10:00 am Break – Visit Exhibitors

William Grant, PhD The Health Benefits of Vitamin D and Estimates of Reductions in Mortality Rates for Canada and the United States

Mental Health Regained

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featuring Orthomolecular Practitioners and Recovered Patients 2:00 pm – 4:00 pm

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2010 Orthomolecular Medicine Today Conference CD

The CD of all fifteen OMT presentations, including slides and audio, is available to order at the OMT Literature Table Special Delegate Price: $95.00 (Non Delegate Price: $195.00)

CSOM Seminar CD on Depression and Bipolar Disorder Integrative Medicine for the Treatment of Depression and Bipolar Disorder - An Orthomolecular Approach Two Day Medical Seminar with James Greenblatt, MD, and William Shaw, PhD Originally held February 6,7, 2010

This seminar contains over 10 hours of an intensive medical training seminar on Depression and Bipolar Disorder covering key topics such as: • • • • • • • •

Toxic Chemicals and Psychiatric Disorders Fatty Acids, Cholesterol, Low Vitamin D: Major Factors in Psychiatric Disorders Nutritional Considerations for Bipolar Disorder The relationship between Celiac Disease and Mood Disorders Amino Acids and their Role in Mental Health Food Allergies, Sensitivities & Abnormal Peptide Metabolism Infection and Dysbiosis as Factors in Psychiatric Illnesses Side effects of antidepressant treatment and nutritional/herbal treatments in Depression

The complete CD is for sale at the OMT Literature Table Special Price: $60.00 10

The Developmental Origins of Modern DiseaseAre We Programmed to Develop Disease In the Womb?

Nigel Plummer, PhD Cardiovascular Disease – Still Our Most Common Chronic Disease.

The Developmental Origins of Modern Disease - Are We Programmed to Develop Disease in the Womb?

ORTHOMOLECULAR CONFERENCE VANCOUVER, MAY 2010 Dr. Nigel Plummer



Number of U.S. adults* with CVD = 80 million (36.3%)

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Mortality

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35% of mortality is before 75 years of age



15% of mortality is before 65 years of age



Total cholesterol above 240mg/dl = 15.7% of population



Little difference in figures for male and female.

*Above 20 years of age

Some Interesting Facts 

Currently accepted etiology of CVD as resulting from a combination of genetic inheritance – approximately 5% and unhealthy lifestyles – approximately 95%

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However this leaves some inexplicable gaps, such as changing incidence and why some people with similar risk factors develop disease and others do not.



It is recognised that people in the lowest risk groups for cigarette smoking, cholesterol level, and blood pressure the most common cause of death is…..heart disease.

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Developing nations such as India and many African countries are showing soaring levels of obesity diabetes and CVD, yet their risk factors are not the same as ‘developed’ countries.



Are we missing something?

= 865,000/year

( American Heart Association 2009)

Early Indications of Another Potential Factor. 

Kermak et al in 1930’s showed that over previous 200 years increased survival and health of infants correlated with increase age of death. They concluded: ‘… these results are consistent with the hypothesis that the important factor from the point of view of health of the individual during his whole life is the environment up to the age of say 15 years, and that improved conditions in later ages have little direct effect’ Kermak et al Int J Epidem 1935

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Rose in 1960’s found that siblings of patients with CHD had still birth and infant mortality rates twice that of individuals with healthy siblings leading them to conclude ‘…CHD tends to occur in in individuals who come from a constitutionally weaker stock.’ Rose D Br J Prev Soc Med 1964

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Forsdahl in 1970’s geographical correlation between CHD in the 1960’s and high infant mortality rates 70 years earlier and concluded that ‘….a poor childhood environment caused permanent damage which left people vulnerable to aspects of a sedentary adult lifestyle’ Forsdahl A Br J Prev Soc Med 1977

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In 1974 Gunter Dorner was the first to postulate the concept of ‘epigenetic’ perinatal programming of the lifetime functioning of fundamental regulatory systems.

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Finally David Barker in 1992 found that the U.K., regions with the highest rates of low birthweight babies and infant mortality also have the highest rates of cardiovascular disease 6-7 decades later.

Developmental origins of Coronary Heart Disease

From The Barker Foundation

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The Developmental Origins of Modern DiseaseAre We Programmed to Develop Disease In the Womb?

Nigel Plummer, PhD Summary of large trial evidence for CHD Hazard Ratio of Death From Coronary heart Disease at 65 Years and All Ages to Weight at Birth and 1 Year

(Studies with over 10,000 subjects)

No. of subjects

LBW

14,611 ( m +f)

<2.5kg

Follow up age

Risk per 1kg BW increase 0.77(m) 0.83(f)

65-80

Leon et al BMJ 1998 317:241

13,517 (m+f)

<2.5kg

0.8 (average)

53-73

Barker et al Int J. Epidemiol. 2002 31:1235

10,803 (m+f)

<2.5kg

0.62 (average)

40-45

Lawlor et al Circulation 2005: 112: 1414

Data from 10 636 men born in Hertfordshire U.K between 1911 and 1930 (Barker 2007 J. Internal Medicine)

66,111 (f)

<2.5kg

0.77

35-79

Rich-Edwards et al BMJ 2005: 330: 1115

Summary of Large Trial Evidence for Stroke (> 10,000 subjects) Number of subjects

LBW

Follow up age

Summary of Evidence for hypertension - the most common cardiovascular disease

Risk per 1kg BW increase IS

HS

0.89(av)

0.61(av)

Number subjects

AS

14,611 ( m +f)

<2.5kg

65-80

10,803 (m+f)

<2.5kg

40-45

---

---

0.38

66,111 (f)

<2.5kg

35-79

0.83

0.86

---

276,000 males

---

22,846 males

This correlates overall to a 20% lowered risk of CVD with every 1kg of higher birth weight.

17-24 yrs

Odds for LBW 1.65

<2.5kg

3.2-3.8kg

40-75 yrs

1.26

<2.4kg 3.18- 3.86

30-35yrs

1.39-1.43

Curhan et al Circulation 1996

The Fetal Link to Heart Disease - Compelling Evidence

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>2.5kg

Age of measure

Curhan et al Circulation 1996

164,000 female

15 out of 16 epidemiological studies over 14 different countries have reported inverse relationships between birth weight and cardiovascular events.

<2.5kg

Ref BW

Lundgren et al 2001 J Hypetension 19:1533

Morley R Fetal and Neonatal Med 2006

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LBW

The Developmental Origins of Chronic Diseases: Barker Hypothesis ‘Adverse influences early in development

and particularly during intrauterine life can result in permanent changes in physiology and metabolism which result in increased risk of disease in adulthood’ from David Barker

“The way a baby grows in the womb affects its adult life”

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The Developmental Origins of Modern DiseaseAre We Programmed to Develop Disease In the Womb?

Nigel Plummer, PhD Developmental Origins Concept Fetal

Preconception Maternal size Metabolism Nutrition

Foetal Fetal Nutrition and Growth

Non-communicable disease risk

life

Neonate Birth size and Neonate Body composition

Infant and childhood growth

Risk factors Morbidity Mortality

1

Infant and childhood

2

Adolescence

Adult life

3

4

Accumulated risk of non-communicable disease

Age (Yajnik 2008, Rev Endocr Metab Disord)

WHO’s life-course model

Developmental Plasticity

Developmental Plasticity and the Thrifty Phenotype



Most higher animals including humans display developmental plasticity – mainly in the perinatal/neonatal stages.



It can be defined as a critical period where a system or organ is plastic in it’s development and sensitive to influences of the environment. This period is followed by loss of plasticity and a fixed functional capacity.



Plasticity allows the individual to adapt to the environment it is likely to be born into, or has recently been born into, and is a ‘non genetic’ mechanism to increase survival.



Plasticity allows for more than one phenotype to be generated from a single genotype.

The Thrifty Phenotype

The Foetal and Neonatal Periods are Plastic 

For the development of most organs and physiological systems the fetal and neonatal periods are the windows of plasticity.



Organ development such as kidney, brain, and pancreas and the development of physiological systems such neuro-endocrineimmune network appear to be mainly plastic in the fetal period, extending to the neonatal period



Sweat gland maturation and further immune system maturation occur in the neonatal period.

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To explain the link between low birth weight and adult cardiovascular disease, Barker developed the concept of the ‘thrifty phenotype.



Low birth weight simply reflects an under or malnutrition of the fetus, in the case of early studies, caused by macro undernutrition during the foetal stages.



As there is no reason to believe that the environment may be different following birth the foetus prepares itself by laying down ‘set points’ in metabolic pathways, which will enable survival in a thrifty environment.

The Developmental Origins of Modern DiseaseAre We Programmed to Develop Disease In the Womb?

Nigel Plummer, PhD ‘Brain-sparing’ during fetal growth

The ‘Thrifty Phenotype’ is insulin resistant 

In this case, limited maternal – fetal glucose flow leads to reduced fetal insulin level , and underdevelopment of pancreatic beta cells.



Limitation of glucose leads to preferential re-direction to the brain and relative under-supply to peripheral organs and muscular tissue.



To assist this, these tissues become more resistant to insulin so directing more blood and glucose to the developing brain. This tendency to insulin resistance then becomes ‘programmed’.

(Yajnik, Proc Nutr Soc 2004)

Low Birth Weight and Catch-Up Growth – An Accumulating Problem

The Thrifty Phenotype expresses increased risk of disease later in life…… or not 

The abundant nutrient availability in post-natal and adult life is physiologically opposed to the programmed pancreatic cell deficiency and inherent ‘nutrient limited’ insulin ‘status’ (resistance) of peripheral tissues laid down in the thrifty phenotype.



Most babies born either at the small end of normal weight range, premature, or SGA will catch up to the average within 2 years – this is termed catch-up growth. It appears that rapid ‘catch-up’ growth particularly in the first year of life comes at a cost.



Rapid catch up growth (i.e crossing more than one centile) in this period is associated with significantly increased risk ( typically 2-3 fold) of obesity, hypertension and insulin resistance, type 2 diabetes and CVD later in life.

Williamson et al Clin End 2007



The thrifty phenotype is unsuited to this environment, and hence the pathophysiological outcomes of glucose intolerance, overt insulin resistance and obesity, and increased risk of CVD ensue.



However, if the thrifty phenotype was maintained in a ‘thrifty’ environment during it’s lifetime these risks would not be expressed.



Experimentation has proven that over-feeding in the neonatal period leads to hyperinsulinism, increased lifelong hyperleptinism and risk of hypercortisolism. The SGA ‘thrifty’ baby is most susceptible to this.



Catch up growth in the childhood and adolescence rather than the infant stage is less associated with obesity, and appears to have no association with increased risk of metabolic syndrome Ekelund et al 2007 J Clin End and Met



The window for ‘safe’ early catch up growth if it exists appears narrow.

Many Diseases Now Linked with Birth Weight

The Causes of Intrauterine Growth Restriction and LBW Experimental models

Human evidence 



Protein deprivation



Vitamin A deficiency



Antibiotic administration





Corticosteroid administration





Insulin resistance



Genetics



     

Hypertension Coronary artery disease Type 2 diabetes Stroke Dislipidaemia

Malnutrition during pregnancy (and before) Low glycemic index diet can reduce birthweights by average of approx. 200g Maternal weight below 50kg Gestation weight gain less than 7kg Chronic infections LBW of mother Diabetes (2) /metabolic syndrome during pregnancy Smoking/alcohol abuse Genetics Social - adolescent pregnancy - family dysfunction



Less widely accepted association with low birth weight

Chronic lung disease Depression Schizophrenia Behavioural problems Fingerprint patterns and left-handedness Precocious puberty and menarche



Association with high birth weight

Polycystic ovary disease Breast cancer Prostate cancer Testicular cancer Childhood leukaemia.

Scholl Nestle Nut Work 2008



Widely accepted association with small birth weight

95% of SGA births are now in developing countries.

Adair and Prentice 2000

14

The Developmental Origins of Modern DiseaseAre We Programmed to Develop Disease In the Womb?

Nigel Plummer, PhD Developmental Origins of Diabetes

Initial Observations Made by Barker on Association of Metabolic Syndrome and Birthweight in 68 Yr Old Men

Original Observations Made By Barker and Colleagues On Association Between Birthweight and Type 2 Diabetes in 68 Yr Old Men Hales and Barker 2001, Br Med Bull)

Odds ratio for impaired glucose tolerance or type 2 diabetes according to birth weight among 370 men aged 64 years born in Hertfordshire (adjusted for adult body mass index)

Odds ratio for the metabolic syndrome according to birth weight among 407 men born in Hertfordshire (adjusted for adult body mass index).

Odds ratio for Type 2 diabetes by birth weight Meta-analysis (1966-2005) Birth weight (g)

No. of estimates*

Odds ratio

95% confidence interval

≤2,000

5

1.00

0.84, 1.19

2,001-2,500

6

0.82

0.69, 0.98

2,501-3,000

10

0.82

0.61, 1.08

3,001-3,500

11

0.72

0.59, 0.89

3,501-4,000

8

0.55

0.48, 0.62

4,001-4,500

7

0.60

0.51, 0.70

>4,500

7

0.92

0.63, 1.34

U-shaped relation between birth weight and Type 2 diabetes risk

* Number of estimates from single studies.

Harder et al 2007, Am J Epidemiol

Harder et al 2007, Am J Epidemiol

Pre-Diabetes in 4 yr olds related to birth weight Published literature- a meta-analysis of 40 studies shows inverse relationships of birth weight and increased risk of diabetes.

(Newsome et al 2003, Diabet Med)



However ……..

.......It is well recognised that obese and diabetic women give have a high risk of giving birth to large babies with a high risk of developing diabetes.

Birth weight (kg) Plot shows plasma glucose and insulin levels 30 mins after oral glucose load 



Low birth weight associated with tendency to hyperglyceamia and hyperinsulinemia (Yajnik et al, Rev Endocr Metab Disord 2008)

15

The Developmental Origins of Modern DiseaseAre We Programmed to Develop Disease In the Womb?

Nigel Plummer, PhD Insulin and Foetal Growth 

Hyperinsulinism In The Fetus

Insulin is the key controller of foetal growth in early foetal life – growth hormone takes over later in foetal life.

The Barker Hypothesis – small babies have high risk of diabetes 

 

A major responsibility for insulin is to provide energy for cell division and growth of muscle tissue. If there is under nutrition in mid gestation, then muscle and other peripheral tissues become resistant to insulin allowing nutrients to be diverted to the brain. In effect the growth of these tissues is sacrificed to allow brain growth, leading to a low birthweight baby.

The important point is that resistance to insulin is then programmed into the foetal physiology.

This is then expressed as a susceptibility to development of insulin resistance and type 2 diabetes in childhood and as a adult.



Offspring exposed to maternal diabetes are at increased risk of developing obesity and diabetes.



This association is largely independent of genetic background, and appears to relate directly to fetal hyperinsulinism resulting from maternal hyperinsulinism.



High circulating fetal insulin leads to high insulin concentrations in developing organs such as the brain, hypothalamus,( blood brain barrier not developed) and pancreas at critical windows of ‘set point’ imprinting.



This leads to hyperinsulinism, and lifelong high risk of obesity, diabetes and CVD in the offspring. This process has been entirely proven in animal experiments and is highly likely to also occur in humans.

The Pedersen Hypothesis – prediabetic and diabetic mothers give birth to large babies with high risk of diabetes. 

Maternal hyperglyceamia causes fetal hyperglyceamia by direct trans-placental imprinting. This leads to excessive fetal insulin secretion (hyperinsulinemia) which facilitates excess foetal growth particularly of fat component. However, insulin resistance then develops.

Renal and Vascular Origin of Hypertension

Transgenerational diabetes related to maternal and fetal nutritional status

Barker

Pederson

Fetal undernutrition

Fetal overnutrition

(‘Marasmus-like’)

(‘Kwashiorkor-like’)

Small baby

Large baby

Fat wasted

Fat retention



Under nutrition of the foetus leads to impairment of development of kidneys leading to lower nephron number. |SGA infants have up to 25% lower nephron number. Barker et al 2008



In clinical hypertension in humans there is a direct relationship of risk with lowered nephron number Franco et al Cardiovascular research 2003



Insulin resistance Metabolic syndrome Prediabetes Diabetes

Several studies have now shown a strong link between low birth weight and impaired endothelial function in both children and adults. The impairment is particularly associated with reduced capacity for endothelial relaxation , leading to pre-disposition to hypertension. Goodfellow et al 1998; leeson et al 2001

Birth weight, fetus under nutrition and depressive disorder In a trial of 882 individuals born in the 1920’s (birth record available) depression is measured at 68 years using the geriatric mental state examination.

Birthweight and Mental Health

These results were corrected for the following risk factors in later life       

16

Current social class Social class at birth Bereavement in past year Living alone Low social contact Illness causing pain Illness preventing activity

These trends persist for weight at 12 months

The Developmental Origins of Modern DiseaseAre We Programmed to Develop Disease In the Womb?

Nigel Plummer, PhD Birthweight predicts hypothalamic-pituitary-adrenal axis response to psychosocial stress in late adulthood

Human Fetal Undernutrion and Schizophrenia Below is pooled analysis of 7 studies measuring schizophrenia and birth weight ( <2500g)

SCHIZOPHRENIA

CONTROL

ODDS RATIO

300 subjects of different birth weights aged between 60-70 were subjected to the Trier Social Stress test.

- Response showed an inverse U shaped relationship between stress response and birth weight with low birthwight showing the lowest response levels.

- Results suggest that hypo and possibly hypercortisolism may be programmed to some extent in –utero Kajante et al 2007 J Clin End Metab

Total 747 schizophrenic subjects



Response showed an inverse U shaped relationship between stress response and birth weight with low birthweight showing the lowest response levels.



Results suggest that hypo and possibly hypercortisolism may be programmed to some extent in –utero.



Over stimulation of the HPA axis of the fetus either from administration of glucocorticoids or from maternal stress, leads to a lasting hyperactivity of the HPA following birth and in later life. Plagemann Physiol and Behav 2005



The consequences of this may be lifetime hyperactivity of the HPA axis leading to risk of impaired glucose regulation hypertension or depression, or development of adrenal fatigue and hypocortisolism leading to risk of CFS, fibromyalgia etc. Kajante et al J Clin End Metab 2007

Foetal Under-nutrition and Rapid Progression Through Puberty Reduced pre-natal growth cause rapid progression through puberty and reduced final height in girls compared to those with unaffected prenatal growth.

Summary    

Fingerprint association with CVD and fetal programming 

Fingerprints formed in-utero in first 19 weeks and pattern depends upon quality of blood flow in the fetus.



Disturbed blood flow, particularly restriction during foetal growth retardation cause specific pattern types with increased fingertip ‘whorls’ predicting increased risk of low birth weight and subsequent development of CVD esp hypertension in childhood and adulthood.



In a study of 35-42 year olds low birth weight babies had an average increase of 4 whorls on their right hand, which correlated with mean systolic blood pressure increase of 8mmHg. Average SBP increased 2mm with each additional whorl.



This disturbed blood flow and fingerprint pattern type is also associated with increasing abdominal adiposity in mother and with risk of CVD in adult.



Worst combination in pregnant woman is high central adiposity with low tricep and bicep skinfolds.



Insulin resistance occurs in growth retardation, and limits growth and development of peripheral tissues including skin fingerprint patterns



Could this be used as a predictor of CVD, type 2 diabetes and metabolic syndrome later in life?

Wheeler et al B.J Ob and Gyn 1998 Godfrey et al BMJ 1993

17

BIRTH WEIGHT ONSET OF PUBERTY MENARCHE FINAL HEIGHT

<2.5kg 8.6 years 11.3 years 153cms

>2.5kg 8.6 years 12.9 years 158.3cms

The Developmental Origins of Modern DiseaseAre We Programmed to Develop Disease In the Womb?

Nigel Plummer, PhD Influence of Birth Weight and Fetal Under-nutrition on Left Handedness 

Left handedness appears to be associated with lower life expectancy and increased susceptibility to autoimmune and allergic disease



Left handedness is associated with low birth weight.

(Mcmanus et al ; The lancet 1999 James 2001, J Theo biol)

Conditions Associated with High Birth Weight

(Saigal et.al 1992, Dev Med Child Neurol) 

Normal blood flow to fetal arms is asymmetrical with greater flow to right arm and left side of brain particularly in conditions of no nutritional constriction. This leads to different fingerprint on left and right hand.



Deficient nutrition to fetus leads to alteration of blood flow to brain.

Domination of left side is balanced- with greater relative flow to right hand side of brain - increase in left handedness (right side of brain).

Perinatal nutrition and risk of breast cancer 

Human breast cancer probably originates in-utero.



Evidence is that Japanese migration to NA takes several generations for breast cancer rates to converge cf- colorectal cancer which converge in single generation. This indicates epigenetic origin, ie modification of expression of genome in-utero, over several generations – this is not a genetic hereditary trait however.



Meta analysis of breast cancer studies 1966 -2007 (Park et al 2008, Breast Cancer Research)

1 = <2500g 2 = reference = 2500-3000g 3 = 3000-3500g 4 = 3500-4000g 5 = 4000g

Etiology is probably multifactorial But high oestrogen exposure inutero is highly implicated.

(Michels et al 1996, The Lancet)

Meta analysis of breast cancer studies 1966 -2007

Mother’s hip size – a possible risk factor for cancer?

(Park et al 2008, Breast Cancer Research)   



Higher birth weights are associated with increased breast cancer risk.

There was no association between birth order, prematurity, or maternal smoking and breast cancer risk.

Higher birth weights have been attributed to higher maternal estrogens levels through epigenetic modification of breast stem cells, increasing risk for development of breast cancer in adulthood.



Helsinki Birth Cohort – 6,370 women born from 1934 to 1944 and whose mothers’ pelvic bones were measured.



All admissions for breast cancer or deaths during 19712003 were recorded.

Breast cancer had been diagnosed in 300 women (48 died from the disease).

(Barker et at, Am J Hum Biol 2008)



Always remember – susceptibility still usually requires trigger factors to produce disease!

18

The Developmental Origins of Modern DiseaseAre We Programmed to Develop Disease In the Womb?

Nigel Plummer, PhD Hazard ratios for breast cancer according to mothers’ pelvic diameters and the length of gestation

Breast Cancer - conclusion

Length of gestation (completed weeks) <40 Maternal pelvic measurement

≥40

Hazard Ratio per cm increase P-value

Hazard Ratio Per cm increase P-Value

Over 27.5cm

Over 27.5cm

Intercristal

0.92

0.27

1.34

<0.0001

Interspinous

0.84

0.01

1.18

0.01

External conjugate

0.80

0.04

1.25

0.01



Higher risk of breast cancer in the daughters of mothers whose hips had large intercristal widths and round iliac crests



Suggestion – hip size and shape are markers of high mother’s sex hormones. High hormone concentrations cause genetic instability in differentiating breast cells in their daughters in utero

(Barker et at, Am J Hum Biol 2008)

Metastatic prostate cancer

Relationship between high birthweight and childhood acute lymphoblastic leukaemia

Odds Ratio

A meta analysis of over 10,000 leukaemia patients concluded that high birth weight (kg) was a risk factor for childhood leukaemia.

The records of 19,000 men born in Norway between 1920 and 1958 were analysed for birth weight related to prostate cancer later in life. Risk factor found to be 1.5 for birth weight above 3.5 kg.

(Nilsen et al 2005 Int.J.Cancer)

Maternal diabetes mellitus during pregnancy

PRIMARY PREVENTION!

Intrauterine Growth retardation (‘low birth weight’)

Early postnatal over-nutrition

Developmental Origins and Role of Nutrition Fetal and/or early postnatal hyperinsulinism hypercortisolism hyperleptinism

Permanent malprogramming of the ‘neuro-endocrine-immune-system’ (particularly of hypothalamic regulatory centres of food intake, body weight, and metabolism)

19

The Developmental Origins of Modern DiseaseAre We Programmed to Develop Disease In the Womb?

Nigel Plummer, PhD

Perinatally acquired disposition to obesity, diabetes mellitus, and the Metabolic Syndrome

Perinatal Undernutrition – Birth Weight is a Blunt Instrument  Low birth weight is a measure of significant undernutrition,

in the foetal period. This has been the measure used because it is the only data source which has a historical base.

Maternal phenotype of female offspring during their pregnancy: overweight and impaired glucose tolerance

However it is merely a blunt measurement of under nutrition, and similar undersupply of certain nutrients which may have major perinatal programming and later disease risk impact, may have no relationship to birthweight. 

Non-hereditary, inter-generational transmission, and multiplication of obesity disposition General concept of ‘functional teratogenesis’ and possible primary prevention of materno-fetal transmission of perinatally acquired obesity disposition, which may pass on epigenetically to succeeding generations of the maternal descendents, leading to a snowball effect, intergenerative multiplication, and thereby considerable contribution to obesity epidemics.



What evidence is there of ‘less visible’ undersupply of nutrients, and what impact may this have on perinatal and adult health?

The Importance of Folic acid – not just for NTD

Preconception and Foetal Nutrition



It is estimated that at least 5% of babies are born with some serious congenital abnormality and that by ensuring folic acid sufficiency in the preconceptual and early fetal periods can reduce this by half. Hall 2000 CMAJ; Eichholzer 2007 The Lancet.



The case for folate and NTD is proven with Canadian rates of NTD falling from 1/1000 births in 1991 to 0.58/1000 births in 1999. This is due in part to increased testing and subsequent termination, but the main supporting reason is the use of folate in supplements and food fortification. Wilson 2007 JOGC



Folic acid in combination with multivitamin supplementation has been shown to reduce the risk of congenital: - NTD ( Odds ratio: 0.67-0.2) - CV defects (Odds ratio: 0.78-0.61) - Limb defects (Odds ratio: 0.48-0.57) - Cleft palate (odds ratio 0.76-0.42) - Urinary tract anomolies (Odds ratio 0.48-0.68)



FOLIC ACID  

 

  

There is a possible link of increased risk of neoplasia and exacerbation of preexisting cancer with increased supplementation levels of folate, but this needs confirmation.

Pre Conception Multivitamin use and Risk of preterm and SGA Birth

Epidemiological study of 38,000 pregnant women in USA. Folic acid taken for one year 100-400mcg/day prior to pregnancy reduced risk of premature delivery by 70% for early prematurity(20-28 weeks) and by 50% in weeks 28-32.

Above data is in addition to benefits of folate effects on neural tube development. US SOC Fetal-Maternal Medicine 2008 Note the neural tube relationship with folate is only relevant for the first 4 weeks from conception when the neural tube closes – preconception folate levels are more important than foetal stage folate.

33% of babies born before 28 weeks die with a further 30-40% facing lifelong disability of varying severity.

Only 25-30% of females take folic acid supplements prior to and during pregnancy.

Folic acid compulsory to women for 12 months before IVF?

Analysis of 1800 women divided into those who had taken a multivitamin daily for minimum of 6 months prior to notification ( 9 weeks after conception), showed the following:

20



1.2% of daily multivitamin users had pre-term births <34 weeks compared to 3.5% of non vitamin users.

Adjusted odds ratio 0.29 ( see graph)



3.6% of daily vitamin users had SGA (<2500kg) compared to 5.9% of non vitamin users. Adjusted odds ratio 0.64.

The Developmental Origins of Modern DiseaseAre We Programmed to Develop Disease In the Womb?

Nigel Plummer, PhD Birthweight and prenatal vitamin/mineral intake

Periconceptional vitamin use and risk of preterm delivery



Vitamin D status has been positively shown to improve birth weight with each additional ug of vitamin D intake associated with an average of 11g increase in birth weight. Mannion et al CMAJ 2006



In Camden NJ, it was found that plasma concentration of α-tocopherol is positively associated with increased fetal growth and reduced risk of small for gestation births. Average gain of 200g birthweight from lowest to highest quintile. Depending on dietary intake – highest quintile equal to supplementation 50-100mg/day



Iron deficiency anemia early in pregnancy was associated with more than 2fold increase in the risks of low birthweight and preterm delivery.



In another study, supplementation with iron (30mg/day as ferrous sulphate) in early pregnancy (<20wks) increased infant birthweight and lower risk of preterm delivery.



Maternal iodine supplements in deficient areas significantly increase birthweight by 157g.

(Scholl et al, Am J Clin Nutr 2006)

(Scholl et al, Am J Clin Nutr 1994)

(Siega-Riz et al, Am J Obstet Gynecol 2006)

(Mahomed et al, Cochrane Database Syst Rev 1997)

(Catov et al , Am J Epidemiol 2007)

Periconceptional vitamin and leukemia risk in children with Down Syndrome  

Children with DS experience nearly a 20-fold increased risk of developing leukemia compared with children without DS. Children’s Oncology Group reported findings on periconceptional vitamin use and leukemia risk in children with Down syndrome.

(Ross et al, Cancer 2005)





The study showed a 63% reduction of risk of leukemia with vitamin supplementation in the periconceptional period. Multivitamin use was assessed as frequent or daily compared with no use in preconception ( 6 months ) and throughout gestation period.

Further when stratified by leukemia type, the significantly reduced risk was observed for acute lymphoblastic leukemia, but not for acute myeloid leukemia.

Vitamin D and Pre-eclampsia 

29% of pregnant black and 5% pregnant white women in north eastern USA are vitamin D deficient ( serum 25-hydroxyvitamin D 25(OH)D < 37.5nmol/litre)



54% of black and 47% of white women have insufficiency of vitamin D (25(OH)D at 37.5-80.0nmol/litre.



Case controlled study of 2200 pregnant women found:



The Importance of Maternal/Foetal Vitamin D



Early Programming and Vitamin D



Vitamin D deficiency in fetal/neonatal stages may effect organ/ physiology development which then has implications in later life and may also alter ‘set points’ for ‘invisible’ health risks such as preeclampsia in the offspring.



Metabolic syndrome in cohort of British 45 yr olds now strongly linked with low vitamin D status in the fetal/neonatal period.



Also association of frequency of multiple sclerosis in northern hemishpere and winter season may have cause in low vitamin D status in fetal/neonatal period.

(Hypponnen et al 2008)



Vitamin D deficiency in the perinatal period may lead to programming of susceptibility in tissues which is exaccerbated by later deficiency in vitamin D. This is supported by evidence of cellular responsivity and organ differentiation in early deficiency of vitamin D. This may predispose to the greater risk of various types of cancer now known to be associated with vitamin d insufficiency.

Vitamin D and risk of pre-eclampsia (Hyppönen et al, Eur J Clin Nutr 2007)



Northern Finland Birth Cohort 1966 (2969 women)



Vitamin D recommendation was 2000IU/day



Risk of pre-eclampsia was halved among women who had received vitamin D supplementation regularly during the first year of life compared to irregular/none users (2.1% vs 3.8%).



Vitamin D intake (large doses) in infancy may affect long-term programming of the immune response pattern.

- 4.9% incidence (59 cases) of pre-eclampsia - Mothers who developed pre-eclampsia had an average of 15% lower vitamin D status than controls 45nmol/litre vs 54nmol/litre.

- Vitamin D status of < 37.5nmol/litre associated with 5-fold increase in preeclampsia risk.

- There is a dose response relationship of decreased pre-eclampsia risk with increased serum level of vitamin D up to levels of 200nmol/litre (Bodnar et al 2007, J.Clin.Endocrin Metab)

21

The Developmental Origins of Modern DiseaseAre We Programmed to Develop Disease In the Womb?

Nigel Plummer, PhD Maternal vitamin D and calcium and musculoskeletal health



Literature suggests that the risk of osteoporosis and fragility fractures in adulthood might be programmed by environmental influences during gestation.



Data from Australia and UK suggests that maternal vitamin D status in pregnancy affects intrauterine skeletal mineralisation and bone matrix turnover “set points” which are then expressed in adulthood. Indications are that low vitamin D status lesds to increased risk of osteoporosis later in life. ( Pasco et al, Medical

Vitamin D and brain development

Hypotheses 2008)

Maternal Vitamin D intake during pregnancy and risk of recurrent wheeze in early childhood



Eyles et al (2003) found that gestational Vitamin D3 deficiency has profound effects on the developing brain including changes in volume, shape, cell proliferation and growth factor expression in study on rats.



The neuropathological findings of enlarged lateral ventricles and reduced cortical thickness are frequently reported in patients with schizophrenia and bipolar disorders.



The pattern of brain structure difference reported with schizophrenia and depressive disorders is consistent with that found in vitamin D deficiency.

Vitamin D intake and risk of recurrent wheeze (con’t)

Project Viva, Massachusetts (Camargo et al. Am J Clin Nutr 2007)  



  

A prospective pre-birth cohort study with 1194 mothers participated A higher maternal intake of vitamin D during pregnancy was associated with lower risk of recurrent wheeze in children 3 years of age (p <0.001).

In addition, among children conceived in the winter months, the inverse association between maternal intake of Vitamin D and risk of recurrent wheeze was stronger.

The vitamin D intake range from 60 to 1145 IU The lowered risk was associated with maternal intake, which was not corrected for by child intake following birth.

Previous studies showed that higher Vitamin D intake by pregnant mothers reduces asthma risk by as much as 40% in 3 to 5 years old children.

Maternal Vitamin and Mineral Supplementation in the Foetal period

Maternal Multivitamin intake and Childhood Cancer (Goh et al, Clin Pharm Ther 2007)

Multivitamin Supplementation and Childhood Cancer 

About 10,000 children under 15 develop cancer in the USA each year.



The most prevalent forms are: leukeamia, malignant brain and spinal cord tumours and neuroblastoma.



In a review of 61 publications, 7 studies met the inclusion criteria for daily or frequent use of multivitamins during pregnancy

Acute lymphocystic leukemia

22

The Developmental Origins of Modern DiseaseAre We Programmed to Develop Disease In the Womb?

Nigel Plummer, PhD Maternal Vitamin intake and Childhood Cancer (con’t)

Maternal Vitamin intake and Childhood Cancer (con’t)

Neuroblastoma

Brain tumor

Summary of Benefits of Increased DHA and AA provision During the Perinatal Period Many studies on the effects of increased levels of DHA and AA provided during the perinatal period have been performed over the past 30 years. Analysis of the whole data strongly suggests the following benefits:

Benefits to infant  Improved cognitive function (benefits lifelong)  Improved visual acuity ( probably by improvement of brain translation of visual information)  Increases in gestation time and birth weight  Improvements in neonate growth rate  Reduction in severity of neonatal allergy Benefits to mother:  Lowered risk of post partum depression

Neonatal and Infant Period and Nutrition

Vitamin D and risk of type 1 diabetes (Finnish Study) 

Retrospective study with a 1966 North Finland birth cohort of 10 366 children



81 children were diagnosed with type 1 diabetes before 1998



Vitamin D supplementation during the first year of children was associated with decreased frequency of type 1 diabetes by age 31 years (regular/irregular vs no supplementation)



In children who received vitamin D supplementation regularlytypically 400-1000iu /day the reduction in risk of type 1 diabetes by age 31 was over 50%. However there was an 8 fold reduction in risk if the supplementation level was at least 2000i.u/day.



Infants suspected of having had rickets during the first year of life had a threefold risk of developing type 1 diabetes compared with others.

Summary

Hyppönen E et al. Lancet 2001

23

The Developmental Origins of Modern DiseaseAre We Programmed to Develop Disease In the Womb?

Nigel Plummer, PhD





Preconceptual, fetal and neonatal health is just now being recognised as having profound direct implications on adult health and risk of major chronic disease. Most authorities now agree that of the accumulating factors which affect our risk of chronic adult disease HALF are acquired during the perinatal period.

As such perinatal programming offers a new paradigm to add to the genetic, and adult environment as determinants of chronic disease.



The relationship with birthweight is likely a blunt instrument of measure of malnutrition or other insult at the perinatal period. Hence the liklihood of U shaped curves for risk with some diseases when related to birthweight.



The relationship is complex throughout the perinatal period, with different developmental stages having greater or lesser importance.



The fetal programming, can be as a result of organ development or suboptimal set point fixing in any part of the neuro-immuno-endocrine system.



Foetal programming increases risk but does not obviate beneficial modifications due to diet and lifestyle later in life. Indeed, it increases the importance of these in individuals who are at increased risk

24



Science is only at the beginning of the process of unravelling this concept, but the implications are enormous.



Elucidation of the impact of preconceptual and perinatal nutrition will be the most exciting and most valuable research area for nutritional medicine in the next 25-50 years, with proof of effect being felt by our grand and great grandchildren long after we’ve gone!

Nutrition in Pregnancy: An Orthomolecular Approach Aileen Burford-Mason, PhD

Nutrition in Pregnancy: The life-long legacy of a healthy pregnancy

An Orthomolecular Approach

Aileen Burford-Mason PhD Orthomolecular Medicine Today Vancouver 29th April 2010

Obstetrician-Assessed Maternal Health at Pregnancy Predicts Offspring Future Health

Obstetrician-Assessed Maternal Health at Pregnancy Predicts Offspring Future Health

Lawlor DA et al. 2007. PLoS ONE 2(8):e666

Lawlor DA et al. 2007. PLoS ONE 2(8):e666

• In the 1950s obstetricians used physical signs to rank the health of 11,106 pregnant women • Signs used included – Vitality of eyes, health of skin, hair and teeth, posture and muscle development – Health of babies tracked for more than 50 years • Research question: Are offspring of mothers in poor (suboptimal?) physical health during pregnancy at higher risk of heart disease or other diseases in adulthood?

• Results: Poor maternal health in early pregnancy was associated with – More pregnancy complications – Low birth weight babies – Children were shorter and weighed less at age 5 years

• Follow-up: Researchers traced 97% babies in 1999

Obstetrician-Assessed Maternal Health at Pregnancy Predicts Offspring Future Health

The Barker hypothesis: the fetal origins of adult disease

Lawlor DA et al. 2007. PLoS ONE 2(8):e666

• As adults, offspring of mothers with poor physical health during pregnancy were at increased risk for – heart disease and stroke

• Hypothesis: undernutrition in utero changes the baby’s structure, function and metabolism

– lung cancer • No association with breast cancer • No difference between male and female offspring

– Brain development spared at the expense of muscle, incl. skeletal, cardiac and smooth muscle

– Developed 25 years ago – Proof of principle now established

• Fetal adaptation to an adverse nutritional environment • This difference in structure and function is a key factor in the development of chronic disease in later life – CVD, metabolic syndrome, diabetes, cancer, etc.

25

Nutrition in Pregnancy: An Orthomolecular Approach Aileen Burford-Mason, PhD

Prenatal nutrition: a critical window of opportunity for mother and child.

Prenatal nutrition: a critical window of opportunity for mother and child.

Shapira N. Womens Health (Lond Engl). 2008 Nov;4(6):639-56.

Shapira N. Womens Health (Lond Engl). 2008 Nov;4(6):639-56.

• Review: Shifts in thinking on prenatal

• Poor prenatal nutrition carries short- and long-term health risks for mother and child

nutrition – Initially focused on undernutrition (i.e., famine, developing countries) 

– obesity, diabetes, dyslipidemia and CVD

• Overconsumption of food does not guarantee adequacy of critical nutrients needed to protect against birth defects or brain development • Multinutrient supplementation better than single-nutrient supplements, e.g., iron, folate

Now also concerned about

– Mismatch between prenatal 'programming' through undernutrition and postnatal overconsumption (low birth weight vs. rapid postnatal growth) – Overconsumption and obesity in pregnancy

– Consider zinc, iodine, choline and n-3 fatty acids

Maternal Nutrition and Fetal Development

What is optimal nutrition?

Wu G. 2004. J. Nutr. 134:2169-2172

• Two themes currently dominate the scientific literature on diet and health. Disease risk is increased by

• Review: Poor in utero nutrition affects fetal development – Alters the way genes are expressed (epigenetics) – Has lifelong consequences for the health of the offspring

– Lack of fruits and vegetables: low dietary phytochemical intake – High glycemic load: excess sugar and starch

• Both are major risk factors for chronic degenerative diseases

• Both under nutrition and over nutrition (high caloric intake) create similar problems • Optimal nutrition is key

– diabetes, heart disease and stroke, cancer, dementia, etc.

• Both factors linked to unhealthy pregnancies

– ensures optimal fetal development – reduces lifelong incidence of chronic diseases

Fruit and vegetable intake and risk of upper respiratory tract infection in pregnant women.

A dietary pattern characterized by high intake of vegetables, fruits, and vegetable oils is associated with reduced risk of preeclampsia

Li L, Werler MM. Public Health Nutr. 2009 Jun 25:1-7

Brantsaeter AL et al. J Nutr. 2009 Jun;139(6):1162-8

• Study: examined link between fruit and vegetable intake prior to conception and incidence of URTI during pregnancy • Methods: Retrospective analysis of fruit and vegetable intake for 6m before pregnancy and occurrence of URTI during pregnancy in 1034 N. American women • Outcome: Dose-dependent ↓ in URTI seen for highest quartile (median 8.54 servings/d) vs. lowest quartile (median 1.91 servings/d)

• Studied: risk of pre-eclampsia and dietary patterns in 23,423 nulliparous Norwegian pregnant women – Given questionnaires at 15 wks gestation – Pregnancy outcomes obtained 

Results: dietary pattern characterized by vegetables, plant foods, and vegetable oils decreased risk

– dietary pattern of processed meat, salty snacks, and sweet drinks increased risk

– Seen during first trimester but not later in pregnancy

26

Nutrition in Pregnancy: An Orthomolecular Approach Aileen Burford-Mason, PhD A prospective study of dietary patterns, meat intake and the risk of gestational diabetes mellitus Zhang C et al. Diabetologia. 2006;49(11):2604-13

• Study: Prospective cohort study – 13,110 women free of CVD, cancer, type 2 diabetes and history of GDM – Diet checked in 1991, and impact of prepregnancy diet on development of gestational diabetes (GDM) in new pregnancies examined

Glycemic Load, Insulin and Insulin Resistance

• Results: A pre-pregnancy diet high in red and processed meat associated with ⇑ risk – Highest compliance with prudent pattern (high in fruit, green leafy vegetables, poultry and fish) protected against GDM

Effect of a low-glycemic-index diet during pregnancy on obstetric outcomes.

Effect of a low-glycemic-index diet during pregnancy on obstetric outcomes.

Moses RG et al.. Am J Clin Nutr. 2006;84(4):807-812

Moses RG et al.. Am J Clin Nutr. 2006;84(4):807-812

• Results: GI fell significantly in the LGI group but not in the HGI group

• Background: maternal glucose is the main energy substrate for intrauterine growth.

Thus dietary glycemic index (GI) is of concern in pregnancy • Study: to compare the effects of low-GI and conventional dietary strategies on pregnancy outcomes in healthy women

• Women in the HGI group gave birth to – infants who were heavier, with a higher proportion of large for gestational age babies (p=0.01)

• Conclusion: Because birth weight and ponderal index may predict chronic disease in later life, a low-GI diet may favorably influence long-term health outcomes

– 62 women given dietary counseling encouraging either low-GI (LGI) carbs or high-fiber, moderateto-high GI (HGI) foods

Muscle cells ↓ storage of glycogen and amino acids (tissue repair)

Typical Canadian Breakfast

Brain cells ↓ storage of precursors for neurotransmitters

• Cereal, toast and fruit juice • Conforms to current healthy eating guidelines – 2 serving of grains, 2-3 serving of fruit • Could provided from 300-750 cals.

• High glycemic load

Insulin resistance – reduced nutrient storage – Pancreatic stress metabolic syndrome type ll diabetes

Tissue hypomagnesemia CVD; depression, etc.

– equivalent to 68 cubes of sugar

27

Nutrition in Pregnancy: An Orthomolecular Approach Aileen Burford-Mason, PhD

Protein needs in pregnancy

Protein • Protein requirements remain the same from day-to-day, and increase in pregnancy

• Required for development and growth of cells and tissues in both mother and infant • Needed for

– RDA is ~50g for a 150 lb non-pregnant, sedentary woman, 75g during pregnancy

– growth of fetus from a single cell to an infinite number in just 9 months – placental development – growth of maternal tissues – increased maternal blood supply: blood volume increases by approx. 50% during pregnancy – amniotic fluid

• Because the body has little capacity to store protein, protein requirements must be met from daily intake • When the daily diet does not provide sufficient, muscles are catabolized to supply needed amino acids within a few days – Relevance to morning sickness, hyperemesis gravidarum?

Fat • Two types of polyunsaturated fats are essential – Omega 3 fatty acids: flax seed, olives, walnuts, soy beans, dark green leafy vegetables, fatty fish/fish oil

Fat and Pregnancy

– Omega 6 fatty acids: vegetable oils (safflower, sunflower, corn, oil, grape seed oil), peanuts and legumes, meat (beef pork, lamb, chicken), borage oil, evening primrose oil

• Omega 3s and 6s need to be balanced – Modern diets provide excess omega 6 relative 3 – Deviates from evolutionary diets (paleo or hunter gatherer diets)

Higher maternal plasma docosahexaenoic acid during pregnancy is associated with more mature neonatal sleep-state patterning. Cheruku SR. Am J Clin Nutr 2002;76(3):608-13

Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children's IQ at 4 years of age. Helland IB et al; Pediatrics 2003;111(1):39-44









Study: RCT. Pregnant women given cod liver oil (omega 3) or corn oil (omega 6) from 18 weeks gestation to 3 months after delivery Cod liver oil contained 1183 mg DHA and 800mg EPA Outcomes: Babies supplemented with CLO had ↑developmental scores at 3, 6, 9 months





Levels of DHA and EPA measured in pregnant women.

Higher levels of DHA and EPA associated with superior maturity of the babies’ nervous systems -



Effect of CLO still evident at 4 years of age

28

infants slept through the night sooner

Researchers think this reflects better brain development and higher IQ

Nutrition in Pregnancy: An Orthomolecular Approach Aileen Burford-Mason, PhD

Omega 3 supplements – flax seed oil or fish oil?

• Vegetable oils (flax, canola) contain short-chain omega 3 fats • Must be elongated in the body to form the long chain omega 3s – EPA and DHA • Some people do not do this conversion very efficiently. Synthesis impaired by

Choline and pregnancy: The forgotten fat?

– stress, infections, alcohol – excess sugar – vitamin or mineral deficiencies

• EPA and DHA are present (preformed) in fatty fish and fish oils or algal sources for vegetarians

Choline: needed for normal development of memory.

Choline

Zeisel SH. J Am Coll Nutr 2000 Oct; 19(5Suppl):528S-531S

• Synthesized in small amounts in the liver • Precursor for acetylcholine, the most abundant neurotransmitter in the body

“The mother's dietary choline during a critical period in brain development of her infant influences the rate of birth and death of nerve cells…...….

– main communication molecule between neurons and muscles – required for the development of spatial intelligence

These changes are so important that we can pick out the groups of animals whose mothers had extra choline even when these animals are elderly.

• Acetylcholine also called the brain’s “memory manager” • Can’t be made without adequate vitamins C, B1, B5, and B6 and minerals zinc and magnesium

Thus, memory function in the aged rat is, in part, determined by what the mother ate.”

Raising gestational choline intake alters gene expression in DMBA-evoked mammary tumors and prolongs survival.

Diet and choline

Kovacheva VP et al. FASEB J. 2009;23(4):1054-63

• Adequate maternal choline is required for fetal neurogenesis • Two fatty foods – eggs and liver – traditionally provided most of our dietary choline intake

• Animal Study: Pregnant rats fed a control, choline-supplemented, or choline-deficient diet • On postnatal day 65, female offspring given 25 mg/kg of dimethylbenzanthracene (DMBA), a synthetic carcinogen

– In Asian diets choline is also obtained from full fat tofu

• In demonizing eggs we may be short-changing not only brains, but also eyes (J Nutr. 2006 Oct;136(10):2568-73) • Maternal reserves of choline are depleted during pregnancy and lactation

– DMBA is used in animal studies as a model for environmental chemicals (POPs) known to promote breast cancer – Produces tumours histologically similar to human breast cancer

Note: Supplement with phosphatidylcholine (3 capsules a day) in those not eating a daily egg

29

Nutrition in Pregnancy: An Orthomolecular Approach Aileen Burford-Mason, PhD Raising gestational choline intake alters gene expression in DMBA-evoked mammary tumors and prolongs survival.

Kovacheva VP et al. FASEB J. 2009;23(4):1054-63

• Results: Approx 70% rats developed tumours

Micronutrient deficiencies and pregnancy - some special concerns

– Breast cancer developed in all groups, regardless of in utero choline exposure

• Tumour growth rate was associated with prenatal choline exposure – 50% longer survival in those fed extra choline in utero compared to those on a choline deficient diet

•   survival linked to gene expression known to confer better prognosis in human cancers

Apoptosis and Cell Proliferation - the yin and yang of normal fetal development

Daily Metabolic Requirement for Nutrients

Cell growth cycle

Maintenance of connective tissue

Apoptosis and cell differentiation

DNA synthesis and repair

Antibody synthesis

– induced either by a stimulus (e.g. radiation, toxins or drugs) or by removal of a repressor agent – controls cell numbers

Hormone synthesis and regulation

Vitamins, minerals, amino acids, essential fatty acids and phytochemicals

Detoxification (carcinogen metabolism)

• Apoptosis: a.k.a. programmed cell death or cell suicide

• Cell Proliferation: Rapid increase in cell numbers – process by which cells multiply during growth to form new tissues and organs

Neurotransmitter synthesis

• Apoptosis and cell proliferation are both necessary for optimal fetal development

The involvement of cell death and survival in neural tube defects: a distinct role for apoptosis and autophagy?

Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis Goh YI. J Obstet Gynaecol Can. 2006;28(8):680-9

Cecconi F et al. Cell Death Differ. 2008 Jul;15(7):1170-7

• Review: Neural tube defects (NTD) are common congenital malformations of the central nervous system (CNS)

• Systematic review and meta-analysis: Protective effect of multivitamins and folic acid and incidence of congenital abnormalities

• Results: Multivitamins protected against

– cause ↑ infant mortality or severe disability

– neural tube defects and hydrocephalus – cardiovascular defects and urinary tract anomalies – limb defects, cleft lip and palate

• Correct morphogenesis in the developing CNS depends on a tuned control of both – cell growth (proliferation) – programmed cell suicide (apoptosis) – cell removal (autophagy)

• No protective effects against Down syndrome, pyloric stenosis, or undescended testis

30

Nutrition in Pregnancy: An Orthomolecular Approach Aileen Burford-Mason, PhD

Symposium on Geographical Influences on Nutrition: Iodine Deficiency in Industrialized Countries

Prenatal Multivitamin Supplementation and Rates of Pediatric Cancers: A meta-Analysis. Goh YI et al. Clin Pharmacol

Zimmermann MB. Proc Nutr Soc. 2009 Dec 8:1-11

Therapeutics; epub 21 Feb 2007

• •

•

• Review: Iodine intake ↓↓ in many industrialised countries

Meta-analysis: Multivitamin use prior to pregnancy and risk of childhood disease Results: Prenatal multivitamins associated with a decreased risk of most common childhood cancers – – –

.

– Globally, insufficient iodine intake affects 2 billion individuals

• Available data suggest that pregnant women in many industrialized countries are now mildly iodine deficient

Neuroblastoma (↓47%) Leukemia (↓39%) Brain tumours (↓29)

– Thought to be due to advice to ↓ salt intake – ↓ iodine residues in milk products due to decreased iodophor use by the dairy industry

These 3 cancers affect about 1,000 Canadian children each year

• Urgent action required to ensure optimal intake during pregnancy and lactation

Why iron deficiency is important in infant development. Beard JL. J Nutr. 2008 Dec;138(12):2534-6

Iodine, pregnancy and lactation

• Review: human and animal studies demonstrate the serious consequences of iron deficiency on brain development • Human studies: Fe deficiency in the first 6-12 m of life

• American Thyroid Association recommends 150 mcg iodine/day during pregnancy and lactation (Thyroid 2006; 16(10):949-52)

• Needed for

– Alters white matter myelination – Changes neurotransmitter metabolism in the striatum – Affects the functioning of the hippocampus

– Adequate production of thyroid hormones – Prevention of mental retardation

• Currently in the US 50% of prenatal multivitamins contain no iodine (N Engl J

• Animal studies: These effects persist into adulthood despite restoration of iron status at weaning

Med. 2009 Feb 26;360(9):939-40)

Folate and vitamin B12 metabolism: overview and interaction with riboflavin, vitamin B6, and polymorphisms.Shane B. Food Nutr Bull. 2008;29(2 Suppl):S5-16

The B Vitamins • Many critical enzymes require B vitamins

• Review article: nutritional and metabolic interrelationship exists between folate and vitamin B12

– include those involved in carbohydrate metabolism, protein and DNA synthesis and red blood cell formation

• B vitamins modulate key metabolic pathways

• Describes

– vitamin B2, B6, B12 and folate help reduce homocysteine levels – Raised plasma homocysteine increases risk of heart disease, cancer and dementia

– effects of some common genetic polymorphisms in folate and vitamin B12 genes on folate and B12 status – the influence of vitamin B6 and riboflavin status on folate and vitamin B12 metabolism

• Vegetarians have a high risk of B12 deficiency • B1, B6, B12 and folate deficiency common

31

Nutrition in Pregnancy: An Orthomolecular Approach Aileen Burford-Mason, PhD New 19 bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR): a risk factor for spina bifida acting in mothers during pregnancy?

New 19 bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR): a risk factor for spina bifida acting in mothers during pregnancy?

Johnson WG et al. Am J Med Genet A. 2004 Feb 1;124A(4):339-45.

Johnson WG et al. Am J Med Genet A. 2004 Feb 1;124A(4):339-45.

• Study: Examined SB mothers, SB fathers and controls for frequency of 19 bp deletion DHFR polymorphisms

• Background: Up to 72% of spina bifida (SB) is preventable with periconceptual folic acid • To be available to mother and fetus folic acid must then be reduced by dihydrofolate reductase (DHFR) • Hypothesis: Polymorphisms in the DHFR gene that diminish this reaction may also contribute to SB

• Results: Homozygosity for this polymorphism was significantly more frequent in SB mothers, compared with SB fathers or controls • Conclusion: Methyltetrahydrofolate - the reduced form of folic acid - is preferred supplemental form of folic acid to prevent SB

Vitamin D synthesis and metabolism Cholecalciferol (vitamin D3)

7dehydrocholesterol in skin

Vitamin D, Health and Pregnancy

25-hydroxylase in liver (CYP 27B1) 25-hydroxy D (stable storage form)

1,25-dyhyroxy D (cacitriol) - active 1-alpha-hydroxylase in kidney (CYP 24) Binding to vitamin D receptors (VDR)

Vitamin D supplementation: Recommendations for Canadian mothers and infants. Position Statement of the

Physiological actions in multiple tissues

Supplementing with vitamin D: How much is enough? How much is too much?

Canadian Paediatric Society. Paediatrics & Child Health 2007;12(7): 583-589

• The intake required for optimal serum levels varies from one individual to another • Depends on season, sun exposure, genes, age, BMI • Clinical experience demonstrates little correlation between serum level achieved and supplementation

• Adequate 25-hydroxy D in mothers during pregnancy and in infants has lifetime implications – prevents childhood and adult diseases such as type 1 diabetes, leukemia

• Emphasis should no longer be on rickets alone – Rickets prevented by a small amount of D

– to raise serum levels into the cancer protective range daily supplementation with vitamin D required

• Supplements of 2000 IU per day required during pregnancy/breast-feeding

– Amount needed varies from person to person

32

Nutrition in Pregnancy: An Orthomolecular Approach Aileen Burford-Mason, PhD

Human Serum 25(OH)D in Sun-Rich Environments “The unpredictable relationship between vitamin D intake and blood levels makes it difficult to recommend a standard supplement dose and supports incorporating measurements of blood levels into recommendations.”

Mean Serum 25(OH)D nmol/L

200

Goodwin PJ. J Clin Oncol 27(13):2117-9, 2009

160

120

80

40

0

Puerto Rico hospital personnel

Puerto Rico farmers St. Louis USA lifeguards

Israel lifeguards

Published data as cited in Vieth, 1999, Amer J Clin Nutrition, 69:842

Low maternal vitamin D status and fetal bone development: Cohort study.

Low maternal vitamin D status and fetal bone development: Cohort study.

Mahon P et al. Journal of Bone Mineral research 2009;25(1):14-19

Mahon P et al. Journal of Bone Mineral research 2009;25(1):14-19

• Results:

• Research question: Does maternal vitamin D insufficiency affect fetal bone development?

• Methods: Maternal 25-(OH)D checked in 424 British pregnant women

– Lower maternal 25-(OH)D was not related to fetal femur length – Femoral splaying index (ratio of femoral metaphyseal cross-sectional area to femur length) was inversely related to 25-(OH)D

– High resolution 3D ultrasound of femur looked for splaying or flaring at the end of the femur – a classical sign of rickets

– Clear evidence of rickets from 19 weeks

• Results: 3 groups of women identified

• Conclusion: Maternal vitamin D insufficiency influences fetal bone development as early as 19 weeks' gestation. Must start supplementation early in pregnancy

– Sufficient or borderline: 25-(OH)D >50 nmol/L (63.4%) – Insufficient: 25 to 50 nmol/L (30.7%) – Deficient : < 25 nmol/L (5.9%)

One Third of Canadian Toddlers Are Vitamin D Deficient Pediatric Academic Societies (PAS) Meeting 2009 : Abstr. 4545.2. May 4, 2009

• Measured 25-hydroxy D between Nov 2007 and June 2008 in 92 children (24-30 m) attending a well children clinic

Magnesium and Pregnancy

– 82% had levels < 75 nmol/L – 32% had levels < 50 nmol/L

• Low milk consumption associated with low vitamin D levels • High body mass index (BMI) also associated with low blood levels

33

Nutrition in Pregnancy: An Orthomolecular Approach Aileen Burford-Mason, PhD

Restless Leg Syndrome (RLS) and Leg Cramps in Pregnancy

Identifying magnesium deficiency • Neither serum nor red cell magnesium are true indicators of tissue stores

• Brain imaging shows RLS related to local CNS dopamine dysfunction . Nutritional causes include

– only 1% total body Mg present in serum and this is tightly controlled – hypomagnesemia can occur when red cell magnesium is normal.

– Magnesium (Hornvak M et al. Sleep.1998;21(5):501-5) – Iron deficiency (Eborn K, Ulfberg J. J Intern Med. 2009

• Individual needs for magnesium hard to predict

Nov;266(5):419-31)

• Leg Cramps increase as pregnancy progresses

– Vary depending on stress levels, diet and medication use, and individual genetics

• Therefore a standard dosing regime may not provide optimal intakes for all individuals

– especially troublesome at night – nutritional causes include magnesium deficiency (Cochrane Database Syst Rev. 2002;(1):CD000121)

Magnesium therapy for periodic leg movements-related insomnia and restless legs syndrome: an open pilot study Hornvak M et al.Sleep.1998;21(5):501-5

Other functional signs of chronic or acute magnesium deficits Smooth muscle: shortness of breath vascular headache wheezing after exercise frequency of urination constipation

• Observation: Sleep disturbances, periodic limb movements and restless leg syndrome (RLS) may be helped with Mg supplementation • Study: open labeled polysomnographic study.

Skeletal: leg cramps muscle tension fasciculations myalgia restless legs

– 10 patients (age 57 +/- 9 yrs); 6 men, 4 women – Magnesium given orally in the evening for 4-6 weeks

Cardiovascular: arrhythmias palpitations ↑ Blood pressure

• Results: Sleep efficiency improved in group as a whole (p>0.01). In those who estimated sleep +/- RLS improved (n = 7), effect of magnesium even more pronounced

Diet and Supplements for Pregnancy

Correcting magnesium deficiency

(1) Diet • High fruit and vegetable

• An alternative approach is to gradually increase magnesium to bowel tolerance

– Minimum 8 servings; aim for 10-12

• Low glycemic load

– A deficit will inhibit normal GI peristalsis, resulting in sluggish bowel function. This observation can be exploited to achieve optimal tissue stores – Excess will cause diarrhea

– Low or no sugar – All starches should be wholegrain

• Don’t forget protein – Protein needs are higher and remain constant regardless of nausea and vomiting

– Aim for 2-3 soft, formed bowel movements daily

• Use amino acid or protein chelated forms

• Good fats at each meal

– Better absorption and tissue retention

– Fatty fish, nuts, seeds, olive oil – I – 3 eggs a day (organic, free-range or omega 3)

34

Nutrition in Pregnancy: An Orthomolecular Approach Aileen Burford-Mason, PhD

Diet and Supplements for Pregnancy (2) Supplements • Multivitamin: higher B-vitamin content (all B vitamins, not just folic acid) – Preferable to have folic acid in coenzyme form

• Fish oil or algal supplement (vegetarians) • Choline supplements if not eating eggs • Vitamin D: minimum 2000 IU/day (check 25hydroxy D) • Magnesium to bowel tolerance

35

A Diet for Health and Longevity: How Do We Get There?

Bruce Ames, PhD

Micronutrients Delay Age-Related Disease

Bruce N. Ames

30 April 2010

Children’s Hospital Oakland Research Institute Vancouver Professor, University of California, Berkeley

Micronutrient Undernutrition in Americans Biotin Folic acid Niacin Pantothenate Riboflavin Thiamine VitA VitB6 VitB12 VitC VitD VitE VitK

• • • • • • • • • • • • • • •

Calcium Chloride Chromium Cobalt Copper Iodide Iron Magnesium Manganese Molybdenum Phosphorus Potassium Selenium Sodium Zinc

% Ingesting < EAR * From Food

• Linolenic acid/DHA [ω-3] • Linoleic acid [ω-6]

Nutrient

• Isoleucine

Mineral s

• Leucine • Lysine • Methionine • Phenylalanine

Population Group

Iron

Menstruating Women

Magnesiu m

All

16 % 56 %

Vitamins

Zinc

All

12 %

• Threonine • Tryptophan

B6

Women > 70 years

49 %

• Valine

Folate

Adult Women

16 %

E

All

93 %

C

All

31 %

• Histidine • Choline

Very low intake:vitamins D & K, calcium, potassium, omega-3 •USDA What we Eat in America (NHANES 2001-2002) Sept. 2005

Micronuclei in: RNA positive erythrocytes RNA negative erythrocytes� 130� Micronuclei per 1000 cells

• • • • • • • • • • • • •

80�

B6� SHMT�

Folic Acid�

Folinic Acid�

Methionine�

Serine�

MTHFR� (polymorphism)�

B12�

CH3-THF� MS�

40�

CH2=THF�

30�

TS�

20� Normal� range�

0� 1 year� preRx�

50�

100�

150�

200�

250�

300�

dUMP�

dTMP�

Homocysteine�

350�

TIME (DAYS) Everson RB, Wehr CM, Erexson GL, and MacGregor JT. (1988) J Natl Cancer Inst 80:525-9.

36

1

A Diet for Health and Longevity: How Do We Get There?

Bruce Ames, PhD

Dose-response on micronuclei induction in cultured lymphocytes Acute exposure to X-rays vs. Folic Acid deficiency

Fenech 2003, Nutrition Research Reviews

Analysis of nonlinear regression models: comparison of an overall model and individual models of Z-transformed values vs. ln- nonheme liver iron

Zinc Deficiency Induces Increased Oxidative Stress in C6 Glioma Cells

3 2.5

Over all

2

DCF-PMNs Rh123-PMNs

1

Rh123-Lymph

0.5

DCF Fluorescence Intensity (RFU)

Z score

*

DCF-Lymph

1.5

mtDNA damage

0

1/RCR

-0.5 -1 -1.5

-1.5

normal -1

-0.5

0

0.5

1

1.5

2

2.5

LN nonheme Fe (Îźmol/g wet liver)

140 120 100 80 60 40 20 Control

Each of the six dependent variables (that were analyzed by nonlinear regression in former figures) were transformed to Z scores and modeled as a quadratic function of the ln-liver nonheme iron as the independent variable. The equation for the RCR ratio's Z score was obtained from inverted RCR values (1/RCR) so that normal rats had the lower instead of the higher values. For presentation purposes each model line was obtained from 9 values of liver iron. All statistics were performed as in materials and methods.

ZnAD

ZnDF

Zinc Deficiency Induces Fapy Glycosylase (Fpg)sensitive Single Strand Breaks in Human Lung Fibroblasts

Control (+Fpg)

ZnAD (+Fpg) *

200

Comet Score

ZnDF (+Fpg)

160 120 80 40 0

Control

ZnAD

ZnDF

37

2

A Diet for Health and Longevity: How Do We Get There?

Bruce Ames, PhD Cellular Cytoplasm

Biotin deficiency accelerates cell senescence

Intermembrane Space

Mitochondrial Matrix

NADH NAD+

FADH2

FAD

Succinate

Fumarate L-Malate NADH

Pyruvate NADH Oxaloacetate Dehydrogenase complex Acetyl-Co-A Citrate Synthase

Micronutrient deficiency and heme synthesis in human cell culture Micronutrient Heme Complex IV Deficiency Deficit Deficit [+] Pyridoxine Zinc Riboflavin

+

#

# [+]

Iron

+

+

[+]

[+] +

[+]

[+]

+

NADH

α-Ketoglutarate Dehydrogenase Complex

α-Ketoglutarate

NADH

Isocitrate

9

++

+

+

+

[+]

Lipoic Acid Pantothenate

Citrate

Succinyl-Co-A

[+]

Copper Biotin

CITRIC ACID CYCLE

ADP ATP

H2O

Magnesium Deficiency Shortens Fibroblast Lifespan

DNA Early Oxidative Damag Senescen e ce Stress

++

ATP

O2

[+]

[+] Killilea DW, Ames BN (2008) PNAS 105:5768-5773.

+ = Atamna/Ames, ++Askree /Ames, #Ho/Ames [+] Literature

Calcium Deciency

Vitamin B12

Folate Deciency

Selenium

Vitamin D Deciency

Omega-3 FA

Magnesium Deciency

Niacin

Zinc Deciency

Choline

Fenech: chromosome breaks Lipkin: colon cancer mice

MacGregor/Ames/Fenech: chromosome breaks mice/humans Willett: epi colon cancer humans Holick: epi many types of cancer

Bell: chromosome breaks humans Larsson: epi colorectal cancer humans Fong: esophageal cancer humans/rodents

Potassium Deciency

Fenech: Chromosome breaks

Rao: DNA damage Combs/Trumbo: Cancer humans

Denkins: Cancer

Kirkland/Depeint: DNA damage

da Costa: DNA damage in humans

Chang: Cardiovascular Disease

38

3

A Diet for Health and Longevity: How Do We Get There?

Bruce Ames, PhD The Triage Theory (Ames, BN (2006) PNAS 103:17589-94) DISPOSABLE FUNCTIONS WITH MINIMAL DISEASE CONSEQUENCES

B

INSIDIOUS DEFICITS LEADING TO FUTURE DISEASES NORMALLY ASSOCIATED WITH AGING

Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage

Increasing Deficiency

A

Proc. Natl. Acad. Sci. USA Vol. 103, pp. 17589-17594, November 2006

Bruce N. Ames Children’s Hospital of Oakland Research Institute, Nutrition and Metabolism Center, 5700 Martin Luther King Jr. Way, Oakland, CA 94609 • Most of the world’s population has inadequate intake of one or more micronutrients.

• Triage theory posits as a results of recurrent shortages of micronutrients during evolution, natural selected developed a metabolic rebalancing response to shortage.

• The rebalancing favors micronutrient-dependent protein needed for short term survival while those only required for long-term health are starved.

• This impairment results in insidious damage (e.g. increased DNA damage) that, over time, leads to the acceleration of age-associated diseases (e.g. increased cancer).

ESSENTIAL FUNCTIONS REQUIRED FOR SURVIVAL TO REPRODUCE

C

Order of biomarker sensitivity to increasing severity of micronutrient deficiency predicted by triage theory

• • • • • • • • • • • • •

Biotin Folic acid Niacin Pantothenate Riboflavin Thiamine Vitamin A Vitamin B6 Vitamin B12 Vitamin C Vitamin D Vitamin E Vitamin K

• • • • • • • • • • • • • • •

Calcium Chromium Cobalt Copper Fluoride Iodine Iron Magnesium Manganese Molybdenum Phosphorus Potassium Selenium Sodium Zinc

(γ glutamyl-carboxylase, vitK quinone reductase and vitK epoxide reductase)

• Linolenic acid/DHA [ω-3] • Linoleic acid [ω-6]

Coagulation Factors

• Isoleucine

Other Proteins

• Leucine • Lysine

F2 (Prothrombin) F7 F9 F10 (Anticoagulant protein C)

• Methionine • Phenylalanine • Threonine • Tryptophan • Valine • Histidine

5 Lethal KO

• Choline

Osteocalcin Gas 6 protein Matrix Gla protein TGFBI Periostin (Anticoagulation Protein Z) 6 nonlethal KO

Four Causes of Functional Deficiency of VKDProteins in Humans

Natto

McCann & Ames (2009) Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? Am J Clin Nutr 90,889-907.

39

4

A Diet for Health and Longevity: How Do We Get There?

Bruce Ames, PhD

An overview of evidence for a causal relationship between iron deficiency during development and cognitive or behavioral function in children

Is docosahexaenoic acid, an n3 long-chain polyunsaturated fatty acid, required for development of normal brain function? An overview of evidence from cognitive and behavioral tests in humans and animals Joyce C McCann and Bruce N Ames American Journal of Clinical Nutrition (2005) 82:281-95

Joyce C McCann and Bruce N Ames (2007) AJCN

Neurons Contain The Enzyme That Activates Vitamin D Is there convincing biological or behavioral evidence linking Vitamin D deficiency to brain dysfunction?

Joyce C McCann and Bruce N Ames Faseb J 22, 982-1001 (2008)

21 30

Eyles, DW et al (2005) J Chem Neuroanat 29,

Immune Risk Phenotype of Aging

Calcitriol Target Genes in the Brain� Gene products whose expression in the brain or brain cells has been reported to be affected by calcitriol �

Lower CD4 and CD8 T-lymphocytes

Neurotrophins and other growth factors: � NGF; NT-3 & NT-4/5; GDNF; TGF-β2�

Increase in anergic effector (CD8+CD28-) T-cells

Calcium-binding proteins:� � Calbindin D28K, parvalbumin, calretinin;�

Protein sub-units for L-Type Voltage Sensitive Ca++Channels (L-type VSCCs); �

Low lymphoproliferative response

Transcription factors or enzymes involved in signal transduction pathways: � N-myc, c-myc, protein kinase C family (PKC);�

Other enzymes: � Choline acetyltransferase, responsible for synthesis of the neurotransmitter acetylcholine; � � �-Glutamyltranspeptidase, involved in recycling of the reactive oxygen species scavenger glutathione);� Hormones:� � [Oxytocin, the “trust hormone”]

Decline in antigen-presenting cells Decreased expression of co-stimulatory molecules

Biochemical or cellular brain functions in which calcitriol target gene products are involved�

Decline in IL-12 production and Th1 response

Synaptogenesis (formation of synaptic connections); Synaptic plasticity (e.g., memory formation); Calcium signaling and homeostasis; Neurotransmission and neurotransmitter synthesis; Survival and differentiation of dopaminergic and other neurons; Control of toxic free radicals;� Behavior affected by target gene product dysfunction� Learning and memory; Motor control; Maternal or social behavior; Aging (neuronal density);�

40

5

A Diet for Health and Longevity: How Do We Get There?

Bruce Ames, PhD Immune Risk Phenotype of Aging epithelial barrier barri barr bar arr er arr a

Lower CD4 and CD8 T-lymphocytes Def: vit A., zinc Increase in anergic effector (CD8+CD28-) T-cells Def: tryptophan, zinc, Low lymphoproliferative response Def: vit C, vit E, zinc. Vit B6 Decline in antigen-presenting cells Def: vit E Decreased expression of co-stimulatory molecules Def: vit E, tryptophan. zinc Decline in IL-12 production and Th1 response Def: vit B6, Vit E, zinc

(Courtemanche et al (2004) J Immunol 173:3186)

Variation in chromosomal DNA damage rates within and between age groups measured as MNC frequency.

Healthy Non-smoking Males

Healthy Non-smoking Females

The Economist, December 13, 2003

Fenech 2007, Forum Nutr.

1. Regular soft drinks 2. Pizza 3. Beer 4. Hamburgers, meat loaf 5. White bread 6. Cake, doughnuts, pastries 7. French fries, fried potatoes 8. Potato chips, corn chips, popcorn 9. Rice 10. Cheese or cheese spread

% total energy 8.8 5.1 3.9 3.4 3.3 3.3 3.0 2.7 2.6 2.5 38.6%

NHANES III (1988-1994) Wakimoto P & Block G. J Gerontol A Biol Sci Med Sci, 2001

Dr. Allen Spiegel, NIDDK/NIH

41

6

A Diet for Health and Longevity: How Do We Get There?

Bruce Ames, PhD

CONCLUSIONS 1. Moderate micronutrient deficiencies are widespread.

2. Triage theory postulates that moderate micronutrient deficiencies can lead to accelerated aging and age-related diseases.

3. RDAs and EARs should be re-examined on the basis of triage theory, which would put nutrition on a firm foundation.

4. The optimum intake of micronutrients will vary among people due to polymorphisms.

GOALS • Bring the world’s population up to optimal intake with inexpensive micronutrients.

CHORI Bar • convenient • complete

Conventional • cumbersome • compliance • incomplete

• Identify people who need increased intakes of micronutrients due to polymorphisms.

Life Expectancy of Men and Women at Birth 80

77.5

75

71.1

70 65.7 65.6

74.9

73.2 66.7

78.9 71.4

67.1

69.9

65 58

60

61.3 61.4

56.3

55 49

50

53.6 50.1

54.5

46.4

“You’re fty-seven years old.

I’d like to get that down a bit.”

45 40

1900

1910

1920

1930

1940

1950

1960

1970

1980

1990

SOURCE: National Institute on Aging

Nutrition & Metabolism Center Scientists

Jung Suh

Joyce McCann

END

Swapna Shenvi Bruce Ames David Killilea

Ash Lal Michele Mietus-Snyder

Mark Shigenaga

Sandy Calloway

42

7

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD

Iodine: The Synergistic Importance of an Underutilized Nutrient

David Brownstein, M.D. Center for Holistic Medicine 5821 W. Maple Rd. Ste. 192 West Bloomfield, MI 48322 248.851.1600 www.drbrownstein.com

Medical Iodophobia

Edgar Cayce

“Medical iodophobia is the unwarranted fear of using and recommending inorganic, nonradioactive iodine/iodide within the range known from the collective experience of three generations of clinicians to be the safest and most effective amounts for treating symptoms and signs of iodine/iodide deficiency (12.550mg/day).”

“There are only four elements in the body: water, salt, soda and iodine.”

“If we have adequate amounts of these four elements in balance, the body is fully capable of creating all other elements in the universe.”

Dr. G. Abraham, 2004

Thyroid Nodules and Iodine

Periodic Table

• Both benign and malignant thyroid nodules have significantly less iodine than normal thyroid tissue Benign thyroid nodules contain 56% of the iodine content as compared to normal thyroid tissue Malignant thyroid nodules contain 3% of the iodine content as compared to normal thyroid tissue Analyst. March 1995, Vol. 120

43

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD

RDA for Iodine

History of Iodine

Life Stage

• First discovered in 1811 • Birth of western medicine • Boussingault (1824) observed that goiter did not occur at many silver mining sites • The use of iodine for treating goiter was the first time that a single item (iodine) was used to treat a specific illness (goiter)

National Health and Nutrition Survey

Adult Male

150µg/d

Adult Female

150µg/d

Pregnancy

220µg/d

Lactation

290µg/d

National Health and Nutrition Survey • 1971-2000 NHANES showed iodine levels declined 50% in the United States • During this time, increased incidence of:

Urinary iodine levels µg/dl

• 1971-2000 NHANES showed iodine levels declined 50% in the United States

RDA

• Thyroid illnesses (hypo, autoimmune, cancer) • Cancers of the breast, prostate, endometrium and ovaries 1970

• All of the above conditions can be caused by iodine deficiency.

2000

CDC

National Health and Nutrition Survey

NHANES 2000

( 2)

• The proportion of the U.S. population with moderate to severe iodine deficiency (<50ug/L in urine) has increased over 400% in the last 20 years

• 16.8% of U.S. women of childbearing age had urinary iodine concentrations <50µg/L

• 2.6% NHANES I vs. 11.7% NHANES 3.

Thyroid 15:692-9.

2005

NHANES CDC

44

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD

Severe Iodine Deficiency in U.S. From 1970-2005 • • • •

1970: 1990: 2005: 2010:

“More than 70% of women with access to dietary iodine may remain at risk for unrecognized iodine deficiency during pregnancy.”

2.6% 11.7% 16.8% ????

FP News.

11.13.08

The Importance of Ensuring Optimal Prenatal Iodine Intake

The Importance of Ensuring Optimal Prenatal Iodine Intake

(2)

(1)

• Three groups of children • Group 1: Supplemented with KI (200ug/day) at 4-6 weeks gestational age.

• Group 2: Supplemented with KI (200ug/day)at 12-14 weeks gestational age • Group 3: No iodine supplementation during gestation.

Supplemented with 200ug/day after delivery All groups supplemented with KI until end of lactation.

All children given a neurocognitive evaluation at 18 months of age Thyroid.Vol. 19. N. 5. 2009. 511-519

The Importance of Ensuring Optimal Prenatal Iodine Intake

Thyroid.Vol. 19. N. 5. 2009. 511-519

The Importance of Ensuring Optimal Prenatal Iodine Intake

(2)

Thyroid.Vol. 19. N. 5. 2009. 511-519

(2)

Thyroid.Vol. 19. N. 5. 2009. 511-519

45

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD

Mean IQ

Why Iodine?

• Iodine deficiency is a worldwide problem • Mental impairment, reduced intellectual ability, ADD, autism • Goiter • Infertility • Increased risk of breast, prostate, endometrial, ovarian and other cancers

I Q

Delayed neurobehavioral performance was observed in 36% of children in group 3 and 25% of children in group 2 and none in group 1. “A delay in 6-10 weeks in iodine supplementation of hypothyroxinemic mothers at the beginning of gestation increases the risk of neurodevelopmental delay in the progeny.”

Thyroid.Vol. 19. N. 5. 2009. 511-519

Breast Milk Iodine

Newborn Thyroid Gland • Only holds a 24 hour reserve of iodine

• 47% of women sampled may be providing insufficient iodine to meet infants’ requirements

• Fresh sources must be supplied in diet

Biochimie 1999, 81, 563-570 J. Pediat. Endocrin. Metabl. 2003, 16,521-28

J. Clin. Endocr. And Metab. 92: 1673-77

Milk and Iodine

Breast Milk and Iodine • 13 breast feeding women

• Between 1965 and 1980, U.S. milk iodine content increased by 300-500%

• Milk

• 12/13 (92%) had inadequate iodine in breast milk • 9/13 (69%) samples high in perchlorate

• Changes in cattle feeds

• 1986, amount of organic iodine ethylenediamine dihydroiodine (EDDI) in cattle limited to 10mg/cow/day

“…we were…dismayed to note that while little of the maternal iodine (21%) finds its way to milk, the bulk of the perchlorate intake ends up in milk.”

Env. Sci. and Tech. Vol. 42. No. 21. 2008

J. Am. Vet. Med. Assoc. 176:1119-1121

46

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD

Iodine Content of U.S. Dairy Whole Milk

Rapeseed and iodine

• 1978: 602µg/L • 1990: 155µg/L • Recent Measurements: <100µg/L

• When rapeseed fed to cows, milk iodine resulted in an increased thiocyanite level • Milk iodine reduced by 17%

• Similar results have been shown in pigs

Environm. Sci. Techn. 2003, 37, 4979-4981 Environ. Sci. Techn. 2005, 39, 2011-17 J. Dairy Sci. 1990. 73, 3421-3427

Br. J. of Nutr. 85:659-70. 2001 Nat. Inst. of Animal Science. Foulum, Denmark. 1995

Why Iodine?

Why Iodine?

• WHO claims iodine deficiency is the world’s greatest single cause of preventable mental retardation • WHO estimates that there are 300,000,000 school-aged children worldwide who are iodine deficient • Over half of the population of Europe live in areas of iodine deficiency • 1/3 of the world’s population live in an iodine deficient area

• 100 consecutive healthy pregnant Bostonians • 50% found to be below the RDA 220 µg/day • 9% below 50 µg/day • WHO recognizes as severe iodine deficiency

• 129 countries • Decreased childhood survival rate in iodine deficient areas • Neonatal mortality declines over 50% when iodine deficiency is rectified

• 72% of world’s population is affected by iodine deficiency

WHO J. Clin. Endocrinand Metabl. 2007;92:437-442 Anderson, M. 2007 Iodine deficiency in Europe: a continuing public health problem. Geneva: WHO. 2007.

Thyroid 2004;14:327-8

Iodine and Autism

Iodine and ADD

• As similar to the U.S., a pattern of iodine decline in a population and a concomitant increase in autism has been seen in other countries

• 16 women from iodine-deficient area of Italy compared to 7 women from higher iodine area • Pregnancy

• England, New Zealand, Australia, Italy

• Women from iodine deficient area had: • Reduced T4, decrease of FT4 with elevated TSH in 50% of pregnant women

BMJ. 2004;328:227 Arch. Des. Child. Fetal Neonatal Ed. 2004. Sep;89(5):F436-9 Med. J. Aust. 2003;178(4):159-162 Asia Pac. J. Clin. Nutr. 2003;12. Suppl. S15 BMJ Letters. 10.13.04. http://bmj.com/cgi/eletters/328/7433/226-c

Clin. Endocr. 1995 APrl.;42(4):409-15

47

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD

Iodine and ADD

Iodine and ADD • 16 Women living in a iodine-deficient area versus 11 women living in an iodine-sufficient area • 10 years follow-up • ADHD diagnosed in 11/16 in iodine-deficient area versus 0/11 in iodine-sufficient area • IQ lower in iodine-deficient area-- 88 versus IQ of 99 in iodine-sufficient area

“It is hypothesized that the imbalance of maternal thyroid hormone homeostasis during pregnancy as a consequence of endemic iodine deficiency may be responsible for the impaired psychoneurological development observed in children from that area.

Appropriate iodine and/or thyroxine prophylaxis to women in that region may prevent the neurobehavioral, cognitive and motor compromise of that population.”

J. Clin. Endocr. 12/04

Clin. Endocr. 1995 APrl.;42(4):409-15

Cholesterol and Iodine

CAD: An Underlying Mechanism

• 1918, researchers demonstrated that feeding iodine to rabbits could prevent the deposition of cholesterol in arteries of rabbits that were fed cholesterol.

(1)

• Researchers looked at the development of atherosclerosis in rabbits • Control group: Rabbits fed high cholesterol diet • Treatment group: Rabbits fed high cholesterol diet and treated with:

Trans. Jpn. Path. 8:221-4, 1918.

• T4 • Desiccated thyroid • Iodine

• These studies were reproduced and similar results reported in the literature four times.

Arch. Exp. Pathol. Pharmokol. 159:265-274, 1931 Z. Gesamte. Exp. Med. 87: 683-702, 1933 J. Exp. Med. 58: 115-25, 1933 Res. Commun. Chem. Pathol. Pharmacol. 1:169-184, 1970

CAD: An Underlying Mechanism

High Cholesterol Diets Can Exacerbate Iodine Deficiency

(2)

• Control rabbits fed cholesterol developed marked aortic atherosclerosis • Rabbits fed cholesterol-rich diet and T4 showed slight to moderate aortic atherosclerosis • Rabbits fed cholesterol-rich diet and either desiccated thyroid or iodine showed an absence of atherosclerotic lesions

• Rats • Iodine deficient diet vs. Iodine sufficient diet • Iodine sufficient diet resulted in a much lower thyroid weight (43.4 v. 10.3mg).

When the rats were fed a high cholesterol diet, thyroid weight significantly increased in both groups. The high-cholesterol diet was also found to increase the body’s excretion of iodine.

This study showed that iodine has an independent positive benefit in a cholesterol-rich diet as well as a synergistic effect with desiccated thyroid hormone.

Metabolism. 15;714-9. 1966

J. Exp. Med. 58: 115-25, 1933

48

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD

Iodine and Cholesterol Levels

Iodine, Cholesterol and CAD

• 136 Subjects • Iodine intake and lipid parameters • Compared to iodine sufficient, non-goiterous controls, iodine-deficient goiterous subjects:

(1)

• Keys (1958) published data that countries with the highest cholesterol levels had the highest rate of cardiovascular disease • Finland had the highest rate of CAD mortality in Europe

Significantly higher average cholesterol levels and LDL cholesterol levels.

• More prevalent in Eastern Finland vs. Western Finland

WHY?

Lancet. 2:175-78. 1958

Klin. Pediat. 208:123-8. 1996

Iodine, Cholesterol and CAD

Finland and CAD: 1970

(2)

• Researchers looked at a variety of dietary components

• Researchers looked at prevalence of cardiovascular diseases in 21 Finnish cities as it related to trace elements in drinking water

• Proteins, fats, carbohydrates, lipids, amino acids, vitamins and minerals • 47 different items studied

• Calcium, chlorine, fluorine, bromine, and iodine • Angina, coronary thrombosis, hypertensive diseases and atherosclerosis

Iodine intake showed the greatest statistical difference between Eastern and Western Finland

The strongest correlation was iodine. The highest intake of iodine associated with the lowest rates of cardiovascular disease.

Risk of death from CAD was 353% higher in individuals with goiter.

There was also a significantly lowered death age in those with goiter.

Ann. Med. Exp. 48: 117-121. 1970

Lancet.2:171-3. 1958

Finland, Mortality and CAD

Iodine and Lipid Profile • • • • •

• Finland increased iodine intake in its population • Added to dairy feed • Added to animal salt

262 (5-14 year old) children in Morocco Iodine deficient area Elevated TSH (>2.5mU/L) 400mg iodine (oral iodized oil) After 6 months: • Decreased TSH • Decreased C-peptide • LDL/HDL fell from 3.3 to 2.4

In the past several decades, cardiovascular mortality has decreased by over 50% and life expectancy has increased by 5 years. Finland currently has the highest iodine intake of any European country.

“Correction of iodine associated subclinical hypothyroidism improves the insulin and lipid profile and may…reduce risk for cardiovascular disease.”

Prev. Med. 29:s124-9. 1999

Thyroid. Vol. 19. 2009. Released ahead of publication. DOI:10.1089/thy.2009.0001

End. Exp. 20:35-47. 1986

49

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD

Why Iodine?

• Only 28% of prescription prenatal vitamins contain iodine • Average iodine content of I-prenatal vitamins was found to be below the RDA for I (119µg) • Of the prenatal vitamins that do contain iodine, only 15% have more than 150µg of iodine per daily dose This is a public health disaster that is unparalleled!

FP News. 11.15.08

Why Iodine?

Iodine: Therapeutic Actions

• Elevates pH

• Alkalinizing agent • Antibacterial • Anticancer • Antifungal • Antiparasitic • Antiviral • Detoxifying agent • Mucolytic agent

• Alkalinizing agent

• Deficiency causes intellectual deficiency, goiter, hypothyroidism, autoimmune thyroid illness, thyroid cancer and other cancers • Production of thyroid hormone • T4, T3, T2, T1

• Necessary for the production of all the hormones of the body • Adrenals, ovaries, testicles, etc.

• Iodine also responsible for formation of normal architecture of the glandular tissue • • • •

Breast Thyroid Ovary Prostate?

Conditions Treated/Prevented With Iodine • • • • • • • • • • •

Different Forms of Iodine

• Infections • Keloids • Liver Diseases (Enterohepatic Circulation) • Nephrotic Syndrome • Breast, ovaries, prostate, thyroid • Ovarian Cysts • Parotid Duct Stones Cerebral Palsy • Peyronie’s COPD • Pre-eclampsia Diabetes • Sebaceous Cysts Dupuytren’s Contracture • Thyroid Disorders Excess Mucous Production • (hypo, autoimmune and cancer) Hypertension ADD Asthma Atherosclerosis Breast Disease Cancer

• Iodine is not very soluble in water • Dr. Lugol (1829) found that when potassium iodide added to water increased the solubility of iodine • Lugol’s solution: 5% iodine and 10% potassium iodide in distilled water • 2 drops of Lugol’s solution contains 5mg of iodine and 7.5mg of iodide

50

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD

Lugol’s Solution

Iodine Content of Desiccated Thyroid

• Widely available at most apothecaries • Recommended for almost any condition

0.17-0.23% Iodine

• Infection

1 Grain of Desiccated Thyroid Contains: 0.20% x 60mg = 120µg I

• Probably the most used medical item before patent medicine took hold

Martindale’s European Drug Index

RDA for Iodine Life Stage

Iodide and Iodine RDA

Adult Male

150µg/d

Adult Female

150µg/d

• Iodine is rare element • 62nd in abundance of the elements of the earth • Bottom third of elements in terms of abundance

• Reduced form of iodine is known as iodide Pregnancy

220µg/d

Lactation

290µg/d

• Extra electron • Full complement of electrons

Iodine/Iodide Bind to Different Areas of Body Iodine

Iodide

Breast

Thyroid

Prostate

Salivary Glands Skin

Stomach

51

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD

Where is Iodine Found in the Body?

How Much Iodine Stored In The Body?

• Every cell in the body contains and utilizes iodine

• Na/I Symporter transports I across the cell membrane, against gradient

• WBC’s cannot effectively guard against infection without adequate amounts of iodine

• Maximum ≈600µg/day I in thyroid gland

• Concentrated in the glandular system • Thyroid gland contains the largest concentration of iodine (50mg adult saturation) • Breasts, salivary glands, parotid glands, pancreas, cerebrospinal fluid, brain, stomach, skin, lacrimal glands, etc.

How Much Iodine Stored In The Body?

First U.S. Iodine Studies • David Marine

• Approximately 1.5-2gm stored in body at sufficiency

• Looked at iodine results in farm animals • Estimated amount of iodine necessary to treat humans

• Fat tissue: 700mg • Striated tissue: 650mg • Thyroid: 50mg

• Akron, Ohio • 56% of school-aged girls had goiter • Higher incidence at puberty • 600% increase in girls versus boys

Every organ and all tissues contain iodine

First U.S. Iodine Studies: Results

First U.S. Iodine Studies: D. Marine Two groups of school-aged girls

Control Group

Treatment Group

• 2305 Students • No iodine given

• 2190 Students • 9mg iodine (averaged daily dose) for 2.5 years

Control Group • 22% goiter • 495 cases/2305 • No Iodine Given

Over 100x RDA for iodine!

52

Treatment Group • 0.2 % incidence of goiter • 5 cases/2190 • 9mg/day Iodine

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD

Michigan Studies • 1900’s goiter was prevalent in large numbers around Great Lakes • 40% of school aged children had goiter

• 1924 iodized salt introduced to the area • By 1928, goiter decreased 75% • United States quickly added iodide to salt for the rest of the country.

How Do You Ingest Iodine?

Iodized Salt

• Trace element, not very common in most foods • Ocean foods

• 1831 J.G. Boussingault proposed iodized salt to prevent goiter • 1920’s iodization of salt implemented in the U.S. to prevent goiter

• Cod, sea bass, haddock, perch • Sea Vegetables such as seaweed

• Can be found in food products if iodine is added to animal feed or the food source • Salt

Iodized Salt

Iodized Salt: Low Bioavailabilty

• Potassium iodide

• 2 Groups

• 74µg iodide/gram of salt

• Group 1: Iodized salt • Group 2: Iodized bread

• Cost effective way to prevent goiter

• ≈750µg/day iodide in both groups

• Effective tool to decrease the presence of goiter • Inadequate to provide the body’s need for iodine

Expected result: 17.2µg/L (Serum)

Pittman NEJM 1969; 280:1431

53

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD

• 1971-2000 NHANES showed iodine levels declined 50% in the United States

Only 10% of iodine in salt is bioavailable

Urinary iodine levels µg/dl

National Health and Nutrition Survey

Iodized Salt: Low Bioavailability

1970

Is this because of competitive inhibition by chloride in salt?

2000

So, who would still recommend iodized table salt?

CDC

Pittman NEJM 1969; 280:1431 Abraham, G. 2004

Center for Holistic Medicine

Iodine Deficiency: CHM

• 94.7% of patients tested had significantly low iodine levels

• Over 5,000 patients tested

Results: 96.4% have tested low via urine or serum testing.

• First 250 patients

Iodine in Food

Why the Soil is Deficient in Iodine

Food Ready to eat Cereal Dairy-based desert Fish Milk

• More inland and mountainous areas • Midwestern United States • Great Lakes Basin • Michigan, Ohio, Indiana, Wisconsin

• Soil Erosion • Glaciers • Deforestation • Poor farming techniques

Overall diary products

Eggs Bread Beans, peas, tuber Meat Poultry

• Pollution • Pesticides and insecticides • Bromide, fluoride and chlorine • National/worldwide problem

54

µg/iodine/serving 87 70 57 56 49 27 27 17 16 15

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD National Health and Nutrition Survey

• Stigma of using salt • Hypertension • <50% of U.S. households use iodized salt

• Radioactive iodine use in medicine Urinary iodine levels µg/dl

• 1971-2000 NHANES showed iodine levels declined 50% in the United States

Why Are People Deficient in Iodine?

• Exacerbate an iodine-deficient state

• Chemical exposures: Goitrogens • Bromine, Chlorine and Fluoride (fluorine) • Drugs • Fluoride, bromide • Competitively inhibit iodine binding as well as decrease iodine uptake

• Declining mineral levels • Soil erosion, poor farming techniques, etc.

• Diet.

Why?

Soy: Goitrogen • Contains compounds that inhibit TPO • Daidzein and genestein • When low iodine levels present, soy compounds block TPO-catalyzed tyrosine iodination by acting as alternate substrates producing mono-, di-, and triiodoisoflavones • Further worsens iodine deficiency • Can occur with low or intermittent doses of iodine

Biochem. Pharmacology. Vol. 54. 1997 1087-96

Dietary Reasons for Iodine Deficiency

What Happened to Bakery Products?

• Diets without ocean fish or sea vegetables • Inadequate use of iodized salt including low sodium diets • Vegan and vegetarian diets • Bromine in food and drink

• 1960’s iodine was added to bakery products as a conditioning agent • 1 slice of bread contained the RDA for iodine: 150µg

• Brominated vegetable oils

• In the 1970’s, bromine was substituted for iodine due to misinformation about iodine

• Some Gatorade products, Mountain Dew and other soft drinks

• Bakery products • Bread, pasta, cereal, etc.

What did this substitution do?

• Contain bromine

55

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD

Bromine

Bromine for Iodine: Double Wammy!!

• Toxic substance with no known value in the body • Family of halides

1. Worsened an iodine-deficiency problem already present in the United States 2. Competitively inhibited iodine in the body by adding a goitrogen (bromine) to bakery products

• Iodine, fluorine, chlorine

• All halides compete with one another • Absorption • Receptor binding

• Bromine interferes with iodine utilization in the thyroid as well as other areas of the body

This could be the most asinine act (amongst many) in the history of the food industry.

• Goitrogen • Breast, prostate, etc.

Halogens MW

• • • • •

Fluorine (Fluoride) Chlorine (Chloride) Bromine (Bromide) Iodine (Iodide) Astatine (Astatide)

19 36 80 127 210

Halogens MW

Fluorine

Chlorine

Bromine

• • • • •

Iodine

56

Fluorine (Fluoride) Chlorine (Chloride) Bromine (Bromide) Iodine (Iodide) Astatine (Astatide)

19 36 80 127 210

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD

Bromine

Pesticides and Bromine

• Animal studies show that bromine intake can adversely affect the accumulation of iodine in the thyroid and the skin • High bromide intake results in iodine being eliminated from the thyroid gland and replaced by bromine • Ingestion of bromine has been shown to cause hypothyroidism in animals

• Pesticides contain organic bromine The amount of bromine in human breast milk has increased 10 fold over the last decade (EPA 2003).

When iodine deficiency is present, the toxicity of bromine is accelerated in the body.

How Much Iodine Stored In The Body?

Iodine Transport

• Thyroid: ≈50mg/day • Breasts: Minimum of 5mg/day(50kg or 110# woman) for maintenance of normal breast tissue

To achieve the maximum transport of iodine ≈600µg/day across the cell membrane, there must be sufficient iodine in the serum: ≈10-5-10-6 M

• Larger woman or woman with larger breasts will have increased requirement • Men have smaller breasts and a lower iodine requirement

These numbers are impossible to reach at the RDA (150µg/day) for iodine!

• Other glandular tissue: Minimum of 2mg/day

However, 50mg/day iodine/iodide can reach a 10-5 M!

• Adrenals, thymus, ovaries, hypothalamus, pituitary and others.

Where is Iodine Found in the Body?

How To Check Iodine Levels

• Every cell in the body contains and utilizes iodine

• Blood levels • Saliva

• WBC’s cannot effectively guard against infection without adequate amounts of iodine

• Saliva/serum

• Concentrated in the glandular system

• Skin testing

• Thyroid gland contains the largest amount of iodine • Breasts, ovaries, salivary glands, parotid glands, pancreas, cerebrospinal fluid, brain, stomach, skin, lacrimal glands, etc.

• Rub iodine on skin and observe for its’ disappearance • Inaccurate measure of body’s iodine status • Approx. 88% of I evaporates from skin •

J. Pharm. Exp. Therap. 1932;45:85-107

• Urinary excretion • Accepted measure • Iodine loading test

57

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD

35 Serum inorganic iodide levels (mg/L)

Iodine Loading Test • FFP Lab • www.ffplabs.org

• Hakala Lab • www.hakalalab.com

30 = Mean of 6 normal female subjects = Patient with Grave’s Disease Prior to intervention – % iodide load excreted = 90% – Baseline serum iodide = 0.016 mg/L

v

hrs Time Post ingestion of Iodoral® 50 mg load Fig. 1

Serum inorganic iodide levels (mg/L)

Serum inorganic bromide levels (mg/L)

but

24 hr urine bromide level = 192 mg

Serum profile of inorganic iodide levels following the iodine/iodide load (50 mg) in 6 normal female subjects; and in a patient with iodide transport defect. Patient excreted 90% of the iodine load, her basal serum inorganic iodide level was very low at 0.016 m/L. This pattern suggests a defect in the iodine retention mechanism.

= Mean of 6 normal female subjects = Patient with iodide transport defect Post 3 months Vitamin C 3g/day – % iodide load excreted = 49.2% – Baseline serum iodide = 0.42 mg/L

v

hrs Time Post ingestion of Iodoral® 50 mg load

hrs Time post ingestion of Iodoral® 50 mg load

Fig. 2

Serum profile of inorganic iodide levels following the iodine/iodide load (50 mg) in 6 normal female subjects; and in a patient with iodide transport defect following 3 months of intervention with a sustained release Vitamin C at 3 gm/day. She excreted 49.2% of the iodine load and the baseline serum level was 0.42 mg/L, evidence of improved function of the iodine cellular transport mechanism.

Iodine Transport Problems

How to Dose Iodine

• When problems develop with iodine use, think detoxification • • • • • •

• Use a combination of iodine/iodide • Lugol’s Solution

Vitamin C Salt Water Liver and kidney support Exercise Clean Diet

• 1 drop: 6.25mg (2.5mg iodine /4mg iodide)

• Iodozyme • 1 capsule: 12.5mg (5mg iodine/7.5mg iodide) Therapeutic doses of iodine/iodide combinations vary between 6-50mg/day.

58

Iodine: The Synergistic Importance of an Underutilized Nutrient David Brownstein, MD

How Much Iodine Should You Take?

Amt. Iodide Ingested (12 days) 10mg

% Uptake Radioactive Iodide by Thyroid 4%

15mg

1.9%

30mg

1.6%

50mg

1.2%

100mg

0.6% Sternthal. N. .Eng. J. Med. 303:1083-1080. 1980

Iodine Dosage Guidelines • • • •

Final Thoughts • Iodine deficiency is common • Not rectified by the use of iodized salt • Iodine deficiency may be the underlying cause of autoimmune thyroid disorders • Using a combination of iodine/iodide more effective than using iodide alone • Best results achieved with a holistic approach

RDA is 150µg/day RDA is inadequate to supply the body’s need Dosage must be individualized Use a combination of iodine and iodide • Iodozyme HP Biotics: 800.437.1298

• Vitamins and minerals, diet, detoxification, hormone-balancing, etc.

• Magnesium supplementation • Electrolyte supplementation

• Appropriate testing pre and post

Final Thoughts

end

(2)

• Impossible to balance the hormonal system without iodine sufficiency • Thyroid and adrenals

• Whole body iodine sufficiency generally requires higher doses of iodine/iodide combinations • 12-50mg/day

59

Integrative Cancer Care: The InspireHealth Experience and Site Specific Immunotherapy Hal Gunn, MD What We Do

InspireHealth

• We help people with cancer integrate the concepts of health, healing and immune system support into cancer treatment and recovery.

• Integrative Cancer Care Centre • Founded in 1997 as the Centre for Integrated Healing • Four physicians (M.D.s) and a variety of integrative practitioners • Over 5,000 cancer patients served to-date • Current capacity of 650 new cancer patients per year

Foundations of Health and Healing Conventional Medical Therapies Complementary Therapies Vitamins and Supplements Sleep, Rest and Relaxation Exercise Healthful Water Healthful Diet Avoidance of Physical Toxins Stress Reduction Emotional Connection Body-Mind Awareness Personal Autonomy Joy and Laughter Spiritual Connection Hope Will to Live

60

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Integrative Cancer Care: The InspireHealth Experience and Site Specific Immunotherapy Hal Gunn, MD

Lowering the Risk of Recurrence for Breast Cancer

LOW-FAT DIET (RCT) (lowered fat from 29% to 20% of calories)

All women 24% lower risk Estrogen receptor negative 42% lower risk Chlebowski RT, Blackburn GL, Thomson CA, et al. Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study. J Natl Cancer Inst 2006;98(24):1767-76.

Lowering the Risk of Recurrence for Breast Cancer EXERCISE

Reversing Rising PSA in Early Prostate Cancer HEALTHY LIFESTYLE CHANGES

(physical activity equivalent to 1 hour of brisk walking)

1 hour per week 3 to 5 hours per week 5 hours per week

20% lower risk 50% lower risk 44% lower risk

Vegetarian diet Exercise Meditation

RCT

•

Control group:

average 6% rise PSA 1 year.

6 of 46 men progressed to surgery/radiation.

•

Treatment group:

average 4% decline PSA 1 year.

None of the men progressed to

surgery/radiation.

• Journal of the American Medical Assoc.; 2005, May 25;293(20):2479-86.

Growth of LNCaP prostate cancer cells inhibited 70% by treatment group serum vs. Only 9% by control group serum.

Journal of urology, 2005, 174:1065-1070

61

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Integrative Cancer Care: The InspireHealth Experience and Site Specific Immunotherapy Hal Gunn, MD Healthful Nutrition and Cancer Treatment

Obesity and Breast Cancer Recurrence

• Consumption of less meat, fat, refined grains and sugar is associated with a substantial reduction (70%) in recurrence and increased survival in patients diagnosed with colon cancer.

• After breast cancer diagnosis, women with obesity and high hip-to-waist ratio are almost twice as likely to develop breast cancer recurrence as women with normal weight and hip-to-waist ratio.

Meyerhardt, JA, D. Niedzwiecki, D. Hollis, et al. Association of Dietary Patterns with Cancer Recurrence and Survival in Patients with Stage III Colon Cancer. J Am Med Assoc. 2007 15 Aug; 2987: 754-764.

Healthful lifestyle reduces the risk of second primary contralateral breast cancer •

Healthful Lifestyle for Chronic Disease Treatment “In our studies, we found that people who already have heart disease or prostate cancer may slow, stop or even reverse its progression just by making intensive changes in diet and lifestyle. The more people changed their diet and lifestyle, the more improvement we saw.”

Obesity, consumption of ≥ 7 alcoholic beverages per week, and current smoking each increase risk of contralateral breast cancer: Obesity: Alcohol consumption: smoking:

40% greater risk 90% greater risk 220% greater risk

•

≥ 7 drinks/week + smoking = 700% greater risk

•

Li CI, Daling JR, Porter PL, Tang MT, Malone KE. Relationship Between Potentially Modifiable Lifestyle Factors and Risk of Second Primary Contralateral Breast Cancer Among Women Diagnosed With Estrogen Receptor-Positive Invasive Breast Cancer. J Clin Oncol. 2009 Sep 8.

“It costs less to eat and live healthfully. Walking, loving, and meditating are free and require no special equipment.”

Dean Ornish, M.D.

Failing to Provide Optimal Integrative Care

Emotional Support 227 patients newly diagnosed with Stage II and III breast cancer were randomized to:

• Only 15-19% of cancer survivors meet even the minimal standards for healthful diet (5 or more servings of fruit and vegetables per day).

Usual care or usual care plus a shared-learning group designed to reduce stress, improve mood and support healthful life-style behaviours (i.e., healthful diet, exercise and smoking cessation).

• Only 30-47% meet minimum activity targets.

These women were followed for a median of 11 years.

• Only 5% of cancer survivors meet minimum standards for diet, exercise and smoking.

Patients in the shared learning group were 45% less likely to have a recurrence and 56% less likely to die from breast cancer.

Anderson, B.L et al. Psychological Intervention Improves Survival for Breast Cancer Patients. Cancer Dec 15, 2008(113)12;3450-3458

62

3

Integrative Cancer Care: The InspireHealth Experience and Site Specific Immunotherapy Hal Gunn, MD Vitamin D and Cancer Prevention

Vitamin D and Cancer Treatment • Vitamin D level (blood) at the time of cancer diagnosis is highly correlated with survival.

Vitamin D supplementation reduces allcancer risk by 60%

• Patients in whom vitamin D levels were high were half as likely to have a recurrence or to die from their disease

(by 78%, if supplementation continued for more than 1 year)

•

Lappe, JM, D. Travers-Gustafson, K.M. Davies, R.R. Recker and R.P. Heaney. Am J Clin Nutr. 2007 Jun; 856: 1586-1591

•

Importance of Vitamin D

[1] Ng, K, J. A. Meyerhardt, K. Wu, et al. Circulating 25Hydroxyvitamin d Levels and Survival in Patients with Colorectal Cancer Journal of Clinical Oncology. 2008 Jun 20; 2618: 2984-2991.

[2] Palmieri, C, T. MacGregor, S. Girgis and D. Vigushin. Serum 25Hydroxyvitamin D Levels in Early and Advanced Breast Cancer J Clin Pathol. 2006 Dec; 5912: 1334-1336.

Green tea and Ovarian Cancer Prevention

A recent review of the research concluded that raising the minimum year-around serum vitamin D level to 100-150 nmol/L would prevent approximately 58,000 new cases of breast cancer and 49,000 new cases of colorectal cancer each year, and three fourths of deaths from these diseases in the United States and Canada.

Such intakes also are expected to reduce casefatality rates of patients who have breast, colorectal, or prostate cancer by half.

Drinking at least 1 cup of green tea per day is associated with a 54% lower risk of developing ovarian cancer.

Consumption of green tea (> 2 gm/day) post-diagnosis is associated with substantially reduced recurrence and improved survival (recurrence and death decreased by 62%).

Coffee, Tea, Colas, and Risk of Epithelial Ovarian Cancer Song, YJ, A. R. Kristal, K. G. Wicklund, K. L. Cushing-Haugen and M. A. Rossing. Cancer Epidemiology, Biomarkers & Prevention. 2008 Mar; 173: 712-716.

Garland et al. Ann Epidemiol. 2009 Jul;19(7):468-83.

Green Tea and Ovarian Cancer Treatment

Tumour Microenvironment and Prognosis • The pattern of gene expression of tumour stromal cells are highly correlated with prognosis – more highly correlated than presence or absence of lymph nodes, tumour grade, use of chemotherapy or any other currently used prognostic indicator.

Consumption of green tea (> 2 gm/day) after diagnosis is associated with a 62% reduction in ovarian cancer recurrence and mortality.

Green tea consumption enhances survival of epithelial ovarian cancer Zhang M, Lee AH, Binns CW, Xie X, Int J Cancer. 2004 Nov 10;112(3):465-9

Finak, G et al, Stromal gene expression predicts clinical outcome in breast cancer.

Nature Medicine 14 ( 5) May 2008 518-27

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Integrative Cancer Care: The InspireHealth Experience and Site Specific Immunotherapy Hal Gunn, MD Opposing Roles of Tumor Associated Macrophages MACROPHAGES: TWO IMPORTANT ROLES



Tissue Repair - Matrix remodeling - Growth factor production - Angiogenesis - Chemokines/cytokines - Suppress immune function - Attract monocytes and other leukocytes - Coordinate tissue growth - Pro-inflammatory

TISSUE REPAIR

MACROPHAGE S

2010 PRESENTATION



Tissue Defense

- Tumor suppression and cytolysis

TUMOR-ASSOCIATED MACROPHAGES

- Promotion cancer growth - Inhibition immune response TUMOR

TISSUE DEFENSE

- Inhibition cancer growth - Tumor cell destruction

CHRONIC INFECTION/INFLAMMATION AND CANCER Chronic infection/chronic inflammation engages macrophages’ tissue repair mode, resulting in a vicious cycle that:

· Comprise a significant portion of tumor mass – up to 50% or more

1) Promotes cancer initiation and development 2) Suppresses immune function, including suppression of the immune function of: - Macrophages - Neutrophils - Cytotoxic T cells - Natural Killer cells - B cells

· Greater the density, the faster growing the tumor and the poorer the prognosis · More highly concentrated at the growing edges of tumors

Effect of Chronic Infection or Chronic Inflammation

MACROPHAGE S

- Promotion cancer growth - Inhibition immune response TUMOR

2010 PRESENTATION

Chronic infection or inflammation TISSUE REPAIR

64

Ben-Baruch A. Host microenvironment in breast cancer development: inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor-microenvironment interactions.

Breast Cancer Res 2003; 5:31.

5

Integrative Cancer Care: The InspireHealth Experience and Site Specific Immunotherapy Hal Gunn, MD ACUTE INFECTION AND RISK OF CANCER DEVELOPMENT History of acute infection decreases cancer risk:

2010 PRESENTATION

Engel: 2.5 – 46.2 RR Remy: 5.7 – 15.1 RR

Condelis J, Pollard JW. Macrophages: Obligate partners for tumor cell migration, invasion, and metastasis. Cell 124 Jan 27, 2006 263-6.

Effect of Acute Infection on Tumor Associated Macrophages

ACUTE INFECTION AND CANCER REGRESSION • Hundreds of published documented reports of remission of advanced cancer following acute infection e.g., Stephenson (1971): 224 cases

TISSUE REPAIR

• Three cases in my clinical practice: - Advanced pancreatic cancer - Advanced prostate cancer - Inoperable lung cancer

MACROPHAGE S

ACUTE INFECTION

TISSUE DEFENSE

• Acute infection during cancer treatment: effect on cancer recurrence and survival e.g., Ruckdeschel (1972): lung infection and lung cancer Papachristou (1979): wound infection and melanoma

TUMOR

- Inhibition cancer grown - Tumor cell destruction

Killed Bacterial Vaccines for Cancer Treatment Clinical Data: 

InspireHealth - Mixed Respiratory Vaccine (MRV) (n=750) - Polyvaccinum Forte Vaccine (PVF) (n=70) - Staphage Lysate Vaccine (n=1)

 Elsewhere - Coley’s toxins - BCG vaccine - Corynebacterium parvum vaccine - Nocardia rubra vaccine - Lactobaccilus casei vaccine - Pseudomonas Aeruginosa vaccine - Mycobacterium w and M. vaccae vaccines - Streptococcus pyogenes vaccine

65

6

Integrative Cancer Care: The InspireHealth Experience and Site Specific Immunotherapy Hal Gunn, MD Treatment of Inoperable Lung Cancer MRV Targeted Treatment of Lung Cancer: Case Report • In January 1994, Patient A (PtA) had a chest x-ray that revealed a large 7 cm x 8 cm mass in the apex of the right lung. A fine needle aspiration was positive for non-small cell lung cancer and an MRI showed invasion of the subclavian arteries making surgical resection impossible. PtA was diagnosed with stage 3B inoperable terminal lung cancer. She underwent a short course of palliative radiation and declined chemotherapy.

• On April 29, 1994, PtA began therapy with MRV vaccine three times per week, indomethicin (NSAID), and a regime of antioxidant supplements and vitamin D in addition to a healthful diet.

• By October 1995, the tumor had markedly reduced in size to 3 cm in diameter and, by May 19, 1998, after 4 years of MRV treatment, only residual scarring remained. · Today, more than 16 years since diagnosis with terminal lung cancer, PtA continues to feel well with no evidence of residual cancer.

Treatment of Breast Cancer with Metastases to Bone Staphage Lysate Targeted Treatment of Breast Cancer with Metastases to Bone: Case Report

SITE SPECIFIC IMMUNOTHERAPY HYPOTHESIS

• May 1989: Patient B (PtB) was diagnosed with stage 4 breast

A killed bacterial cell (or viral) injection stimulates macrophages within the organ or tissues in which that pathogen typically causes infection to cease their dysfunctional pro-cancer tissue repair functions and shift to their anti-cancer defensive role, resulting in an anti-cancer innate immune response within that targeted organ or tissue. 

cancer with multiple metastases to the bone. Treated with radiation and Tamoxefen.

• November 1993, she began treatment with Staphage Lysate 2010 PRESENTATION

(Staphylococcus aureus) vaccine, which she continued regularly for 5 years.

• PtB survived for more than 17 years after diagnosis with metastatic

breast cancer, passing away in June 2006.

2010 PRESENTATION

LUNG CANCER MOUSE MODEL: PHOTOGRAPH

2010 PRESENTATION

SKIN CANCER MOUSE MODEL: GROWTH KINETICS (MELANOMA)

66

Row 1: Mice treated with K. pneumoniae SSI (experimental group) Row 2: Mice not treated with SSI (experimental control group) Row 3: Lungs of normal mice (control group)

7

Integrative Cancer Care: The InspireHealth Experience and Site Specific Immunotherapy Hal Gunn, MD

TABLE 1: LUNG MOUSE MODEL: TUMOR NUMBER

TABLE 2: LUNG MOUSE MODEL: TUMOR WEIGHT INHIBITION Group SSI Median Weight Tumour Weight Inhibition (%)

Number of lung tumours each mouse

1

S. pneumoniae

1

S. pneumoniae

398.5

30

2

K. Pneumoniae cells+broth 0, 0, 1, 1, 2, 10, 50

1, 1, 7, 13, 20, 35, 38, 50

2

K. pneumoniae

231

73

3

S. aureus

1, 3, 5, 10, 15, 38, 43, 57

3

S. aureus

520

32

4

E. coli

0, 3, 3, 4, 9, 16, 42, 40

4

E. coli

301

57

5

S. enterica

0, 0, 2, 2, 5, 52, 57

5

S. enterica

245

66

6

S+K. pneumoniae

226

57

7

K. pneumoniae (cells only)

187

74

8

Experimental control (media only)

470

-

9

Control (healthy mice)

173

-

6

S. + K. pneumoniae

0, 0, 1, 5, 6, 8, 47, 48

7

K. Pneumoniae cells-only

0, 0, 0, 0, 1, 3, 46, 49

8

Experimental Control

2010 PRESENTATION

2010 PRESENTATION

Group SSI

2, 3, 12, 25, 26, 39, 39, 62, 78

2010 PRESENTATION

Mice/ Group

SSI

HUMAN USE PROGRAM: AUSTRIA

*MST (Days)

**ILS (%)

Number Cured

8

S. pneumoniae

27

12

0

8

S.aureus

30

25

2

8

K. pneumoniae

36

50

3

8

E.coli (colon isolate)

35

46

3

8

E. coli (prostate isolate)

>78

>100

4

8

S. enterica

>78

>100

5

12

Experimental Control

24

0

0

2010 PRESENTATION

TABLE 3: COLON MOUSE MODEL: SURVIVAL

p= 0.004

p= 0.004 *MST: Median Survival Time **ILS: Increase in Life Span compared to control



Program initiated in September 2008



Austrian oncologist, Dr. Ralf Kleef

 As of July 15, 2009, 64 patients with progressive metastatic cancer had been treated with SSIs  29 of these patients had begun treatment at least 3 months prior to July 15. These 29 patients were assessed by Dr. Kleef regarding objective response (tumor markers, scans) to Site Specific Immunotherapy

CHALLENGES FOR ASSESSMENT OF AUSTRIAN HUMAN USE PROGRAM • Given subcutaneously every second day

 Diversity of cancer types with progressive cancer; many with advanced metastatic terminal disease

• Dose gradually increased until 1-2 inch diameter pink/red reaction at injection site



Insufficient compliance in some patients

2010 PRESENTATION

2010 PRESENTATION

• No significant side-effects • Very safe • 2 months treatment to achieve clinical benefit • Minimum 6 months treatment for optimal benefit

67

8

Integrative Cancer Care: The InspireHealth Experience and Site Specific Immunotherapy Hal Gunn, MD

BEFORE TREATMENT: 9/2008

RECURRENCE MELANOMA

2010 PRESENTATION

2010 PRESENTATION

OBJECTIVE RESPONSE TO SSI TREATMENT

2010 PRESENTATION

12/2008

2010 PRESENTATION

11/2008

2010 PRESENTATION

END TREATMENT: 4/2009

2010 PRESENTATION

1/2009

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Integrative Cancer Care: The InspireHealth Experience and Site Specific Immunotherapy Hal Gunn, MD

DEVELOPING A PROMISING INNOVATIVE CANCER THERAPY

DEVELOPING A PROMISING INNOVATIVE CANCER THERAPY



Positive retrospective studies in lung cancer and colon cancer



Supportive published clinical research done elsewhere



Supportive epidemiological and laboratory research published elsewhere





Clinical treatment program initiated in Austria (Dr. Ralf Kleef) with promising early results



Very positive mechanism of action studies

 Preparation for a clinical trial well underway: to commence Q1 2011

SITE SPECIFIC IMMUNOTHERAPIES FOR CANCER PREVENTION

CLINICAL DEVELOPMENT PLAN – Phase I/II Trial

Childhood vaccination with smallpox vaccine is associated with a decreased risk of melanoma later in life, as well as significantly better survival in those who do develop melanoma. 

 Phase I/II trial in Canada in patients with inoperable lung cancer :randomized, double-blind, placebo-controlled, multi-center trial  Study Population. 75 patients to be recruited – 50 in the treatment arm and 25 in the placebo arm

2010 PRESENTATION

2010 PRESENTATION

5 SSIs manufactured to GLP standard

 Very positive results of animal studies (3 different tumor models): proof of principle 2010 PRESENTATION

2010 PRESENTATION

 Promising clinical results based on use in more than 800 cancer patients at InspireHealth

 Study Duration. 3.0 years (1.5 years recruitment, 1.5 years treatment)  Study Objective. To determine the safety and effectiveness of SSI therapy in addition to standard care in late-stage lung cancer versus standard care alone

 Cotton textile workers and dairy farmers, who are exposed to high concentrations of airborne bacteria, have a significantly reduced risk of developing lung cancer.  A history of acute viral gastroenteritis is associated with a reduced risk of subsequent development of colon cancer (no effect on nongastrointestinal cancers).

2010 PRESENTATION

SITE SPECIFIC IMMUNOTHERAPY 

Simple – can be done at home by the patient



Safe and side-effect free



Fully compatible with standard cancer therapies



Synergy with other cancer immunotherapies



Compelling clinical data



Very positive animal study data

Promising, potentially revolutionary approach to cancer treatment

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10

Secondary Plant Metabolites and Cytochome P450 Enzymes in Cellular Regulation Dan Burke, PhD Plant secondary metabolites  Attractants

Secondary Plant Metabolites and Cytochrome P450 Enzymes in Cellular Regulation

 Repellents

Professor Dan Burke

Image from University of Arkansas

Human CYP (cytochrome P450) enzymes

The pharmacological importance of natural compounds

Medicines & Poisons

“More than 60% of the world’s population relies entirely on

CYP1A 1 CYP1A 2 CYP1B 1 CYP2A 6 CYP2B 6 CYP2C 8

plants for medication. Of the 520 new drugs approved between 1983 and 1994, 39% were natural products, of which 60-80% were antibiotics and anti-cancer drugs from natural products. Of the 20 best-selling non-protein drugs in 1999, 9 were derived or developed as the result of leads generated by natural products.”  Cao Y., et al, J. Nutr. Biochem. (2002)13: 380-390

1012

total number 109 of cancer cells in body 106 (log scale) 103 101

CYP2C 9 CYP2C 19 CYP2D 6 CYP3A 4 CYP3A 5 CYP2E 1

fatal (1 litre tumour)

1012

total number 109 of cancer cells in body 106 (log scale)

detectable (1 cm3 tumour)

diagnosis

103

death

101

years

Eicosanoids, Fatty acids, Steroids & Vitamins CYP2G

CYP21

CYP7A

CYP2J

CYP8A

CYP24

CYP2R

CYP26 CYP27 A1 CYP27 B CYP51

CYP4F

CYP8B CYP11 A CYP11 B1 CYP11 B2 CYP17

CYP5A

CYP19

CYP2S CYP4A CYP4B

CYP46

fatal (1 litre tumour) detectable (1 cm3 tumour)

diagnosis

death years

*American Cancer Society 2007

70

1

Secondary Plant Metabolites and Cytochome P450 Enzymes in Cellular Regulation Dan Burke, PhD What to do ?  Many breast cancers found in routine screening

fatal (1 litre tumour)

1012

destined never to harm patients

total number 109 of cancer cells in body 106 (log scale)

 More old men die with prostate cancer than from it

detectable (1 cm3 tumour)

103

 Cancers growing slow & staying small not

diagnosis

101

always dangerous

death years

 But ... microtumours are always forming  Slow-down and kill some cancer cells every day

Breast cancer statistics (2004-2007; UK and USA)  26% of all female cancers  15% of all female cancer deaths  1st or 2nd cause of female cancer deaths

Breast Cancer

 5 yr survival :

98% if still localized in

breast 23% if widespread (metastatic)  Cancer Research UK and The American Cancer Society

Estrogen receptors (ER) in breast cancer

Estrogen receptors (ER) in breast cancer Stop estrogen production by: Surgical removal of ovaries; Chemical castration with Goserelin

ER negative : Cancer grows without estrogens

ER ER negativ positive e 25% 75%

ER ve Chemotherapy www.breastcancer.org (2009)

71

premenopaus al

ER

post+ve postmenopaus menopaus alal

Block estrogen action at ER with: Tamoxifen Fulvestrant _________ Block estrogen production with: Aromatase inhibitor – Anastrozole Exemestane

2

Secondary Plant Metabolites and Cytochome P450 Enzymes in Cellular Regulation Dan Burke, PhD Aromatase enzyme (CYP19) in breast cancer

The difference between men and women ?

Cholesterol Pregnenolone

Progesterone

Aldosterone

HydroxyPregnenolone

HydroxyProgesterone

Cortisol

Androstene Estron dione AROMATAe

Dehydroepiandrosterone

estradiol Aromatase Inhibitors

SE CYP19 Estradio lEstroge

Androstenediol

Testosterone

n Recepto r

After Bickenbach K. & Jaskowiak N., J. Am. Coll. Surg. (2006) 203:

Breas t Cance r growt

Just two carbon double bonds added by aromatase

Natural aromatase inhibitor

Inhibition of aromatase active site amino acids makin g up the active site

Physiological aromatase substrate (steroid hormone)

testosterone

testosterone

bulk of aromatas e molecule iron in haem

Karkola S. & Wahala K., Mol. Cell. Endocrinol. (2009) 301: 235-244

Kao Y., et al., Env. Health Perspec. (1998) 106: 85-92

Natural flavone aromatase inhibitor

Natural flavone aromatase inhibitor aromatase enzyme

aromatase enzyme iron atom haem group active site testosterone estradiol

chrysin

72

3

Secondary Plant Metabolites and Cytochome P450 Enzymes in Cellular Regulation Dan Burke, PhD Bioavailability

Natural phytochemical aromatase inhibitors

 What affects “poor bioavailability” ?

1.

 Flavonoids  24 Flavones  3 Isoflavones  8 Flavanones  5 Catechins

2.

absorption from gut metabolism after absorption

 Extensive glucuronide conjugation 

Flavonoid glucuronides generally inactive

 But ... high conc. glucuronidases around cancers  So ... active compound regenerated at cancer  → Specificity for cancer versus normal tissue  Best not inhibit aromatase in healthy premenopausal

 Strength of aromatase inhibition (IC50, µM)  First exptl AI (aminoglutethimide) ........5.4  Clinically used AIs ..............................0.002 0.043  Effective natural flavonoid AIs ..............0.2 – 12.0

Green tea against breast cancer  Centuries of use of GT extracts in TCM for chronic disease

Clinical Evidence for Phytonutrient

 5 separate studies (1998-2009) totalling 11,673 Japanese, Chinese & Filipino women found that green tea consumption ...

Protection against



Breast Cancer 



Reduced risk of occurrence of breast cancer (~20% less) Reduced risk of recurrence of breast cancer & metastasis More GT drunk, more often, for longer → more protection

Green tea and epigallocatechin-3-gallate (EGCG) as protectants and treatments against cancer : opinion from The Mayo Clinic, USA  > 400 sci/med research publications & reviews worldwide

Green tea and epigallocatechin-3-gallate (EGCG) as protectants and treatments against cancer : opinion from The Mayo Clinic, USA  > 400 sci/med research publications & reviews worldwide

 EGCG is main anticancer active compound in green tea

 EGCG is main anticancer active compound in green tea

 Catechins are 30-40% of dry weight of green tea

 Catechins are 30-40% of dry weight of green tea

Research supports use of green tea for cancer prevention and treatment ... high potential as anti-carcinogenic agent

 Research supports use of green tea for cancer prevention and treatment ... high potential as anti-carcinogenic agent

EGCG’s potential for use in human cancer prevention and treatment seems very promising

 EGCG’s potential for use in human cancer prevention and treatment seems very promising

 Carlson, J., et al., Mayo Clin. Proc. (2007) 82: 725-732.

 Carlson, J., et al., Mayo Clin. Proc. (2007) 82: 725-732.

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Secondary Plant Metabolites and Cytochome P450 Enzymes in Cellular Regulation Dan Burke, PhD The opinion of Prof. E.A. Klein MD, currently Head of Urological Oncology at The Cleveland Clinic, USA “Prostate cancer is an attractive and appropriate target for primary prevention ... Despite PSA [testing and] a high cure rate for localized disease [i.e. early stage prostate cancer] ...

Prostate Cancer

most men who develop [the] metastatic disease are still destined to die of prostate cancer. It is [also] clear that the majority of men treated for localized disease in the community pay a substantial price [in terms of] incontinence, ... bowel problems ... and sexual performance ...”  Klein E., Crit. Rev. Oncol./Hematol. (2005) 54: 1-10

Early stage prostate cancer (PC) Androgen dependent:

needs testosterone (T) in blood to grow

GosereliCYP17 n

Advanced stage AndrogenPC independent

Cholesterol

Abirateron Progesterone Pregnenolone e CYP17 Abirateron Hydroxypregnenolo Hydroxyprogestero e ne ne CYP17

↑ T biosynthesis in cell

T acts via androgen receptors (AR) in PC cells Treat with drugs to ↓ …  T levels in blood  T → more potent DHT

↑ AR level in cell ↑ AR sensitivity to T Can lack AR yet still grow Drugs targeting blood T no longer effective

Dehydroepiandrostero ne

cell

Prostat e Cancer growth

Androstenedione Flutamide ;

Bicalutamid Androge Testosteron e n Finasteride Recepto e Dihydror After Bickenbach K. & Jaskowiak N., J. Am. Coll. Surg. (2006) 203:

Hong M., et al., J. Nutr. Biochem. (2008) 19: 848-855

testostero ne

CYP17

Phytochemical inhibitors of CYP17

 Green Tea catechins ‡  Epigallocatechin gallate (EGCG)  Black Tea theaflavins ‡  Theaflavin gallate

prostate cancer

Androstenediol

In 30% of patients within 3 years of diagnosis Poor prognosis

 Norharman (a β-carboline) *

enzyme in prostate cancer

IC50 (µM)

17-Hydroxypregnenolone Pregnenolone

2.6

CYP17

24.5 12.0

* Kuhn-Velten, W. Eur. J. Pharmacol. 250: R1-R3 (1993) ‡ Kimura, K. et al. Biosci. Biotechnol. Biochem. 71: 2325-2328 (2007)

---------------------------------------------------------------------------------------------------------------------------------------------------------------------------

 Ketoconazole (established drug)  Abiraterone (in clinical trial)

35.0 0.05

74

5

Secondary Plant Metabolites and Cytochome P450 Enzymes in Cellular Regulation Dan Burke, PhD CYP17

CYP17 Abiraterone *

17-Hydroxypregnenolone

Norharman

CYP17

CYP17

Norharman $

CYP17

Harman $

Tetrahydroharman

 $

Kuhn-Velten, W. Eur. J. Pharmacol. 250: R1-R3 (1993)

* Haidar, S. et al. J. Ster. Biochem. Mol. Biol. 84: 555-562 (2003)

CYP17 Epigallocatechin gallate $

CYP17

Natural Anti-cancer Prodrugs

Kimura, K. et al. Biosci. Biotechnol. Biochem. 71: 2325-2328 (2007)

anticanc er prodrugsinactive

innocuou s

GDEP T

NEPT

natural prodrugs

Gene Directe d Enzym e Prodrug Therap y

inactive innocuou s

75

Natural Enzym e Prodrug Therap y

CYP1A 1 CYP1A 2 CYP1B 1

6

Secondary Plant Metabolites and Cytochome P450 Enzymes in Cellular Regulation Dan Burke, PhD CYP17

CYP17 Abiraterone *

17-Hydroxypregnenolone

Norharman

CYP17

CYP17

Norharman $

CYP17

Harman $

Tetrahydroharman

 $

Kuhn-Velten, W. Eur. J. Pharmacol. 250: R1-R3 (1993)

* Haidar, S. et al. J. Ster. Biochem. Mol. Biol. 84: 555-562 (2003)

CYP17 Epigallocatechin gallate $

CYP17

Natural Anti-cancer Prodrugs

Kimura, K. et al. Biosci. Biotechnol. Biochem. 71: 2325-2328 (2007)

anticanc er prodrugsinactive

innocuou s

GDEP T

NEPT

natural prodrugs

Gene Directe d Enzym e Prodrug Therap y

inactive innocuou s

76

Natural Enzym e Prodrug Therap y

CYP1A 1 CYP1A 2 CYP1B 1

6

Secondary Plant Metabolites and Cytochome P450 Enzymes in Cellular Regulation Dan Burke, PhD Specificity of a natural prodrug for cancer CYP1B1 - a Janus enzyme cells determined by (i) the CYP enzymes that  Oppressive  Beneficent activate it & (ii) the locations of the CYPs  CYP1A2 : major CYP in normal hepatocytes  CYP1A1 : extrahepatic cancer cell lines normal small intestine, lung etc down-regulated in some cancers

 Activates chemical carcinogens  mRNA in normal cells & in cancer cells  Protein inducible in normal cells by chemical exposure

%$ ()$

 CYP1B1 : virtually exclusive to cancer cells in all types of cancer



Oesophageal cancer stained for CYP1B1 : Immunohistochemical stain for CYP1B1 (black) Counterstained with H&E (purple)

 Activates natural anticancer prodrugs  Protein is constitutive only in cancer cells (a little in A cancer cell is already a normal cancer cell – activation of breast, carcinogens is of no ovary & consequence to it uterus)

Prostate cancer stained for CYP1B1 : Immunohistochemical stain for CYP1B1 (brown) Counterstained with H&E (blue) Cancerous Stromal

Carnell, Smith, Daley et al. Int. J. Radiation Oncology Biol. Phys. (2004) 58: 500-509

Murray, Melvin, Greenlee & Burke. Annu. Rev. Pharmacol. Toxicol. (2001) 41: 297-316

Cervical Intraepithelial Neoplasia stained for CYP1B1 : Immunohistochemical stain for CYP1B1 (brown) Counterstained with H&E (purple)

CIN 1

cervica l canal

CIN 2

CIN 3

Cytochrome P450 1B1 is a Universal Tumor Antigen ...

Normal Precancerous

... CYP1B1 is overexpressed in all primary human

cervic al lining

tumors and minimally expressed in normal critical tissues …

Stanley, Ball, Butler, Hoang, Potter & Burke. Drug Metabolism Reviews (2001) 33: 77

77

7

Secondary Plant Metabolites and Cytochome P450 Enzymes in Cellular Regulation Dan Burke, PhD Daidzein

CYP1B1 – a Trojan Horse

Effect on MCF-7 cell growth & death

Atherton K. et al. Biochem. Pharmacol.

(2006) 72, 624-631

 Inside cancer cells activates natural phytochemical anticancer prodrugs we get from the fruit, vegetables and herbs that we eat

M1 (6-hydroxydaidzein) M3 (8hydroxydaidzein)

CYP CYP Daidzein

CYP > CYP3A4 CYP1B1 > CYP1A1 > CYP1A2

 Why do cancer cells tolerate CYP1B1?

M2 (3’-hydroxydaidzein)

 But for CYP1B1 would we have survived to

Salvestrols – natural anticancer CYP1B1 prodrugs

 Discovered 2002 after 15+ years research

 Phytochemicals in dietary fruit, vegetables, herbs  Professor Gerry Potter first realised importance  Salvestrols are various types of chemicals

Resveratrol

Piceatannol

 Activated in cancer cells via metabolism specifically by CYP1B1  Active metabolites stimulate apoptosis  Inhibit tyrosine kinases

Natural sources of Salvestrols Vegetables

 Apples  Blackcurrants  Blueberries  Cranberries  Grapes (& wine)  Oranges  Strawberries  Tangerines

 Avocados  Cabbage  Broccoli  Brussels Sprouts  Cauliflower  Chinese Leaf  Olives  Paprika

Tan H. et al. J. Pharm. Pharmacol. (2007) 59: S158

Herbs  Artichoke  Basil  Dandelion  Milk Thistle  Mint  Parsley  Rosemary  Sage  Scutellaria  Thyme

MCF-10A non-tumourigenic mammary epithelial cells (no CYP1 enzymes) IC50 = 12.7 µM

100

% live cells remaining

Fruit

Salvestrols selectively cytotoxic to cancer cells

80 60 40 20 0

MDA-MB-468 tumourigenic mammary adenocarcinoma cells (CYP1A1 and CYP1B1) 1 IC .01 = 0.9 µM .1 50

(Mean ± SEM)

78

10

100

Salvestrol concentration (µM)

8

Secondary Plant Metabolites and Cytochome P450 Enzymes in Cellular Regulation Dan Burke, PhD DMU713 : a selective inhibitor of CYP1B1

Salvestrols selectively cytotoxic to cancer cells

Tan H. et al. J. Pharm. Pharmacol. (2007) 59: S158

Tan H. et al. J. Pharm. Pharmacol. (2007) 59: S158

inhibition by 1 µM DMU713 CYP1A1 = 55

75

% live cells remaining

% CYP1 enzyme activity (EROD)

100

100

% CYP1A2 = 11 % CYP1B1 = 57

50

%

25 0

.001

(Mean ±

.01

.1

1

10

80 60 40 20 0

100

Inhibitor (DMU713) concentration (µM)

(Mean ±

Bioavailability and pharmacokinetics of Salvestrols *350 points = 3.5x estimated daily amount in paleolithic diet

MDA-MB-468 tumourigenic mammary adenocarcinoma cells (CYP1A1 and CYP1B1) 1 10 IC50 .01 = 0.9 µM .1 Salvestrol concentration (µM)

MCF-10A non-tumourigenic mammary epithelial cells (no CYP1 enzymes) IC50 = 12.7 µM MDA-MB-468 breast cancer cells (CYP1A1 and CYP1B1) plus 1µM DMU713 (CYP1B1 inhibitor) 100

Reasons for Salvestrol deficiency

‡ Testimonials of 5 cancer patients, in J. Orthomol. Med. (2007) 22: 177-182

2000 points twice daily

rescue‡

Solution for overcoming Salvestrol deficiency Nutritional supplement ?

More and more research scientists advocate supplements for many different phytonutrients

Thank You

1) Discover important health effects in laboratory 2) Realise insufficient amount in average diet But ... Regulators not in favour –

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Orthomolecular Medicine Today Optimal Nutrition Conference

from an Evolutionary Perspective

Dag Poleszynski, PhD

Food and genetic selection

Optimal nutrition from an evolutionary perspective

39th Annual International Conference

Orthomolecular Medicine Today Vancouver, May 1, 2010 ©Dag Viljen Poleszynski, PhD

Mankind’s “first mother”?

Genetic stability in extremis

Ardi was reconstructed from skeletal remains of 110 individuals excavated in the Afar Valley, Ethiopia (120 cm tall) First published in 2009 after 17 years of analyses Possibly the first erect creature of the Homo species Lived ~4.4 m yrs ago Ape-like characteristics: Big toes, long arms

Estimated change in the human genome is in the order of 0.5% per million years Since the advent of agriculture, the human genome has changed approximately 0.005% Variations in local food sources, climate and glacial periods have exerted selection pressure The human genome contains approximately 3.2 million polymorphisms

Mankind adapted to many variants of a Paleolithic diet

Composition of the human body indicates best energy substrates

 Natural

variations in geography, climate, seasons and glacial periods  Man has been able to adapt to living all over the world

Energy source

Weight (kg)

Energy (kcal)

Survival time

Fat tissue (TAG)

12

110,000

55 days

Muscle protein

6

24,000

12 days

0.4

1,600

18 hours

0.1

400

5 hours

0.014

56

40 minutes

136,056

68 days

Muscle glycogen Liver glycogen Glucose (plasma) Total energy

80

Optimal Nutrition from an Evolutionary Perspective

Orthomolecular Medicine Today Conference

What is a rational survival strategy?

Dag Poleszynski, PhD

 Goal: Maximize energy yields harvested relative to energy spent while hunting and gathering!  How: Choose foods according to energy yield. First hunt for the largest and fattest animals, then smaller animals.  Why: Animal foods contain more energy, have higher food quality than most plants.  If in need: Pick energy rich plants (like avocado), find honey.  Therefore: Huntergatherers prefer the fattest parts of the animal.

Paleolithic diets were rich in fat High-fat diet desired: Up to 85 % of total food energy Long-chain PUFAs: Big game/grazing animals have more PUFA than barn-fed Low ω-6:ω-3 ratio: Paleolithic >1-2:1 US today >10:1 (up to 50-60 : 1) Norway today 7-10:1

Paleolithic vs. modern foods

The absence of vegetarians…

More raw food (inner organs, fat meat, bone marrow/brain, fish, fowl, insects, nuts, berries, vegetables, tubers, fruits) 30-40% more energy Higher nutrient density More protein Low-carbohydrate, often only 2 E% (10125 gm/d) Lots of fat, cholesterol Soluble fiber, herbs

Analyses of pre-historic settlements indicate that our ancestors’ diet was dominated by meat for > 2 million years Data from analyses of 229 groups of hunters and gatherers: 56-65% of their diet was of animal origin In 9 groups the diet consisted of at least 86% animal food No vegetarians ever found  Cordain (2000).

Advantage of cooking/roasting

Animal foods spurred evolution

Food easier to chew and digest Smaller volume, better taste, more appetizing, more energy, improved digestion of nutrients Heat kills off micro-organisms Natural selection favored smaller guts, mouth and lips, chewing muscles, etc. Less digestive work promoted growth in brain volume Heating foods – decisive for the gap between apes and Homo?

Given the size of earlier hominids’ bodies and brains, the anatomical and kinetic characteristics of their digestive organs, the most adaptive was to gradually increase the intake of animal foods. This was the only realistic nutritional strategy for the emerging human development lin Heat treatment improved the nutritional quality of plant and animal foods The earliest agriculturists used technological innovations to increase the quality of wild plants by fermentation, sprouting and grinding/milling  Wrangham (2009).

81

Optimal Nutrition from an Evolutionary Perspective

Orthomolecular Medicine Today Conference

Dag Poleszynski, PhD

Humans – small gut, large brain

Size of the digestive system is related to brain and body size Great apes eat 87-99% low quality plant foods Digesting foods with much indigestible fiber requires a large body (gorilla 160 kg ♂/93 kg ♀, orangutan 69 kg ♂ /37 kg ♀) and digestive system Human brain uses 23 % of total resting energy (newly-born: 87 %, 5 year-olds: 44 %) The brain could not grow without more concentrated foods = animal foods, and cultural adaptations, the most important being control of fire

Milton (2003)

Nutritional needs of newly-born

Cereal grains are not optimal foods Marginal or deficient in key nutrients:

Because of the increase in the relationship between metabolic demands [for the brain] and the gut volume by infants, a diet containing a lot of fibrous plant material would lead to nearly insurmountable problems for small children. Meat, inner organs, brain, entrails and marrow are easily digestible, concentrated sources of iron, calsium, iodine, sodium and zink, as well as vitamin A, B1, B6, B12, folic acid, vitamin K and other micro nutrients, protein of high quality and essential fatty acids.

Protein: low biologic quality (low in lysine/isoleucine) No vitamin A, C, D, K or B12 Long-chained, polyunsaturated fatty acids (arachidonic acid, DHA, EPA) Unfavorable ratio Ω6:Ω3 fatty acids (7-18:1)

Low biologic availability of minerals/vitamins Fungi and mycotoxins (Ergot, Fusarial, Oosporein) Humans cannot neutralize defence chemicals and anti-grazing agents in grain phytates, protease inhibitors, lectins, phytoestrogens

 Milton (2003)

Grain agriculture - a two-edged sword for mankind (L. Cordain)

Why humans became farmers… Around 12,000 BC a total of only 4,000-5,000 people roamed the earth Around 8,000 -10,000 BC systematic domestication of grasses was begun in the Middle East/Anatolia (Turkey) Was farming a necessity because of dwindling animal resources and starvation? Did stone-age humans foresee a world populated with 6.8 billion people in 2010?

+ Precondition for technological and cultural development? + More people could be fed: Grains alone supply approximately 2/3 of all world protein and energy 15 plants supply 85-90% of all food energy (grains, beans, potatoes/cassava, bananas, sugar cane/beets) Large gap between man’s nutritional needs 10,000 years B.C. and the nutrient content in various grass types Many humans became ill/functioned poorly as a direct consequence of eating the new food Unfavorable genes not eliminated by selection pressure

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Orthomolecular Medicine Nutrition Today Optimal Conference

from an Evolutionary Perspective

Dag Poleszynski, PhD

A “universal” desire to get stoned?

Hunting/gathering vs. farming On the average, hunter-gatherers worked 17 hrs/wk The agricultural transition led to deteriorating health: malnutrition, osteomyelitis, periostitis, intestinal parasites, yaws, syphilis, leprosy, tuberculosis, anemia, rickets in children, osteomalacia in adults, retarded childhood growth, short stature among adults Agriculturalists work from dawn to dusk and then some…in modern US the average citizen works about 40 hrs/wk Why did our ancestors become farmers?

Bighorn sheep chew their teeth down to the gums to eat psychoactive lichen off rocks… Cattle will eat locoweed until it kills them… Birds get stoned on cannabis seeds… Jaguars eat the bark off the yaje vine to hallucinate… Elephants make wine from palm sap… Birds eat fermented berries until drunk and disoriented… Monkeys and dogs love opium smoke… Chimps will smoke cigarettes, and tobacco is addictive to parrots, baboons, hamsters… Reindeer ignore food to pursue hallucinogenic mushrooms... Humans use mushrooms, peyote, cannabis, tobacco, cocoa leaves, opium, LSD…

Did humans get addicted to grains?

Gluten/gliadin as disease agents

Many cereal grains and milk contain exorphins working like opioids when ingested The ingestion of cereals and milk, in normal modern dietary amounts by normal humans, activates reward centers in the brain Foods that were common in the diet before the advent of agriculture did not have those properties.

~200 chronic diseases are associated with the intake of gluten containing grains Only one in 40 with celiac disease diagnosed in the US US: ~ 90 million of total 300 mill. poorly tolerate wheat, rye, barley and spelt Genes for celiac disease are also found in populations not consuming gluten containing grains

Chronic hyper-/hypoglycemia an important etiologic factor

High-fat diet prevents cancer…? Canadian anthropologist and Arctic explorer Vilhjalmur Stefansson (1879-1964) searched for cancer among Inuit in Alaska and Northern Canada 1906-60 - found hardly any!

Ancestral genes were adapted to foods with low GI/GB High glycemic food (wheat, rye) introduced 10,000 B.C. Carbohydrates (= sugar) today provide 50-70 % of all food energy compared with 2-20 % in ancestral diets Refined sugar only in common usage last 100 years (35-60 kg/person/yr)

 Stefansson (1960)

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Orthomolecular Medicine Today Optimal Nutrition from an Evolutionary Conference Dag Poleszynski, PhD

Can humans live by meat alone?

Perspective

Conclusions from the meat experiment Man may live well on an exclusive meat diet. Meat diets are well tolerated if sufficient fat. Effects: Moderate weight reduction, less flatulence,

good intestinal peristalsis, mild ketoses, normal stomach and bowel function, slightly higher blood cholesterol (KA), normal blood pressure and kidney function. Too much protein caused loss of appetite, nausea, diarrhea (at ca. 44% protein – recommended protein intake = < 33%). The meat diet contained little calcium and vitamin C, but not signs of scurvy (low blood glucose increases uptake) were noticed.

1928-29: Stefansson (48) & Andersen (38) live for 375/367 days on a diet composed of meat/innards/bone marrow, bacon and fat from cattle, lamb, calf, swine, chicken Energy intake: 2400-2500 kcal/d Energy distribution: Prot 15-25%, Fat 75-85%, Carb 1-2%

Letters of corpulence…(1864)

The root cause(s) of obesity

 Could eating the wrong foods be the cause of obesity?  Banting started on a LC diet at the age of 66. BW >90 kg, and with a statute of 165 cm he walked backwards down the stairs and was unable to tie his own shoe laces.  Many health problems, including deafness. Doctor William Harvey recommended a low-carbohydrate diet.  Banting lost 22 kg and 31 cm around the waste in one year!

Observations of eating habits after a long life with dinner parties Since fat deposits […] are caused by flour and starches…it may be deduced that a more or less strict abstinence from all [such] foods… leads to the loss of body fat 

Jean-Anthelme Brillat-Savarin (1755-1826) (La physiologie du goût, Paris 1825)

 Brillat-Savarin (1825).

William Banting (1797-1878)

Medicinal effects of fat

Clinical experiences from 1921

N.Y. Scottish MD (1892) completed internship in 1913. Mange people ingested large quantities of meat and fat without gaining weight. Hypothesis: Fat does not make you fat. Clinical practic:An optimal meal should consist of 3 parts of meat to one part of fat (> 70% fat). First anti-obesity cure included 30 min. walk before breakfast. Treated >17,000 patients with low-carb diet during 48 yrs.

Diet for diabetics Most strict: No carbohydratecontaining foods, up to 120 g protein (600 g meat) and the rest fat.  Strict: 500 g boiled/fried meat or fish/eggs, 100-200 g fat (butter, lard, oils), vegetables (salad, cucumber, tomatoes, spinach, mushrooms).  Least strict diet: Same as strict plus until 100 gm bread, small carrot, milk, potato, etc.

84

Optimal Nutrition from an Evolutionary Orthomolecular Medicine Today Conference Dag Poleszynski, PhD Fat does not cause obesity

Perspective

Pioneer Wolfgang Lutz, MD/PhD Born in Austria, 1913 Treated his own health problems in 1957 with an “Eskimo diet” During 40 years, treated more than 10.000 patients with a high-fat, lowcarbohydrate diet (72-84 g/d) Published results of clinical research with patients in scientific journals and books

 Opened the first UK obesity/food allergy clinic in 1960.  “I am convinced that the animal fat and cholesterol scare is a red herring in the search for the cause or causes of coronary thrombosis […]  ..it is inconceivable that a food (fat meat) which has been man’s staple diet for ninetenths of his time as a human, should suddenly become the cause of a disease which was unknown before the turn of the century” (p. 12).  Patient advice: Eat fat and protein in the relation of one part of fat to three parts of protein-containing foods.

Boy at 13, weight 122 kg Cushing’s syndrome or bad diet?

Is there an optimal diet for all?

Examples of recommended foods

Foods to avoid (examples)

 Jan Kwaśniewski (f. 1937) explored the relationship between nutrition and health during the 1960’s  H: Macronutrients most important  Tested his hypothesis first with rodents, then in clinical trials with volunteers (including his future wife)  A fat-rich diet dominated by saturated fatty acids always produced the best results  Protein: fat: carbohydrates should be = 1:2,5-3,5: 0,5-0,8  40-60 g carbohydrates/day  Energy needs are lower when fat contributes 75-85 % of total food energy

 All kinds of cheese, in particular fat cheeses.  At least 4 eggs per day.  Innards, animal gelatin with cartilage/skin; stock cooked from marrow bone.  Fatty meats, e.g. pork ribs.  Meat sausages, pâtées, meat pudding, blood pudding.  Fish, including smoked/canned.  Fowl, in particular duck/goose (fat).  Animal fat the best: Butter, lard, fat from pigs and geese, ghee  Vegetable oils: olive, macadamia, solsikke, coconut, margarines without trans fatty acids

 Sugar in any form, including all sweets.  Honey.  Fruit/conserves (jams, jellies). Berries may replace potatoes and vegetables, up to 300 g per day (avoid apples and pears because of the negligible protein and fat content).  Rice, corn, breakfast cereals.  Bread and other baked goods.  Wheat products: cakes, donuts, bagels, etc.

85

Orthomolecular Medicine Today Optimal Nutrition Conference

from an Evolutionary Perspective

Dag Poleszynski, PhD

Food pyramid - optimal nutrition

Metabolic effects of fat and sugar

Select foods from the bottom of the pyramid and pick successively less of foods higher up Fat animal foods and egg yolks constitute the most important basis for good health.

12 healthy males ingested evening meals with varying fat (62 or 16 E%) and carbohydrate (31 or 76 E%) content Breakfast: Either 100 gm of glucose (GTT) or 40 gm fat (FTT), and blood parameters measured 4-6 hrs Conclusion: A fat rich evening meal gave slightly higher blood sugar on the GTT the morning after, but lower TG, insulin response and bit higher FFS. Fat (FTT) does not increase blood insulin, in contrast to glucose Black squares after high-fat meal; open squares after carbohydrate-rich meal.

 Szczepanek T. Prawda o zymiewniu optimalnym, 2004. (The truth about optimal diets. Course material from The Polish Association for Optimal Diet).

 Robertson, AJCN 2002.

Effects of chronically high insulin levels

Glucose produces insulin rise

Reduces insulin sensitivity, causing chronic hyperglycemia. More cardiovascular disease – inhibits degradation of fibrin, increases blood clotting, ↑ TG and blood pressure, leads to vasoconstriction, damages blood vessels. May cause gall stone and kidney damage (vasoconstriction). Increases fat deposits from surplus of blood glucose. Blocks availability of body fat, causes hunger pangs. ↑cancer risk in breast, prostate, colon, liver, pancreas. ↑dementia risk. ↑blood cortisol, inhibits DHEA (cancer protective) excretion from adrenal glands. ↑Increased Mg secretion from kidneys (leading to ↑ blood pressure, ↑heart attack risk, more muscle cramps, vasoconstriction, osteoporosis)

After 100 gm glucose

After 40 gm fat

Evolution shaped CNS energy use

Glucose needs for the brain

No metabolic difference between fasting or a longterm, high-fat diet The body conserves muscle protein when the brain uses ketones instead of glucose (improves survival) Humans survived glacial periods during the last 100,000 years because of earlier fat adaptation Fatty foods therefore must be beneficial physically as well as mentally

Misconception: The brain needs125-150 g glucose/24 hrs During fasting/highfat diet only 30-40 g glucose is needed ~2/3 of energy may be replaced by ketone bodies  Owen (2005)

86

Optimal from an Evolutionary Orthomolecular Medicine Nutrition Today Conference Dag Poleszynski, PhD

Perspective

Pathophysiological effects of hyperglycemia after meals

Sugar and heart disease Blood sugar spikes after meals damage arterial endothelial cells. Inflammation and oxidative stress damage arteries, including coronary arteries. Epidemiologic and mechanistic data indicate that a high blood sugar after meals and poorly regulated blood sugar may cause cardiovascular disease. Blood sugar control ought to be central in all clinical investigations to prevent cardiovascular disease.  Node K, Inoue T (2009).

Hyperglycemic diets unhealthy Sugar/starches

Hyperglycemia

Direct effects: Dental decay Mineral losses Osteoporosis Changed gut flora

Physical Cognitive Mental

Evolutionary adaptation to ketones

Evolutionary defense mechanisms

Evolution made it possible for humane cells to use different energy substrates interchangeably Glucose is not the best fuel for the brain (or nerves) Hominid brains and many other tissues prefer ketone bodies as fuel Rationale: Mild ketosis was the “normal state” before the agricultural (“glucose”)revolution Ketones are considered as “super fuel” because the body synthesizes ATP more effectively from ketones than from glucose & fatty acids. The use of ketones as energy substrate contributed to humans’ large brain!

1) Kidney threshold 2) ↑ insulin from β-cells 3) ↑ fat storage (insulin) 4) Insulin resistance limits fat storage

Hypoglycemia

Hormone imbalance (↓ testosterone/DHEA, ↑ estrogen/cortisol/TxA2), increased blood lipids (↑ TG), ↑ cardiovascular disease (↑ BT, ↓ Mg, arteriosclerosis), ↓ immunity/wound healing, ↑ diabetes/obesity/cancer infections/PCOS/impotence/myopia, ↑ blindness and cataracts, premature aging, more wrinkles (AGE)/gangrene (500 amputations/yr)

Selected references

Conclusions

 Colagiuri S, Miller JB. The ‘carnivore connection’ – evolutionary aspects of insulin resistance. EJCN 2002; 56: 30-5.  Cordain L. Cereal grains: humanity’s double-edged sword. World Rev Nutr Diet 1999; 84: 19-73  Cordain L, Miller JB, Eaton BS et al. Plant-animal subsistence ratios and macronutrient energy estimations in worldwide hunter-gatherer diets. AJCN 2000; 71: 682-92.  Cunnane SC. Survival of the fattest: the key to human brain evolution. Hackensack, NJ: World Scientific Publishing, 2005.  Larsen CS. Biological changes in human populations with agriculture. Ann Rev Anthropol 1995; 24: 185-213.  Leonard WR, Robertson ML, Snodgrass JJ et al. Metabolic correlates of hominid brain evolution. Comp Biochem Physiol and Mol Integr Physiol 2003; 136: 5-15  Miller JC, Colagiuri S. The carnivore connection: Dietary carbohydarte in the evolution of NIDDM. Diabetologia 1994; 37: 1280-6.  Milton K. The critical role played by animal source foods in human (Homo) evolution. J Nutr 2003; 133 (suppl.): 3886-92.  Neel JV. When some fine old genes meet a “new” environment. World Rev Nutr Diet 1999; 84: 1-18.  Node K, Inoue T. Postprandial hyperglycemia as an etiological factor in vascular failure. Cardiovascular Diabetology 2009; 8: 23 (www.cardiab.com/content/8/1/23).  O’Keefe JH, Cordain L. Cardiovascular disease resulting from a diet and lifestyle at odds with our Paleolithic genome: how to become a 21st-century hunter-gatherer. Mayo Clin Proc 2004; 79: 101-8.  Owen OE. Ketone bodies as fuel for the brain during starvation. Biochem Molecular Biol Edu 2005; 33: 246-51  Robertson DM et al. Extended effects of evening meal carobohydrate-to-fat ratio on fasting and postprandial substrate metabolism. Am J Clin Nutr 2002; 75: 505-10.  Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother 2002; 56: 365-79.  Stefansson V. Cancer: Disease of civilization. An Anthropological and Historical study. New York: Hill and Wang, 1960

o Humans may survive on many different combinations of foods – we are omnivores! o Most people may adapt well to low-carb diets, hardly anybody will thrive on high-glycemic foods o Individual variations and genetic polymorphism means that diets should be tailor-made to each o Dietary principals should be adapted to human genetics as they have been shaped through our evolutionary history o Optimal diets adapted to each individual is the best foundation for superior physical and mental health, a maximal life span and a healthier humankind

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The Health Benefits of Vitamin D and Estimates of Reductions in Mortality Rates for Canada and the United States William Grant, PhD

Disclosure The Health Benefits of Vitamin D; Estimates of Reductions in Mortality Rates for Canada and the United States

I am pleased to acknowledge funding from these organizations: UV Foundation (McLean, Virginia) www.uvfoundation.org The Vitamin D Society (Canada) www.vitamindsociety.org Sunlight Research Forum (Veldhoven) Bio-Tech-Pharmacal (Fayetteville, AR) The Vitamin D Council (San Luis Obispo, CA)

A presentation at Orthomolecular Medicine Today, May 1, 1010

by William B. Grant, Ph.D. Sunlight, Nutrition, and Health Research Center San Francisco, California www.sunarc.org

Outline

Vitamin D

 Introduction to Vitamin D  Diseases linked to low serum 25(OH)D  Causality, types of evidence from human studies  Health disparities, United States and Canada  Estimates of reductions in mortality rates for 42 ng/mL (105 nmol/L) for Canada and the U.S.  Sources of vitamin D  Actions  Additional resources

 Vitamin D3 (cholecalciferol) is made by the action of ultraviolet-B (UVB) on 7-dehydrocholesterol in the skin, followed by a thermal process.  Solar UVB extends from 290-315 nm UVA extends from 315-400 nm  Vitamin D3 is converted in the liver to 25hydroxyvitamin D3 [25(OH)D], the circulating form.  25(OH)D is converted in the kidneys and other organs to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active hormonal form of vitamin D.

Vitamin D Pathways for non-Calcemic Effects

Vitamin D, continued  Vitamin D receptors (VDRs) are activated by 1,25(OH)2D and affect gene expression.  VDRs come in different alleles, with different effects.  The half life of 25(OH)D in the body is about 4-6 weeks.  Vitamin D is stored in adipose tissue; 25(OH)D is stored in muscles, and along with 1,25(OH)2D, circulates on vitamin D binding proteins in the blood.  Vitamin D2 (ergocalciferol) is made from yeast, and is less effective as vitamin D3; however, MDs can prescribe it but not vitamin D3.

Holick, NEJM, 2007

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The Health Benefits of Vitamin D and Estimates of Reductions in Mortality Rates for Canada and the United States William Grant, PhD Vitamin D Receptors (VDRs) Gene Activation

Evidence that Vitamin D Reduces the Risk of Many Types of Disease The major diseases with strong evidence that vitamin D reduces risk include:

 Hormonal vitamin D, 1-25(OH)2D, binds to intracellular receptors that then function as transcription factors to modulate gene expression.  The vitamin D receptor has hormone-binding and DNAbinding domains. It forms a complex with another intracellular receptor, the retinoid-X receptor, and that heterodimer is what binds to DNA.  In most cases studied, the effect is to activate transcription, but situations are also known in which vitamin D suppresses transcription.

300 300

350

350

 Cancer – at least 18 types  Cardiovascular disease (coronary heart disease, cardiovascular disease) and congestive heart failure  Diabetes mellitus, types 1 and 2  Bacterial and viral infections  Autoimmune diseases, e.g., multiple sclerosis  Falls and Fractures  Dental caries, periodontal disease

Colon cancer mortality rates, males, 1970-94; Index of annual solar radiation 300

350

300 350

400 400 450

Higher UVB in the west is due to higher surface elevation and thinner stratospheric ozone layer

500

500 450

? Use UVb c agrt again here?

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The Health Benefits of Vitamin D and Estimates of Reductions in Mortality Rates for Canada and the United States William Grant, PhD

Colorectal Cancer Incidence vs. Serum 25(OH)D

Serum 25(OH)D Level-Disease Outcome It is important to determine relations between serum 25(OH)D level and incidence or death from various diseases. The way this is generally done is to do a metaanalysis of disease outcome with respect to serum 25(OH)D level quantiles from cohort studies. Data from various studies can be combined by overlaying results to minimize the data spread.

(nmol/L) (nmol/L)

Breast Cancer Incidence vs. Serum 25(OH)D

RCT and All-Cancer Incidence Recent prospective study of vitamin D3 and calcium and cancer risk in post-menopausal women in Nebraska1  1100 IU of vitamin D3 and/or 1400 mg of calcium per day, or placebo.  Serum calcidiol levels rose from 71.8 nmol/L (28.7 ng/mL) to 96.0 nmol/L (38.4 ng/mL)  The all-cancer incidence for women over the age of 55 years at time of enrollment was reduced in those on Vitamin D + calcium by 77% between the ends of the first and fourth years of the study.

1. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007 Jun; 85(6): 1586-91.

(nmol/L) (nmol/L)

All Except First Year Cases

18 Vitamin D-Sensitive Cancers P < 0.01 Relative Risk = 0.23

Fraction Cancer-Free

1.00

Vitamin D-sensitive cancers [i.e. with strong support after accounting for other factors] Gastrointestinal: colon, esophageal, gallbladder, gastric, pancreatic, rectal Urinary: bladder, kidney Other: lung, melanoma Male: prostate (progression, not incidence) Female: breast, cervical, endometrial, ovarian, vulvar Blood: Hodgkin’s and non-Hodgkin’s lymphoma

Calcium and Vitamin D 0.98

77% reduction Calcium only

0.96

40% reduction 0.94

Placebo 0.92

0.90 0

1

2

3

4

Time (yrs)

Source: Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85:1586-91.

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The Health Benefits of Vitamin D and Estimates of Reductions in Mortality Rates for Canada and the United States William Grant, PhD Enter the International Agency for Research on Cancer (IARC)

Vitamin D and Cardiovascular Disease

 An IARC working group reviewed the evidence that vitamin D reduces the risk of cancer. It dismissed almost all evidence, but accepted that vitamin D reduces the risk of colorectal cancer [IARC, 2008].  I reviewed their review, pointing out the many errors and omissions involved in reaching their conclusion.

Several recent observational studies found that those with lower serum 25(OH)D had higher risk of cardiovascular disease (coronary heart disease and/or stroke) incidence or mortality rate. The hazard or odds ratios were as high as a factor of two or more for <25 nmol/L vs. >75 nmol/L.

 IARC Working Group Report 5: Vitamin D and Cancer (Nov. 25, 2008) http://www.iarc.fr/en/Media-Centre/IARCNews/Vitamin-D-and-Cancer.  Grant WB. A critical review of Vitamin D and cancer: A report of the IARC Working Group on vitamin D. DermatoEndocrinology. 2009a;1:25-33.

 Dobnig et al., 2008; Giovannucci et al., 2008; Ginde et al., 2009; Kilkkinen et al., 2009.

Pooled Analysis – Cardiovascular Disease Incidence and Mortality Rate

Vitamin D and Cardiovascular Mortality Follow-up period of 6.2 years: 51 subjects died including 20 deaths due to cardiovascular causes Hazard ratio for CVD mortality in the lowest vs. the upper three 25(OH)D quartiles:

5.38 (95% CI, 1.28-14.34, p<0.001

Adjusted for age, sex, diabetes mellitus, Smoking status, hypertension, HDL-C, GFR and WHR Pilz S, Dobnig H, Nijpels G, et al. Vitamin D and mortality in older men and women. Clin Endocrinol (Oxf). 2009

Mechanisms for Diabetes Risk Reduction from Vitamin D and Calcium

Type 2 Diabetes Mellitus

The mechanism of action of vitamin D in type 2 diabetes mellitus is thought to be mediated not only through regulation of plasma calcium levels, which regulate insulin synthesis and secretion, but also through a direct action on pancreatic beta-cell function [e.g., Palomer et al., 2008].

Vitamin D and calcium have been found inversely correlated with incidence and prevalence of type 2 diabetes mellitus.

 Palomer X, et al., Role of vitamin D in the pathogenesis of type 2 diabetes mellitus. Diabetes Obes Metab. 2008 Mar;10(3):185-97.

Pittas, Diabetes Care.

2006 Mar;29(3):650-6.

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The Health Benefits of Vitamin D and Estimates of Reductions in Mortality Rates for Canada and the United States William Grant, PhD Vitamin D Antimicrobial Actions

Influenza and Pneumonia

The hormonal metabolite of vitamin D, 1,25dihydroxyvitamin D [1,25(OH)2D] induces production of cathelicidin and defensins, which have both antimicrobial and anti-endotoxin properties. These polypeptides have been found effective in fighting tuberculosis, pneumonia, septicemia, and oral bacteria, as well as Epstein Barr virus, influenza, and rhinovirus.

Vitamin D, through induction of cathelicidin and defensins, reduces the risk of several bacterial and viral infectious diseases. Influenza is largely seasonal due to lower solar UVB doses in winter; however, there is also a contribution from lower temperature and absolute humidity (the virus survives longer at lower humidity).

Susceptibility to A/H1N1 Influenza

1918-19 Pandemic Influenza  In the United States, those living at higher latitudes had higher case-fatality rates from influenza than those at lower latitudes. The primary cause of death was pneumonia.  Vitamin D reduces the cytokine storm following influenza infection.  Vitamin D, through cathelicidin and defensins, fights bacterial pneumonia.

The groups most susceptible to A/H1N1 influenza (swine flu)  Pregnant women  Australian Aborigines  Canadian First Nation People  Diabetics, obese people  Children with neurological problesm

 Grant WB, Giovannucci D. The possible roles of solar ultraviolet-B radiation and vitamin D in reducing case-fatality rates from the 1918–1919 influenza pandemic in the United States. DermatoEndocrinology 2009;1(4): 215-9.

These groups have one thing in common: low serum 25(OH)D levels.

Multiple Sclerosis Prevalence vs.

Latitude, an Index for Wintertime UVB

Autoimmune Diseases  Several types of autoimmune diseases appear to follow viral infections, especially early in life:

Wallin et al., 2004; Grant and Holick, 2005; Grant, 2008

 Asthma  Diabetes mellitus, type 1  Multiple sclerosis (Epstein-Barr virus as risk factor)

 The primary beneficial roles of vitamin D in reducing risk of autoimmune diseases appears to be reduced risk of viral infections and suppression of autoimmune responses to infections.  An additional mechanism is regulation of cytokine production by 1,25(OH)2D, shifting from production of Th1 cells and inflammatory cytokines (IL-2, IL-5, IFNgamma, and TNF-alpha) to Th2 cells and other cytokines (IL-4, IL-10).

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The Health Benefits of Vitamin D and Estimates of Reductions in Mortality Rates for Canada and the United States William Grant, PhD Dental Caries, 12-14 Year Old Males, vs.

Hours of Sunlight per Year, in Four US Regions, early 1930s

Serum 25(OH)D and Mortality Rates, Amsterdam, 1995-2004

East BR. Mean annual hours of sunshine and the incidence of dental caries. Am J Public Health Nations Health.

1939;29:777-80.

Kaplan-Meier curves for mortality according to categories of serum 25-hydroxyvitamin D [25(OH)D] concentration from the Longitudinal Aging Study Amsterdam. [Visser et al., 2006]

Dental Health First Half 20th Century Compared with July Solar UVB

Periodontal Disease (PD)

Dental Health, ca. 1918, 1940 Dunning JM. The influence of latitude and distance from seacoast on dental disease. J Dent Res. 1953;32:811-29.

There is mounting evidence that low vitamin D is a risk factor for PD. Mechanisms have been identified:

Higher UVB in the west is due to higher surface elevation and thinner stratospheric ozone layer

 Regulation of calcium absorption and metabolism  Anti-bacterial actions  Reduced matrix metalloproteinases levels

Many systemic and infectious are linked to PD. My hypothesis is that low serum 25(OH)D levels explain the links.

Causality in a Biological System

Causality for Vitamin D, Cancer

AB Hill laid down the criteria in 1965, including:

 Results for breast and colorectal cancer satisfy the criteria best, but there is also good evidence that other cancers do as well, including bladder, esophageal, gallbladder, gastric, ovarian, rectal, renal and uterine corpus cancer, as well as Hodgkin's and non-Hodgkin's lymphoma. Several cancers have mixed findings with respect to UVB and/or vitamin D, including pancreatic and prostate cancer and melanoma.

 Strength of association  Consistent findings in different populations  Dose-response relation, possibly linear  Mechanism(s)  Analogy with other findings  Experiment (e.g., randomized controlled trial)

Later, two more factors were added:

 Grant WB. How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer? An examination using Hill’s criteria for causality. Dermato-Endocrinology.

2009;1(1):17-24.

 Accounting for confounding factors  Removing bias

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The Health Benefits of Vitamin D and Estimates of Reductions in Mortality Rates for Canada and the United States William Grant, PhD From Grassrootshealth.net

Types of Evidence for Vitamin D Effects  Ecological studies  Index of solar UVB, other factors, geographic region

 Cross-sectional studies  National Health and Nutrition Examination Surveys

 Observational – cohort studies  Harvard’s Nurses Health Studies and Health Professionals Follow-Up Studies

 Observational – case-control studies  Laboratory studies, animal studies  Randomized controlled trials

Health Disparities, United States

Health Disparities, United States

 There are quite significant health disparities between African-Americans and White-Americans.  The usual explanations include socioeconomic factors (e.g., education, employment, and income), lifestyle behaviors (e.g., physical activity and alcohol intake), social environment (e.g., educational and economic opportunities, racial/ethnic discrimination, and neighborhood and work conditions), and access to preventive health-care services (e.g., cancer screening and vaccination [Williams et al., 2003].

Disease

 Williams DR, Neighbors HW, Jackson JS. Racial/ethnic discrimination and health: findings from community studies.

Am J Public Health. 2003;93:200-208.

Health Disparities, United States

White Mort Rate 200

Ratio, B/W

Heart

Black Mort Rate 258

Stroke

62

42

1.47

Diabetes

45

20

2.25

Cancer

217

185

1.18

COPD

28

44

0.63

Influ, pneum

20

18

1.10

Septicemia

22

10

2.2

All-cause mortal

982

777

1.26

1.29

Health Disparities, Canada First Nation and Inuit health status is lower than for White-Canadians. In the past, First Nation and Inuit people obtained much of their food from the ocean, thereby providing them with adequate vitamin D. Currently, they have changed diet to a largely Western one, with little vitamin D. Increasing vitamin D intake would reduce their disease rates.

 The mean serum 25(OH)D level for African-Americans is 16 ng/mL; that for White-Americans is 26 ng/mL.  Serum 25(OH)D level-disease outcome relations for cancer, cardiovascular disease, and all-cause mortality rate indicate that there is about a 25% increased risk of disease for 16 ng/mL vs. 26 ng/mL.  Thus, differences in serum 25(OH)D levels largely explain the higher mortality rates for African-Americans compared to White-Americans.

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The Health Benefits of Vitamin D and Estimates of Reductions in Mortality Rates for Canada and the United States William Grant, PhD Reduction in Deaths with More Vitamin D: Estimate for U.S. for 2002 for a Mean Serum 25(OH)D Level of 42 ng/mL Disease CVD Cancer Diabetes, T2 Lower respir.

Septicemia Hip fractures TB Total, vit. D Total, all

Deaths (x1000) 923 559 77 60 31 14 1 1665 2401

Vitamin D Reduction % 25 25 10 25 30 30 30 24 17 (9-24)

Reduction in Deaths with More Vitamin D: Estimate for Canada for 2005 for a Mean Serum 25(OH)D Level of 42 ng/mL (105 nmol/l

Deaths Reduction 231,000 139,000 8,000 15,000 9,000 4,000 300 406,000 406,000

Disease CVD Cancer Diabetes Lower respir.

Septicemia Fractures, falls

Dementia Total, vit. D Total, all

Benefits of Vitamin D for Europe

Vitamin D Reduction % 25 25 15 30 25 20 20

Deaths Reduction 16.5 16.8 1.2 1.8 0.4 0.3 2.0 39.0

17 (10-23)

Benefits of Vitamin D for North America

 Grant WB, Cross HS, Garland CF, Gorham ED, Moan J, Peterlik M, Porojnicu AC, Reichrath J, Zittermann A. Estimated benefit of increased vitamin D status in reducing the economic burden of disease in Western Europe. Prog Biophys Mol Biol. 2009 Feb-Apr;99(23):104-13.

 Grant WB. In defense of the sun: An estimate of changes in mortality rates in the United States if mean serum 25-hydroxyvitamin D levels were raised to 45 ng/mL by solar ultraviolet-B irradiance. DermatoEndocrinology, 2009;1(4):207-14.  Grant WB, Schwalfenberg GK, Genuis SJ, Whiting SJ. An estimate of the economic burden and premature deaths due to vitamin D deficiency in Canada, Molec Nutr Food Res in press (August 2010)

 Grant WB, Schuitemaker G. Health benefits of higher serum 25-hydroxyvitamin D levels in The Netherlands.

J Steroid Biochem Molec Biol, in press.

Serum 25(OH)D levels

Risks of High Vitamin D Intake  There are very few adverse effects of higher vitamin D intake:

The consensus of scientific understanding of ‘cutoffs’ in serum 25(OH)D levels appears to be:  Deficiency

Deaths (x1000) 66 67 8 6 2 2 10 161 230

 For most people hypercalcemia will not occur for <20,000 IU/day.  For those with active TB, sarcoidosis or granulomatous diseases and some with lymphoma, adverse effects from hypercalcemia may occur at lower intakes due to increased serum 1,25(OH)2D formation by the innate immune system.  Note that the current “upper tolerable limit” of vitamin D supplementation, 2000 IU/day, was based on a study in India with patients who had tuberculosis and developed hypercalcemia at 3800 IU/day.

<20 ng/mL (50 nmol/L)

 Insufficiency in the range: 20-32 ng/mL  Gray area – almost sufficient 32-40 ng/mL  Optimal in the range: 40-80 ng/mL  Vitamin D excess: >100 ng/mL

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The Health Benefits of Vitamin D and Estimates of Reductions in Mortality Rates for Canada and the United States William Grant, PhD

Sources of Vitamin D

Vitamin D Production Rate, Season

 Solar UVB, especially near solar noon, with as much skin exposed as possible, but without turning pink or red.

Gradual increase in UV in spring/summer leads to tanning and development of a SPF value of 2-4.  Supplements, 1000-7000 IU/day (each 1000 IU/day increases serum 25(OH)D by about 10 ng/mL)  Diet, provides only 250-300 IU/day in the U.S.  Artificial UVB sources such as in indoor tanning facilities with 3-5% UVB of total UV but with care not to overdo it.

Young person, pale skin, 10% of body exposed, near solar noon, IU/minute

 One can produce 10,000-15,000 IU in a few minutes in a sunbed.

Suggested Action Items

Vitamin D Scientists’ Call to Action

Urge your family and friends to learn about the importance of vitamin D. Urge your doctors and organizations to promote vitamin D awareness. Ask your local, state, and federal officials to consider vitamin D as a way to reduce health care expenditures. Determine your own serum 25(OH)D levels and increase to 40-80 ng/mL, e.g.

Organized by www.grassrootshealth.net 16 leading vitamin D researchers calling for a standard vitamin D intake of 2000 IU/day and the achievement of a serum level of 40-60 ng/ml. Signed by JJ Cannell, CF Garland, FC Garland, E. Giovannucci, ED Gorham, WB Grant, J Hathcock, RP Heaney, MF Holick, BW Hollis, C Johnson, JM Lappe, AW Norman, DL Trump, R Vieth, and WC Willett.

www.grassrootshealth.net ($60)

Conclusion

Additional Resources

 Low serum 25(OH)D is a significant risk factor for most of the chronic and infectious diseases in Canada and the United States.  If the mean serum 25(OH)D levels in both countries were raised to 42 ng/mL (105 nmol/L), the mortality rates could fall by 17%, corresponding to about a 2 year increase in life expectancy.  Increasing serum 25(OH)D levels seems to be the single most efficient way to reduce disease incidence and mortality rates.

http://www.grassrootshealth.net/ http://www.healthresearchforum.org.uk/ http://www.pubmed.gov http://www.sunarc.org/ http://www.vitamindcouncil.org/

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Antimicrobial Effects of Vitamin D Adrian Gombart, PhD

Disclosures

Antimicrobial Effects of Vitamin D

We thank the following for funding the research: NIH/NIAID 5R01AI065604

Adrian F. Gombart, Ph.D. Linus Pauling Institute Department of Biochemistry & Biophysics Oregon State University

Linus Pauling Institute

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We get Vitamin D from

What is Vitamin D?

Skin Vitamin: organic substances that are present in natural foodstuffs

Diet Vitamin D

or

Liver

25(OH)-Vitamin D (inactive)

Hormone: a product of living cells that circulates in body fluids

Kidney/ Renal

Cyp27B1 1a-hydroxylase

Extra-Renal

1,25(OH)2-Vitamin D (active)

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Antimicrobial Effects of Vitamin D Adrian Gombart, PhD

Vitamin D3 synthesis in skin

C A

D

Conversion to the active Vitamin D3 form in the body

UV or sunlight

B

Liver CYP27A1

skin

Kidney CYP27B1

Cholecalciferol Vitamin D3

7-dehydrocholesterol

OH

OH HO

Cholecalciferol Vitamin D3

Is diet a good source of vitamin D?

25-hydroxyvitamin D3

1,25-dihydroxyvitamin D3

Light (UV)-treated Mushrooms

Conversion to the active Vitamin D2 form in the body

Vitamin D2 synthesis in fungi

Liver CYP27A1

Kidney CYP27B1

OH

C A

D

OH HO

UV or sunlight

B

fungi Ergosterol

Ergocalciferol Vitamin D2

Ergocalciferol Vitamin D2

25-hydroxyvitamin D2

1,25-dihydroxyvitamin D2

OH HO

1,25-dihydroxyvitamin D3

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Antimicrobial Effects of Vitamin D Adrian Gombart, PhD

Dietary Sources of Vitamin D IUs per serving

Percent DV

Cod liver oil, 1 table spoon Salmon (sock e ye ), cook e d, 3 ou n ce s Mushrooms t h at h ave be e n

Food

1,360

340

794

199

e xpose d to u ltraviole t ligh t to in cre ase vitam in D, 3 ou n ce s (n ot ye t com m on ly available ) Mackerel, cook e d, 3 ou n ce s

400

100

388

97

Tuna fish, can n e d in wate r, drain e d,

154

39

115-124

29-31

100

25

80

20

60

15

46

12

46

12

40

10

25

6

6

2

Sources of Vitamin D

3 ou n ce s

Milk, n on fat, re du ce d fat, an d wh ole , vitam in D-fortifie d, 1 cu p

Orange juice f ortifie d with vitam in D, 1 cu p

Yogurt, fortifie d with 20% DV, 6 ou n ce s

Margarine, fortifie d, 1 table spoon Sardines, can n e d in oil, drain e d, 2 sardin e s

Liver, be e f, cook e d, 3.5 ou n ce s Ready-to-eat cereal, fortifie d, 0.75-1 cu p Egg, 1 wh ole (vitam in D is fou n d in yolk ) Cheese, S wiss, 1 ou n ce *IUs = In te rn ation al Un its.

© 2008 TrustTanning.com

RDA 400 IU

http://ods.od.nih.gov/factsheets/vitamind.asp

Vitamin D Deficiency: A major health risk for young and old

Why is Vitamin D good for you?

• • • • • •

Normal bone growth and mineralization Reduces risk of falls in elderly Reduces risk of bone fractures in elderly Reduces memory loss Reduces cancer risk Reduces risk of autoimmune diseases

• Estimated 1 billion worldwide – Deficient (<20 ng/ml) or – Insufficient (21-29 ng/ml) – Sufficient (>30 ng/ml)

• 40-100% of US and European elderly (not in nursing homes) deficient • 70% of US children insufficient; 10% deficient • Numerous associated health problems

– Rheumatoid arthritis, type 1 diabetes, multiple sclerosis, Crohn’s disease

• Reduces risk from infectious diseases • Decreased risk of mortality from any cause

Classical (Renal) Activities

Rickets & Osteomalcia

• Normal bone growth and mineralization

Adapted from LPI

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Antimicrobial Effects of Vitamin D Adrian Gombart, PhD

Increasing serum 25(OH)D reduces circulating PTH levels

How much vitamin D do you need?

• • • • •

US RDA 400 IU, adults; 200 IU, children AAP 400 IU, children Elderly, 600 IU Linus Pauling Institute 2000 IU, adults IOM will revise Summer 2010

Holick M F Mayo Clin Proc. 2006;81:353-373

Best source of vitamin D

What does 400 IU do for you?

•Consider: 100 IU raises serum level ~ 1ng/ml

Vancouver, BC 49.13o N (dark caucasian) Time outside at noon to make 1,000 IU vitamin D December 20th (overcast): 24 h April 20th (broken clouds): 17 min August 20th (clear skies): 8 min

•Average winter levels of 25(OH)D in adults: •Caucasian 18-22 ng/ml •African American 15-18 ng/ml •Want to reach >30 ng/ml

http://nadir.nilu.no/~olaeng/fastrt/VitD-ez_quartMED.html

What Factors affect synthesis by skin and serum levels of 25(OH)D?

Summary • Best source of vitamin D is sunshine, but not in winter above 35-40o latitude • Some dietary sources, but supplement most reliable • Chronic deficiency leads to poor health • Affects numerous bodily functions

•Climate •Season/Geographical location •Skin color •Clothing •Sun screen usage •Age •Diet and Supplement usage •Obesity

How?

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Antimicrobial Effects of Vitamin D Adrian Gombart, PhD

Vitamin D receptor regulates gene expression

How does Vitamin D mediate its effects?

Steroid-hormone nuclear receptors

T hermo-Fisher

T ata, JR. Nature Reviews Molec ular Cell Biology 3, 702-710 (September 2002)

HRE

RGKTCANNNRGKTCA

Lack of vitamin D leads to abnormal T-cell function

Nonclassical (Extra-renal) Activitites • A variety of cells express VDR and CYP27B1 – Paracrine, autocrine & intracrine signaling by increasing local levels of 1,25(OH)2 D

• Reduces cancer risk in colon, breast, prostate • Decreases risk of autoimmune diseases • Reduces risk from infectious diseases

Cantorna, Prog Biophys Mol Biol, 2006

Historically sources of vitamin D were used to treat TB

Role of Vitamin D in Innate Immunity • Insufficiency/deficiency correlates with increased susceptibility to bacterial infection (e.g. Mycobacterium) • Activated macrophages metabolize 25(OH)D to 1,25(OH)2D

Cod liver oil

Sanatoriums • 1,25(OH)2D confers increased phagocytic and antimycobacterial activity on macrophages

Mycobacterium tuberculosis

101

Antimicrobial Effects of Vitamin D Adrian Gombart, PhD

Vitamin D increases bactericidal protein expression?

Induction by vitamin D mediated

by VDRE in promoter

• Induction of cathelicidin antimicrobial peptide or CAMP/hCAP18 by 1,25(OH)2D

IF

ELISA

Western medium

U937 cells

Gombart et al., FASEB J, 2005

Antimicrobial peptides

Neutrophil

Defensins a-

human neutrophil peptides, HNP1-4 neutrophil 1o granules human defensins, HD5 & -6 paneth cells

b-

human b-defensins, HBD1-4 keratinocytes, epithelial cells, immune cells

Cathelicidins CAMP/hCAP18 (human) neutrophil 2o granules

Levy, J. Leukocyte Biology, 2004

CAMP/hCAP18 Protein Structure

CAMP/hCAP18 expressed in tissues exposed to environmental microbes

Elastase or Proteinase 3

•Skin, oral mucosa, tongue and colon

SP

Preproprotein

Z

Cathelin prosequence C C C C s

•salivary & sweat glands, epididymis and testis

s

Conserved

s

s

Mature AMP

Variable

Cathelin-derived precursor stored in neutrophil specific granules

•various white blood cell populations Cathelin domain

•significant levels in plasma (~1mg/ml)

FALL39 or LL37

Amphipathic a-helix

Bactericidal activity Cysteine protease inhibitor

102

Bactericidal activity Binds endotoxin and protects against sepsis Promotes angiogenesis Promotes wound healing Chemoattractant for inflammatory cells Pro- and anti-inflammatory properties

Antimicrobial Effects of Vitamin D Adrian Gombart, PhD

Cathelicidin is important for innate immunity

Disrupts integrity of bacterial membrane

• Murine knockout susceptible to: – Skin and urinary tract infections – Colonization of the gut – eye infection

• Reduced levels in atopic dermatitis – Increased skin infections

• Lack of expression in patients with neutrophil disorders – susceptible to bacterial infections Oren et al., Bioc hem J. 1999; 341: 501–513

Activation of Innate Immune Response via TLR

TLR activation of CAMP is vitamin D-dependent

CAMP is not directly induced by this pathway.

Macrophage

Science 24 Marc h 2006: Vol. 311. no. 5768, pp. 1770 - 1773

Low serum levels of 25(OH)D do not support induction of CAMP FEBRUARY 2008 VOL 4 ADAMS AND HEWISON NAT URE CLINICAL PRACT ICE ENDOCRINOLOGY & MET ABOLISM

http://www.biken.osaka-u.ac.jp/act/act_akira_e.php

Vitamin D-induced CAMP expression is not observed in mice

Lack of VDRE in mouse, rat and dog CAMP Promoters

VDRE

QRT-PCR

VDRE present in Alu-Sx SINE (Short Interspersed Element )

Gombart et al., FASEB J, 2005

Gombart et al., FASEB J, 2005

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Antimicrobial Effects of Vitamin D Adrian Gombart, PhD

Alu-S SINEs play role in gene expression

A

K18 Keratin

RARE

CD8

Lyf-1, bHLH, GATA-3

g chain Fc receptor

+ and - elements

PTH

- Ca2+ RE

BRCA-1

ERE

WT-1

silencer

hGH

silencer

MPO

RRE & TRE

OWM

NWM

sa pie P. tro ns glo P. pa dyt e n G. isc s go us ril la P. py g m M . m ae us u M . n latta em es C. trin ae L. thio a lag ps ot A. ric hia ge S. offr lab oy iat i us A. tr C. ivirg jac atu ch s us

hominids

Regulatory element

H.

GENE

The Alu-Sx is conserved in non-human primates

*

1018 506/517

B

*

*

AluSx SINE present in genomes of primates not prosimians

ALU Sx

All others ALU Ya3

M. mulatta ALU Sc

C. jacchus S. labiatus ALU Sq VDRE Batzer & Deininger, Nature Rev iews Genetics 3, 370-379 (2002)

Primate VDREs are conserved & functional

Vitamin D regulation may prevent suppression of CAMP gene expression by pathogens

Rhesus monkey monocytes

CAMP/18S (ng)

Reporter assays

Adams et al., J Immunol , 2009

-

+ #1

-

+

1,25(OH)2D3

#2

Developed a humanized mouse model

How can we study biological importance of vitamin D –cathelicidin pathway in human disease?

1. 6.2kb genomic fragment contains entire phylogenetically conserved 5’ promoter and 3’ regions.

2. Responds to 1,25D3 and myeloid transcription factors.

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Antimicrobial Effects of Vitamin D Adrian Gombart, PhD

Human CAMP responds to 1,25(OH)2D CAMP/18S (ng)

lu ng

ki dn ey

S gl aliv an ar d y

PM N BM

+

to ng ue

us

M NC

th ym

-

CAMP/18S (ng)

ey e

s thy mu

- + - + - + - + - + - + - + 1,25D3

BM

MN BM C PM N sk in to ng Sa ue liva ry gla nd lun g kid ne y Sm li ve all r inte s ti ne co lon

Plasma levels (ng/ml) WT: 0 Tg: 6,000-12,000

BM

CAMP/18S (ng)

Human CAMP expressed in mouse tissues

Liver

hCAMP18 expression in spleen and BM of transgenic mice

-

+

Small Intestine

-

+

Colon

+ 1,25D3

Eye

hCAMP18 expressed in Neutrophils

Spleen Gr-1 + gated cells Bone Marrow

Tg6

Tg16

Macrophage killing assay for salmonella comparing Wt to Transgenic Camp-18

Transgenic expression of Camp-18 induced by Vitamin D In BM derived Macrophages after 2 days

CFU/ml

untreated

Vit D3 10-8

Vit D3 10-9

Vit D3 10-7

8 hrs post infection

105

Antimicrobial Effects of Vitamin D Adrian Gombart, PhD

Summary The VDRE in the human CAMP gene may allow regulation by compounds other than vitamin D

• Antimicrobial peptides are critical for innate immune response • Vitamin D important for innate immune function • CAMP induction requires activation of vitamin D pathway via TLR signaling • Induction of CAMP mediated by primatespecific transposable element carrying a VDRE • Humanized mouse model for infectious disease models

Alternative Receptors may bind VDRE

Alternative ligands for VDR Lithocholic acid

Curcumin

Acknowledgements

Beyond vitamin D and the VDR Cholesterol

Liver/biliary epithelium Primary bile acids

FXR Xenobiotics

RXR

VDR

Oregon State University Tsuyako Saito Malcolm Lowry Mary Fantacone Brian Sinnott Jennfier Lam Daniel Calles

Intestinal bacteria Secondary bile acids

RXR

Xenobiotics or alternative ligands VDRE Activate antimicrobial peptide gene expression

106

CSMC Phillip Koeffler James O’Kelly George Liu Terry Doherty

UCLA John Adams Martin Hewison

Jianfei “Jim” Ji University of Copenhagen Niels Borregaard Charlotte Horn

Orthomolecular Psychiatry: Past, Present and Future John Hoffer, MD, PhD This presentation will review the history, present status and possible future development of orthomolecular psychiatry, both as a field of scientific endeavour, and as a grassroots movement that can improve health and empower people with serious mental illnesses.

The term orthomolecular psychiatry was first coined by the renowned American chemist, Linus Pauling, in an article published in the journal Science in1968. In his article Pauling described a biochemical framework for investigating potential nutritional therapies for mental diseases, defining orthomolecular therapy as the treatment of mental diseases by providing the optimum molecular environment for the brain, especially the optimum concentration of substances normally present in the body. The notion that the brain is affected by its molecular environment is not controversial; what made Pauling’s contribution novel was its presentation of a conceptual framework for generating hypotheses about the pathogenesis and treatment of mental diseases.

He identified a number of mechanisms by which variations in the concentration of a vitamin or other naturally-occurring molecule that serves a metabolic regulatory role could improve brain function, such as by changing an enzyme’s catalytic activity through a shift in the equilibrium between co-enzyme and apo-enzyme. Pauling’s notion that different molecular disorders might benefit from high concentrations of certain nutrients has been fully supported by recent findings in the molecular biology, notably as summarized by the renowned molecular biologist Bruce Ames.

Pauling’s interest in orthomolecular psychiatry was first stimulated by reading the work of Abram Hoffer and Humphrey Osmond, two Saskatchewan psychiatrists whose careful clinical trials of niacin and vitamin C indicated that patients with acute schizophrenia who received this therapy had much better short- and long-term clinical outcomes than patients treated with the best psychiatric therapy of the day. However, despite its publication in mainstream research journals, niacin-ascorbic acid therapy for schizophrenia was ignored by academic psychiatrists. Dating from the mid-1960’s, many practicing psychiatrists and primary care physicians began to include niacin and ascorbic acid in a multi-faceted, empirical therapy that included other micronutrients (especially pyridoxine, zinc, and essential fatty acids), and a “junk food-free” low-carbohydrate diet, as well as test exclusions of certain foods such as dairy or wheat, always in combination with the best pharmacotherapy available.

High rates of sustained clinical remission were claimed in case reports and case series, but regrettably, despite its promise, appropriately designed, modern randomized clinical trials have yet to be carried out, and orthomolecular therapy remains an unproven, widely disregarded approach for the treatment of major mental illness.

Current views about schizophrenia are in keeping with the notion that patients in the early stage of the disease may respond to a therapy that is far less effective after it has progressed to a fixed chronic state. High-dose niacin, widely used to treat hyperlipidemic conditions, is safer and freer from side effects than conventional antipsychotic drugs. Modern investigators, using a quantitative skin patch technique, have confirmed that patients with schizophrenia tend not to flush when exposed to niacin. A recent, landmark publication demonstrated that expression of the newly described niacin receptor, which mediates the niacin flush, is diminished in critical areas of the brains of people with schizophrenia. The possibility remains to be tested that resistance to the niacin flush indicates patients more or less likely to respond favorably to niacin therapy. There is recent interest in the possibility that large doses of the long-chain fatty acid, eicosapentaenoic acid, can ameliorate the abnormal biochemistry responsible for schizophrenia.

New ideas are needed in schizophrenia research and therapy, and vitamin therapy for acute schizophrenia should be one of them. However, clinical trials of vitamin therapy would have to compete for funding from public grant agencies, and for patient enrollment with large pharmaceutical industry-sponsored trials that provide much-needed money to psychiatric research institutions. In addition to these financial barriers are the well-known practical difficulties of conducting meaningful randomized clinical trials in acute schizophrenia, with the additional problem of interpreting their results, given the possibly diverse etiologies targeted by the vitamin therapies. A strong case has been made for a pragmatic strategy of small-scale, carefully conceived and objectively documented open clinical trials and case studies which assemble, through enlightened clinical experience, the elements of an effective therapeutic program which would only then be put to the final test of a randomized clinical trial. Empirical trials of this kind are ethical, since the nutritional approach is biologically and clinically plausible, and the vitamins that would be used lack the side effects and toxicity of the antipsychotic drugs. If they proved effective, these nutrients could reduce the exposure of young people to prolonged and potentially harmful drug therapy.

Practitioners of orthomolecular psychiatry owe it both to their individual patients and to the possible wider benefit of this therapy, to carefully describe the treatment regimen they use and document the responses they observe, with a view to publishing high quality rigorous case reports in the Journal of Orthomolecular Medicine or elsewhere. Supporters of orthomolecular therapy should continue to point out the inadequacies of modern conventional psychiatry and the need for new ideas, to agitate for better nutrition for the mentally ill, and to demand more openness to nutritional therapies for mental illness on the part of mainstream psychiatry.

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William Shaw, PhD

Mitochondrial dysfunction in autism and other neurological and psychiatric diseases William Shaw Ph.D. The Great Plains Laboratory, Inc. Lenexa, KS. USA 913 341-8949 wshaw@gpl4u.com

Arch Otolaryngol Head Neck Surg. 2002;128:355-362

Arch Otolaryngol Head Neck Surg. 2002;128:355-362

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Respiratory complexes I-V

Unique mitochondria DNA

Central role of Krebs cycle Pyruvate

Glucose

• Mitochondria DNA uses different genetic code from nuclear DNA • Mitochondria DNA not attached to histones, proteins that bind to DNA and regulate the expression of genes • Histones protect DNA from free radical damage and assist in repairing DNA damage • Mitochondria DNA does not have this histone protection; more subject to chemical damage and mutations • Mitochondria may be descendants of bacteria that invaded cells a billion years ago

Thiamine, vitamin B1,B2, niacin, lipoic acid

Acetyl CoA Oxalacetic Citric

Krebs cycle for energy production in cell Fumaric Malic

Aconitic

Isocitric Succinic Succinyl CoA

2-oxoglutaric

Unique mitochondria DNA

Mitochondria general

• Each mitochondrion contains 2 to 10 copies of the mitochondrial DNA (mt DNA).

• Circular, double-stranded DNA molecule 16569 base pairs (bp) in length.

• Mitochondrial DNA encodes only 13 of the more than 1000 proteins required for mitochondrial biogenesis and function.

• 16-100,000 mitochondria per cell • 16 in tail of sperm-none enter fertilized egg • 100,000 in oocyte- all mitochondrial DNA comes from mother • Mitochondria found in all cells except red blood cells • Produce 90% of the energy in the cell • Uses 85% oxygen in the cell • Krebs cycle and electron transport chain (ETC) are 2 major biochemical functions • Highest number in heart and skeletal muscle, liver, and brain which are organs that require greatest amount energy

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William Shaw, PhD Signs of mitochondrial dysfunction Cohen and Gold, 2001

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 7 JULY 2001 625-642

• Muscles-low muscle tone, weakness, low exercise tolerance, muscle pain, cramps • Brain-developmental delay, mental retardation, autism, dementia, seizures, migraines, stroke • Nerves-nerve pain, absent deep tendon reflexes, lack of or excessive sweating, abnormal temperature regulation • Gastrointestinal problems-reflux, constipation,

Diseases associated with mitochondrial disorder • Autism • Diabetes • Cancer • Alzheimer’s • Anxiety • Chronic fatigue syndrome • Exercise intolerance

Tiglylglycine as a marker of mitochondrial dysfunction

• Parkinson’s • Bipolar disorder • Aging • Schizophrenia • Heart disease • Toxic chemical exposure

Tiglylglycine is specific Marker for mitochondrial function

Isoleucine-branched chain amino acid

Autism rates in Texas 2-oxo-3-methylvalerate 2-methylbutyryl CoA tiglyl-CoA

2-methylbutyrylglycine Associated with autism

tiglylglycine

2-methyl-3-hydroxybutyryl-CoA NAD+ MHB-CoA Dehydrogenase Therapy: NADH High doses of NAD+ 2-methylacetoacetyl-CoA

1990-1993

Measured in organic acid test 2-methyl-3-hydroxybutyric acid

x

Mitochondrial Respiratory ChainComplex I

1998-2001

Succinyl CoA

2-MAA Thiolase Acetyl CoA + Propionyl CoA

Methylmalonyl CoA

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William Shaw, PhD

Comparison of autism rates and industrial pollution in Texas

Autism rate1998-2001

Pounds of industrial toxic release

Environmental mercury release, special education rates, and autism disorder: an ecological study of Texas Raymond F. Palmer, et al

Hair metals in boys with autism n=40 boys per group, age matched

• There has been a significant increase in the proportion of children in special education and autism associated with mercury released into the environment.

• For every 1000 lb of mercury liberated into the environment, there has been a 43% increase in the rate of special education students and a 61% increase in the percentage of students with autism.

Autism 9:290-298,2005

Environmental Health Insights 2008:2 55–59

The area of highest ASD cases coincides with the highest density of toxic landfill sites while the area with lowest ASD cases has the lowest density of toxic landfill sites.

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William Shaw, PhD

Impaired mitochondrial energy metabolism and neuronal apoptotic cell death after chronic dichlorvos (organophosphate) exposure in rat brain.

NeuroToxicology Volume 28: 1208-1219,2007 • Decreased mitochondrial electron transfer activities of cytochrome oxidase (complex IV) along with altered mitochondrial complex I, and complex II activity • An increase in lipid peroxidation, and as well as protein and mtDNA oxidation.

• All this could have been because of enhanced oxidative stress, decreased GSH levels and also decreased MnSOD activity in the mitochondria • Evidence of impaired mitochondrial bioenergetics and apoptotic neuronal degeneration after chronic low-level exposure to dichlorvos

E. Guillette et al, "An Anthropological Approach to the Evaluation of Preschool Children Exposed to Pesticides in Mexico," ENVIRONMENTAL HEALTH PERSPECTIVES 106: 347-353,1998.

Pesticide Application

The pesticide-exposed children ● Far less physical endurance in a test to see how they could keep jumping up and down

long

● Inferior hand-eye coordination ● Could not draw a simple stick figure of a human being, which the nonexposed children could readily do.

E. Guillette et al, "An Anthropological Approach to the Evaluation of Preschool Children Exposed to Pesticides in Mexico," ENVIRONMENTAL HEALTH PERSPECTIVES 106:347-353,1998.

Eric M. Roberts, et al Maternal Residence Near Agricultural Pesticide Applications and Autism Spectrum Disorders among Children in the California Central Valley Environ Health Perspect. 115 (10): 1482–1489, 2007

• Children exposed to pesticides called organophosphates used to kill insects had more than twice the risk of developing pervasive developmental disorder (PDD).

• For organochlorines,there was 7X autism rate • Mothers exposed to such pesticides were also likely to have shorter pregnancies and their children to have impaired reflexes .

"Some valley (pesticide-exposed) children were observed hitting their siblings when they passed by, and they became easily upset or angry with a minor corrective comment by a parent. These aggressive behaviors were not noted in the [pesticide-free] foothills [children]."

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Mitochondrial changes in hepatocytes of rats chronically exposed to vinyl chloride and ethanol M. L. Miller Environmental Research Volume 29, 1982, Pg 272-279

Environmental Health Perspectives Vol 114, Sept 2006 Autism Spectrum Disorders in Relation to Distribution of Hazardous Air Pollutants in the San Francisco Bay Area G. C. Windham,et al

• Chronic exposure of male rats to 600 ppm vinyl chloride (VC) or VC and 5% ethanol (EtOH) in drinking water induced ultrastructural changes in the mitochondria of hepatocytes • In animals receiving VC alone, large floccular densities in the mitochondrial matrix were seen occasionally after 6 months of VC inhalation.

• The numbers and severity of changes in mitochondria increased with duration of exposure and age.

• Objective: To explore possible associations between autism spectrum disorders (ASD) and environmental exposures, we linked the California autism surveillance system to estimated hazardous air pollutant concentrations compiled by the U.S. EPA • The individual compounds that contributed most to ASD associations included mercury, cadmium, nickel, trichloroethylene, and vinyl chloride.

An analysis of the associations between indoor environmental variables in 2000 as well as other background factors and the ASD diagnosis indicated five statistically significant variables: (1) maternal smoking (2) male sex (3) economic problems in the family (4) condensation on windows, a proxy for low ventilation rate in the home (5) PolyVinylChloride (PVC) flooring, especially in the parents’ bedroom.

Government concedes vaccines cause autism in Poling case. March 6, 2008

Why did government concede?

• Health officials knew Poling case was a strong case and that they might lose, setting a precedent for future cases and possibly destroying the credibility of the vaccine program • Father was MD PhD neurologist and professor at major medical school-John Hopkins University • Mother was an attorney and nurse • Case was published in peer reviewed journal • Government decided to set precedent (go to trial) on weaker cases with weaker evidence and less educated and less affluent parent advocates?

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Toxic Chemicals, Mitochondria and Mental Health William Shaw, PhD Hannah Poling Case

Within 48 hours after 9 immunizations to diphtheria, tetanus, and pertussis; Haemophilus influenzae B; measles, mumps, and rubella; polio; and varicella (Varivax), the patient developed a fever to 38.9°C, inconsolable crying, irritability, and lethargy and refused to walk.

Four days later, the patient was waking up multiple times in the night, having episodes of opisthotonus (arching), and could no longer normally climb stairs.

Instead, she crawled up and down the stairs. Lowgrade intermittent fever was noted for the next 12 days. Ten days following immunization, the patient developed a generalized erythematous macular rash beginning in the abdomen. The patient’s pediatrician diagnosed this as due to varicella vaccination.

Poling JS, et al. J Child Neurol 2006;21(2):170-172

A 19-month-old girl was born after a normal fullterm pregnancy. There was no family history of autism or affective, neuromuscular, or hearing disorders. Her development was progressing well, with normal receptive and expressive language and use of pre-linguistic gestures, such as pointing for joint attention. Imaginary play and social reciprocity were typical for age.

She used at least 20 words and could point to five body parts on command. Several immunizations were delayed owing to frequent bouts of otitis media (ear infection) with fever.

Defective respiratory complexes (I,II,III,IV) in Hannah Poling’s biopsy

For 3 months, the patient was irritable and increasingly less responsive verbally, after which the patient’s family noted clear autistic behaviors, such as spinning, gaze avoidance, disrupted sleep/wake cycle, and perseveration on specific television programs. All expressive language was lost by 22 months. The patient continued to have chronic yellow watery diarrhea intermittently for 6 months... Four months later, an evaluation with the Infant and Toddlers Early Intervention program for possible autism was initiated. Along with the regression, her appetite remained poor for 6 months and her body weight did not increase. This resulted in a decline on a standard growth chart for weight from the 97th to the 75th percentile.

E n z y m e A c t i v i t y

IVb III IVa

II+III Ia

Ib

I+III I+III

E n z y m e

A c t i v i

How common is mitochondria dysfunction in autism?

Hannah Poling case

• Dr. Oliveira in Portugal tested 69 children with autism and found that five of them (7.2%) had proven mitochondrial disorders.

• Fourteen of the children (20.2%) had high amounts of lactic acid in the blood, a characteristic of mitochondrial disorders.

11 of the 14 children with high lactic acid had a muscle biopsy performed on them.

• Five of the 11 children had subnormal values for the mitochondrial respiratory chain enzyme deficiencies (the critical machinery that generates energy) and thus proven mitochondrial defects, but mitochondrial abnormalities could not be ruled out in the other 6.

• Another study found that lactic acid was absent in 50% mitochondrial disease.

• Thus, 40% of individuals with autism may have mito disorder

• In Hannah Poling’s case , a muscle biopsy revealed deficiencies of the mitochondrial respiratory chain in three of the four respiratory complexes in the mitochondria with the value for the fourth complex near the lower limit of normal.

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William Shaw, PhD

Point mutations are associated with low dose mercury, mitochondria more susceptible to mutations

Properties of tetrachloroethylene (TCE)

Tetrachloroethylene (PERC) toxicity • Tetrachloroethylene is a dry-cleaning agent and industrial degreaser that often goes under the name perchloroethylene (PERC).

• The National Institute of Occupational Safety and Health estimates that 650,000 U.S. workers are exposed to PERC annually.

• PERC enters the environment through evaporation or through transport into groundwater and drinking water supplies.

• Through widespread use it has become a frequent drinking water contaminant, and it is present in approximately half of the nation's Superfund sites.

• Dry cleaning agent, pharmaceutical manufacturing, metal degreaser, grain fumigant.

• Contamination of ground water from industrial contamination • Dermatitis, irritation of the eyes, nose, and throat.

• Acute exposure has been known to cause depression of central nervous system.

• Malaise, dizziness, headaches, increased perspiration, cardiac arrhythmias, renal injury, carcinogenic

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Normal Brain

Gash DM et al. Trichloroethylene: Parkinsonism and complex 1 mitochondrial neurotoxicity.

Ann Neurol. 2008 Feb;63(2):184-92.

Parkinson’s Brain

• Workers exposed to trichloroethylene (TCE) by chronic inhalation and dermal exposure from handling trichloroethylene-soaked metal parts had Parkinson's disease.

• Nearby coworkers receiving chronic respiratory exposure, displayed many features of parkinsonism, including significant motor slowing.

• TCE was toxic to animals exposed for 6 wks. The animals had selective complex 1 mitochondrial impairment in the midbrain with striatonigral fiber degeneration and loss of dopamine neurons, simulating human Parkinson disease.

• TCE, used extensively in industry and the military and a common environmental contaminant, joins other mitochondrial neurotoxins and some pesticides, as a risk factor for parkinsonism.

Loss of neurons in the substantia nigra

Gash DM et al. Trichloroethylene: Parkinsonism and complex 1 mitochondrial neurotoxicity Ann Neurol. 2008 Feb;63(2):184-92.

Gash DM et al. Trichloroethylene: Parkinsonism and complex 1 mitochondrial neurotoxicity Ann Neurol. 2008 Feb;63(2):184-92.

• Eddie Abney worked for more than 20 years at a factory in Kentucky which used trichloroethylene (TCE) to remove grease from equipment, • He had little protection and absorbed the solvent by inhalation and direct contact with the skin • At night in bed, he reeked of the smell of TCE. • Developed severe Parkinson’s disease • Two coworkers who also were exposed developed Parkinsons • 27 other people nearby developed neurological symptoms like tremors

• Rats were exposed to TCE and were found to have mitochondria damage.

• Complex 1, a mitochondria enzyme important in energy production, was significantly reduced in the substantia nigra, the brain area damaged in Parkinson’s syndrome.

• Dopamine neurons in this area also showed degenerative changes following TCE administration

Cerebro con Alzheimer

Alzheimer’s Disease

Alzheimer’s disease • Alzheimer’s disease is by far the most common form of adult onset dementia, affecting over 4 million individuals in USA. • Approximately 14 million individuals in the US alone will have AD by the year 2050 unless preventive measures are found.

• The economic burden of AD is estimated to be over 100 billion dollars per year.

• AD is not the only adult onset dementia but its prevalence reflects approximately 60% to 75% of all cases, given that AD often coexists with other dementia disorders.

Normall Cerebro Normal

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William Shaw, PhD Kukull WA, et al. Solvent exposure as a risk factor for Alzheimer’s disease: a case-control study. Am J Epidemiol 1995;141(11):1059–79

Freed DM, Kandel E. Long-term occupational exposure and diagnosis of dementia.

Neurotoxicology 1988;9(3):391–400.

• 139 individuals diagnosed with Alzheimer’s disease and 243 controls • History of exposure to one or more solvent groups (benzene and toluene, phenols and alcohols, and ketones plus other solvents) resulted in an adjusted Alzheimer’s Disease odds ratio of 2.3 for both sexes • For men the odds ratio increased to 6.0 (95% CI, 2.1–17.2).

• Serum levels of tetrachlorethylene, dry cleaning solvent (745 parts per billion) were approximately 15 times that seen in a normal population.

• Man worked as a dry cleaner for over 30 years and was subsequently diagnosed with probable Alzheimer’s Disease.

Toxicol Pathol. 2008 Mar 18 Long-Term Air Pollution Exposure Is Associated with Neuroinflammation, an Altered Innate Immune Response, Disruption of the Blood-Brain-Barrier, Ultrafine Particulate Deposition, and Accumulation of Amyloid {beta}-42 and {alpha}-Synuclein. Calderón-Garcidueñas L et al (PMID: 18349428)

Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders. Sas K et al. J Neurol Sci. 2007 257:221-39.

• Quinolinic acid is a specific agonist at the N-methyl-d-aspartate receptors, and a potent neurotoxin with a marked free radical-producing property.

• Implicated as major neurotoxin in Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS),schizophrenia • Kynurenine protects against quinolinic acid damage

• Performed brain pathology studies on deceased residents in highly polluted cities.

• Exposure to air pollution should be considered a risk factor for Alzheimer's and Parkinson's diseases.

• Carriers of the APOE 4 allele could have a higher risk of developing Alzheimer's disease if they reside in a polluted environment.

Quinolinic Acid Production

Implications of the kynurenine pathway and quinolinic acid in Alzheimer's disease. GUILLEMIN Gilles J. ; BREW Bruce J. • Aβ 1-42, a cleavage product of amyloid precursor protein, induces production of quinolinate, in neurotoxic concentrations, by macrophages. and, more importantly, microglia.

• Senile plaques in Alzheimer's disease are associated with evidence of chronic local inflammation (especially activated microglia).

• Major aspect of quinolinate toxicity is lipid peroxidation and markers of lipid peroxidation are found in Alzheimer's disease.

• These data imply that quinolinate may be one of the critical factors in the pathogenesis of neuronal damage in Alzheimer's disease.

Increases neurotoxic Quinolinic acid

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William Shaw, PhD

Suggested treatments to lower quinolinic acid • Avoid tryptophan supplementation which increases quinolinic acid. Use 5hydroxytryptophan instead. Not converted to quinolinic acid.

• Use niacin (causes flushing) or flush-free niacin inositol (hexaniacinate) that reduces conversion of tryptophan to quinolinic acid • Avoid multiple vaccinations which produce cytokines that stimulate enzymes producing excess quinolinic acid • Reduce stress in your life

Even attenuated measles virus cause the Induction of Indoleamine 2,3 dioxygenase which induces production of toxic quinolinic acid

Organic acid testing

Thank you!

• 96 different metabolites • Additional screening for 73 different non-metal toxic chemicals that form organic acids including trichloroethylene, vinyl chloride, and organophosphates • Quinolinic acid • Tiglyglycine-most sensitive mitochondrial marker • 5-hydroxyindoleacetic acid-serotonin marker • Nutritional deficiencies-B12, B6, biotin, vitamin C, • Genetic disorders • Other Mitochondrial markers • Comprehensive interpretations • Markers for metal toxicity (HVA, VMA)

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Vitamin B12 and Psychiatry

Inaugural Abram Hoffer Memorial Lecture: Jonathan Prousky, ND, MSc Inaugural Abram Hoffer Memorial Lecture: Vitamin B-12 and Psychiatry

Inaugural Abram Hoffer Memorial Lecture: Vitamin B-12 and Psychiatry

 Abram Hoffer (AH), the founding father of orthomolecular medicine, was instrumental in using vitamins therapeutically, i.e., the vitamin-astreatment paradigm.  He recognized the therapeutic value of prescribing various B vitamins (e.g., vitamins B-3, B-6, and B12) when treating psychiatric disorders.

Jonathan E. Prousky, ND, MSc The Canadian College of Naturopathic Medicine Editor, Journal of Orthomolecular Medicine Email: jprousky@ccnm.edu

 AH believed that patients responding to vitamin treatments were likely suffering from vitamin dependencies (i.e., vitamin dependency disorders).

Inaugural Abram Hoffer Memorial Lecture: Vitamin B-12 and Psychiatry

Inaugural Abram Hoffer Memorial Lecture: Vitamin B-12 and Psychiatry

 If we examine vitamin B-12 and not the other B-vitamins, we find that it has been the subject of a tremendous amount of psychiatric reports and research for many decades.

 After carefully reviewing numerous reports and research articles on vitamin B-12, it is evident that there is a lack of consensus on using vitamin B-12 therapeutically when administered to patients not “classically” deficient in the vitamin.  Vitamin B-12 therapy continues to be viewed by many mainstream-minded clinicians as dubious at best, quackery, and sacrilege.

 A simple search on PubMed reveals more than one hundred reports that span more than 50 years.

Inaugural Abram Hoffer Memorial Lecture: Vitamin B-12 and Psychiatry

Cobalamin absorption & transport

 The overarching purpose of this lecture is therefore to show the rationality of using vitamin B-12 therapeutically, even in the absence of “classical” vitamin B-12 deficiency. To accomplish this I will:

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The presence of HCl and pepsin sever cobalamin from dietary (animal) protein.

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The free cobalamin is then bound to R-protein, released from parietal cells of the stomach and salivary cells.

Review the absorption, metabolism and biochemical properties of vitamin B-12.

Review the underlying conditions that predispose to vitamin B-12 insufficiency/deficiency.

Review relevant psychiatric publications Discuss why vitamin B-12 works Show a reasonable diagnostic scheme to assist clinicians in their evaluation of vitamin B-12 status.

Discuss effective treatment options

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Intrinsic factor (IF) is also released in the stomach, but does not bind with vitamin B-12 until it reaches the first part of the jejunum.

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The B-12-IF complex travels to the terminal ileum and attaches.

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B-12 is actively transported from the terminal ileum into the blood. Transfer of B-12 in the blood depends on specific binding proteins (transcobalamin I, II, and III).

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Vitamin B12 and Psychiatry

Inaugural Abram Hoffer Memorial Lecture: Jonathan Prousky, ND, MSc

Cobalamin absorption & transport

Minimum requirements

 Absorbed B-12 is stored in the liver for up to four years, excess is secreted in the urine.  Some reports have even suggested that it can take up to 20 years for stores to be depleted resulting in significant signs and symptoms.

 RDA (US): 2µg  RNI (Canadian): 1 µg

A closer look

Vitamin B-12 & fatty acids

 Example vitamin B-12 content:    

 In the cytoplasm, B-12 is required for the conversion of homocysteine to methionine  THF is generated from methyl folate via a B-12dependent enzyme  Methyl folate is the dominant form of folate in human serum and liver (and other storage sites)  Methyl folate (inactive) can only return to the body’s folate pool via a B12-dependent step

Beef liver 3 oz., 93.5 µg Chicken 3 oz., 0.3 µg Brewers yeast 2 T., 2.0 µg Blue-Green algae 3 g, 23.1 µg

 In the mitochondria B12 is needed for the conversion of methylmalonyl CoA to Succinyl CoA  This pathway contributes to the body’s Succinyl CoA supply, a compound which is integral to Kreb’s cycle and heme synthesis

Some of the major causes of vitamin B-12 deficiency?

Additional biochemical properties of vitamin B-12  Because Vitamin B-12 participates in the production of S-adenosylmethionine (SAM), a donator of methyl groups, it plays a decisive role in the functioning of the neuropsychiatric system by stimulating:

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 The formation of phospholipids that are a component of neuronal myelin sheaths and cell receptors (Karakula 2009).  The formation (i.e., synthesis) of monoamine neurotransmitters (Hutto 1997, Karakula 2009).

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Poor intake in the diet (e.g. vegans) Malabsorption (e.g. celiac disease) Elderly (e.g., food-cobalamin malabsorption) Deficient HCl (e.g., hypochlorhydria, achlorhydria) Deficiency of intrinsic factor (e.g., pernicious anemia) Small intestinal disorder affecting ileum (e.g. regional enteritis) Drugs interfering with B-12 absorption (e.g. metformin) Parasites (e.g. tapeworm) Gastrectomy, gastric bypass surgery Increased requirement (e.g. pregnancy, hyperthyroidism) Increased excretion (e.g. liver disease - cannot store B12 properly)

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Vitamin B12 and Psychiatry

Inaugural Abram Hoffer Memorial Lecture: Jonathan Prousky, ND, MSc What happens in vitamin B-12 deficiency?

Some of the main signs/symptoms of “classical” vitamin B-12 deficiency  Parasthesias and numbness in lower extremities progressing to complete paraplegia  Decreased vibration and/or position sense  Poor muscular coordination with ataxia  Mental slowness, poor memory, confusion, agitation, depression, moodiness  Weakness, fatigue  Indigestion, diarrhea  Smooth, beefy tongue  Megaloblastic cells, hypersegmented neutrophils, high MCV

 Increased homocysteine levels  Decreased methionine & SAM supply, leading to impaired methylation and, consequently impaired metabolism of neurotransmitters, phospholipids, myelin and receptors  Decreased THF available for DNA synthesis  Folate is “trapped” in its inactive form  Incomplete fatty acid metabolism  Decreased Succinyl CoA supply affecting carbohydrate metabolism and heme synthesis

Biochemically, a patient is considered to be deficient in vitamin B-12 when:

Neurological and/or PSYCHIATRIC manifestations CAN precede hematological changes

 The serum cobalamin level is < 74 pmol/L (100 pg/ml) (OH 2003).  The serum cobalamin level is less than 150 pmol/L (200 pg/ml) on 2 separate occasions; OR serum cobalamin level is < 150 pmol/L (200 pg/ml) AND total serum homocysteine level is > 13 µmol/L OR methylmalonic acid > 0.4 µmol/L (Andrès 2004).  Most Ontario labs consider a patient to be deficient in vitamin B-12 if the serum level is less than 110 pmol/L (150 pg/ml).

 It is less well known that psychiatric symptoms may be the first symptoms of vitamin B-12 deficiency and may antedate hematological and neurological symptoms by a long period.  Can be subtle/mild psychiatric complaints to numerous psychiatric signs/symptoms

 Neurologic complaints can include subtle changes in executive functioning to neuropathy, polyneuropathy, and the classical presentation of combined sclerosis of the spinal cord.

Ellis FR, Nasser S: A pilot study of vitamin B12 in the treatment of tiredness. Br J Nutr, 1973;30:277-283.

Select Review of Publications Pertaining to Vitamin B-12 and Psychiatry

 Twenty-nine subjects (7 male and 22 female; mean age 41.5 years old) complaining of idiopathic fatigue or tiredness completed a double-blind crossover trial of injections of hydroxocobalamin (5 mg twice weekly for 2 weeks) followed by a rest period of 2 weeks and then a similar course of matching placebo injections.  Symptoms were assessed by a daily self-rating card that assessed appetite, general feeling of wellbeing, fatigue, mood (i.e., level of happiness), injection response (i.e., how the injection made the subject feel), and sleep.

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Vitamin B12 and Psychiatry

Inaugural Abram Hoffer Memorial Lecture: Jonathan Prousky, ND, MSc Ellis FR, Nasser S: A pilot study of vitamin B12 in the treatment of tiredness. Br J Nutr, 1973;30:277-283.

Ellis FR, Nasser S: A pilot study of vitamin B12 in the treatment of tiredness. Br J Nutr, 1973;30:277-283.

 Those subjects who received the placebo in the first 2-week period showed a favorable response to hydroxocobalamin in the second period on all measurements made.  The results showed statistical significance with respect to general well-being (p=0.006) and ‘happiness’ (P=0.032).

 The initial mean serum vitamin B-12 level was 358.4 pg/ml, range: 200-625 pg/ml (264.4 pmol/L, range 150-461 pmol/L).  By the end of treatment serum concentrations had risen to more than 2000 pg/ml (approximately, 1476 pmol/L) in all but 3 of the total 29 subjects.  16 of the subjects were subjected to psychiatric interviews (3 were considered to be under stress, 1 was diagnosed with anxiety neurosis, and 4 were psychiatrically unstable).

Ellis FR, Nasser S: A pilot study of vitamin B12 in the treatment of tiredness. Br J Nutr, 1973;30:277-283.

van Tiggelen CJM, Peperkamp JPC, Tertoolen JFW: Vitamin B12 levels of cerebrospinal fluid in patients with organic mental disorders. J Orthomolec Psych, 1983;12:305-311.

 These results support the notion that vitamin B-12 has a ‘tonic’ effect.  Response to vitamin B-12 was presumed to be related to pharmacological factors such as the ability of the vitamin to penetrate into brain or neurons, or to an influence of vitamin B-12 on neural metabolism.

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van Tiggelen CJM, Peperkamp JPC, Tertoolen JFW: Vitamin B12 levels of cerebrospinal fluid in patients with organic mental disorders. J Orthomolec Psych, 1983;12:305-311.

van Tiggelen CJM, Peperkamp JPC, Tertoolen JFW: Vitamin B12 levels of cerebrospinal fluid in patients with organic mental disorders. J Orthomolec Psych, 1983;12:305-311.

 When the serum levels of vitamin B-12 were tested, normal values (200-800 pg/ml; 150-590 pmol/L) were found in 45 of the 49 patients from groups 1-3.

All 12 patients in the control group had serum B-12 levels in the normal range.  Deficient CSF levels of vitamin B-12 (<5 pg/ml; <3.7 pmol/L) were found in 30 of the total 49 patients (or in 26 of the 45 patients with normal serum levels). All 12 patients in the control group has CSF levels in the normal range (>10 pg/ml; >7.4 pmol/L).  There was a marked difference between both compartments when measured.

 In group 3, 10 patients had postnatal depression. All of them had normal serum B-12 levels, yet 8 of the 10 patients had pathologically low CSF B-12 levels (<5 pg/ml; <3.7 pmol/L).

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This study sought to determine to what extent vitamin B-12 in the serum is a real reflection of vitamin B-12 status of brain tissue.

Involved 3 groups of patients and 1 control group (group 1 involved 23 patients aged 60-85 with dementia; group 2 involved 16 patients aged 30-60 with organic affective syndrome; group 3 involved 10 female patients aged 25-40 with post-natal depression (and complaints of neurasthenia); and group 4 involved a control group of 12 patients aged 2550).

All were normal hematologically, had normal liver function and kidney function tests, but did have evidence of ‘soft’ neurologic symptoms (i.e., some combination of encephalopathy and/or polyneuropathy or neuropathy).

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Vitamin B12 and Psychiatry

Inaugural Abram Hoffer Memorial Lecture: Jonathan Prousky, ND, MSc van Tiggelen CJM, Peperkamp JPC, Tertoolen JFW: Vitamin B12 levels of cerebrospinal fluid in patients with organic mental disorders. J Orthomolec Psych, 1983;12:305-311.

van Tiggelen CJM, Peperkamp JPC, Tertoolen JFW: Vitamin B12 levels of cerebrospinal fluid in patients with organic mental disorders. J Orthomolec Psych, 1983;12:305-311.

 10 patients were given 6 weeks of twice weekly treatment of parenteral hydroxycobalamin (1000 mcg IM) plus daily treatment with an oral supplement containing 50 mg zinc-DL-Aspartate and 250 mg of taurine.  2 patients were given 6 weeks of a daily supplement containing cyanocobalamin (0.1 mg) plus 50 mg zinc-DL-Aspartate and 250 mg of taurine.

Group

Pretreatment serum B-12 (pg/ml)

Pretreatment CSF B-12 (pg/ml)

Posttreatment serum B-12 (pg/ml)

Posttreatment CSF B-12 (pg/ml)

IM injection (n=10)

310 (230 pmol/L) (average)

<5 (<3.7 pmol/L) (average)

>2400 (>1771 pmol/L) (average)

70 (52 pmol/L) (average)

Oral (Patient #1)

430 (317 pmol/L)

14 (10 pmol/L)

2400 (1771 pmol/L)

21 (15 pmol/L)

Oral (Patient #2)

450 (332 pmol/L)

<5 (<3.7 pmol/L)

>2400 (>1771 pmol/L)

9.6 (7.1 pmol/L)

van Tiggelen CJM, Peperkamp JPC, Tertoolen JFW: Vitamin B12 levels of cerebrospinal fluid in patients with organic mental disorders. J Orthomolec Psych, 1983;12:305-311.

van Tiggelen CJM, Peperkamp JPC, Tertoolen JFW: Vitamin B12 levels of cerebrospinal fluid in patients with organic mental disorders. J Orthomolec Psych, 1983;12:305-311.

 In group 1 (patients with dementia), the authors speculate that zinc deficiency and its corresponding high levels of copper block the transport of B-12 in the choroid plexus, similar to the effects of free radical chain reaction inducers like mercury, cadmium and other neurotoxins.

 In group 3 (patients with post-natal depression) the authors suggest that estrogens or estrogen-receptor binding chemicals (e.g., halogenated hydrocarbons) have an effect on B12 transport through the blood-brainbarrier (BBB) and choroid plexus.

van Tiggelen CJM, Peperkamp JPC, Tertoolen JFW: Vitamin B12 levels of cerebrospinal fluid in patients with organic mental disorders. J Orthomolec Psych, 1983;12:305-311.

van Tiggelen CJM, Peperkamp JPC, Tertoolen JFW: Assessment of vitamin B12 status in CSF. Am J Psychiatry, 1984;141:136-137. 

 These results indicate that a potentially treatable vitamin B-12 deficiency will be overlooked in a significant portion of patients if CSF B-12 levels are not included in the assessment.

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16 geriatric patients aged 60-85 years with dementia or organic affective syndrome with co-existing dementia. All patients had normal liver function and no gross hematological abnormalities. These patients did, however, have signs and symptoms of polyneuropathy.

3 patients had low levels of serum B-12, and low levels of CSF B-12.

The remaining 13 patients had normal serum B-12 levels (220-540 pg/ml; 162-400 pmol/L), with 9 of them also having deficient CSF B-12 levels.

5 patients that had normal serum levels and deficient CSF levels were given 3 months of treatment (parenteral hydroxocobalamin). After 3 months, they experienced considerable clinical improvement and had a rise in their CSF B-12 levels (50-90 pg/ml; 37-66 pmol/L).

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Vitamin B12 and Psychiatry

Inaugural Abram Hoffer Memorial Lecture: Jonathan Prousky, ND, MSc Mitsuyama Y, Kogoh H: Serum and cerebrospinal fluid vitamin B12 levels in demented patients with CH3-B12 treatment--preliminary study. Jpn J Psychiatry Neurol, 1988;42:65-71.

van Tiggelen CJM, Peperkamp JPC, Tertoolen JFW: Assessment of vitamin B12 status in CSF. Am J Psychiatry, 1984;141:136-137. 

  

 The vitamin B-12 (VB12) parameter was studied in the serum and cerebrospinal fluid (CSF) of 14 demented patients.  11 of these patients were in a state of dementia of the degenerative type such as Alzheimer's disease, senile dementia and Pick's disease.  The serum VB12 concentration in all the patients was within normal limits, i.e. 5001,300 pg/ml (369-959 pmol/L). There was no significant difference between the CSFVB12 levels and the severity of dementia.

In a second group of 13 patients (29-50 years of age) with neurasthenic symptoms, the vitamin B-12 levels were assessed in both the serum and CSF. All patients had normal liver function and no gross hematological abnormalities. These patients did have ‘soft’ neurological signs of encephalopathy and neuropathy.

All 13 patients had normal serum levels of vitamin B-12 (range, 280-750 pg/ml; 206-553 pmol/L), but 11 of them had deficient CSF levels (<5 pg/ml; <3.7 pmol/L).

By not performing routine CSF analysis, the majority of these patients would not have been found to have a vitamin B-12 deficiency.

The authors concluded their report by stating that all patients displaying organic mental symptoms should have their CSF levels of vitamin B-12 assessed.

Mitsuyama Y, Kogoh H: Serum and cerebrospinal fluid vitamin B12 levels in demented patients with CH3-B12 treatment--preliminary study. Jpn J Psychiatry Neurol, 1988;42:65-71.

Newbold HL: Vitamin B-12: placebo or neglected therapeutic tool. Med Hypotheses, 1989;28:155-165.

 The serum and CSF-VB12 levels of the demented patients did not show any significant elevation after the oral administration of methylcobalamin (CH3B12), 2 mg per day.  On the other hand, there was a marked elevation of both the serum and CSF-VB12 after an oral medication (2 mg per day) plus intramuscular administrations (500 micrograms per day) of CH3B12.  These results confirm that the intramuscular administration of CH3-B12 is an effective way to get a higher value of the serum and CSF-VB12 levels.

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Newbold HL: Vitamin B-12: placebo or neglected therapeutic tool. Med Hypotheses, 1989;28:155-165.

Newbold HL: Vitamin B-12: placebo or neglected therapeutic tool. Med Hypotheses, 1989;28:155-165.

 Hydroxocobalamin injections were then discontinued for 5 to 7 days. The patients took another serum vitamin B-12 test and another MMPI.  With the higher vitamin B-12 levels, the MMPI patterns were at or closer to normal (average: 465,173 pg/ml; 343,204 pmol/L). With lower serum vitamin B-12 levels, MMPI patterns showed much more emotional distress (average: 110,611 pg/ml; 81,609 pmol/L).

 The author suspects that vitamin B-12 dependency disorders are common and are neglected by the medical profession because of the following possibilities:

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All patients were 16 years of age and older and not on any medication. There were, however, on a variety of supplements.

Patients with normal serum vitamin B-12 levels (115-800 pg/ml; 85-590 pmol/L) were given injections of hydroxocobalamin (vitamin B-12b) interspersed with injections of sterile water. Doses ranged from 3000 mcg 4 times each week to 9000 mcg daily.

Those who felt better with B-12b had additional injections to establish the amount of B-12b that gave the maximum feeling of well-being.

Serum vitamin B-12 tests were performed to record the level at which the patients felt best. On the same day they took a Minnesota Multiphasic Personality Inventory (MMPI), an objective computerized psychological test.

 We do not know the body level of any vitamin needed for full biological efficiency;  Patients might have a deficiency in transporting vitamin B-12 into their tissues (low levels of transcobalamin II);  A lower reaction rate due to an enzyme having a decreased binding affinity for its coenzyme (i.e., a vitamin) – meaning that a large increase in a vitamin level would be needed to “force” an abnormal chemical reaction to proceed normally.

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Vitamin B12 and Psychiatry

Inaugural Abram Hoffer Memorial Lecture: Jonathan Prousky, ND, MSc Newbold HL: Vitamin B12b as an antidote to over-sedation. Med Hypotheses, 1989;30:1-3.

Newbold HL: Vitamin B12b as an antidote to over-sedation. Med Hypotheses, 1989;30:1-3.

 Report of a patient that was administering 6000 mcg of hydroxocobalamin to her “customers” that would become over-sedated with sedatives/tranquilizers and/or alcohol.

This dose of B-12 would effectively stimulate her customers and enable them to leave her place of residence without a need for medical care.  The author himself had an opportunity to treat a patient that became over-sedated from “bootleg Quaaludes” and vodka. He used 9000 mcg of hydroxocobalamin to revive this patient.

 In view of these cases, the author made the recommendation that physicians in emergency rooms provide trial injections of B-12 to revive patients in or near coma from overdoses of sedatives/tranquilizers and/or alcohol. He further recommended that the initial dose should be 9000 mcg and increased to 18,000-27,000 mcg if necessary.

Ohta T, Ando K, Iwata T, et al: Treatment of persistent sleep-wake schedule disorders in adolescents with methylcobalamin (vitamin B12).

Sleep, 1991;14:414-418.

Ohta T, Ando K, Iwata T, et al: Treatment of persistent sleep-wake schedule disorders in adolescents with methylcobalamin (vitamin B12).

Sleep, 1991;14:414-418.

 Two adolescent patients suffering from persistent sleep-wake schedule disorders appear to have responded to treatment with vitamin B12 (methylcobalamin).  We will look at the case involving a 15-year-old girl with delayed sleep phase syndrome (DSPS). She complained of not being able to attend school despite many trials of medication.  The improvement of her sleep-wake rhythm disorder appeared immediately after the administration of high doses (3,000 micrograms/day) of methylcobalamin.

 This patient did not show any laboratory or clinical evidence of vitamin B-12 deficiency or hypothyroidism (which can cause B-12 deficiency).  Serum concentrations of vitamin B-12 during treatment were in the high range of normal or above normal.  The duration of the sleep period of the DSPS patient decreased gradually from 10 hours to 7 hours, and the time of sleep onset advanced from 2 a.m. to midnight.

Yamada N: Treatment of recurrent hypersomnia with methylcobalamin (vitamin B12): a case report.

Psychiatry Clin Neurosci, 1995;49(5-6):305-307.

Yamada N: Treatment of recurrent hypersomnia with methylcobalamin (vitamin B12): a case report.

Psychiatry Clin Neurosci, 1995;49(5-6):305-307.

 A 32 year old male patient suffered from recurrent hypersomnia for 12 years was successfully treated with vitamin B-12.  Episodes of hypersomnia lasting a few days occurred repeatedly a few times each year. Furthermore, the frequency of episodes had increased during the last 2 years.  During the administration of vitamin B12, the patient had no episodes of hypersomnia for 6 months.

 In addition, he did not have any episodes during a follow-up observation period of 17 months after cessation of the treatment.  Thus, this case suggests that vitamin B-12 may be effective for preventing recurrent hypersomnia.

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Inaugural Abram Hoffer Memorial Lecture: Jonathan Prousky, ND, MSc Hintikka J, Tolmunen T, Tanskanen A, et al: High vitamin B12 level and good treatment outcome may be associated in major depressive disorder. BMC Psychiatry, 2003;3:17.

Hintikka J, Tolmunen T, Tanskanen A, et al: High vitamin B12 level and good treatment outcome may be associated in major depressive disorder. BMC Psychiatry, 2003;3:17.

 Our aim was to determine whether there were any associations between the vitamin B-12 and folate level and the six-month treatment outcome in patients with major depressive disorder.  Because vitamin B12 and folate deficiency may result in changes in hematological indices, we also examined whether these indices were associated with the treatment outcome.

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Hintikka J, Tolmunen T, Tanskanen A, et al: High vitamin B12 level and good treatment outcome may be associated in major depressive disorder. BMC Psychiatry, 2003;3:17.

Hintikka J, Tolmunen T, Tanskanen A, et al: High vitamin B12 level and good treatment outcome may be associated in major depressive disorder. BMC Psychiatry, 2003;3:17.

 No relationship was found between hematological indices and the 6 month outcome.  A positive correlation was found between both the vitamin B-12 level at baseline (r = 0.39, p < 0.001) and on follow-up (r = 0.26, p = 0.006), and the decline (i.e., improvement) in the HDRS score during six months of treatment.  The vitamin B-12 level and the probability of recovery from major depression may be positively associated.

 Possible reasons for this were:

Vogiatzoglou A, Refsum H, Johnston C, et al: Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology, 2008;71:826832.

Vogiatzoglou A, Refsum H, Johnston C, et al: Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology, 2008;71:826832.

 To investigate the relationship between markers of vitamin B-12 status and brain volume loss per year over a 5-year period in an elderly population.  A prospective study of 107 community-dwelling volunteers aged 61 to 87 years without cognitive impairment at enrollment.  Volunteers were assessed yearly by clinical examination, MRI scans, and cognitive tests. Blood was collected at baseline for measurement of plasma vitamin B-12, transcobalamin (TC), holotranscobalamin (holoTC), methylmalonic acid (MMA), total homocysteine (tHcy), and serum folate.

 The decrease in brain volume was greater among those with lower vitamin B-12 and holoTC levels and higher plasma tHcy and MMA levels at baseline.  Linear regression analysis showed that associations with vitamin B-12 and holoTC remained significant after adjustment for age, sex, creatinine, education, initial brain volume, cognitive test scores, systolic blood pressure, ApoE epsilon4 status, tHcy, and folate.

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Hematological indices, erythrocyte folate and serum vitamin B12 levels were determined in 115 outpatients with DSM-III-R major depressive disorder at baseline and serum vitamin B-12 level again on 6 month follow-up.

The 17-item Hamilton Depression Rating Scale was also compiled, respectively.

At baseline, none of the patients had a deficient vitamin B12 level.   

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Non-response (n=40) had an average baseline measurement of 347.2 pmol/L (468.72 pg/ml).

Partial response (n=34) had an average baseline measurement of 396.0 pmol/L (534.6 pg/ml).

The full response (n=41) had an average baseline measurement of 439.1 pmol/L (593 pg/ml).

Higher baseline vitamin B-12 levels significantly associated with a better outcome.

 Might reflect a lower intake of vitamins from food or assimilation from the GI tract;  A higher rate of metabolism;  An issue in the synthesis of monoamines; and/or  An accumulation of homocysteine, which can lead to excitotoxic reactions that might enhance depression.

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Vitamin B12 and Psychiatry

Inaugural Abram Hoffer Memorial Lecture: Jonathan Prousky, ND, MSc Vogiatzoglou A, Refsum H, Johnston C, et al: Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology, 2008;71:826832.

Vogiatzoglou A, Refsum H, Johnston C, et al: Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology, 2008;71:826832.

 Using the upper (for the vitamins) or lower tertile (for the metabolites) as reference in logistic regression analysis and adjusting for the above covariates, vitamin B-12 in the bottom tertile (<308 pmol/L; 415.8 pg/ml) was associated with increased rate of brain volume loss (odds ratio 6.17, 95% CI 1.25-30.47).  The association was similar for low levels of holoTC (<54 pmol/L) (odds ratio 5.99, 95% CI 1.21-29.81) and for low TC saturation.

 Low vitamin B-12 status should be further investigated as a modifiable cause of brain atrophy and of likely subsequent cognitive impairment in the elderly.

Kaplan BJ, Crawford SG, Field CJ, et al: Vitamins, minerals, and mood. Psychol Bull, 2007;133:747760.

Why does vitamin B-12 work?

 Correction of inborn errors of metabolism: “…brain dysfunctions (including unstable mood) represent the same type of genetic mutation, whereby the affected individual requires higher (perhaps pharmacological) amounts of specific micronutrients for normal metabolic functioning.”

Kaplan BJ, Crawford SG, Field CJ, et al: Vitamins, minerals, and mood. Psychol Bull, 2007;133:747760.

Kaplan BJ, Crawford SG, Field CJ, et al: Vitamins, minerals, and mood. Psychol Bull, 2007;133:747760.

 Correction of deficient methylation process (Regland 1994, Regland 1995)  Correction of altered gene expression by nutrient deficiency

 Correction of long-latency deficiency diseases: “…perhaps long-term nutrient insufficiency results in altered brain development, low hippocampal amino acid concentration, and subsequent mental symptoms. On the other hand, it is equally plausible, especially in patients with early childhood symptoms, that long-term psychologic stress alters nutrient absorption or even directly (perhaps via elevated cortisol secretion) influences brain development. In either case, the inference that clinically identified mental disorders reflect progressive brain changes fits with the concept of long-latency disorders.”

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Vitamin B12 and Psychiatry

Inaugural Abram Hoffer Memorial Lecture: Jonathan Prousky, ND, MSc Miller J: Vitamin B12 deficiency, tumor necrosis factorα, and epidermal growth factor: a novel function for vitamin B12? Nutr Rev, 2002;60:142-151.

Miller J: Vitamin B12 deficiency, tumor necrosis factorα, and epidermal growth factor: a novel function for vitamin B12? Nutr Rev, 2002;60:142-151.

 Reduces inflammation since vitamin B-12 functions as an anti-inflammatory agent in the brain

 If the findings relating B-12 to TNF-α are clinically relevant, this suggests that B-12 deficiency could play a role in Alzheimer’s disease (and perhaps other neuropsychiatric disorders) by exacerbating the disease-induced inflammatory response in the brain.

B-12 deficiency may cause neurologic damage by increasing in tumor necrosis-α (TNF-α) and decreasing the neurotrophic agent, epidermal growth factor (EGF).  The altered levels of TNF-α and EGF may simply be reflective of the inflammatory response to neuronal injury caused by impairment of methylation reactions or disruption of odd-chain fatty acid metabolism. 

Diagnostic scheme to assist clinicians in their evaluation of vitamin B-12 status

 I have created/adapted my diagnostic scheme by combining some aspects of an article by OH (2003) to vitamin B-12 laboratory standards as developed by several medical laboratories in Ontario.

 If the serum cobalamin result is between 110-295 pmol/L (150-400 pg/ml), further testing is still required to rule-out vitamin B-12 deficiency.

 If the serum cobalamin result is below 110 pmol/L (150 pg/ml), then the patient has vitamin B-12 deficiency and underlying causes need to be investigated.

 At this point, urine methylmalonic acid (uMMA) testing should be done since it can identify tissue vitamin B-12 deficiency when serum levels are considered normal or in the possible deficient range (Matchar 1987, Donaldson 2000).  I use the Normal Clinic Laboratory for my uMMA tests (http://www.b12.com/)

 Even if uMMA does not come back abnormal (i.e., elevated), patients might derive significant benefits from therapeutic trials of vitamin B-12.

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Vitamin B12 and Psychiatry

Inaugural Abram Hoffer Memorial Lecture: Jonathan Prousky, ND, MSc

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How should vitamin B-12 be administered?

If serum cobalamin levels come back above 295 pmol/L (>400 pg/ml), the patient would not be considered as having vitamin B-12 deficiency in the ‘classical’ sense, but this can be debated: There is published evidence of vitamin B-12 deficiency in the cerebrospinal fluid among patients with normal serum vitamin B-12 values as high as 593 pmol/L (800 pg/ml) (van Tiggelen 1984).

Based on the work of Newbold (1989), some patients require extremely high serum vitamin B-12 levels to have favorable neuropsychiatric outcomes (the average serum vitamin B-12 of his patients that benefited from aggressive vitamin B-12 therapy was: 343,204 pmol/L; 465,173 pg/ml).

Patients having neuropsychiatric symptoms with serum vitamin B-12 levels above 295 pmol/L (>400 pg/ml) should still be provided with therapeutic trials of vitamin B12 to assess if individualized treatment can reduce symptoms.

Sohler A, Pfeiffer CC, Kowalski T: Effectiveness and route of administration of vitamin B12. Int Clin Nut Rev, 1989;9(2):64-65.

Berlin H, Brante G, Pilbrant A: Vitamin B12 body stores during oral and parenteral treatment of pernicious anemia. Acta Med Scand, 1978;204:81-84.

 A healthy, 23-year-old fasting male received two 1000 mcg tablets of B12 resin as cyanocobalamin orally, the same preparation sublingually, 10 mcg hydroxocobalamin parenterally, and 10 mcg cyanocobalamin parenterally. His initial vitamin B-12 levels in the 4 trials was 228 ± 64 pg/ml (168 ± 47 pmol/L).

 64 patients with pernicious anemia and other cobalamin deficiency states were treated with 1000 mcg of oral cyanocobalamin daily, with 61/64 treated for > 3-years. Clinical and hematological remission, normalization of serum levels, and full replenishment of hepatic stores were observed in all patients.

Sohler A, Pfeiffer CC, Kowalski T: Effectiveness and route of administration of vitamin B12. Int Clin Nut Rev, 1989;9:64-65.

Sohler A, Pfeiffer CC, Kowalski T: Effectiveness and route of administration of vitamin B12. Int Clin Nut Rev, 1989;9(2):64-65.

 The amount of vitamin B-12 recovered from an oral or sublingual dose is negligible as compared to an injected dose, and is not an effective alternative to a parenteral injection.

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Vitamin B12 and Psychiatry

Inaugural Abram Hoffer Memorial Lecture: Jonathan Prousky, ND, MSc Lederle FA: Commentary. Oral cobalamin for pernicious anemia. Medicine’s best kept secret?

JAMA, 1991;256(1):94-95.

My opinion about dosing…  Based on the published data and my clinical experience, increasing serum vitamin B-12 levels to high amounts usually reduces clinical symptoms.  Even though serum levels might significantly increase, the frequency, dose, and method of administration MUST be individualized to each patient.  For neuropsychiatric complaints, I am in favor of hydroxocobalamin and/or methylcobalamin injections. Some patients respond clinically to 1000 mcg of either form each month, while other patients, for example, might require 5000 mcg twice each week of methylcobalamin to control their symptoms.  It is really a trial and error approach.

 Oral cobalamin, given without intrinsic factor, at daily doses of at least 100-250 mcg daily (2000 mcg twice daily for the first month to be assured of replenishing body stores) provides adequate treatment of vitamin B-12 deficiency, probably because there is an efficient mechanism of cobalamin absorption that is independent of intrinsic factor.  Previous concerns about the unpredictable absorption are no longer relevant due to more recent absorption data.

References (not cited in the PowerPoint slides)

Concluding Remarks   

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The evaluation of Vitamin B-12 is of vital importance when assessing patients with neuropsychiatric complaints.

Deficiency, insufficiency, or suboptimal serum vitamin B-12 levels are often overlooked.

Symptoms associated with deficiency, insufficiency, or suboptimal vitamin B-12 levels can arise insidiously and progress for years without appropriate diagnosis and treatment.

Patients with deficient or insufficient serum levels can have symptoms long before hematological changes occur.

Urinary methylmalonic acid might pick up vitamin B-12 tissue deficiency even when serum levels are normal.

Patients can significantly benefit from vitamin B-12 therapy.

Vitamin B-12 has many important therapeutic uses that extend beyond the neuropsychiatric system (e.g., antiinflammatory and analgesia properties). It is very effective and safe. Side effects, such as a transient acne-like eruptions or allergic reactions, are extremely rare.

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Andrès E, Loukili NH, Noel E, et al: Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ, 2004;171:251-259.

Donaldson MS: Metabolic vitamin B12 status on a mostly raw vegan diet with follow-up using tablets, nutritional yeast, or probiotic supplements. Ann Nutr Metab, 2000;44:229-234.

Hutto BR: Folate and cobalamin in psychiatric illness. Compr Psychiatry, 1997;38:305-314.

Karakula H, Opolska A, Kowal A, et al: Does diet affect mood?

The significance of folic acid and homocysteine. Pol Merkur Lekarski, 2009;26:136-141.

Matchar DB, Feussner JR, Millington DS, et al: Isotope-dilution assay for urinary methylmalonic acid in the diagnosis of vitamin B12 deficiency. Ann Intern Med, 1987;106:707-710.

References (not cited in the PowerPoint slides)  OH RC, Brown DL: Vitamin B12 deficiency. Am Fam Physician, 2003;67:979-986, 993-994.  Regland B, Johansson BV, Gottfries CG: Homocysteinemia and schizophrenia as a case of methylation deficiency. J Neural Transm Gen Sect, 1994;98:143-152.  Regland B, Johansson BV, Grenfeldt B, et al: Homocysteinemia is a common feature of schizophrenia. J Neural Transm Gen Sect, 1995;100:165-169.

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Chronic Fatigue Syndrome: A Disorder of Microcirculation Jonathan Prousky, ND, MSc

Chronic Fatigue Syndrome: A Disorder of Microcirculation • Chronic fatigue is a syndrome (CFS) in which the entire human organism has gone awry and is out of kilter.

Chronic Fatigue Syndrome: A Disorder of Microcirculation

• Effective treatment poses an incredible challenge to doctors and patients alike.

Jonathan E. Prousky, ND, MSc Chief Naturopathic Medical Officer Professor, Clinical Nutrition The Canadian College of Naturopathic Medicine 416-498-1255 ext. 235 Email: jprousky@ccnm.edu

Diagram used with permission from: Prousky J. The vitamin cure for chronic fatigue syndrome. Laguna Beach, CA. Basic Health Publications, Inc. 2010.

Chronic Fatigue Syndrome: A Disorder of Microcirculation • Many factors are implicated in the genesis of CFS.

Chronic Fatigue Syndrome: A Disorder of Microcirculation

Chronic Fatigue Syndrome: A Disorder of Microcirculation

• Not a single one has been fully endorsed by medical science as the principal cause of CFS.

• Today, you will learn the following: – Altered red blood cell (RBC) shape changes underlie many of the pathological and clinical features of CFS; and – Orthomolecular treatment options

• There is one cause, however, that does hold promise, and has an emerging body of evidence suggesting that an organic basis underlies CFS.

• Before we review the evidence, let us first review some aspects of RBC physiology.

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RBC Physiology

RBC Physiology

• Transport hemoglobin, which in turn carries oxygen from the lungs to the tissues.

• The shapes of RBCs can change remarkably.

• They are sometimes referred to as ‘bags.’

• ‘Normal’ RBCs are biconcave discs having a diameter with a range of 6-9 micrometers (microns).

• The normal shape has a great amount of cell membrane for the quantity of material inside.

RBC Physiology • There is a tremendous pressure difference that causes oxygen to diffuse rapidly from the blood into the tissues.

• Abnormally-shaped RBCs occur in normal (healthy) individuals and in a wide variety of disease states.

• Oxygen is released from the hemoglobin by diffusion to cells of our tissues.

• Stomatocytes – described as cells that appear as a "smiling face" or a fish mouth. They are seen in normal individuals and in those with hereditary stomatocytosis, liver disease, and acute alcoholism.

• Acanthocytes - crenated RBCs which have distinctive spiky outlines.

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Burr cells may occur in cases of heart disease, uremia, bleeding ulcers, and stomach cancer

• Burr cells - crenated RBCs known as echinocytes

What does all of this have to do with CFS?

Slide courtesy of: Dr. Ross Richards, School of Community Health, Faculty of Science, Charles Sturt University, PO Box 789, Albury, NSW, 2640.

• Let us review some of the published literature…

Mukherjee TM, Smith K, Maros K. Abnormal red cell morphology in myalgic encephalomyelitis.

Lancet 1987;2:328-329.

Simpson LO, Shand BI, Olds RJ. Blood rheology and myalgic encephalomyelitis: a pilot study. Pathology 1986;18:190-192.

• In a study comparing blood filterability, samples of blood from acutely unwell CFS subjects were shown to be less filterable than blood from similarly aged blood donors.

• Prescence of abnormal RBC shape changes among CFS patients in a state of relapse. Several different RBC shape changes were identified: spherocytes, stomatocytes, and some other unusual forms described as dimpled spherocytes.

• The acutely unwell subjects had prolonged blood filtration times that normalized to that of the aged blood donors once their acute illnesses had passed.

• The cell membranes of the altered RBC shapes were thought to be more rigid, thus impairing the delivery of oxygen and other nutrient materials to the remote areas of body where the smallest capillaries reside.

• Based on these findings, the investigators concluded that the numerous symptoms of CFS might result from impaired microcirculatory blood flow.

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Simpson LO. Nondiscocytic erythrocytes in myalgic encephalomyelitis. N Z Med J 1989;102:126-127.

Simpson LO. The role of nondiscocytic erythrocytes in the pathogenesis of myalgic encephalomyelitis/chronic fatigue syndrome. In: Hyde BM, ed. The Clinical and Scientific Basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Ottawa, ON: The Nightingale Research Foundation. 1992; 597605.

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Another study sought to determine if the observed microcirculatory blood flow abnormalities in CFS involved abnormally shaped RBCs.

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Blood samples from 102 CFS patients, 99 multiple sclerosis patients, and 52 healthy controls were compared.

• In a similar study, the RBC shapes of 99 individuals suffering from symptoms of chronic tiredness and easy fatigability were compared against 52 healthy individuals.

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The results showed that the CFS patients had the highest percentage of cup or non-discocytic RBCs and the lowest percentage of normal RBCs.

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There was an inverse correlation between the percentages of nondiscocytic RBCs and wellbeing among the CFS patients.

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It was concluded that these results provided evidence that CFS has an organic cause.

• The RBC shapes from the individuals suffering from chronic tiredness and easy fatigability had increased numbers (higher percentages) of non-discocytic RBCs. • There was no inverse correlation between the percentages of non-discocytic RBCs and wellbeing among the patients, but these patients DID NOT have CFS.

Simpson LO, Herbison GP. The results from red cell shape analyses of blood samples from members of myalgic encephalomyelitis organisations in four countries. J Orthomol Med 1997;12:221-226.

Simpson LO, Herbison GP. The results from red cell shape analyses of blood samples from members of myalgic encephalomyelitis organisations in four countries. J Orthomol Med 1997;12:221-226.

• Simpson and Herbison evaluated RBC shapes from 620 male and 1558 female members of CFS organizations from New Zealand, Australia, South Africa, and England (most of the members were presumed to have CFS).

• In each blood sample, approximately 320 RBCs were assessed and classified.

Simpson LO, O’Neill DJ. Red blood cell shape, symptoms and reportedly helpful treatments in Americans with chronic disorders. J Orthomol Med 2001;16:157-165.

Simpson LO, Herbison GP. The results from red cell shape analyses of blood samples from members of myalgic encephalomyelitis organisations in four countries. J Orthomol Med 1997;12:221-226.

•

The results showed a much higher percentage of flat cells among the members of CFS organizations from the four countries.

• Simpson and O’Neill evaluated blood samples from 632 American subjects (most of whom had CFS or some variant of it).

•

These findings suggest that the increased percentages of flat cells would adversely affect blood rheology and consequently capillary blood flow as well.

• The results demonstrated a greater percentage of flat cells among all the subjects with 4% having increased cup forms as well.

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Simpson LO. Myalgic encephalomyelitis (ME): a haemorheological disorder manifested as impaired capillary blood flow. J Orthomol Med 1997;12:69-76.

• The clinical consequences of having RBC morphological abnormalities include the following: – Impaired deformability of RBCs; – Reduced rate of capillary (microcirculatory) blood flow; – Reduced capacity to load and to release oxygen; and – The presence of small foci (locations) of ischemic necrosis due to irresolvable stasis within the small capillaries.

– In other words, a disorder of microcirculation

• These studies point to a common pathological finding (i.e., increased nondiscocytic RBCs) among individuals with CFS.

Arnold DI, Radda GK, Bore PJ, et al. Excessive intracellular acidosis of skeletal muscle on exercise in a patient with a post-viral exhaustion/fatigue syndrome.

Lancet 1984;1:1367-368.

• Poor microcirculatory blood flow would account for the unrelenting tiredness, postexertional malaise, and central nervous system dysfunction (i.e., disturbances in concentration, memory, focus, and mood) that all of these patients experience.

• Arnold and colleagues reported a CFS case documenting early intracellular acidosis following moderate exercise.

• An insufficient supply of oxygen and nutrient substrates would eventually lead to clinically recognizable findings in metabolically active tissues or organs like muscle and nervous tissue.

Jammes Y, Steinberg JG, Mambrini O, et al. Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. J Intern Med 2005;257:299-310.

Behan PO, Behan WM, Bell EJ. The postviral fatigue syndrome--an analysis of the findings in 50 cases. J Infect 1985;10:211-222.

• Another decades-old study evaluated clinical, pathological, electrophysiological, immunological and virological abnormalities in 50 patients with postviral fatigue syndrome (an older name for CFS).

• A more recent study found an increased amount of oxidative stress and marked alterations of muscle membrane excitability among CFS patients that were subjected to incremental exercise.

• Many of the patients demonstrated prolonged weakness in several bodily areas (i.e., the arms and legs) following specific exercises. Muscle biopsies were performed on 20 of them and the results demonstrated necrosis in many muscle fibers, increased mitochondria, as well as evidence of early intracellular acidosis.

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• Therefore, it is conceivable that an inadequate supply of oxygen and nutrient substrates to the muscles (due to increased non-discocytic RBCs) would alter the metabolic functioning of muscle tissue, and henceforth explain the observed changes in CFS such as muscle weakness, postexertional fatigue, and abnormal muscle metabolism.

• Another study using a specialized diagnostic imaging technique found impaired regional brain blood flow among CFS patients, but not among subjects without CFS (Costa DC, Tannock C, Brostoff J. Brainstem perfusion is impaired in chronic fatigue syndrome. QJM 1995;88:767773).

•

Other published data might establish a link between altered (nondiscocytic) RBC shape changes and central nervous system dysfunction.

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When CFS patients were subjected to magnetic resonance imaging, lesions in the white matter of the brains were identified (Lange G, Wang S, DeLuca J, Natelson BH. Neuroimaging in chronic fatigue syndrome. Am J Med 1998;105:S50-853).

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Perhaps the lesions were directly the result of small foci of ischemic necrosis due to impaired microcirculatory blood flow as a consequence of altered RBC shape changes.

•

This is significant since the frontal lobes, which reside in the white matter of the brain, are involved in memory and in reactions to emotional events. Patients with CFS usually have problems with memory and are known to be emotionally very sensitive.

• Simpson has suggested that triggering events like viral infections, bacterial infections, or even an exposure to a toxic stimulus could have perturbed the RBC environment leading to RBC shape transformations.

• Once again, the impaired blood flow might have resulted from abnormal RBC shape changes.

Richards RS, Roberts TK, Mathers TK, et al.

Erythrocyte morphology in rheumatoid arthritis and chronic fatigue syndrome: a preliminary study.

J CFS 2000;6:23-25.

• More recent data, however, has identified oxidative stress as perhaps the principle cause of altered RBC shapes among CFS patients.

• The most common correlation in CFS was with stomatocytes, as there were 17 out of 31 significant correlations with symptoms and these morphological changes.

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Chronic Fatigue Syndrome: A Disorder of Microcirculation Jonathan Prousky, ND, MSc Richards RS, Roberts TK, Mathers TK, et al.

Erythrocyte morphology in rheumatoid arthritis and chronic fatigue syndrome: a preliminary study.

J CFS 2000;6:23-25.

Richards RS, Roberts TK, Mathers TK, et al.

Erythrocyte morphology in rheumatoid arthritis and chronic fatigue syndrome: a preliminary study.

J CFS 2000;6:23-25.

• Whole blood viscosity was not significantly different between the CFS group, the normal group, and the RA group.

• The formation of stomatocytes in CFS was thought to be the result of oxidation of the RBC membrane.

• There are predictable morphological changes in certain subgroups of CFS patients, which confirms in part, some of the findings described by Simpson.

Richards RS, Roberts TK, Mathers D, et al.

Investigation of erythrocyte oxidative damage in rheumatoid arthritis and chronic fatigue syndrome. J CFS 2000;6:37-46.

•

Richards RS, Roberts TK, Mathers D, et al.

Investigation of erythrocyte oxidative damage in rheumatoid arthritis and chronic fatigue syndrome. J CFS 2000;6:37-46.

RBC 2,3-diphosphoglyceric acid (2,3-DPG) and methemoglibin (metHb) were raised in both the RA and CFS groups compared to the control group. These results achieved statistical significance (p<0.05).

• One cluster of CFS patients had reduced glutathione (GSH) levels that were significantly lower than the control group (p<0.05), whereas another cluster had GSH results that were significantly higher than the control group (p<0.05).

– Increased 2,3-DPG increases RBC fragility and decreases deformability.

– 2,3-DPG also acts as a regulator of hemoglobin oxygen affinity; increased levels decrease oxygen affinity and would allow for more oxygen to be delivered to the tissues in these cases.

•

– The increased GSH in one cluster of CFS patients might be a compensatory response.

– The decreased GSH in the other cluster of CFS patients might be due to inadequate antioxidant mechanisms and/or increased utilization of them.

The malondialdehyde (MDA) was also raised in the CFS group compared to the control group (p<0.05).

– Peroxidation of membrane lipids with the formation of MDA on the surface of RBCs causes recognition by macrophages, which may lead to damage by phagocytosis.

• Therefore, oxidative damage might be a contributor to the morphological changes in CFS, which might result in decreased deformability and altered rheology.

Richards RS, Wang L, Jelinek H. Erythrocyte oxidative damage in chronic fatigue syndrome.

Arch Med Res 2007;38:94-98.

Richards RS, Wang L, Jelinek H. Erythrocyte oxidative damage in chronic fatigue syndrome.

Arch Med Res 2007;38:94-98.

• Unlike the previous study, the level of GSH was not significantly different.

• These results suggest: – That free radical formation contributes to the pathology of CFS; – That oxidative damage is most likely a contributor to the biochemical and morphological changes in CFS; and – These aforementioned issues result in decreased RBC deformability and altered rheology, which contributes to the clinical symptoms of CFS.

• Like the previous study, the levels of 2,3-DPG, metHb, and MDA were all significantly increased compared to the control group (p<0.05, 0.005, and 0.01 respectively).

• The CFS patients had significantly more stomatocytes in their blood than the normal subjects (p<0.005).

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Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction.

Int J Clin Exp Med 2009;2:1-16.

•

This study assessed patients mitochondrial function by using a test called the ‘ATP profile.’

•

The results showed mitochondrial dysfunction among the CFS patients, with the degree of dysfunction correlating strongly to the severity of the illness among the study subjects.

•

The authors concluded that the damage to the mitochondria may be a primary phenomena or may be secondary to one or more primary conditions, including cellular hypoxia or oxidative stress.

Diagram used with permission from: Prousky J. The vitamin cure for chronic fatigue syndrome. Laguna Beach, CA. Basic Health Publications, Inc. 2010.

How do we treat this?

• By using various orthomolecular substances that reduce oxidative stress (damage) and/or that facilitate the normalization of RBC morphology.

How do we treat this?

• Antioxidants to consider include vitamins C, E, alphalipoic acid, and reduced glutathione.

Orthomolecular antioxidants

• Agents to normalize RBC morphology include vitamin B12, evening primrose oil (GLA content), and possibly fish oil (EPA content).

(1) Shiva Shankar Reddy CS, Subramanyam MV, Vani R, Asha Devi S. In vitro models of oxidative stress in rat erythrocytes: effect of antioxidant supplements. Toxicol In Vitro 2007;21:1355-64. (2) Traber MG, Frei B, Beckman JS. Vitamin E revisited: do new data validate benefits for chronic disease prevention? Curr Opin Lipidol 2008;19:30-8.

Ali M. Ascorbic acid reverses abnormal erythrocyte morphology in chronic fatigue syndrome. Am J Clin Pathol 1990;94:515. Abstract #117.

• Vitamin E possesses considerable antioxidant activity against lipid peroxidation and protects RBC membranes from oxidative damage.

• Vitamin C was shown to reverse RBC shape changes and increase membrane pliability when administered at doses of 15 grams parenterally to chronically disabled CFS patients in a clinical study published in abstract form only.

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(1) Bested AC, Saunders PR, Logan AC. Chronic fatigue syndrome: neurological findings may be related to blood-brain barrier permeability. Med Hypotheses 2001;57:231-7. (2) Logan AC, Wong C. Chronic fatigue syndrome: oxidative stress and dietary modifications.

Altern Med Rev 2001;6:450-9.

•

Both alpha-lipoic acid and reduced L-glutathione help to maintain glutathione levels within the RBCs and protect the RBC membranes from oxidative damage.

•

This is important since depletion of glutathione is associated with increased blood-brain permeability and is believed to play a role in the pathogenesis of CFS (1). Perhaps, supplemental reduced Lglutathione would directly increase the levels of glutathione in the plasma and possibly within the RBCs.

•

Alpha-lipoic acid indirectly raises glutathione levels (2).

How do we treat this?

Orthomolecular agents that normalize RBC morphology

Simpson LO. Myalgic encephalomyelitis (ME): a haemorheological disorder manifested as impaired capillary blood flow. J Orthomol Med 1997;12:69-76.

Simpson LO. The role of nondiscocytic erythrocytes in the pathogenesis of myalgic encephalomyelitis/chronic fatigue syndrome.

In: Hyde BM, ed. The Clinical and Scientific Basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Ottawa, ON: The Nightingale Research Foundation, 1992: 597-605.

•

Parenteral vitamin B-12 (as hydroxycobalamin) was demonstrated to normalize RBC shapes in approximately 50% of CFS patients given the vitamin.

• When using parenteral vitamin B-12 for CFS, your patient should report an improvement within 24 hours.

•

Twenty eight patients with “acute” or new-onset CFS were studied and each patient was administered 1 mg (1000 mcg) of injectable hydroxocobalamin.

• The symptoms will inevitably return, and when they do another injection is needed.

•

Blood samples from each patient were taken pre- and post-vitamin B-12 treatment. The patients that improved were found to have reduced numbers of cup forms and had a loss of their symptoms within 24 hours while the non-responders did not exhibit favorable RBC changes or feel subjectively better.

• Apparently, there are cases where CFS patients have lived virtually normal lifestyles while receiving vitamin B12 injections at 12-20 day intervals. The reason for vitamin B-12’s effectiveness in only 50% of cases is unknown.

(1) Simpson LO. Myalgic encephalomyelitis (ME): a haemorheological disorder manifested as impaired capillary blood flow. J Orthomol Med 1997;12:69-76. (2) Puri BK. Long-chain polyunsaturated fatty acids and the pathophysiology of myalgic encephalomyelitis (chronic fatigue syndrome). J Clin Pathol 2007;60:122-4.

(1) Kury PG, Ramwell PW, McConnell HM. The effect of prostaglandin E1 and E2 on the human erythrocyte as monitored by spin labels. Biochem Biophys Res Commun 1974;56:47883. (2) Simpson LO. Myalgic encephalomyelitis (ME): a haemorheological disorder manifested as impaired capillary blood flow. J Orthomol Med 1997;12:69-76. (3) Manku MS, Horrobin DF, Morse N, et al. Reduced levels of prostaglandin precursors in the blood of atopic patients: defective delta-6-desaturase function as a biochemical basis for atopy. Prostaglandins Leukot Med 1982;9:615-28.

•

Evening primrose oil (EPO) is another valuable treatment for CFS patients. EPO contains gamma-linolenic acid (GLA), which is an essential orthomolecule having important therapeutic properties.

•

Since GLA is an omega-6 essential fatty acid, it must be obtained from dietary sources or must be converted in vivo from dietary sources of linoleic acid.

• Being able to generate enough GLA in vivo cannot be understated. It is necessary for the biosynthesis of adequate amounts of prostaglandin E1 (PGE1), which in turn increases the fluidity of the RBC membranes and increases RBC flexibility as well (1).

•

The conversion of linoleic acid to GLA requires the delta-6desaturase enzyme and is known to be impaired as a result of aging, diabetes, viral infections, and even radiotherapy (1).

•

A report in 2007 linked some of the signs and symptoms of CFS to delta-6-desaturase enzymatic damage, possibly resulting from a persistent viral infection (2).

• EPO sources of GLA appear to be effective in some 70% of CFS cases (2). The therapeutic dose of EPO should be 4000 mg per day, which is based upon a study that demonstrated significant increases in PGE1 among patients with atopic eczema (3).

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Chronic Fatigue Syndrome: A Disorder of Microcirculation Jonathan Prousky, ND, MSc (1) Fischler L, Meredith DO, Reinhart WH. Influence of a parenteral fish-oil preparation (Omegaven) on erythrocyte morphology and blood viscosity in vitro. Clin Hemorheol Microcirc 2003;28:79-88. (2) Simpson LO, McQueen EG, Shand BI, et al. Changes in red cell shape in healthy elderly subjects taking low dose fish oil: pilot study. N Z Med J 1991;104:316-8.

Simpson LO. Myalgic encephalomyelitis (ME): a haemorheological disorder manifested as impaired capillary blood flow. J Orthomol Med 1997;12:69-76.

• If there are no observable benefits after 6 weeks of use, the EPO should be stopped and replaced with orthomolecules of the omega-3 variety.

• Being a precursor to prostaglandins of the 3series, fish oil sources of EPA do affect RBC membrane functions (1) and have been shown to reduce the percentage of altered RBC shapes when given orally to healthy elderly subjects (2).

• Fish oil sources of omega-3 essential fatty acids contain eicosapentaenoic acid (EPA) and docosahexaenoic acid. It is likely the EPA component that produces favorable effects upon the RBC membranes.

Concluding Remarks •

Increased RBC morphological changes appear to occur in greater frequency among CFS patients than normal (‘healthy’) patients.

•

Oxidative stress is likely responsible for these morphological changes.

•

The cause of oxidative stress is an area rich in debate, but some factors that have been considered include: viral, bacterial, or fungal infections; a toxic stimulus; and/or some other unknown factor.

•

Orthomolecular treatments aimed at reducing oxidative stress and normalizing RBC morphology show promise, but clinical studies are desperately needed to investigate this.

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Orthomolecular Detoxification for Inflammatory Conditions Elson Haas, MD

ORTHOMOLECULAR DETOXIFICATION for INFLAMMATORY CONDITIONS

NATURE is Simplicity • DOCTORS - Teachers of Health Basics • What about Philosopher/Physicians?

• Sunlight, Air, Water and Earth are the Elements of Life.

• Reconnection and Honor of Earth, Cycles, Seasons and Spirit • ALL Connected to our Vital Care • Without NATURE, there is No Healing!

Elson M. Haas, MD Orthomolecular Medicine Today May 2, 2010 www.elsonhaas.com www.pmcmarin.com

EDUCATION & HEALING

WHAT AFFECTS OUR HEALTH?

• PREVENTIVE MEDICINE requires new knowledge applied to LIFE • NEW component of medical practice is ancient practice--Role of Healer • LIFESTYLE Support in every office • Basics of Nutrition, Exercise Motivation, Psychological Health and Physical/Energetic Alignment

• • • •

What we Eat and If/How we Exercise How we Sleep and Deal with Stress What we Think, our Attitudes of Life All affect our Energy Level, Moods, Behavior, and our Health Outcome.

• If we want a different result, we need to change our life and lifestyle, from the relevant contributing negative habits & create positive ones.

Five Basics for STAYING HEALTHY

Five Basics of Staying Healthy • Looking for & correcting contributing factors of disease is the beginning step to protect your health. It is key to an Integrated Medicine approach.

• Usual Causes/Factors are: Five Basics of Preventive Medicine.

These are the key areas where you can motivate your patients to make positive changes for better health.

•Nutrition •Exercise •Sleep •Stress Management •Healthy Attitudes

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Orthomolecular Detoxification for Inflammatory Conditions Elson Haas, MD

The Primary Problem: Cell Malfunction

Orthomolecular Health • Drs. Pauling and Hoffer focused on the “right molecules in the right amounts in the right places (to cells and tissues).”

• Let’s add Toxicity issues and the process of Detoxification to the complete picture • Thus, causes of disease are Stress/Toxins and Malnutrition/Deficiency • Vitamins, Minerals, Amino Acids, Fatty Acids and PhytoNutrients needed for function, minimizing toxin exposure

• Two Basic causes of Dis-ease: Deficiency of needed nutrients; Toxicity from exposure to polluted air, water, and foods, and stress.

• Acid/Alkaline Balance is a key.

• Balancing Oxidative Stress and Inflammation are also keys

SOME PROBLEMS OF CONGESTION/INFLAM

Issues of Nutrient Deficiencies

• • • •

Skin eruptions and any -itis Allergies, i.e. sinus, asthma Constipation and GI problems Colds, viral infections & mucus discharge (also Immune Deficiency) • Back and other pains • Headaches • Cardiovascular problems

• • • • • • • •

Fatigue, low energy Cold hands, feet, body Hair loss Dry skin Anemia Low or High Blood pressure Hypothyroidism Tense or cramping muscles

Nutritional Keys to Health

Nutrient Deficiencies

• Antioxidant nutrients protect against oxidative stress (XS free radicals and low antioxidant levels)

• Inadequate intake (poor diet) – Loss of taste and smell - Zinc deficiency – Inadequate knowledge of what’s essential to create balance and support • Drug Interactions (can cause depletions) – Coenzyme Q10 and Statins common • Disease states – Cancer, GI tract dysfunction, IBS, Stress

– They include Vitamins A, C & E, carotenes & flavonoids, selenium and zinc

• • • •

Adequate Hydration and Minerals B vitamins for energy production Vitamin D--recent focus as key nutrient Omega-3 Fats

• Sulfur-containing Amino Acids

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NUTRITIONAL PROBLEMS: What to Avoid--Toxicity?

Make a Difference

• Refined Sugar and Flour foods • Excess Animal Proteins/Fats • Hydrogenated & partially hydrogenated fats, i.e. Trans fats • Chemicals in foods, household and personal care products • Caffeine, Alcohol, Nicotine, other Drugs

• Wiser Choices support and

Create Better Health.

• Eat Nutritious Foods and Detoxify Your Body • Look at Habits and Begin there

WATCH OUT FOR THE SNACCs

SNACC Problems • S=Sugar--energy, mood, hormones • N=Nicotine--toxic and inflammatory • A=Alcohol--sugar metab, weight, and brain function • C=Caffeine--acidic, adrenal, sleep • C=Chemicals--toxins, cell damage

S==Sugar N==Nicotine A==Alcohol C==Caffeine C==Chemicals • Handling these Habits (breaking from Abuses and Addictions) is often the first level of support and guidance for improved HEALTH.

Natural Medicine Theory-Acid-Alkaline Body Chemistry

Eliminate Abuses • Many problems come from long-term habits and persistent chemical exposures.

• NEEDS—HABITS—ABUSES—ADDICTIONS

• Understanding and Application is important in the future of medicine • Overall effect/result of dietary balance and especially tissue pH • Related to Inflammatory Process • Buffering XS acid in tissues is Aging • More fresh fruits and vegetable support an alkaline body state

Key for Detoxification & Healing ************************ • Emotions and gratification with foods and substances affect our energy level and moods, and may create diseases.

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ACID & ALKALINE in DIET

ACID FOODS

• What happens to a food after it is processed and utilized by the body?

• The “ash” and/or waste products affect body tissues.

• The key is the overall balance of diet.

• Our body and tissues thrive under slightly alkaline conditions, GI tract more acidic.

• Phosphorus and Sulfur in foods seem to create a more acid chemistry.

• Protein/Animal Foods, Nuts/Seeds, Dairy Products cause more body acidity.

• Refined Flour and Sugar Products as many Baked Goods and most Packaged Foods are problematic as “Congestors.”

• Theory: acid-alkalinity is affected by the mineral makeup of foods.

INFLAMMATION

ALKALINE FOODS

• ACID-ALKALINE DRIVEN • TOXICITY & DIET-RELATED • NUTRITIONAL DEFICIENCY – WEAKENED PROTECTION • HORMONE ACTIVATED—ADRENAL, PROSTAGLANDINS • RESPONSE MEDIATED LEADS TO INFLAMED TISSUES, DEGENERATION AND AGING

• Most Fruits and Vegetables support alkaline chemistry and balance • The Alkaline Minerals are Potassium, Magnesium, and Calcium.

• The more Alkaline Grains include millet, buckwheat, and quinoa.

• Greens are particularly alkalinizing.

Inflammation

INFLAMMATION

Purpose is Protection & Repair

•Initiating factors: pathogens, FOOD,

• ACIDITY from Dietary excesses of Refined Flours/Sugars, Meats and Fried Foods, plus Stress, Exercise, Pollutants • Biochemical Inflammation through Prostaglandins E1 and 3, Histamine • Circulation, redness and swelling leads to inflammation and pain and then to: • Tissue changes and damage, to stiffness, more pain and aging

tissue damage, irritants, overuse, injury, nutrient depletion, stress, metabolic or hormonal imbalance, free radicals, aging

•Chemical triggers: Histamine,

Serotonin, Cytokines, Prostaglandins

•Signs: swelling, heating up of the tissues, pain, redness. Brings blood supply, immune cells and nutrients to area.

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Affecting Histamine (HA)

Anti-inflammatory Support • Multi-vitamin & mineral supplement • B6 - Pyridoxine is anti-inflammatory • Vitamin A and Zinc improves GI mucosa as tissue healers • Omega-3 increases anti-inflam PGE 1 & 3 • Antioxidants lower free radicals • Quercetin lowers histamine, stabilizes mast cells, 250-500 mg before meals with C & bioflavonoids • Herbs, as Tumeric (curcumin), Rosemary & Ginger

• Magnesium deficiency INCREASES HA release during allergic reactions • Calcium can help neutralize effect of HA but if Calcium deficient, inflammation worsens • Vitamin C, 3-4 grams daily as ascorbic acid –At higher levels lowers histamine levels –At lower levels helps tissue repair –Patients can begin at 1g/d, increase by 1g/d until bowel tolerance • Niacin, small doses lower histamine stores by releasing histamine

Quercetin: Anti-Allergy

FLEXIBILITY AND VITALITY

• Flavonoid - plant pigment - serves as backbone for other flavonoids like rutins • Considered to be most active flavonoid • Anti-oxidant, -inflam, -viral, -allergy, -cancer • Most studies not clinical • Sources: onions, apples, tea, red grapes, broccoli, leafy greens, cherries, cranberries, organic tomatoes, honey, and the white inner rind of citrus

• When we decrease our flexibility, we feel older and less vital (inflam and pain) • Yoga Proverb: “We are as young as our spine is flexible.” Stretch and Stay Open • When we eat wholesome, natural foods and drink good water, we maintain our Nature/God-given Health.

• We protect our health with a more alkaline diet, vits/mins, & antioxidants

DETOXIFICATION HELPS INFLAMMATORY CONDITIONS

Detox Goals • Nourish with wholesome, vital foods • Avoid toxins from environment & food • Protect yourself from toxins being made in the body and being released • Support body’s elimination systems • Correct Deficiency & Toxicity together • Detox Programs rest the body/cells, support longevity and reduce inflam • Find the Right Plan for YOU

• JOINT PAINS AND ARTHRITIS • CARDIOVASCULAR ISSUES—HBP, LIPIDS, ATHEROSCLEROSIS • MYALGIAS AND MANY BACK PAINS • OBESITY & PRE-DIABETES • ANY –ITIS CONDITIONS • ENERGY & MOOD DISORDERS • DIGESTION & ALLERGY ISSUES

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Levels of Dietary Detoxification

Detox Challenges

• • • • • • • • •

• What do people confront during detox? How do we help them be successful?

• The biggest challenges are motivation, getting started, and long-term changes.

• Having the right plan is also a key to consistent success.

• With your experience, inspiration, and guidance, patients will be successful.

Basic Diet Reduced Toxins and Elimination Diet Big 5 Elimination Diet or Sensitive 7 Big 5: wheat, dairy, sugar, caffeine, alcohol Vegan and/or Raw Food Diet Fruits & Vegetables and/or Smoothies Juices of fruits & vegetables Specific Juice Cleanse, like Master Cleanse Water Fast

Special Care in Detox: Deficiency Concerns & Signs

Many Benefits from Detoxification • Positive Side Benefits-Life & Health • Better Moods, Energy and Sleep • Less Meds needed with BP, Sugar & Cholesterol down, and feeling better • More flexible, less aches and pains • More fun to be around and inspiring • More open and communicative • Better digestive function/assimilation

• Fatigue and coldness • Dry skin and hair loss • Anemia and mineral deficiency • Hypothyroidism and Hypo-adrenalism • Low blood pressure • Malnourishment and underweight • Wasting diseases like cancer • Medical Conditions need medical guide

Basic Plans for Detox

Detoxification Systems

• Individual programs as with the Detox Diet, Smoothie Cleanse, or Juicing

• GI tract--liver, colon, the whole tube • Urinary--kidneys and bladder • Respiratory--lungs and bronchial tree • Lymphatic--lymph channels and nodes • Skin and Dermal--sweat & sebaceous glands • Sinuses-- an extra outlet for eliminating mucus congestion

• Integrated program that combines several approaches and steps/layers.

• Transitional plan and understanding of this process to move them into their New Healthy Diet and Eating Program.

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THE NEW DETOX DIET

THE NEW DETOX DIET

• Use Better Butter, a mix of organic butter and olive, flaxseed or organic canola oil • If needed for Energy, Protein (4 oz) 3-4pm.

Ideally legumes (soaked and sprouted) or some fish or poultry • Herb Tea only after dinner--mint and/or chamomile tea, for example • Exercise, sweat, sauna, skin brush, meditate • Make sure bowels are working smoothly and regularly

• Chew Well • Drink Good Water first in am –--2 Glasses w/ Lemon

• BREAKFAST--Fruit followed by Whole Grain • LUNCH (12-1pm) & DINNER (5-6pm) –Mixed Steamed Vegetables

• SNACK - Drink Veggie Water (saved from steaming) at about 11am & 3pm, usually with Nutrients included like C powder & Greens

SEASONAL DETOX-Groups in the Office

Spring and Summer Juice Cleansing

• January is great time for people to change habits and do 3-week dietary detox program, like the Detox Diet & warm Soups • Spring and Summer months can be good times for Juice Cleansing • September is time for new habits and discrimination, emphasizing the alkaline programs with lots of fresh and steamed veggies, juices and broths

• This is more focused, 7-10 days • Need more awareness in the process • Make adaptations if needed • Master Cleanser & Fresh Juices • Greens as wheatgrass & barley grass, or mixed green powders

The Master Cleanser Fast

The Master Cleanser

IMPORTANT NOTES: Mix and drink 8–12 glasses throughout the day.

Recipe for one glass • 2 Tablespoons of fresh-squeezed Lemon or Lime juice • 1 Tablespoon pure Maple Syrup (up to 2 tablespoons if you want to drop less weight) Can use blackstrap molasses if desired or for sensitive blood sugars.

• 1/10 teaspoon Cayenne Pepper (taste) • 8 ounces Spring Water

1. Drink ONLY water, laxative herb tea, and peppermint or chamomile tea.

2. Keep the Cleanser in a glass container (not plastic) or make it fresh each time. The cayenne heats up over the day when it sits in the solution.

3. Rinse your mouth with water after each glass to prevent the lemon juice from hurting the enamel of your teeth.

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Other Supplements for The New Detox Diet

Simple Supplement Program for The New Detox Diet • Multivitamin/Mineral (one a day type) Take one tablet or capsule after breakfast • Antioxidant Combination, 1-2 caps or tabs twice daily, between meals • Vitamin C or buffered powdered C with minerals (Ca, Mg, & Potas): 500-1,000 mg Vitamin C, or 1/2-1 tsp twice daily of powder mixed into liquid • Calcium/Magnesium at bedtime or for cramps (if no buffered C powder, use Ca at 500-1,000mg and Mg at 350-800mg total)

• Blue-green algae, Spirulina, Chlorella or Green

Powder 2-4 tabs/caps or a scoopful after B and L • Herbal Colon tablets or Laxative tea 1-2 tabs twice daily in the a.m. and eve, or about 1/2 to one cup of tea a.m. and eve (varies depending on individual sensitivity & product being used) • Herbal extracts can support or balance other body systems or enhance energy. Siberian or other ginsengs (adaptogens), echinacea for immune support, ginger for circulation, milk thistle for the liver, etc.

Dietary Ideas for Longevity

Foods that Protect Us

• Regularly Undereat with Nourishing Foods, and maintain light weight.

• Eat local, seasonal, fresh, whole, organic, and simply • Fresh Fruits and Veggies for functional PhytoNutrients • Add supplements to include B-

 Leafy Greens and Sprouts  Fresh Fruits and Vegetables, some raw foods provide Enzymes & PhytoNutrients  Olive oil and fatty Fish  Fiber and Water to assist elimination

•

Eat Right, Age Well

Changing Habits

• Research shows us we can make a

• Address Underlying Emotions & Attitudes • Gather Willpower and Create Plan • Having Loving Support helps • Detoxification Diet Alkalinizes Body & Reduces Inflammation • Water and Exercise • Add Greens and Herbs

difference in our health as we age •

•

•

vitamins, Antioxidants, Omega-3 fats, and consider good Proteins and Minerals Probiotics and Healthy Digestion

Antioxidant, low fat, anti-inflammatory Mediterranean-like Diet recommended for healthy heart and brain, helps prevent or delay Alzheimers, RA, many other diseases. DETOX is helpful transition.

High calcium-Vitamin D and Minerals recommended to prevent osteoporosis may also prevent many types of cancers Most choices are under our control.

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OrthoMolecular Detox

Our Health is important and essential, yet we often don’t realize this until we lose it.

Take care of yourself.

It Matters.

Be Happy & Healthy!

Thank you & Stay Healthy Elson M. Haas, MD, The Detox Doc™ Integrated Medicine Physician Preventive Medical Center of Marin San Rafael, California 415-472-2343 Websites:

Bio--Elson M. Haas, MD Dr. Haas is a practicing physician of Integrated Medicine for 35 years, Founder/Director of Preventive Medical Center of Marin in San Rafael, CA, and author of many books on health and nutrition: Staying Healthy With the Seasons, Staying Healthy With Nutrition, The New Detox Diet and More Vegetables, Please! Other books include Vitamins for Dummies andThe False Fat Diet. He is currently working on educational health entertainment programs for children and families, with new products such as The Anatomix Comix™ & Count Broccula.

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www.elsonhaas.com www.pmcmarin.com

Orthomolecular Stress Management Ron Hunninghake, MD

The Fight or Flight Movie

Orthomolecular

• A special animation depicting STRESS • Courtesy of the University of Texas Counseling and Mental Health Center

Stress Management

http://cmhc.utexas.edu/stressrecess/

• “Stress Management and Reduction” • Permission given for this special presentation • Available for viewing by the general public at:

Ron Hunninghake, MD Chief Medical Officer The Riordan Clinic

• http://cmhc.utexas.edu/stressrecess/animations/fofmoviestart.swf

What is Stress?

• Dr. Selye’s famous definition of stress: – The nonspecific response of the organism to any pressure or demand

• Two Types of Stress – Acute (short-term) – Chronic (long-term) Teachers and students are permitted to use these case studies for non-profit educational purposes. Doing Biology was originally published by Harper Collins (Glenview, IL, 1996).

Acute Stress

Chronic Stress is Different

• Dr. Hans Selye defined “fight or flight” as the organism’s response to acute stress • Adrenaline surges through the body to help us prepare to meet the challenge…or run!

• Think of it as pressing down on “the gas pedal of life” • In pre-civilization, this was a survival response

• In “civilized” society, the acute stress response can be triggered by non-life-threatening but demanding situations over which we have little control • Stuck in a job we hate, married to a spouse we can’t stand, bombarded by demands we can’t begin to fulfill…stress gets chronically triggered • With this kind of stress, we can neither fight nor run…we can only “suck it up” • Chronic stress is like pushing down on the gas pedal and the brake at the same time!

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Orthomolecular Stress Management Ron Hunninghake, MD Dr. Gabor Mate – The Role of Chronic Stress in the Genesis of Disease

Chronic Stress is Emotional • When stuck in a chronic stress situation, a measurable series of events occur • The brain is challenged with three universal elements of chronic stress: 1. Uncertainty 2. Lack of information 3. Loss of control

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• Emotional responses feed into an elaborate hormonal system involving the hypothalamus, the pituitary gland, and the adrenals

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Adrenal cortisol Oxidative Cortex Stress adrenalin adrenachrom Adrenal e depletes evitamin C Medulla requires CH3

It’s NOT “All in Your Head”

One Foot on the Accelerator…

Other Foot on the Brake

• Emotion is a COMPOSITE entity consisting of subjective experience, objective observations, and scientific (measurable) physiology

• The body gears up to deal with the threat • But what IF the “threat” NEVER RESOLVES • The emotional component of our response to stress can GET STUFFED and SUPPRESSED • This pattern of emotional suppression can become subconsciously established in the way we [MAL-]ADAPT to the perpetual threat

• Psycho-logical experiences trigger…

• Neuro-logical responses that result in an …

• Immuno-logical cascade of inflammation with …

• Endocrino-logical long-term consequences • Biochem-ical underpinning for all of above!

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Psycho - neuro - immuno P Nendocrino…

I E

Psycho-

• Stress is TRANSMUTED into illness via – Painful memories (psycho) – Imbalanced neuro-chemicals (neuro) – Excessive immuno-inflammation (immuno) – Disrupted hormonal (endocrinologic) systems

Immuno -

• Working as a WHOLE MIND-BODY SYSTEM • MIND-BODY-CELLULAR coping with life events • Psycho-neuro-immuno-endocrino- B biochemical !

Endocrino -

“The Mind and Body Are Separate” th

NeuroPNIEB

Biochem-

Why Has the Stress Link Been Ignored?

• Descartes, the famous 15 Century philosopher of science, first introduced the mind-body dichotomy (also termed “dualism”) • Descartes’ dualism was the basis of modern medicine’s positivism – “evidence based”

• Fear of casting blame on the patient “At a time when patients are already burdened by disease, they should not be further burdened by having to accept responsibility for the outcome.”

• “It is time to acknowledge that our belief in disease as a direct reflection of mental state is largely folklore.” - 1985

- 1985 NEJM article

• Ascent of the pharmaceutical model • The global invasion of medical insurance and universal diagnostic coding for fee payment • The “medicalization” of all life experiences • The profession vs. the business of medicine

NEJM editorial

• Of course, every doctor whose wife has a headache, KNOWS that her headache is real …and that HE’S PROBABLY THE CAUSE!

Response-Ability

Mary – the Mother and Wife

• Rather than blaming anyone for their illness, the mind-body-cellular model can empower the patient to become more response-able • Western medicine has inadvertently put the doctor on the pedestal of “ultimate authority” while casting the patient into the role of passive recipient of medical treatment (vs. co-learner) • The mind-body-cellular view is not only a key to understanding of the underlying causes of illness, but can serve as a pathway to regaining health!

• Married, in her early 40’s with three children • A sewing-needle puncture that should have healed…but didn’t • Her progressive Raynaud's phenomenon (spasms of the small arteries of her fingers) eventually led to their gangrenous amputation

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Mary’s Life Pattern

The Suppression of Self

• Captured in a single phrase:

• She had learned not to express her feelings to anyone, not even herself • To be self-expressive, vulnerable, and questioning in her childhood would have put her at risk • Her only security was to be hypersensitive to others’ feelings, never to her own

repressed emotion • • • •

Abused as a child Abandoned Shuttled from one foster home to another Age 7 - a memory of huddling in the attic, cradling her younger sister, while her drunken foster parents fought and yelled below

She Was Unable to Recover Her Self

The Unmapped Terrain of MindBody Dr. Gabor Mate’s Book – When the Body Says No

• She was trapped in a role forced upon her as a child • She was unaware that she herself had a right to be taken care of, listened to, and thought worthy of attention • She described herself as being incapable of saying No

“Work on this book has also been an inner exploration of the ways I have repressed my own emotions…” (“…and ignored my own biochemistry.”)

[Dr. Ron’s Addition]

An Incident in Dr. Mate’s Life

Victims of Nazi Genocide

• Visiting his 76 y.o. mother in a nursing home • Limping down the hallway the afternoon after arthroscopic repair of torn knee cartilage • As he opened the door to her room, his limp unconsciously shifted to a nonchalant, NORMAL GAIT

• Dr. Mate’s grandparents were murdered in Auschwitz when he was only 5 months old • He lived in the despair of a Budapest ghetto on the brink of starvation with his mother • In an attempt to ease his mother’s despair…

“I learned early to burden my mother as little as possible and that my anxiety and pain were best suppressed.”

• Why?

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Emotional Repression…

The Betrayal of Self

Fixed Personality Patterns

• The dynamics of repression operate in all of us • We are all self-deniers and self-betrayers to one extent or another • This happens in ways we are no more aware of than was Dr. Mate’ when he “decided” to disguise his limp.

• In the matter of illness, it is this emotional predisposition, often triggered by other factors (genetics or environment) that serves as the hidden genesis of a horrible disease

• Under these adverse circumstances of his mother being unable to provide him the maternal care a young child would otherwise receive…

“I became my mother’s protector—protecting her in the first instance against awareness of my own pain. What began as the automatic defensive coping of the infant soon hardened into a fixed personality pattern that, fifty-one years later, still caused me to hide even my slightest physical discomfort in front of my mother.”

Chronic Illnesses or Chronic Stress?

• Scleroderma • ALS (Lou Gehrig’s disease) • MS (multiple sclerosis) • Crohn’s disease • Chronic Fatigue Syndrome • Fibromyalgia

Mate’s Conclusions • Hidden stress is, as stated … HIDDEN • Hidden stress can show up as physical symptoms … when the body says No • The seven A’s of healing …

• Psoriasis • Migraine syndrome • Breast cancer • Melanoma

Acceptanc Awareness e Autonomy Attachment

• Endometriosis • Rheumatoid Arthritis

Anger

Assertion

Affirmation

• …can help you in the recovery of self • Biochemistry, Nutrition, Lifestyle are not mentioned!

Searching Under the Light

Final Lines of Mate’s Book

• The 12th century fool and sage – Nasruddin • On his hands and knees searching under a bright street light • “What are you looking for?” … “My key.”

• Soon, all have joined him in his search. No luck.

• “Wait…where did you lose the key?”

• “In my house.” “Why are you looking here?!!”

• “Because I can see better here, under the light.”

“When it comes to healing, if we look only in the easy places, we usually find what Nasruddin and his neighbors found under the street light: nothing. Nasruddin, in his role as fool, did not know that. In his role as sage and teacher, he did.

Nasruddin, fool and sage, exists in all of us.”

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A Cellular Model of Health and Healing

Orthomolecular Model of Health and Healing

• Health – balanced redox • Injury – disruption

• Health – balanced redox Nutrients • Injury – disruption

• Signal – oxidation • Repair – inflammation • Healing – restoration

• Signal – oxidation Stress • Repair – inflammation Disease • Healing – restoration Toxins

Toxin s

Health Healing

Injury

 Injury   

Psycho-

Stress Nutrient s



NeuroPNI EB

Endocrino -

Diseas e

What is Stress?

Immuno -

Biochem -

Now

Stress Now

Toxins Nutrients

Injury

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What is Stress Management?

Now

• Every book ever written is indirectly about “stress management” – how we cope with life • All of life, every moment of it, every decision made by the human organism, can be characterized as “stress management” • In modern times, this great human endeavor has been trivialized to “the relaxation response” • The General Adaptation Syndrome was Selye’s name for “stress management”

Pas t

Orthos is “Stress Managed” • Nutrients well-chosen to satisfy redox need • Injuries well-attended to restore function • Stress signals well-heeded to direct action • Diseases well-treated to promote healing • Toxins well-processed to restore health

Eustress

Stress

Stress Optimization

Nutrient s

Injury

Toxins

Nutrient s

Orthos

Injury

Disease

Adaptation

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Detoxificatio Toxins n Orthos

Disease Regeneratio n

Orthomolecular Stress Management Ron Hunninghake, MD

Pathos is “Stress Un-managed”

Mate’s Vision

• Nutrients insufficient to satisfy redox need • Injuries un-attended to restore function • Stress signals ignored to direct proper action • Diseases mis-treated to delay healing • Toxins un-processed to perpetuate disease

Nutrient s

Stress Toxins

Injury

Nutrient s

Pollution

Injury

Disease Degeneratio n

Dysfunction

Disease

Mate’

Distress Pathos

Toxins

Injury

Stress Nutrient Starvation s

Stress

Eustress

Ortho s

Toxins

O.S.M .

Disease

True Stress Management

Stress Distress Optimization

Nutrient Starvation s Adaptation

Injury Dysfunction

Orthos Pathos

Detoxificatio Toxinsn Pollution Pathos Regeneratio n Disease Degeneratio n

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Orthos

Orthomolecular Stress Management Ron Hunninghake, MD

“Take Your Niacin!”

Stress Nutrient s

Toxins Choices

Injury

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Toxins Pathos

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Imbalance d Redox +CH3

Disease

CH3

Orthomolecular Stress Management

Nutrient Regulators

• Redox and methylation (biochemical) balancing

Electron Donors

– Electron donors – Electron receivers – Methyl donors – Methyl receivers – Regulators

Methyl Donors

(all other nutrients, phytonutrients, enzymes, neurotransmitters)

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Nutrient Orthos

Electron Receive rs Methyl Receive rs

Orthomolecular Stress Management Ron Hunninghake, MD

Stress

Pituitary

Imbalanced Hormones

Thyroid

Toxins

Nutrient s

Hormone Orthos

Pathos

Injury

Disease

Thymic

Poor concentration Depression Feeling faint Frustration Headaches Inflammationprone Hair loss Infection-prone Cravings for sweets

Hypoglycemia Neck/back pains Frequent infections Irritability

Flank (adrenal) pain Stomach aches

• Redox + CH3 balancing • Hormonal balancing (bio-identicals)

Food allergies Confused moments Weakness Light-headedness Low blood “Brown-outs” pressure Alcohol Heart palpitations intolerance Indigestion Irritable bowel Scanty Low body temp. perspiration Can’t build muscle Dry, thin skin Insomnia

– pituitary, thymus, thyroid, adrenal, gonadal

PMS

Stress Nutrient s

Gonadal

Orthomolecular Stress Management

Symptoms of Adrenal Stress Fatigue Memory issues

Adrena l

Survival Toxins

Freedo m

Pathos

Fun Basic Needs Pathos

Injury

Disease

Powe r

Imbalance d Basic Needs

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Dr. Mate’ as a child in the Budapest ghetto

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Orthomolecular Stress Management Ron Hunninghake, MD

Orthomolecular Stress Management

Stress

• Redox balancing • Hormonal balancing • Basic needs balancing

Vitamin D3 Nutrient s

– Survival, Fun, Freedom, Love, and Power

Toxins Pathos

Imbalanced Environmen t

Injury

Disease

Rehydration

Orthomolecular Stress Management

Air Sunshin e

• Redox balance • Hormonal balance • Basic needs balance

Space Environmental Orthos

Water

• Environmental balance – food, water, air, sunshine, space

Food

Orthomolecular Stress Management

Repressed Stress Emotion Imbalanced

• Redox balancing • Hormonal balancing • Basic needs balancing

Emotions

Nutrient s

Toxins Pathos

• Environmental balancing • Emotional (relationships) balancing – body, heart, people, mind, soul

Injury

Disease

Scleroderm a

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Balanced Emotions

Peopl e

Heart

Orthomolecular Stress Management

Sou l

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Mind Emotional Orthos

Body

Mind solve

Soul hope

powe purpos r e truth peace

awar love e clarit Orthos y

How To Characterize Our Orthos Stress? Pathos

What Is Orthos?

(Eu)Stress

• Orthos is Greek for right, correct, true, straight, leading to the desired result.

• Orthos implies true quality and optimal functioning.

• Orthos Health is optimal health…the true and desired result of quality health care.

• Orthos Health is a process of healing where patient individuality, co-learnership, and orthomolecular health is placed above the mere absence of disease.

(Dis)Stress

• Relational

• Isolational

• • • •

• • • •

Response-able Habitual Regenerative Repletional

• Wellness • Life

What Is Eustress?

Ir-response-able Compulsive Degenerative Depletional

• Sickness • Death

Stress Mate’

• Choices that make you stronger • Creative tension that leads to results • Life’s challenges met with courageously

Nutrient s

Ortho s

Toxins

• You’s stress… the stressors you have embraced as your self-chosen path to a desired goal

Injury

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O.S.M .

Disease

Orthomolecular Stress Management Ron Hunninghake, MD

Eustress

Stress

Stress Distress Optimization

Nutrient Starvation s

Orthos Pathos

Detoxificatio Toxinsn Pollution

Nutrient s

Orthos

Regeneratio

Adaptation

Injury

Injury

n Disease

Dysfunction

Disease

Degeneratio n

Mind-Body Heart-Soul People Medicine Soul

People

Orthomolecular Stress Management Orthos: Body Hear People t Stress escap fight talk e fun freedom Nutrient food s Toxins detox will politics Injury heal no! forgive colearner Disease ortho patho s

Mind Orthos

Heart

Toxins

Body

Mind solve

Soul hope

powe purpos r e truth peace

awar love e clarit Orthos y

Five Layersâ&#x20AC;Ś Past and Present

Now

Pas t

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Orthomolecular Stress Management Ron Hunninghake, MD

Orthos is a Philosophy of Health!

"To find health should be the object of the doctor.

Anyone can find disease."

• Comprehensive pathway to better health • Involves PERSONAL health care reform • Respects individuality and asserts the primacy of the individual’s quest to be healthy • Acknowledges the role of stress (both distress and eustress) in all health and healing • Deals with fundamental underlying causes rather than simply treating symptoms

A.T. Still, MD, DO

Orthos and The Four Cardinal Virtues • • • •

Orthos – Final Key Idea

Prudence – correct perception Justice – correct relationship Fortitude – correct attitude Temperance – correct balance

• Learning about, adopting, growing, and sustaining…

Habits of Health • This is the essence of Orthomolecular Stress Management

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