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CALL 800.755.3402 Tel: 805.693.1802 • Fax: 805.693.1806 • CustomerService@ResearchedNutritionals.com www.ResearchedNutritionals.com | Available only through healthcare professionals *These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure or prevent any disease.

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JULY/AUGUST 2016, VOL. 22, NO. 4

TABLE OF CONTENTS EDITORIAL 8

Molds and Mycotoxins: A Brief Review Andrew W. Campbell, MD

12

Nicholas Gonzalez, MD Andrew W. Campbell, MD

PERSPECTIVES 14

Dr Gonzalez as a Practice Colleague: A Memoir Linda L. Isaacs, MD

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Dr Gonzalez as a Colleague: A Memoir Julian Hyman, MD

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Reporting on Dr Gonzalez for a Quarter Century: A Memoir Peter Barry Chowka

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Dr Gonzalez as a Colleague: A Memoir Colin A. Ross, MD

ORIGINAL RESEARCH 36

Improvement of QOL and Immunological Function With Lentinula Edodes Mycelia in Patients Undergoing Cancer Immunotherapy: An Open Pilot Study Keishi Tanigawa, MD, PhD; Yusuke Itoh, BS; Yasunobu Kobayashi, PhD

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The Effects of Ozonated Olive Oil and Clotrimazole Cream for Treatment of Vulvovaginal Candidiasis Fatemeh Tara, MD; Ziba Zand-Kargar, MD; Omid Rajabi, PharmD, PhD; Fariba Berenji, MD, PhD; Farideh Akhlaghi, MD; Mohammad Taghi Shakeri, PhD; Hoda Azizi, MD, PhD

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Effects of Balsamodendron mukul Gum Resin Extract on Articular Cartilage in Papain-induced Osteoarthritis Jayanand Manjhi, PhD; Maneesh Gupta, PhD; Anvesha Sinha, PhD; Beena Rawat, MPhil; Durg V. Rai, PhD

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Smartphone-based Music Listening to Reduce Pain and Anxiety Before Coronarography: A Focus on Sex Differences Stéphane Guétin, PhD; Luc Brun, MD; Maelle Deniaud; Jean-Michel Clerc, MD; Julian F. Thayer, PhD; Julian Koenig, DrScHum

CASE REPORT 24

A Case of Insulin-dependent Diabetes Nicholas Gonzalez, MD

Table of Contents

ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 3

REVIEW ARTICLE 64

Profiling the Australian Consumer of Complementary and Alternative Medicine: A Secondary Analysis of National Health Survey Data Matthew J. Leach, RN, BN (Hons), ND, DipClinNutr, PhD

CONVERSATIONS 74

Edwin Lee, MD: Treating the Cause and Teaching the Young Interview by Craig Gustafson

DEPARTMENTS 78

Conference Calendar

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Table of Contents

Outsmart the Effects of Aging Mood1,5,6 Synaptic Plasticity2

Neuroprotection3

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Emotional Coping5

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2013;20(24):2953-63. 3. Lynch AM, Loane DJ, Minogue AM, et al. Eicosapentaenoic acid confers neuroprotection in the amyloid-beta challenged aged hippocampus. Neurobiol Aging. 2007;28(6):845-855. 4. Heinrichs SC. Dietary omega-3 fatty acid supplementation for optimizing neuronal structure and function. Mol Nutr Food Res. 2010;54(4):447-456. 5. Saunders EF, Reider A, Singh G, Gelenberg AJ, Rapoport SI. Low unesterified:esterified eicosapentaenoic acid (EPA) plasma concentration ratio is associated with bipolar disorder episodes, and omega-3 plasma concentrations are altered by treatment. Bipolar Disord. 2015;17(7):729-742. 6. Sinn N, Milte CM, Street SJ, et al. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial. Br J Nutr. 2012;107(11):1682-93. 7. Data on file, Prevention Pharmaceuticals Inc. New Haven, CT. omax3 is a registered trademark of Prevention Pharmaceuticals, Inc. ProResolv is a trademark of Prevention Pharmaceuticals, Inc. ©2015 Prevention Consumer Health Products. All rights reserved. OMPS007 12/2015

*These statements have not been evaluated by the US Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.

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editor in chief Andrew W. Campbell, MD CONTRIBUTING EDITORS

Michael Balick, PhD • Mark Hyman, MD • Jeffrey Bland, PhD, FACN, FACB • Roberta Lee, MD • Tieraona Low Dog, MD Editorial Board Sidney MacDonald Baker, MD ◆ Autism Research Institute

Gerard Mullin, MD ◆ Johns Hopkins University

Mark Blumenthal ◆ American Botanical Council

John Neely, MD ◆ Pennsylvania State University

David M. Brady, ND, DC, CCN ◆ University of Bridgeport Kelly Brogan, MD, ABIHM ◆ George Washington University

Paula J. Nenn, MD, ABIHM ◆ Optimal Health and Prevention Research Foundation Garth L. Nicolson, PhD ◆ The Institute for Molecular Medicine

Jeffrey Dach, MD ◆ TrueMedMD, Davie, Florida

Xie Ning, PhD ◆ Heilongjiang University of Traditional Chinese Medicine

James Dillard, MD, DC, LAc ◆ Integrative Pain Medicine Jeanne Drisko, MD ◆ University of Kansas

Thomas O’Bryan, DC, CCN, DACBN ◆ Institute for Functional Medicine, National Univ. of Health Sciences Dean Ornish, MD ◆ Preventive Medicine Research Institute

Andrea Girman, MD, MPH ◆ Genova Diagnostics

Nicole Pietschmann, PhD ◆ Berlin, Germany

Ajay Goel, PhD ◆ Baylor Research Institute

Joseph E. Pizzorno, ND ◆ Seattle, WA

Garry F. Gordon, MD, DO ◆ Gordon Research Institute

Lawrence A. Plumlee, MD ◆ Chemical Sensitivity Disorders Association

Junfeng He, PhD ◆ Hunan University of Traditional Chinese Medicine

Keith S. Rayburn, MD ◆ Santa Clara County Health and Hospital System

Yuxin He, LAc, PhD ◆ Academy of Oriental Medicine at Austin

William J. Rea, MD ◆ Environmental Health Center – Dallas

Robert Hedaya, MD, DLFAPA ◆ National Center for Whole Psychiatry

Sandeep Saluja, MD ◆ Saran Ashram Hospital, Dayalbagh

Leila Jabbour, PhD ◆ Franklin Pierce University

Eric R. Secor Jr, PhD, ND, MPH, MS, LAc ◆ Helen & Harry Gray Cancer Center, Hartford Hospital Ellen Kamhi, PhD, RN, AHG, AHN-BC ◆ Stony Brook University Stephen T. Sinatra, MD, FACC, FACN, CNS ◆ University of Connecticut School of Medicine Anup Kanodia, MD, MPH ◆ Ohio State University Martha Stark, MD ◆ Harvard Medical School, Massachusetts Mental Health Center Datis Kharrazian, DC, DHSc, MS, MNeuroSci ◆ Bastyr University of California; Alex Vasquez, DC, ND, DO ◆ University of Texas Institute for Functional Medicine Günver Kienle, DrMed ◆ Institute for Applied Epistemology Aristo Vojdani, PhD, MSc, CLS ◆ Immunosciences Lab, Inc James B. Lago, EMT, DDS, BA ◆ Chicago Dental Health

Roeland van Wijk, PhD ◆ International Institute of Biophysics

Changzheng Li, PhD ◆ Department of Chinese Internal Medicine, Nanfang James M. Whedon, DC, MS ◆ Southern California University of Health Sciences Hospital, Southern Medical University, China Erqiang Li, PhD ◆ East West College of Natural Medicine Shi Xian, MD, PhD ◆ General Hospital of the Chinese People’s Liberation Army Holly Lucille, ND, RN ◆ Humility Inc Cuauhtemoc Hernandez Maya, MD ◆ Tao Healing Arts Center

Arthur Yin Fan, CMD, PhD, LAc ◆ McLean Center for Complementary and Alternative Medicine Qinhong Zhang, MD, PhD ◆ Stanford University

Pamela Miles, Reiki Master ◆ New York, NY

Shun Zhongren, PhD ◆ Heilongjiang University of Traditional Chinese Medicine

Daniel A. Monti, MD ◆ Thomas Jefferson University

Managing Editor, CRAIG GUSTAFSON • Creative Director, RANDY PALMER • Associate Editor, MICHAEL MILLER Editorial Assistant, CARALIN WALSH • Science Editor, PEGGY WRIGHT • E-mail: ATHM@innovisionhm.com Web: www.alternative-therapies.com

6 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

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EDITORIAL

Molds and Mycotoxins: A Brief Review

I

n the second book of the Bible, in Chapter 14 of Leviticus, Moses describes what needs to be done to a dwelling in which there is an eruptive plague on the wall. It is a wise and correct protocol for the remediation for mold growing indoors that still holds true in our modern times. It also shows that the issue of molds causing disease is as old as the Bible itself.

Diseases caused by ergot alkaloids from the mold Claviceps purpurea have been recognized since ancient times.

It grows on rye, barley, and other grains; when made into flour then bread and eaten, the ergot alkaloids cause the symptoms. A reference to a “noxious pustule in the ear of grain” on an Assyrian tablet from 600 BCE is one of the first writings about ergot.1 In the middle ages, people suffered from hallucinations and “madness” from ergotism: It was called St Anthony’s fire. As late as in 1951, this same “fire” killed several people in a village in France.2 There were 132 epidemics of ergotism in Europe between the sixth and 18th centuries documented by the 3-volume work by August Hirsch titled Handbook of Geographical and Historical Pathology, published in London in 1886.3 There are many instances of molds triggering diseases throughout history, as well as causing a number of epidemics. For example, an epidemic of alimentary toxic aleukia killed approximately 100 000 in Russia in 1944 when people ate moldy bread. The culprit was a mycotoxin known as trichothecene.4 Today, with modern technological methods used to clean grain, ergotism has been almost eliminated in humans.

There are two basic forms of ergotism: one that affects circulation of blood causing a dry gangrene of the extremities, and the other affecting the central nervous system and causing convulsions. It is known to cause painful seizures, diarrhea, paresthesias, mania, psychosis, and headaches. I’ve personally asked a number of neurologists if molds can cause seizures, and they all said that they have never heard of that; then, I ask them if they have ever read about ergotism, and their eyes light up.

In past times, midwives used ergot alkaloids either to induce uterine contractions for women in labor or to bring about abortions.5 More recently, methylergonovine maleate was prescribed to stop postpartum hemorrhage and migraine headaches were sometimes treated with ergotamine. Lysergic acid diethylamide (LSD) got its start at Sandoz Laboratories in Switzerland during research on ergot alkaloids. It was named Delysid and touted as a treatment for schizophrenia.6 There are more than 100 000 species of molds; approximately 2 dozen can cause health problems in humans.

Mycoses are when fungi grow on and in us and are either aggravating, such as athlete’s foot, or critical, such as invasive aspergillosis. Molds can be found everywhere on this planet.

Cold or warm, wet or dry environments, mold spores are omnipresent, and they can grow on anything once wet. They are like seeds in a packet that one buys in a store: without water, they do very little. Once they get wet and remain wet for 24 to 48 hours, molds start to multiply and sporulate.

Attached to these spores is a secondary metabolite, mycotoxins. Mycotoxins are there for survival of the fittest: When you pull out that plastic bag from the back of your refrigerator with the heel of a loaf of bread left in it, with various colored spots on it, these are bacteria and molds feeding on the bread. The mycotoxins destroy the bacteria so that the food remains only for the molds. This effect of mycotoxins on bacteria was the inadvertent finding of Sir Alexander Fleming when, after returning from a vacation, he noticed that one of the petri dishes with staphylococci was contaminated by the mold Penicillium notatum and that the colonies of staphylococci surrounding the fungus had been destroyed. From this he eventually developed the first antibiotic, penicillin, and it is estimated that more than 200 million lives were saved as a result of patients being given this antibiotic.7 Today, when patients get a bone marrow transplant, they are given a potent immune suppressant derived from mycotoxins: cyclosporine. The toxic and immunogenic byproducts of molds are not limited to mycotoxins; they include 1,3-α-D glucans, extracellular polysaccharides, and volatile organic compounds (VOCs).

Occupants of dwellings and workplaces affected by mold growth due to leaks or water intrusion can develop one or all of the following, some due to mycotoxins:

8 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

Campbell—Molds and Mycotoxins

1. Mycotic infections (mycoses).

2. Fungal rinosinusitis.

3. Immunoglobulin E (IgE)-mediated sensitivity and asthma.

4. Hypersensitivity pneumonitis and related inflammatory pulmonary diseases.

5. Cytotoxicity.

6. Immune suppression/modulation.

7. Mitochondrial toxicity.

8. Carcinogenicity.

9. Nephrotoxicity.

10. The formation of nuclear and mitochondrial DNA adduct.

Table 1. Mold, Mycotoxins, and Their Effects8 Mold Stachybotrys chartarum

Mycotoxins Satratoxins, verrucarin; trichothecene

Aspergillus flavus Aspergillus fumigatus

Aflatoxin B1 Fumitoxins; gliotoxins

Aspergillus niger Aspergillus versicolor Chaetomium globosum

Ochratoxin Sterigmatocystin Chaetoglobosin

Penicillium brevicompactum Penicillium expansum Penicillium polonicum

Mycophenolic acid Patulin, citrinin Verrucosidins; nephrotoxic glycopeptides Trichothecenes; gliotoxins

Trichoderma species

Effects Pulmonary hemosiderosis; induce proinflammatory cytokines; neurotoxic; immune suppression Carcinogenesis, aspergillosis Tremors and CNS injury; immune dysregulation; aspergillosis Nephropathy Carcinogenesis; aspergillosis Cytotoxicity; inhibition of cell division Toxic: mutagenic Immune toxicity; tremorgenic Tremors; cytotoxicity, nephropathy Neurotoxic; immune suppression

Abbreviation: CNS, central nervous system.

Slightly less than 1 year after Hurricane Katrina struck New Orleans and the surrounding areas, the Centers for Disease Control and Prevention (CDC)9 published its findings in Morbidity and Mortality Weekly Report in an article titled “Mold Prevention Strategies and Possible Health Effects in the Aftermath of Hurricanes and Major Floods.” The CDC concluded that “excessive exposure to mold-contaminated materials can cause health effects in susceptible persons regardless of the type of molds or the extent of contamination.”9 A few years later, in 2009, the World Health Organization published in its Guidelines for Indoor Air Quality: Sufficient epidemiological evidence is available from studies conducted in different countries and under different climactic conditions to show that the occupants of damp or moldy buildings, both houses and public buildings, are at increased risk of respiratory symptoms, respiratory infections and exacerbation of asthma …

Toxicological evidence obtained in vivo and in vitro support these findings showing the occurrence of diverse inflammatory and toxic responses after exposure to microorganisms including their spores, metabolites, and components isolated from damp buildings.10

they had chronic fatigue syndrome, fibromyalgia, intractable Lyme’s disease, and so forth.

Treatment starts once the first rule of toxicology is achieved: Get the patient away from the toxin or the toxin away from the patient. If the water intrusion is in the home and has lasted a few days, then it is likely that all in the home may be contaminated: bedding, curtains, fabrics on living room furniture, towels, etc. Here again, Moses told us what to do. In public buildings or schools, remediation must be started as soon as possible, preferably before the spread of mold spores through the heating/ventilation/air conditioning (HVAC) system. However, the needed rapidity of remediation is rarely achieved due to delays.

The symptoms of indoor mold exposure depend on the length of time of the exposure and the amount as well as the types of molds. They are general and nonspecific: fatigue, unusual headaches, confusion, palpitations, shortness of breath, blurred vision, muscle and joint aches and pains, short-term memory loss, tremors, mood swings, and sleep disturbance are the most common.8 Patients affected by molds and mycotoxins are frequently shuttled from one specialist to another, with their diagnoses being more of symptoms than disease. I have treated many that were told

MYCOTOXINS Mycotoxicoses differ from mycoses in that these are toxins and are, therefore, similar to the health problems caused by heavy metal exposures or pesticides or other toxins. Mycotoxins usually enter the body by inhalation, ingestions, or dermal absorption. Studies have shown that when Stachybotrys chartarum is present in an indoor environment, mycotoxins are also present in the sera of the exposed individuals.11 Symptoms vary depending on the mycotoxin, the amount of mycotoxin and the duration of the exposure, as well as the general health of the exposed person.12 A number of mycotoxins are known to affect the neurological system, causing cognitive function problems, tremors, and inflammatory neuropathies. Several papers have demonstrated chronic inflammatory demyelinating neuropathy caused by exposure to elevated levels of molds in the environment and, therefore, mycotoxins. Many mycotoxins induce tremors as a neurological effect.13

Campbell—Molds and Mycotoxins

ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 9

AFLATOXINS Exposure to aflatoxins in the diet is considered an important risk factor for the development of primary hepatocellular carcinoma, particularly in individuals already exposed to hepatitis B. Extrahepatic neoplasms of the lungs are also associated with aflatoxin. The International Agency for Research on Cancer (IARC) has classified aflatoxin B1 as a group I carcinogen, the worse group, causing liver cancer.

Acute aflatoxicosis results in death; chronic aflatoxicosis results in cancer, immune suppression, and other “slow” pathological conditions. Exposure to aflatoxins can result in hepatocellular carcinoma, especially in a person already affected by hepatitis B.14 FUMONISINS The mycotoxins known as fumonisins are associated with esophageal cancer. Charleston, South Carolina, has the highest incidence of esophageal cancer in African Americans in the United States. This has been linked to elevated levels of fumonisins in corn meal and corn grits, and 7 samples from a supermarket there were found contaminated.15 As fumonisins can cause the development of neural tube defects in experimental animals, it has been suggested that a cluster of anencephaly and spina bifida in southern Texas along the Mexican border may have been caused by contaminated corn products.16 The IARC has classified fumonisins as group 2B: probably carcinogenic.17 OCHRATOXINS Animal studies show that ochratoxin A is an immune suppressant, a carcinogen, a potent teratogen, and hepatoxic.18 It has been detected in human milk and is regularly found in pork for human consumption.19 Porcine nephropathy is endemic in Denmark, and it would behoove the medical community to consider ochratoxin toxicity in patients presenting with symptoms of renal disorders.20 IARC has classified ochratoxin 2B, a possible human carcinogen.21

INDOOR AIR QUALITY AND SICK-BUILDING SYNDROME Sick-building syndrome is used when there is no etiology identified to cause symptoms; when there is a causal factor, then the term building-related illness applies.25,26,27 Most homes in the United States are built by homebuilders and not by architects, increasing the likelihood of problems related to construction that allow for water intrusion. Respiratory problems including asthma and allergies are known to be exacerbated by dirty HVAC ducts, vents, and filters, dust stirred up during reconstruction, and in the aftermath of water intrusion to interiors of dwellings or buildings due to broken water pipes, faulty installation of clothes washers, refrigerators with ice makers and water dispensers, roofs, windows, and chimney leaks, poor flashing placements, and floods, among others.

SUMMARY It is an uncontested medical and scientific fact that molds and mycotoxins cause diseases in humans. Both are health hazards, and both are often overlooked and not part of clinicians’ differential diagnosis. Molds produce metabolites such as mycotoxins and solvents, shed antigenic materials such as spores, hyphae, extracellular polysaccharides, and enzymes, which are toxic and cause immunologic responses.

Forgacs28 called mold mycotoxicosis “the neglected disease.”

Clinicians should include molds and mycotoxins in their evaluation of patients and help this become “the accepted disease.”28 (Altern Ther Health Med. 2016;22(4):8-11.)

Andrew W. Campbell, MD Editor in Chief REFERENCES

TRICHOTHECENES Trichothecenes are produced by the molds Stachybotrys, although Myrothecium and Trichothecium species can produce them as well. The Trichothecenes produced by Stachybotrys chartarum include satratoxins, roridins, verrucarins, and atranones.22 Molds, chiefly Stachybotrys, easily grow on numerous building materials that have high cellulose content: ceiling tiles, wood fiber boards, and gypsum boards, among others. Dust-lined heating, air conditioning, and ventilations ducts (HVACs) are also areas where Stachybotrys has been found and, therefore, also Trichothecenes. Presence of these has been linked to pulmonary bleeding in infants.23 In another link to the Bible, it has been proposed that the 10th plague of Egypt was Stachybotrys infestation.24

10 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

1. Hofmann A. Ergot—A rich source of pharmacologically active substances. In: Swain T, ed. Plants in the Development of Modern Medicine. Cambridge, MA: Harvard University Press; 1979:236-260.

2. Richards IS. Principles and Practice of Toxicology in Public Health. Sudbury, MA: Jones & Bartlett; 2008.

3. Joffe AZ. Toxicity of Fungi on Cereals Overwintered in the Field: On the Etiology of Alimentary Toxic Aleukia [dissertation]. Leningrad, Russia: Inst.

Bot. Acad. Sci.; 1950.

4. Haller JS Jr. Ergotism. In Kiple KF, ed. The Cambridge World History of Human Disease. Cambridge, United Kingdom: Cambridge University Press; 1993:718-719.

5. Riddle JM. Eve’s Herbs. A History of Contraception and Abortion in the West.

Cambridge, MA: Harvard University Press; 1997.

6. Hofmann A. Ergot—A rich source of pharmacologically active substances. In: Swain T, ed. Plants in the Development of Modern Medicine. Cambridge, MA: Harvard University Press; 1972:236-260.

7. Cruickshank R. Sir Alexander Fleming, F.R.S. Nature. 1955;175(4459):663.

8. Campbell AW, Thrasher JD, Gray MR, Vojdani A. Molds and mycotoxins: Effects on the neurological and immune systems in humans. Adv Appl Microbiol.

2004;55:375-406.

9. Centers for Disease Control and Prevention. MMWR: Recommendations and Reports. 2006;55(RR08):1-27.

10. World Health Organization. WHO guidelines for indoor air quality: Dampness and mould. http://www.who.int/indoorair/publications/7989289041683/en/.

Accessed July 8, 2016.

Campbell—Molds and Mycotoxins

11. Brasel T, Campbell AW, Demers RE, et al. Detection of trichothecene mycotoxins in sera from individuals exposed to Stachybotrys chartarum in indoor environments. Arch Environ Health. 2004;59(6):317-323.

12. Bennett J, Klich M. Mycotoxins. Clin Microbiol Rev. July 2003;497-516.

13. International Agency for Research on Cancer. The Evaluation of the Carcinogenic Risk of Chemicals to Humans. IARC Monograph Supplement 4. Lyon, France: International Agency for Research on Cancer; 1982.

14. Hsieh D. Potential human health hazards of mycotoxins. In: Natori S, Hashimoto K, Ueno Y, eds. Mycotoxins and Phytotoxins. Third Joint Food and Agriculture Organization/WHO/United Nations Environment Program International Conference of Mycotoxins. Amsterdam, Netherlands: Elsevier; 1988:69-80.

15. Sydenham EW, Shephard GS, Thiel PG, Marasas WFO, Stockenstrom S. Fumonisin contamination of commercial corn-based human foodstuffs. J Agric Food Chem. 1991;39:2014-2018.

16. Hendricks KA, Simpson JS, Larsen RD. Neural tube defects along the TexasMexico border, 1993–1995. Am J Epidemiol. 1999;149L:1119-1127.

17. Rheeder JP, Marasas WF, Vismer HF. Production of fumonisin analogs by Fusarium species. Appl Environ Microbiol. 2002;68:2102-2105.

18. Kuiper-Goodman T, Scott PM. Risk assessment of the mycotoxin ochratoxin A. Biomed Environ Sci. 1989;2:179-248.

19. Marquardt RR, Frohlich AA. A review of recent advances in understanding ochratoxicosis. J Anim Sci. 1992;70:3968-3988.

20. Creppy EE. Human ochratoxicosis. J Toxicol Toxin Rev. 1999;18:277-293.

21. Beardall JM, Miller JD. Disease in humans with mycotoxins as possible causes.

In: Miller JD, Trenholm HL, eds. Mycotoxins in Grains: Compounds Other Than Aflatoxin. Saint Paul, MN: Eagan Press; 1994:487-539.

22. Hinkley SF, Jarvis BB. Chromatographic method for Stachybotrys toxins. In: Trucksess MW, Pohland AE, eds. Mycotoxin Protocols. Totowa, NJ: Humana Press; 2001:173-194.

23. Etzel RA, Montana E, Sorenson WG, Kullman GJ, Allan TM, Dearborn DG. Acute pulmonary hemorrhage in infants associated with exposure to Stachybotrys atra and other fungi. Arch Pediatr Adolesc Med. 1998;152:757-762.

24. Schoental R. Mycotoxins and the Bible. Perspect Biol Med. 1984;28:117-120.

25. Environmental Protection Agency. Sick Building Syndrome: Indoor Air Quality Fact Sheet 4. Washington, DC: Environmental Protection Agency; 1991.

26. Godish T. Sick Buildings: Definition, Diagnosis, and Mitigation. Boca Raton, FL: Lewis Publications; 1995.

27. Rylander R. Microbial cell wall constituents in indoor air and their relation to disease. Indoor Air. 1998;4(Suppl):59-65.

28. Forgacs J. Mycotoxicoses: The neglected diseases. Feedstuffs. 1962;34:124-134.

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EDITORIAL

Nicholas Gonzalez, MD

J

ust over a year ago, we learned of the sad news that one of medicine’s most distinguished practitioners had unexpectedly passed away. Nicholas Gonzalez, MD, approached medicine with the inquisitiveness and determination he developed as an award-winning investigative journalist in his first career. Once exposed to the trophoblast theory of cancer and the efficacy of a nutritional approach pioneered by William Donald Kelley, DDS, he switched professions and dedicated his professional life to refining and expanding knowledge of this promising and effective treatment protocol. He did so with brilliance and compassion.

In this edition, we are proud to present a final article by our distinguished colleague, Dr Gonzalez, which as you will learn, was completed on the very day he died. The case report appears along with a handful of tributes and testimonies penned by colleagues and contemporaries of Dr Gonzalez, including one by a doctor originally selected to help disprove his protocol.

These types of therapies, as well as many of those published in Alternative Therapies in Health and Medicine (ATHM), are often assailed as not falling within the realm of “science” or as having employed some sort of “pseudoscience” in order to cast an illusion of credibility. Dr Gonzalez allowed only true science to guide his exploration and, as such, was a beacon for researchers in all areas of alternative medicine.

Despite repeated attempts to discredit him and his research, his work was so sound that these attempts were never successful.

Over the past year, ATHM has collected and published a number of tributes, histories, and interviews involving Dr Gonzalez. Together, with the articles previously mentioned, we published them in a commemorative book, highlighting this outstanding doctor and his unique perspective on cancer, and indeed, general health and wellness. It is available through Amazon.

It is our hope, as it was Dr Gonzalez’s, that there will be others to grasp the torch and carry this work forward so that 12 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

this protocol might gain the general acceptance that is so needed and the credibility that it so deserves. Educational resources are available through the Nicholas Gonzalez Foundation (http://www.drgonzalez.com/).

We would like to thank Mary Beth Gonzalez for supporting our efforts in collecting these materials, and all of Dr Gonzalez’s colleagues, all those he mentored, and the patients who contributed to either the journal or the book.

We hope you enjoy reading these offerings. (Altern Ther Health Med. 2016;22(4):12.)

Andrew W. Campbell, MD Editor in Chief

Campbell—Introduction

DANIEL AMEN, MD

AMEN CLINICS Costa Mesa, CA Brain Scans in PTSD and Trauma

KELLY BROGAN, MD

PRIVATE PRACTICE New York, NY Radical Holism for Anxiety and Depression

TERRY WAHLS, MD

VETERANS AFFAIRS HEALTH CARE SYSTEM Iowa City, IA Feeding the Brain for Mental Health

PERSPECTIVES

Dr Gonzalez as a Practice Colleague: A Memoir Linda L. Isaacs, MD

Linda L. Isaacs, MD, graduated with a undergraduate degree in biochemistry, with high distinction, from the University of Kentucky. She went on to receive her medical degree from Vanderbilt University School of Medicine in 1985. She completed a residency in internal medicine at the Department of Veteran’s Affairs Medical Center at New York University Medical School, and she is board certified in internal medicine. Since 1985, Dr Isaacs had researched with Nicholas Gonzalez, MD, until his untimely passing in 2015. She currently practices internal medicine in New York, New York. Please visit her website at http://DrLindaI.com/. (Altern Ther Health Med. 2016;22(4):14-15.)

A

s I was finishing my internal medicine training in 1991, the other residents in my year were discussing their future plans for fellowships in various subspecialties. But there was no doubt in my mind about my next step: I was going to work with Nick Gonzalez in his nutritional practice.

I had met Nick when I was a medical student and he was an intern at Vanderbilt University Medical Center. At that time, he was engaged in studying the work of William Donald Kelley, a brilliant and controversial dentist who had developed an alternative treatment protocol for cancer. Nick had told me about some of the cases he had discovered in Dr Kelley’s files: a patient with widespread prostate cancer who had been admitted to the hospital for pain control, who after beginning the Kelley program had completely recovered; a patient with uterine cancer metastatic to the lungs whose disease had completely regressed after starting the treatment plan Dr Kelley had given her; and many more. As a medical student, I had been impressed, but by the time I had completed my internal medicine residency, I had a more solid understanding of how unusual these patient histories were, because I had seen the relentless downhill course of similar patients in my training.

By this time, Nick had been in practice in New York City for several years, working to recreate Dr Kelley’s methods and collecting case histories of his own. I joined him in his 14 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

small shared office space on Park Avenue; there was no space for me to see my own patients, but there was plenty to do.

Every night, I would listen to him return telephone calls from patients, learning the management skills he had developed to help patients deal with the implementation of their nutritional protocols. And during the day, I reviewed the charts of successful patients, studying Nick’s treatment plans, and working to collect any documentation the patients or their physicians had not previously provided.

The year 1993 was eventful for us. Nick was contacted in the spring, by the then associate director of the Cancer Therapy Evaluation Program at the National Cancer Institute (NCI), inviting him to present cases. With my assistance, Nick compiled 25 cases into a short monograph. This presentation included some very striking stories, such as a woman with breast cancer metastatic to the liver and brain, with documented resolution of disease on the therapy; and a man with renal cancer who had a metastatic lesion the size of an egg protruding from his skull, whose tumor regressed after he began his protocol.

In July, 1993 Nick traveled to Bethesda, Maryland, with a heavy bundle of supporting documents and films, to speak to a group of NCI scientists. After the session, the associate director suggested a pilot study with pancreatic cancer, though no funding for such a study was volunteered. Shortly thereafter, funding was provided through Dr Pierre Guesry at Nestlé, and the study began in September, 1993. At the same time, we were able to move into new office space that gave me room to see patients myself. Nick and I would work together there for the next 22 years.

The pilot study ended in 1998, and the results were published in the June 1999 issue of Nutrition and Cancer.1 Of 11 patients followed in the trial, 8 of 11 suffered stage IV disease. Nine of 11 (81%) lived 1 year, 5 of 11 lived 2 years (45%), 4 of 11 lived 3 years (36%), and 2 lived longer than 4 years. In comparison, in a trial of the drug gemcitabine, of 126 patients with pancreatic cancer, not a single patient lived longer than 19 months.2 In 1998, the NCI, in conjunction with the National Center for Complementary and Alternative Medicine, approved funding for a large-scale, controlled trial evaluating our approach against chemotherapy, again in patients Isaacs—Memoir

diagnosed with pancreatic cancer. Unfortunately, despite our initial enthusiasm for the project, it was ineptly managed by the academicians involved, who published an article about it without our consent in 2009.3 Nick’s book, What Went Wrong: The Truth about the Clinical Trial of the Enzyme Treatment of Cancer,4 details the problems with the trial quite thoroughly, and it spells out why we did not think the published paper’s results were valid.

This was a bitter disappointment for both of us, but we had seen too many miraculous results in our office to choose to give up. Nick’s favorite word to describe himself was relentless, and he would live up to this in the following years. In the January/February 2007 issue of Alternative Therapies in Health and Medicine,5 we published a series of 31 case histories of successfully treated patients. Nick also finally published his monograph about Dr Kelley’s work6 and a book on the science backing the use of pancreatic proteolytic enzymes for cancer.7 At the time of his death, he was working on a lengthy book of patient cases.

In the days after his death, as I struggled in the midst of my own grief to care for those who already had appointments booked and plane reservations made, his patients expressed so much gratitude for his devoted care that had transformed their lives. Their stories help give me the determination to do what I can to keep Nick’s memory alive and to continue the work so that perhaps a future generation of researchers can pick up where we left off.

REFERENCES 1. Gonzalez NJ, Isaacs LL. Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support. Nutr Cancer. 1999;33(2):117-124.

2. Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol. 1997;15(6):2403-2413.

3. Chabot JA, Tsai WY, Fine RL, et al. Pancreatic proteolytic enzyme therapy compared with gemcitabine-based chemotherapy for the treatment of pancreatic cancer. J Clin Oncol. 2010;28(12):2058-2063.

4. Gonzalez NJ. What Went Wrong: The Truth Behind the Clinical Trial of the Enzyme Treatment of Cancer. New York, NY: New Spring Press; 2012.

5. Gonzalez NJ, Isaacs LL. The Gonzalez therapy and cancer: A collection of case reports. Alt Ther Health Med. 2007;13(1):46-55.

6. Gonzalez NJ. One Man Alone: An Investigation of Nutrition, Cancer, and William Donald Kelley. New York, NY: New Spring Press; 2010.

7. Gonzalez NJ, Isaacs LL. The Trophoblast and the Origins of Cancer: One Solution to the Medical Enigma of our Time. New York, NY: New Spring Press; 2009.

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PERSPECTIVES

Dr Gonzalez as a Colleague: A Memoir Julian Hyman, MD

I

n the late 1980s, I was contemplating my retirement from my medical practice when I received a call from Dr Jonah Goldstone, who served with me in the Department of Oncology at Roosevelt Hospital. He knew about my plans and asked whether I would like to take over on an interesting problem that he believed would be a good match for me.

Dr Goldstone had been hired as an expert for a case of a physician who was practicing serious alternative medicine and was told that his license to practice was being revoked by the Professional Medical Board on the basis of a complaint filed by another physician.

Dr Goldstone was then hired to represent Dr Nicholas Gonzalez in a court of law. At the hearing, it was decided that Dr Gonzalez would be given 1 year to prove that he deserved to maintain his practice of medicine. Part of this process was developing a program of study about treatments for patients with malignancies. This would have to be coordinated with a physician who was accepted by the New York State Board.

After much thought, I realized this was a significant opportunity and was then accepted by the board to take on this role.

I was told that at any time during the duration of this program, Dr Gonzalez could be examined without notification and would be observed by a member of the State of New York Board of Medical Examiners and also by the Professional Board of New York State.

I agreed to these conditions and arranged to visit Dr Gonzalez at his office in Manhattan. We worked out a plan that was acceptable to both of us, and this included a weekly visit to his office at a time when a patient was there for a follow-up evaluation.

It was evident that he had excellent medical training. He was a graduate of Cornell Medical School. Following his graduation, he continued to study with an expert from the university who interested him in the importance of diet. This led to his interest in alternative medicine.

Part of our plan also included a weekly visit to the Oncology Clinic at Roosevelt Hospital. At first, Roosevelt did not want to accept hosting this program because Dr Gonzalez was not on the staff there, but I was able to negotiate with the head administrator and they became willing to make an exception that was a very important piece in this process. At the clinic sessions, we looked at many types of malignancies, although pancreatic cancer was the area of special interest for Dr Gonzalez.

16 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

The third part of our plan was to visit an oncologist who had shared an office with me. This enabled Dr Gonzalez to observe a more traditional approach to treatments. The visit to the clinic required a complete history and physical examination and a complete discussion of the case. One day, there was a surprise visit from 2 representatives of the State Board and the Professional Medical Board of New York.

Dr Gonzalez did so well that they never believed they needed to examine him again. I kept up by sending frequent reports to the New York State Department of Medical Examiners.

Following the completion of the year, the Professional Board of Examiners dismissed the charges and reinstated Dr Gonzalez’s medical license. After this meaningful outcome, there were still a few patients who were suing Dr Gonzalez for possible malpractice.

Because I believed in his work, I was willing to go to court as a professional witness. I was pleased to learn that many of these cases ended favorably. Although I trained and practiced only traditional approaches to treatment of malignant disease, I learned from Dr Gonzalez that the practice of alternative medicine could also be effective.

From the time I first met Dr Gonzalez, I was impressed by his level of integrity and caring. It was clear that he was always extremely devoted to the individual needs of his patients. The patients I met all seemed very confident in the care they received. It impressed me that the results of his treatment indicated that many of his patients were doing better than their predicted life expectancy.

We often had lunch together in a small kitchen in his office. We talked about his family and his interest in music and also in American history. His family came from Italy and they were particularly interested in classical music. For a short period, he played a classical instrument.

When all of these cases were resolved, Dr Gonzalez and I established a lasting friendship. We both respected each other and continued to see each other and included my wife and his wife, Mary Beth Gonzalez, at these very pleasant meetings. We continued to discuss medical problems that involved both of us.

His sudden passing is a huge loss to his family, friends, and patients. Fortunately, Dr Gonzalez had trained a colleague, Dr Linda Isaacs, who can continue with his protocols. (Altern Ther Health Med. 2016;22(4):16.)

Hyman—Memoir

PERSPECTIVES

Reporting on Dr Gonzalez for a Quarter Century: A Memoir Peter Barry Chowka

Peter Barry Chowka majored in English at Georgetown University. His journalism career began with coverage of national politics, but for the past 4 decades he has focused on health care with an emphasis on alternative medicine. Peter has held editorial positions with groundbreaking publications including East West Journal, New Age, and Whole Life Times. His work has been cited by Congressional committees and in 1992 he was among the first advisory panel members appointed to the NIH’s new Office of Alternative Medicine. Peter has interviewed most of the modern pioneers of alternative medicine, including Larry Dossey, William Donald Kelley, and Nobel Laureates Linus Pauling and Albert Szent-Gyorgyi. Peter’s investigation of the Hoxsey Therapy was instrumental in bringing that long neglected herbal cancer treatment to the attention of the public and the NIH. Peter’s work in the area of alternative cancer treatments was the subject of a chapter in Professor David Hess’s book, Evaluating Alternative Cancer Therapies (1999, Rutgers University Press). Peter has appeared on hundreds of major radio and TV talk shows and has published more interviews with and articles about Dr Nicholas Gonzalez than any other journalist. (Altern Ther Health Med. 2016;22(4):18-20.)

N

icholas J. Gonzalez, MD (“Nick” to his friends) was, in this author’s opinion, the most impressive and accomplished clinical practitioner of nutritional cancer therapy during the past 2 decades. In the early 1970s, I began covering the nascent field of alternative medicine. It was my privilege to meet, and to report on, many of the most notable innovative medical pioneers— including Linus Pauling, PhD; Mildred Nelson, RN; Dean Burk, PhD; and William Donald Kelley, DDS, who was destined to become Nick’s mentor in nutritional therapies. After Nick began practicing medicine, he unquestionably became the peer of the best of these early pioneering clinicians and researchers.

During my first meeting with Nick in New York City in March 1990—an unforgettable encounter—it was immediately clear to me that he had the potential to do great work. He was smart, extremely dedicated, focused, energetic, without pretense—and very likable. For the next 2.5 decades, my first impressions of him never wavered.

With the support of his academic mentor, Robert A. Good, MD, PhD, the chief scientist, president, and director of the Sloan-Kettering Institute for Cancer Research in New 18 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

York and widely credited as the founder of modern immunology,1 Nick had spent 5 years evaluating and confirming the efficacy of Dr Kelley’s enzyme-based, nutritional cancer therapy. In 1987, Nick and his partner, Linda Isaacs, MD, began practicing their version of Dr Kelley’s therapy in Manhattan. It soon became known as the Gonzalez therapy. In early 1990, there was already a buzz about Nick in alternative medicine circles.

Prior to becoming a physician, Nick studied English and graduated with honors from Brown University. He worked as a journalist in New York and made his mark early on with a long investigative cover story in the July 31, 1972, issue of New York Magazine that exposed questionable goings on at an exclusive private prep school2; Nick’s influential article led to the school’s being closed down.

In 1978, Nick switched his career to medicine. Like many of the earlier, and most impressive, cancer therapy innovators, Nick embraced alternative medicine after first excelling in mainstream conventional academic medicine, which he found wanting, especially after he began investigating the work of Dr Kelley.

I had known and reported on Dr Kelley, dating from before the period when Dr Kelley gained national attention for treating actor Steve McQueen. McQueen had developed a deadly and conventionally untreatable form of lung cancer and there was evidence that Dr Kelley’s therapy had helped him.3 People who did not know Dr Kelley personally or who lacked an open mind might have easily dismissed the complicated and controversial clinician out of hand. In a field of iconoclasts, Dr Kelley was a quirky original and unconventional to the hilt. And yet, he impressed me and many others as a uniquely bright, compassionate, and caring man who had synthesized earlier innovators’ work into a novel clinical model of treating cancer, and other diseases, exclusively with nutrition. In the 1970s and 1980s, Dr Kelley was widely known in alternative medicine circles as one of the most successful and outstanding innovative clinicians treating people with advanced cancer.

Nick respected Dr Kelley as much as I did—and this opinion that we shared helped to fast-track our lifelong friendship from the time when we first met.

During the 1990s, the first decade of our interaction, my conversations with Nick were mostly about the results of his Chowka—Memoir

(and Dr Isaacs’s) promising results with cancer patients, which he always shared with great enthusiasm. Nick never failed to acknowledge and fully credit Dr Kelley’s work as the basis for his own. I was less concerned with the details of the legal struggles that Nick was subjected to during the 1990s, because these sorts of distracting developments were par for the course: Almost every alternative clinician I had ever reported on, no matter how well motivated and credible (including Nobel Prize winners), had been targeted for hostile legal and government regulatory action on the part of opponents of clinical innovation.

In 1999 and for the next 5 years or so, the challenges of the 1990s gave way to a period that looked very promising for Nick. He seemed on the verge of mainstream recognition. His work found support among members of the US Congress.4 The positive Gonzalez-Isaacs pilot study of pancreatic cancer patients was published in a scientific journal5 and made national news, and the National Institutes of Health (NIH) had quickly followed suit with an unprecedented $1.4 million grant to fund a prospective clinical trial of the Gonzalez-Isaacs enzyme therapy under the direction of Columbia University.6 It appeared that a high-level, objective, mainstream evaluation of the therapy was finally in the offing.

There was even a change in some of the mainstream media reporting about Dr Gonzalez’s work. Most notably, in February 2001, The New Yorker magazine published a largely positive, 9000-word article about Nick, “The Outlaw Doctor,” featuring a 2-page studio photo of Nick and 11 of his successfully treated patients.7 Before 5 years of the new century had elapsed, however, the government-funded study degenerated into a political morass and it would never be completed. In fact, an unfairly negative journal article about the unfinished study would be published in 2009, without Nick’s or Dr Isaacs’s participation or review.8,9 Meanwhile, national health care reform was looming on the horizon while alternative medicine—the kind practiced by Drs Gonzalez and Isaacs—was being supplanted by complementary or integrative medicine.

A brief history is necessary here. In the 1970s and 1980s, nontoxic alternative cancer therapies represented a vigorous area of independent scientific inquiry and enjoyed considerable popularity with the American public. Pockets of promising clinical innovation ranged from New England and New York City, across the continent to California and south of the border to Tijuana, Mexico, which, for a time, was known widely as a healing Mecca. In the early 1980s, Dr Kelley had a presence at an alternative cancer clinic in Baja California, Mexico. Alternative cancer’s leading proponents and its most popular therapies were frequently in the news and hundreds of thousands of Americans supported the concept of medical freedom and for a time composed a viable grassroots political movement that was active on behalf of medical freedom of choice.10 Looking back, the period was a Renaissance of alternative medicine—especially alternative cancer—and it represented the high point for the field of primary alternative cancer Chowka—Memoir

treatments in the United States. The disfavor that the medical establishment and its allies—including government bureaucracies, academic medicine, and the pharmaceutical industry—have always heaped on the proponents of medical alternatives took new and different strategic turns starting around 1990.

On the heels of the US Government Office of Technology Assessment’s flawed 1990 study Unconventional Cancer which gave Dr Kelley’s and Treatments, 11 Dr Gonzalez’s work short shrift, the US Congress, with good intent, created and funded at the NIH a brand new Office for the Study of Unconventional Medical Practices, later changed to the Office of Alternative Medicine (OAM). But instead of validating credible alternatives, which the Congress intended as the OAM’s primary mission,12 the OAM and the much larger agencies it morphed into ultimately served to diminish the availability of many primary clinical alternatives. The inexorable path downhill to this ignominious outcome was long and convoluted. The original, independent-minded pioneers were getting old and passing on, and the new generation of young proponents tended to be susceptible to seduction and co-optation by federal agencies proffering the lure of generous funding grants and—after decades of disregard—a smattering of official approval. A watering down, or winnowing, of the primary alternative therapy model was beginning to take hold.

In 1981, Albert Szent-Gyorgyi, MD, PhD, who was awarded a Nobel Prize in 1937 for his discovery of vitamin C, and who, in the last years of his life, was working on alternative cancer therapies but was getting little attention, cautioned me: “The purpose of science and medicine has become not to make discoveries but to get grants granted.”13 Szent-Gyorgyi was talking about conventional science and medicine. But within a decade, the proliferation of government grants that were suddenly being made available to alternative clinicians and researchers began to influence and permanently alter the landscape of alternative medicine, as well. Inspired by the government’s new largesse, a variety of much more palatable—and fundable—models of complementary alternative medicine (CAM) and integrative medicine emerged. This new, nonthreatening alt med “light” started to replace primary alternative medicine, which was unfortunate because it was primary alternative medicine that had inspired the promising, paradigm-changing challenges to conventional medicine to begin with.

In a sign of the times, the OAM changed its name to the National Center for Complementary and Alternative Medicine and then to the National Center for Complementary and Integrative Health. In this newly evolving scientific and political milieu, Nicholas Gonzalez stuck to his principles and continued to practice his primary alternative (rather than complementary or integrative) treatment approach, but he was not always in sync with the times.

The record of Gonzalez’s largely unsuccessful 2-decade quest for fair evaluation of his work is well documented, including in his 2012 book, What Went Wrong.14 In particular, ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 19

the collapse of the NIH’s clinical trial of the Gonzalez-Isaacs therapy is merely one of the most recent examples of how government-funded tests have always treated promising medical alternatives going back decades (including Linus Pauling’s work on vitamin C).15 It’s also emblematic of the systemic obstruction that continues to be placed in the path of primary alternative treatments to this day.

Notwithstanding the myriad and never ending obstacles and disappointments, during all of the years that I knew him, Nick remained upbeat and doggedly focused on his work— treating patients, seeking new clinical insights, keeping up with the state of the art in science and medicine, writing articles, responding to media requests, and lecturing.

According to Nick, his status as “one man, alone” (the title of an article about him that I published in 2002, inspired by the title of Nick’s own book about Dr Kelley) changed in 2001 when he met and married the talented, accomplished, and dedicated Mary Beth Pryor. With her support and assistance, Nick became even more prolific, and he wrote or coauthored 4 major books between 2009 and 2012. He was nearing completion of his latest work, presenting over 100 of his best cases, when he passed away suddenly on July 21, 2015.

In recent years, as the last of the original alternative cancer pioneers left the scene, Nick and I frequently commiserated privately about the fact that truly alternative, primary natural approaches to treating cancer were becoming harder and harder to find. This realization seemed to increase Nick’s sense of urgency and dedication to documenting the details of his therapy and its clinical successes in order to leave a signpost for the future of medicine.

During the last decade, I often compared notes with Nick—and I published several long interviews with him— about larger issues affecting the future of medicine in society.

We agreed that handing the direction and control of medicine over to large bureaucracies was a prescription for disaster that would adversely influence clinical innovation and the sanctity and success of the doctor-patient relationship. Still, Nick was convinced that in time (he often cited the implosion of the Soviet Union as evidence) the momentum toward socialized medicine would be seen for what it is—a Faustian bargain—and be replaced by the public’s support for a return to a more traditional American model of competition, medical freedom, and personal responsibility.

Nick always maintained an optimistic public, and private, persona. In late 2014, in the course of 3 months, Nick and I exchanged more than 200 e-mails. He was working on his magnum opus—the collection of his best cases—and he was in a very reflective frame of mind. Our wide ranging discussions included issues and personalities in medicine and his motivation. He confirmed that the patients whom he and Dr Isaacs had successfully treated throughout the years kept him grounded and focused on his practice, no matter what the controversies of the moment. In addition, Nick cited his deep Christian faith that was further reinforced by his extensive knowledge of Biblical scholarship.

Nick wrote in an e-mail to me on September 25, 2014: 20 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

You inquired how I could stand the criticism. It’s only because of God, and my belief in Him. God led me to Kelley, and I trust Him completely. If He wants my work to survive, it will survive, no matter how stupidly I personally behave. If He doesn’t want it to survive, it won’t, no matter how perfectly and smart I behave.

It’s all up to Him. My job is to do the best job possible.

The death of a friend such as Nick Gonzalez was not only a disorienting shock on a personal level to everyone who knew him—it was deepened by the realization that the important work of this remarkable individual had come to an end.

Considered in retrospect, several months later now, his extraordinary accomplishments are highlighted anew and brought into clearer focus. Nick’s thoughts and words as I recorded and documented them, and as he shared them in his prolific writings and in other interviews and media appearances, all assume new and profound levels of meaning and importance.

In reality, Nicholas Gonzalez’s work has not ended. Like all great men and women, his legacy survives him. A large part of that legacy and a testament to his success are the people who Nick helped or cured of cancer and who are alive to this day, long after their original prognoses predicted they would be dead. Fortunately, Nick was not only a remarkable clinician and a healer of the sick—he was an equally talented and inspired writer and speaker. The considerable body of work that he left us, including the many interviews, will, I expect, continue to inform, enlighten, and inspire both laypeople and a new generation of healers—aided by the efforts of his widow, Mary Beth Gonzalez, committed to helping to keep the recognition of Nick’s work alive and growing; and by his colleague and close friend of 30 years, Dr Linda Isaacs, who remains in clinical practice in New York, offering the continued promise of the Gonzalez-Isaacs therapy.

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

Wright P. Robert Alan Good. Lancet. 2003;362(9390):1161.

Gonzalez NJ. Showdown at Sands Point. New York Magazine. July 31, 1972:36-43.

Chowka PB. Steve McQueen: Legacy of a medical outlaw. New Age. 1981;6(7):28-37.

No author listed. Burton Lauds Gonzalez’s research results in fighting pancreatic cancer. http://tinyurl.com/burton-lauds-gonzalez. Published June 25, 1999.

Accessed October 8, 2015.

Gonzalez NJ, Isaacs LL. Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support. Nutr Cancer 1999;33(2):117-124.

Chowka PB. Government funds test of the Gonzalez nutritional cancer therapy. http:// tinyurl.com/1999-gonzalez-test. Published August 15, 1999. Accessed October 8, 2015.

Specter M. The outlaw doctor. The New Yorker. February 5, 2001:48-61.

Chabot JA, Tsai WY, Fine RL, et al. Pancreatic proteolytic enzyme therapy compared with gemcitabine-based chemotherapy for the treatment of pancreatic cancer. J Clin Oncol. 2010;28(12):2058-2063.

Ross CA. Methodological flaws in the Chabot trial of pancreatic enzymes for cancer therapy. Int J Cancer Prev Res. 2015;1(1):1-4.

Petersen JC, Markle GE. Politics and science in the Laetrile controversy. Soc Stud Sci. 1979;9(2):139-166.

US Government Printing Office. Unconventional Cancer Treatments. US Congress, Office of Technology Assessment, OTA-H-405. Washington, DC: US Government Printing Office; September 1990.

Boyle EW. The politics of alternative medicine at the National Institutes of Health. Federal History Online. http://tinyurl.com/boyle-politics-am. Published 2011. Accessed October 8, 2015.

Chowka PB. Is alternative medicine dead? http://tinyurl.com/2005altmed-dead.

Published March 1, 2005. Accessed October 8, 2015.

Gonzalez NJ. What Went Wrong: The Truth Behind the Clinical Trial of the Enzyme Treatment of Cancer. New York, NY: New Spring Press; 2012.

Richards E. The Politics of therapeutic evaluation: The vitamin C and cancer controversy. Soc Stud Sci.1988;18(4):653-701.

Chowka—Memoir

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PERSPECTIVES

Dr Gonzalez as a Colleague: A Memoir Colin A. Ross, MD

S

everal years ago, a friend of mine suggested that I read The Trophoblast and the Origins of Cancer.1 He handed me his copy, and I opened it to the introduction. I was struck immediately by how much sense the trophoblast model of cancer makes: Here was a highly specified model of cancer formation rooted in research and with remarkable patient outcomes. I then recalled that I had read about Dr Gonzalez in Suzanne Somers’s book, Knockout.2 Subsequently, I read Dr Gonzalez’s other books and papers3-5 and wrote 2 papers about his work.6,7 I had lunch with him in New York in March 2015, at which time we discussed my 2 papers, which he and Dr Isaacs had read prior to my submitting them to journals. During the lunch conversation, Dr Gonzalez made an almost off-hand comment that illustrated the nature of his thinking about cancer. He said that chemotherapy selects for the most malignant cancer cells: Initially, the least malignant cells are killed off by the chemotherapy and there is a treatment response but, then, after a few months, the selected-for, more malignant cells that survived the chemotherapy take over, and the person declines rapidly and dies.

What an interesting and potentially important hypothesis! It may or may not be true, in many or some cancers, but it is a scientifically testable hypothesis, one that could be investigated in tissue culture, animal models, and humans. The idea is plausible, and there is a precedent for it with antibiotics and antibiotic-resistant bacteria, even though the mechanisms of antibiotic resistance must be very different from those in the response of cancer to chemotherapy. If Dr Gonzalez’s idea is correct, in a subset of cancers, this by itself would be an important contribution to medicine, one that could affect both research and clinical practice.

As I read Dr Gonzalez’s books, I also read the paper on the National Cancer Institute (NCI)-funded trial of pancreatic enzymes for treatment of pancreatic cancer8 and visited the page about Dr Gonzalez on the NCI Web site.i The NCI Web site contains inaccurate and distorted information about the Gonzalez protocol. When I wrote to the NCI about these inaccuracies, it declined to make any revisions.

Also, I submitted my paper about the Chabot et al8 trial to the journal that published it, The Journal of Clinical Oncology, and to the Journal of the National Cancer Institute, 22 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

both of which rejected it. I began to grasp the resistance Dr Gonzalez encountered from organized medicine throughout his career. The Chabot trial was plagued with so many problems—none of them acknowledged in the published paper, on which neither Dr Gonzalez nor Dr Isaacs were coauthors—that it should never have been published and should be disregarded. It purports to show that the treatment of pancreatic cancer with pancreatic enzymes is ineffective compared with chemotherapy.

Problems include the fact that only 1 patient of 39 assigned to the pancreatic enzyme arm of the study fully complied with the protocol: 30 patients either took no enzymes, or followed the protocol incompletely or for a very short period.

There were numerous such problems with the study.

The following is a typical outcome from Dr Gonzalez’s practice: In January 1992, Ms S. found a mass in her abdomen and consulted her gynecologist. A CT scan showed a large pelvic mass, as well as 2 subcentimeter lesions in the hepatic dome. In February 1992, she underwent a total abdominal hysterectomy and bilateral oophorectomy. The pathology report showed a moderately differentiated serous cystadenocarcinoma; the tumor measured 10 × 8 × 4 cm. She was advised to immediately begin aggressive chemotherapy because of the size of the tumor and the possibility of liver metastases. Her oncologist warned her that without chemotherapy, the cancer would prove deadly. Instead, she proceeded with Dr Gonzalez’s treatment. An ultrasound of the abdomen and pelvis in August 1996 was completely clear, with no evidence of recurrent disease, or the previously described liver lesions. A CT scan of the abdomen and pelvis on June 29, 2009, done to evaluate her for kidney stones, describes the liver to be normal, without mention of the 2 hepatic lesions noted in the preoperative scan from January 1992, 17.5 years earlier.

At the time of his sudden death on July 21, 2015, Dr Gonzalez had completed a review of 106 such cases in an intended series of 150. It is, on the one hand, astounding that organized medicine ignores and discredits such results, and, on the other hand, business as usual. I doubt that there is a conventional oncologist anywhere who has these kinds of outcomes, in biopsy and MRI-confirmed advanced cases of i. Please visit http://www.cancer.gov/about-cancer/treatment/cam/hp/gonzalez-pdq

Ross—Memoir

highly malignant cancers. I imagine that one could survey a considerable number of oncologists, and all together they would have fewer survivors of stage III and IV pancreatic cancer alive after 10 years than Dr Gonzalez had in his practice. These outcomes cannot be accounted for by selection bias, spontaneous remission, or any other mechanism besides a treatment effect.

Week after week, we see reports in the media of celebrities who have been diagnosed with cancer. These are people with the supports and resources to be treated with the Gonzalez regimen. Most of them die. This is unnecessary.

Many of these people (but not all) would be alive today if they participated fully in the Gonzalez protocol. There is no rational, biological, medical, or scientific reason to ignore the treatment outcomes in Dr Gonzalez’s practice. They are unmatched by any combination of surgery, radiation, and chemotherapy. Not only that, treatment responders, of whom there are many, start feeling better quickly on the Gonzalez regimen, which is very different from the quality of life experienced with surgery, radiation, and chemotherapy.

Is the Gonzalez regimen a panacea? No. Does it cure everyone? No. But it should be studied on a large scale, at the level of tens of millions of dollars. This is a gift to humanity that should not die with Dr Gonzalez. Dr Isaacs carries on alone, but she cannot practice forever. Given the resistance by organized medicine and oncology, most likely a private philanthropist is going to have to step forward.

I am very glad that my 2 papers were published before Dr Gonzalez died, so that he could read them, and I am very glad that I got to meet him in person. I have studied

Dr Gonzalez’s work because, like everyone, I have family members and friends who have died of cancer. I consider it my ethical obligation as a physician to speak up about the trophoblast model of cancer and Dr Gonzalez’s work. Hence the special book by the publishers of Alternative Therapies in Health and Medicine in tribute to him. The special issue has relied on support provided by Andrew Campbell, MD; Mary Beth Gonzalez; Linda Isaacs, MD; and Kelly Brogan, MD. The paper by Dr Gonzalez on a case of insulin-dependent diabetes, included in this issue, was written by Dr Gonzalez prior to his death. Dr Gonzalez had been corresponding about his paper with Dr Campbell, the editor of Alternative Therapies in Health and Medicine, prior to his death. Dr Ross and Dr Brogan reformatted the paper for publication and did some light editing of it after Dr Gonzalez’s death. (Altern Ther Health Med. 2016;22(4):22-23.)

REFERENCES 1. Gonzalez NJ, Isaacs LL. The Trophoblast and the Origins of Cancer: One Solution to the Medical Enigma of Our Time. New York, NY: New Spring Press; 2009.

2. Somers S. Knockout: Interviews with Doctors Who Are Curing Cancer—And How to Prevent Getting It in the First Place. New York, NY: Three Rivers Press; 2010.

3. Gonzalez NJ. One Man Alone: An Investigation of Nutrition, Cancer and William Donald Kelley. New York, NY: New Spring Press; 2010.

4. Gonzalez NJ. What Went Wrong? The Truth Behind the Clinical Trial of the Enzyme Treatment of Cancer. New York, NY: New Spring Press; 2012.

5. Gonzalez NJ, Isaacs, LL. (1999). Evaluation of pancreatic enzyme proteolytic enzyme treatment of adenocarcinoma of the pancreas. Nutr Cancer.

1999;33(2);117-124.

6. Ross CA. The trophoblast model of cancer. Nutr Cancer. 2015;67(1);61-67.

7. Ross CA. Methodological flaws in the Chabot trial of pancreatic enzymes for the treatment of pancreatic cancer. Int J Cancer Prev Res. 2015;1;1-4.

8. Chabot JA, Tsai WY, Fine RL, et al. Pancreatic proteolytic enzyme therapy compared with gemcitabine-based chemotherapy for the treatment of pancreatic cancer. J Clin Oncol. 2010;28(12):2058-2063.

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CASE REPORT

A Case of Insulin-dependent Diabetes Nicholas Gonzalez, MD

ABSTRACT Background • There is a paucity of information on alternative, nutrition-based treatments for insulin-dependent diabetes.

Primary Study Objective • This case report provides detailed information on the nutrition-based treatment of a man with insulin-dependent diabetes.

Methods/Design • This is a single case report taken from the author’s private practice.

Setting • The treatment was provided at a private office in New York, NY, USA. Participants • A single patient in the author’s practice is reported.

Intervention • The patient was treated with a combination of pancreatic enzymes, supplements and nutrients, and cleansing and detoxification procedures, plus amber lenses for severe insomnia.

T

he treatment of cancer with pancreatic enzymes according to the Gonzalez protocol has been well described,1-3 as has the trophoblast model of cancer on which the protocol is based.3 A trial of gemcitabine versus pancreatic enzymes for the treatment of pancreatic enzymes4 is so flawed methodologically that its findings, which suggest that the Gonzalez protocol is ineffective for pancreatic cancer, should be ignored.5,6 Gonzalez and Isaacs have reported individual cases and a small case series in which patients with advanced, magnetic resonance imaging (MRI)-confirmed, and biopsy-confirmed pancreatic cancer have had remarkably long survival times, often exceeding a decade.1,3,5 To date, however, the use of the Gonzalez protocol for medical problems other than cancer has not been reported.

The purpose of this case report is to describe the case of a man with insulin-dependent diabetes, extreme fatigue and insomnia, paresthesias, and a host of other symptoms, who improved dramatically on the Gonzalez protocol.

CASE REPORT Patient G is a 44-year-old white male medical device salesman from the northeastern United States who first presented for consultation in late June, 2011. Family history 24 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

Primary Outcome Measures • The outcome measures were patient self-report of symptoms, overall well-being, and function at work and in leisure time; observation of the patient by the physician; and blood work.

Results • The patient described dramatic, sustained improvement in terms of symptoms, function, well-being, and life satisfaction. Improvement in blood sugar control was documented by blood work.

Conclusion • The complex, tailored nutritional protocol combined with detoxification procedures, resulted in marked improvement in a patient who had been treated by numerous different physicians without benefit prior to his consulting with the author. (Altern Ther Health Med. 2016;22(4):24-35.)

was notable for paternal grandmother with fatal myeloma, paternal grandfather, a smoker, with fatal lung cancer, and a paternal uncle with fatal liver cancer. Multiple family members had been diagnosed with hypertension. At the time Patient G first presented, his mother was being treated for adult onset non-insulin-dependent diabetes, whereas his maternal grandmother had developed the insulin-dependent form of the disease as an adult.

Patient G presented with a complicated history during the 4 years previous to his first consultation, though the genesis of his problems seemed to have occurred much earlier. A serious athlete in college, he played hockey, ran track, and lifted weights regularly. After graduation, he continued playing “aggressive” contact hockey in a local adult league. During a game in 2007, he experienced a serious fall and injury around the net, twisting his back as he fell and immediately developing “excruciating” lower back pain. The pain persisted for approximately 4 weeks during which time he was unable to work full time. When his situation did not improve, he consulted with his primary care physician, who arranged for an extensive diagnostic workup complete with a computed tomography (CT) scan of the abdomen as well as colonoscopy. All testing was within Gonzalez—Insulin-dependent Diabetes

normal limits. Eventually, when his pain improved and he was able to resume his vigorous work schedule, he assumed the problem was resolved.

In June, 2008, 1 year after his accident, Patient G’s general health suddenly worsened within a period of several weeks; he developed persistent, chronic fatigue that he would describe later as “incredible fatigue all the time.” His eyes felt heavy, and his muscles, in all muscle groups, became uncharacteristically weak, which for this weight lifter was an unusual circumstance.

When the symptoms persisted, Patient G returned to his primary care physician who ordered blood studies that came back within normal limits except for a slightly elevated thyroid stimulating hormone (TSH), thought to be due to an autoimmune thyroiditis. Lyme and a variety of other infectious markers were all negative. Patient G’s physician prescribed levothyroxine for the hypothyroidism but suggested no other treatment at the time.

Despite the thyroid supplementation, Patient G’s severe fatigue persisted, though he “pushed” himself through his work and forced himself to continue his vigorous exercise regimen. However, his work, which demanded increasingly long hours each day and standing for hours in operating rooms, became increasingly difficult to sustain.

By July, 2008, Patient G was falling asleep easily during the day, while experiencing what he would describe to me as “brain cloudiness or fog.” To complicate the situation he developed persistent, “terrible” insomnia, as well as episodes of anxiety and obsessive worrisome thoughts. All the while, his muscle weakness continued to worsen.

Through his own contacts he learned about a wellknown internist at Hahnemann Medical College (Philadelphia, PA, USA) known to handle “difficult” and enigmatic cases, who could be seen only by referral, which Patient G’s primary care physician provided. After an initial consultation at Hahnemann, this physician began an intensive workup, checking for all manner of common as well as rare illnesses. The testing revealed a single abnormality, an elevation in acetylcholine receptor antibodies indicating possible myasthenia gravis. With that finding, Patient G then underwent continued evaluation at Hahnemann including muscle resistance testing, which was negative; a CT scan of the chest to rule out thymoma (also negative); and endoscopy to check esophageal function, which proved to be normal. A multifiber electromyogram (EMG) to assess muscle firing activity in patients with presumed myasthenia gravis revealed no abnormality consistent with the disease. Importantly, in terms of what would eventually play out, his blood sugars throughout this period were all within the normal range.

Despite the negative results, the Hahnemann physician decided, because of the borderline acetylcholine receptor antibodies, to start a course of the anticholinesterase pyridostigmine, the standard treatment for myasthenia.

Patient G dutifully took the medication for 3 weeks but discontinued the drug when he could see no positive effect.

As he continued to deteriorate, Patient G took a leave of absence from work to concentrate on finding a solution to Gonzalez—Insulin-dependent Diabetes

his condition. At that point, his insomnia had progressed to such a degree that his primary care physician prescribed zolpidem. With growing frustration at the lack of answers, on his own he decided to consult at the Myasthenia Gravis Specialty Center at Jefferson Medical College (Philadelphia, PA, USA). There, a single fiber EMG test, the most sensitive for neuromuscular disorder, showed nothing, so the doctors ruled out myasthenia as a diagnosis. Instead, deciding his whole problem to be psychological in nature, they referred him for psychiatric evaluation and treatment. Desperate for any solution, Patient G agreed to the plan and, subsequently, as he would later tell me, he was prescribed “every different antidepressive medication on the market,” none of which led to improvement in any of his symptoms and most of which left him feeling much worse.

Through sheer dint of will he returned to work, though he experienced relentless exhaustion complicated by the continuing insomnia unresponsive to sleep medication. His muscles throughout his body chronically ached and he felt perpetually weak. He reported that during this time he was constantly “miserable from not being able to get any answers about my condition.” Though depressed, he felt more anger than depression because no one had any solution to his situation.

In January, 2009, for the first time, he developed daily severe headaches but nonetheless continued pushing himself in his work. In frustration, he then decided to consult with a local neurologist who did extensive titers for Lyme and other infectious agents. This physician ruled out myasthenia but despite the negative antibodies decided Patient G’s problems were due to Lyme disease. After placement of an intravenous (IV) port, Patient G began a 6-week course of IV high dose ceftriaxone, learning to administer the antibiotic himself at home and even on the job so he could continue working. But at the end of the 6 weeks, he experienced no improvement; in fact, he felt only worse.

By September, 2009, he had deteriorated to such a degree that he could no longer work. December, 2009, proved to be a particularly difficult time for him, to the point that he began feeling he might be dying because of the severity of his muscle weakness, fatigue, and diffuse muscle pain. In desperation, he began looking into unconventional medical approaches, eventually consulting with a wellknown alternative physician in New Jersey whom he found open-minded and sincerely concerned about his situation.

This physician once again raised the issue of myasthenia gravis because of the persistent muscle pain and weakness, though extensive blood testing this time around revealed only borderline positive Lyme titers. The physician started Patient G on an intensive supplement program then admitted him to a local hospital for 3 days of intensive antibiotic treatment. After completing the course of IV antibiotics, Patient G was discharged with plans for him to continue oral antibiotics. Despite the therapy he would experience “absolutely no improvement” in any of his symptoms.

Nonetheless, Patient G continued under the care of this alternative physician for 3 months before discontinuing the ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 25

relationship because of his lack of improvement and his ongoing decline. During this period he developed new symptoms, including eyelid twitching and bags under his eyes so severe that it appeared, as he would later report, that he had swollen cheeks. His hands began to “shake” with tremors; he developed severe burning pain bilaterally in his feet; and he rapidly lost all the hair on his arms, legs, and chest, and even his eyebrows began to thin. In addition, he developed acute onset severe periodontal disease and potency issues.

He then decided to consult with another well-known alternative practitioner in New Jersey, who prescribed a course of IV vitamin C and weekly testosterone injections after blood testing revealed low levels of the androgen. In addition, under this doctor’s direction, Patient G underwent extensive allergy testing, all of which proved negative.

Patient G continued under the care of this physician for approximately 5 months before stopping the aggressive treatment when he felt no improvement.

Throughout the early part of 2010, Patient G continued his downward spiral, developing new-onset paresthesias in his feet, worsening muscle weakness and pain, ongoing terrible insomnia, and debilitating persistent exhaustion. Finally, during the latter part of 2010, he consulted with yet another “difficult case” internist, hoping this physician might have a solution to his situation. Because of the patient’s family history of diabetes, this physician ordered a hemoglobin A1C. This time around testing revealed a blood sugar close to 500 mg/dL associated with a very high hemoglobin A1C near 10%. Oddly, all prior blood sugars had been normal.

Because of the very high blood sugars, Patient G was hospitalized for 2 days with the goal of aggressive supervised insulin treatment of his apparent diabetes along with diabetic teaching, but when discharged his blood sugars remained unstable. At that point, he began experiencing polydipsia, polyphagia, and polyuria. He said that he was thirsty all of the time without ever having a break.

Patient G believed the diabetic teaching given to him in the hospital for self-management of his condition, including the dietary instructions, to be inadequate. Once home he continued the recommended insulin schedule and tried to incorporate the prescribed eating plan into his life, but nonetheless he could not regulate his sugars properly. He simply did not know how to administer the insulin because the protocol given him seemed unduly complicated, nor was he consistent with the recommended diet. Apparently his doctors did not insist on close medical supervision.

After his hospitalization, Patient G continued experiencing “terrible polyuria and polydipsia” as well as new onset mood swings; at times his temper would go out of control, a new experience for him and his family because he was normally quite mild mannered. During that period the burning and paresthesias in his feet worsened considerably, particularly if he stood for any length of time.

By the end of 2010, his condition was no better despite the insulin and dietary treatment. Then in January, 2011, Patient G developed a severe flu-like illness with fevers, 26 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

chills, and sweats, so severe he could barely get out of bed.

His throat hurt so badly he could only consume fluids; at one point his breathing became labored and he developed newonset severe midabdominal pain.

In late February, 2011, after recovering from his acute flu symptoms he remained so weak he could barely walk, and at one point he passed out when attempting to stand up. When he awoke, he felt as if he had “a ton of bricks on his chest.” After calling 9-1-1, he was admitted to a local hospital with a body temperature of less than 90°F, in what turned out to be, according to doctors at the hospital, diabetic ketoacidosis with respiratory failure, pneumonia, metabolic acidosis, as well as acute pancreatitis secondary to diabetic ketoacidosis and acute renal failure with secondary acute tubal necrosis from the diabetic ketoacidosis. He was diagnosed as well with mastoiditis and uncorrected hypothyroidism, and he began a 13-treatment course of emergency dialysis for his renal failure. Comorbidly, he developed Clostridium difficile pseudomembranous colitis as a result of antibiotic treatment for his pneumonia.

One might question the diagnosis of diabetic ketoacidosis made in this hospital and instead consider a hyperosmolar hyperglycemic state. This differential diagnosis cannot be resolved now and does not bear directly on his nutritional treatment under my care, but it is included as part of his medical history.

After a difficult 2-week hospitalization, Patient G continued the dialysis as an outpatient. This time around the endocrinologist (with a history of diabetes himself) assigned to his case prescribed insulin lispro 4 units, 3 times per day, with meals and insulin glargine 50 units at night, and insisted on close monitoring of his condition. Patient G was also placed on a variety of supplements for his kidney failure including calcium acetate, magnesium oxide, and vitamin B complex. He underwent a course of oral metronidazole for the Clostridium and was prescribed furosemide 40 mg per day, escitalopram 10 mg daily, levothyroxine 100 mg daily, and a probiotic. With careful management, Patient G’s diabetes seemed finally under if not ideal, at least better control.

In early June, 2011, 2 weeks before his first consultation with this MD, Patient G consulted an ophthalmologist who found, fortunately, no damage to his eyes.

My evaluation of all new patients, whatever their underlying problem might be, involves 2 lengthy sessions.

The first, the intake history and physical, usually takes 2 hours because the majority of our patients tend to present to us, as in this case, with complicated medical histories.

During the second session, again usually lasting 2 hours, I review the recommended nutritional protocol in some depth.

At the time of our first meeting together, Patient G appeared very fatigued, worn out, and pale. He did not smile once through the 2-hour session and at times talking seemed to be an effort. He still was out of work but did explain that in recent weeks, with close medical management, better dietary compliance, and a regular program of insulin lispro and insulin glargine, his blood sugars had been fairly well regulated and some of his symptoms had lessened in severity.

Gonzalez—Insulin-dependent Diabetes

He reported that the hair on his arms and legs had begun regrowing; his gums showed some improvement, but he still required zolpidem for persistent severe insomnia and the paresthesias in his feet had actually worsened. He described burning in his feet so intense he could not stand for any length of time and he experienced persistent odd “electricalshock” type symptoms in various places in his body.

His endocrinologist had arranged teaching for intensive foot care, which Patient G followed to the letter, washing his feet 3 to 4 times daily. His sexual function, though improved, remained problematic, perhaps, as he said, 20% of his former self. He had some time earlier discontinued the testosterone prescribed by one of his alternative doctors because he felt it did nothing. He still could not exercise because of his persistent weakness and fatigue as well as the paresthesias in his feet that made activity like running or walking impossible.

He described chronic loose, watery stool associated with some urgency maybe twice per day, some lower back pain, and muscle cramping at night in his calves.

He reported occasional chills but no sweats and bouts of nausea, which he related to low blood sugars. Because Patient G could go from hyperglycemia to hypoglycemia very quickly, his endocrinologist had advised him not to use the insulin lispro if he had not eaten.

His most recent blood work from early May, 2011, showed a hemoglobin A1C high at 7.8%; a normal TSH at 4.01 mIU/L; a high glucose at 133 mg/dL; and normal blood urea nitrogen (BUN), creatinine, electrolytes, and liver function. A complete blood count from March indicated a low hemoglobin at 9.8 g/dL with a hematocrit at 29.4%. A recent CT scan of his brain had revealed some cerebral edema.

Under “Past Medical History,” the following problems were listed: 1. Insulin-dependent diabetes.

2. Acute renal failure requiring 13 treatments of dialysis in February/March 2011.

3. Hypothyroidism.

4. Diabetic ketoacidosis.

5. Pancreatitis.

6. Pseudomembranous colitis.

7. Periodontal disease.

8. Occasional migraines.

9. Hypoglycemia with syncope if he does not eat.

Two MRI scans have been negative.

10. Pneumonia when he was admitted into the hospital in February, 2011.

11. Chronic diarrhea.

12. Borderline hypertension.

At the time of his first visit with this MD, Patient G’s medications included hydrochlorothiazide 20 mg per day; duloxetine 30 mg per day for muscle pain; insulin lispro 4 units, 3 times per day with meals’ and insulin glargine 50 units at bedtime. He remained on levothyroxine 100 mg each morning.

Gonzalez—Insulin-dependent Diabetes

On physical examination, Patient G’s blood pressure was mildly elevated at 136/100 mm Hg. Other than lack of hair on his extremities, he appeared otherwise normal.

During the second session, we reviewed at length the proposed treatment plan. In general, our therapy can be broken down into 3 basic components: individualized diet, individualized supplement protocols, and detoxification routines such as coffee enemas. Unlike many alternative practitioners, we do not prescribe one diet for everyone but recommend very detailed and individualized eating plans based on our assessment of each patient’s underlying metabolism. Our prescribed diets can range from largely raw-food plant-based—though we never recommend a purely vegetarian diet—to an Atkins-type diet emphasizing multiple courses of fatty red meat daily, with all manner of diets in between. Similarly, we prescribe a variety of supplements, including vitamins, minerals, trace metals, enzymes, and glandular products (made for us in New Zealand), the doses, forms, and proportions varying, again depending on our assessment of the patient’s metabolic needs. For all patients, whatever their problem and whatever their prescribed diet and supplement regimen, we require the coffee enemas as well as other procedures such as a liver flush, colon cleanses, juice fasts, and various baths.

NUTRITION AND THE AUTONOMIC NERVOUS SYSTEM The nutritional component of our multipronged treatment protocol involves a large number of nutrients and supplements.

The total package is not supported by empirical data, other than the remarkable survival times of many of my patients.

This includes many patients with MRI and biopsy-confirmed stage III or IV pancreatic cancer who are alive and well 10 years later, with no evidence of tumor on repeat MRI. The nutritional component of my regimen is not a treatment of cancer—it is for nutritional support of the person while the cancer is being treated with pancreatic enzymes. The same is true for a number of noncancerous diseases I have treated.

I evaluate the patient’s autonomic nervous system (ANS) balance and consequent dietary requirement using a proprietary analytical system that has not been published or subjected to independent scientific scrutiny. I realize that this is a limitation in our protocol, but as a clinician in private practice, I do not have the many millions of dollars in research funding that would be required to validate the nutritional analyses. I proceed based on information I have gleaned from the peer-reviewed medical and nutritional literatures. In my mind, it is hard to argue with aggressive nutritional support for seriously ill, even cachectic patients.

We base our dietary and supplemental prescriptions on the state of the patient’s ANS, whose 2 branches, the sympathetic and parasympathetic, regulate all or most all metabolism including respiration, cardiovascular function, digestion, endocrine activity, and immunity. Certain patients we believe have a genetically determined tonically active, even hyperactive, sympathetic nervous system (SNS) and a correspondingly weak parasympathetic nervous system ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 27

(PNS). In these patients, all those tissues, organs, and glands normally stimulated by the SNS such as the organs of respiration, cardiovascular function, and endocrine secretion, tend to be highly developed and overly efficient, whereas those tissues, organs, and glands normally stimulated by the weak parasympathetic system, such as all the digestive organs including the liver and pancreas as well as the immune system, tend to be weak and inefficient. These patients, we find, respond best to a plant-based diet, though the exact composition varies depending on the degree of what we call “sympathetic dominance.”

Other patients, we find, possess an overly strong, genetically determined parasympathetic system and a correspondingly weak sympathetic system. In these patients those tissues, organs, and glands normally stimulated by the PNS, particularly those of digestion and immunity, tend to be highly active, even overactive, whereas those tissues, organs, and glands normally stimulated by their weak SNS, such as the lungs and heart, tend to be inefficient.

The third category demonstrates a balanced autonomic system, with both branches equally developed and equally efficient. In this group, all the various physiological systems and their associated tissues, organs, and glands, work equally effectively.

Such a construct is of more than only esoteric interest, and in our model it helps explain the origins of much disease while providing insight into beneficial treatment approaches.

Fundamentally, we perceive that much if not most illness including malignancy develops either because of autonomic imbalance, or in the case of “balanced metabolizers,” combined inefficiency in both the SNS and PNS divisions.

The concept that autonomic imbalance or autonomic inefficiency underscores much disease did not originate in our office, but to the contrary has a long and well-researched history going back nearly 100 years. Francis Pottenger Sr, MD, son of the famed Pottenger medical family with now 4 generations of American physicians to its roster, described the critical role of autonomic activity, autonomic imbalance, and autonomic inefficiency in his classic text Symptoms of Visceral Disease with 6 editions beginning in 1922, and the last dating to 1944.7 The great University of Minnesota physician and neuroscientist, Ernest Gellhorn, MD, PhD, with more than 400 papers and 8 books to his credit, spent decades investigating the role of autonomic imbalance and inefficiency as the root cause of much human illness.8 Succeeding Pottenger and Gellhorn, the more unconventional alternative practitioner, the dentist William Donald Kelley, combined the work of these 2 scientists into a complex nutritional therapy based on autonomic dysfunction.9 It was Kelley who first proposed that the typical solid epithelial tumors, that is tumors of the breast, lung, pancreas, colon, liver, uterus, ovaries, and prostate, tend to develop in those with a strong sympathetic system and weak parasympathetic system. In contrast, immune malignancies such as leukemia, lymphoma, and multiple myeloma, and the 28 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

embryologically related connective tissue cancers such as the sarcomas, occur in those with a strong PNS and a weak SNS. Balanced autonomic metabolizers tend to avoid cancer, though they can experience other illnesses and syndromes such as chronic fatigue if both branches weaken.

In these models of Pottenger, Gellhorn, and Kelley, restoration of health, whatever the underlying problems, requires bringing an out-of-balance autonomic system into balance and homeostatic equilibrium, or in the case of balanced metabolizers, improving efficiency and synergy in both autonomic divisions.

Both Pottenger and Gellhorn, independently of each other, had discovered that certain nutrients, particularly minerals such as calcium, magnesium, and potassium, whatever else they might do in the body have an enormous influence on autonomic firing. For example, Pottenger discovered that calcium stimulates the SNS, magnesium blocks sympathetic firing at the ganglion, and potassium stimulates the PNS in central nuclei. By judicious use of nutrients such as these, Pottenger, in his clinical work with patients, could successfully bring an out-of-balance autonomic system into balance, or improve the efficiency of each. Gellhorn, in his research, further confirmed the profound influence of various nutrients on autonomic function, showing again, as had Pottenger, that by their precise use autonomic balance and autonomic efficiency would improve, with often startling positive results in his clinic patients.

Though these pioneering researchers concentrated on certain nutrients, it was Kelley who would more thoroughly investigate the effect of foods and the various individual nutrients—the vitamins, minerals, trace elements, fatty acids, etc—on autonomic activity. And in his dietary and supplement prescriptions, Dr Kelley always sought to bring an out-ofbalance ANS into efficient equilibrium—or with his “balanced metabolizers,” strengthen both branches equally.

Dr Kelley believed that his “sympathetic dominant” patients, whatever the underlying problem, required for improvement a plant-based diet that included a wide variety of fruits, vegetables, nuts, seeds, and organic whole grain products but limited animal protein—eggs, yogurt, and cheese, with some additional food from animal sources depending on the extent of sympathetic activity; the stronger the SNS, the fewer animal products he would allow.

As more conventional nutritional scientists know, vegetables and fruits have an alkaline ash, and an alkaline extracellular fluid environment tends to suppress sympathetic, while increasing parasympathetic, firing. Further, fruits and vegetables provide significant amounts of the minerals magnesium and potassium, which as Pottenger had shown, respectively suppress sympathetic tone while increasing that of the parasympathetic nerves.

Red meat and to some extent poultry provide certain nutrients in relatively high amounts such as phosphates, sulfates, the amino acids phenylalanine, tyrosine, aspartic acid, glutamic acid, and saturated fats, all of which, via unique pathways, stimulate the SNS while suppressing the Gonzalez—Insulin-dependent Diabetes

PNS. The phosphates and sulfates, for example, convert in the body into phosphoric and sulfuric acid, acidifying extracellular fluids and in turn activating the SNS while suppressing the PNS—a scenario that would be counterproductive for a sympathetic dominant metabolizer.

Phenylalanine and tyrosine, which serve as the precursors to the sympathetic neurotransmitters norepinephrine and epinephrine, similarly have a SNS stimulating effect. So in a sympathetic dominant patient we restrict these animal foods and the amounts allowed, again depending on the degree of sympathetic dominance. In an extremely strong sympathetic dominant we forbid all red meat and poultry; for a patient only slightly on the side of sympathetic dominance we might allow small amounts of both weekly.

In summary, a largely plant-based diet specifically suppresses the sympathetic division while activating the parasympathetics.

In his day, Dr Kelley prescribed, and we recommend today, precise forms, doses, and proportions of the various vitamins, minerals, trace elements, at times herbs, and often glandular products from New Zealand animals, again designed, like diet, to bring about autonomic balance and efficiency. ANS balance is always our main concern in any of our dietary or supplement prescriptions. Of course all the various individual nutrients have multiple metabolic roles— magnesium, for example, serves as a cofactor in more than 300 reactions—but our concern is always their effect on the autonomic system.

Specifically, Kelley found and we find that β-carotene; the B vitamins thiamine, riboflavin, niacin, pyridoxine, and folic acid; and vitamins C and D either suppress the SNS or stimulate the PNS. Certain minerals and trace elements including magnesium, potassium, manganese, and chromium have a similar SNS-inhibiting, PNS-activating action as does the plant-based omega-3 essential fatty acid, α-linolenic acid.

All of these observations are based on my clinical assessments and a proprietary analytical system, which is not my own, but belongs to a person with whom I contract.

For the parasympathetic-dominant patients, Kelley prescribed—and we prescribe today—a diet high in animal fats and protein, sometimes red meat twice daily, which with its specific complement of nutrients such as the phosphates sulfates, phenylalanine, tyrosine, aspartic acid, glutamic acid, and saturated fatty acids will stimulate the weak SNS and suppress the strong PNS, helping to bring the out-of-balance ANS in the parasympathetic-dominant patients into more efficient equilibrium. With their acid-forming, sympatheticstimulating activity, meat and poultry represent ideal foods for this group of patients—again, the frequency and amounts varying according to the degree of parasympathetic dominance; the more parasympathetic a patient, the more fatty red meat we prescribe.

Parasympathetic dominant patients do well with certain vegetables, particularly root vegetables and those in the cruciferous family, which we find to be not particularly alkalinizing, but the diets limit or forbid leafy greens, which, Gonzalez—Insulin-dependent Diabetes

because of their high magnesium content, will suppress the SNS. For our parasympathetic patients, we allow varying amounts of whole organic grains, again the amount depending on the extent of PNS dominance; the more parasympathetic a patient, the fewer servings of grains we allow. The diet does permit beans, but limited or no fruit. Fruit, with its alkaline ash, its high content of potassium and other SNS-suppressing nutrients, would be counterproductive for this group. For a patient with an extremely strong PNS, we restrict fruits and grains to the point that, at times, we allow none at all.

Parasympathetics do best with certain nutrients, specifically preformed vitamin A; certain B vitamins including B12, choline, inositol, PABA, and pantothenic acid; and the calcium salts of vitamin C and vitamin E. Appropriate minerals include large doses of calcium, which we find stimulates strongly the SNS (but minimal amounts of magnesium and potassium); the trace minerals selenium and zinc; and the animal-derived omega-3 fatty acids eicosapentaenoic acid (EPA) and docosapentaenoic acid (DHA), which we find best suited to their metabolic needs.

Balanced metabolizers do best with a diet and supplement regimen that provides all the food classes and nutrients but in moderate doses that will effectively stimulate and support both autonomic branches equally, helping to promote and maintain efficient autonomic function and autonomic balance. For this group the diet allows all the various fruits, vegetables, nuts, seeds, whole grains, eggs daily, organic raw milk and raw cheese, fish 2 to 3 times weekly, poultry 2 to 3 times weekly, and red meat 2 to 4 times weekly. In terms of supplements, for these patients we prescribe all the various vitamins, minerals, trace elements, and essential fatty acids (from both plant and animal sources) but in moderate doses so as not to excessively stimulate or suppress either autonomic branch.

I realize that our nutritional treatment is viewed with great skepticism by many physicians and nutritionists, and I realize that it lacks a sufficient evidence base (other than the remarkable survival times of my patients). My goal here is not to provide a review of the nutritional literature; rather, it is to outline my approach so that others can investigate it in human and animal models. I would like nothing better than for my nutritional approach to autonomic system balance to be validated in the laboratory by a wide range of different experiments and studies. Because such data are not available, I proceed with a private practice clinical approach that makes sense to me and that is grounded in prior textbooks.

OUR APPROACH TO DIABETES Kelley recognized, as do endocrinologists, 2 forms of diabetes, an insulin-deficient type and an insulin-excess variety, what we would today call insulin resistance. But his approach, as does ours today, differed considerably from conventional wisdom, always focusing as he did on autonomic activity and imbalance as the underlying culprit needing to be addressed.

If for a moment we think of diabetes in autonomic terms, indeed when the sympathetic system fires it does ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 29

suppress both the exocrine and endocrine pancreas while at the same time stimulating gluconeogenesis, leading to a combination of diminished insulin secretion, increased glucose production, and, consequently, chronically low blood insulin, elevated blood sugars, and elevated hemoglobin A1C. In Kelley’s model, a sympathetic dominant individual who might follow the typical American eating plan including 150 pounds of white sugar per year, and an additional regular intake of refined and processed grains and food, will end up with an insulin-deficient form of the disease prompted by carbohydrate excess in the absence of β-cell reserve.

When the parasympathetic nerves fire, they increase both the synthesis and the release of insulin, while stimulating the storage of glucose either as glycogen or in adipocytes as triglycerides. In these patients, an intake of white sugar and refined grains leads first to reactive hypoglycemia due to the hyperinsulinemia, followed by classic insulin resistance. In this situation, the excessive blood levels of insulin provoke insensitivity in the insulin receptor of target cells, which when functionally normal will activate the downstream glucose membrane receptor so the sugar can enter cells to be used for energy, In the world of mainstream diabetic thinking physicians believe the “insulin-dependent, type 1,” or childhood, diabetes results from alleged autoimmune attack on and destruction of the insulin-secreting β cells of the pancreas often occurring at quite young ages. Kelley believed this type of insulin-deficient diabetes could occur in adults as well as children, and even in the group of child patients, the real culprit remained an excessively active SNS, perhaps beginning during fetal growth and development. The traditional “type 2” form, more easily regulated by diet, would be consistent with Stanford researcher Dr Gerald Reaven’s concept of insulin resistance, persistent insulin excess in response to a high intake of poor quality refined carbohydrates, leading eventually to receptor insensitivity and the paradoxical situation of high blood insulin and high blood glucose.

In the case of Patient G, the initial evaluation of his autonomic status indicated that he fell moderately into sympathetic dominance but not extremely so. For him, I prescribed what we call the “Balanced Vegetarian Metabolizer Diet” designed for those patients who are essentially balanced in terms of autonomic efficiency but leaning toward sympathetic dominance.

CASE REPORT CONTINUED: PATIENT G’S SPECIFIC DIET As a first principle for all our patients, whatever their autonomic state and whatever their prescribed diet, we strongly advise that their food be organic, as clean as possible, and always non-GMO. Studies going back to the great English agronomist Sir Albert Howard repeatedly have demonstrated the superior nutritional value of “organically” raised foods and livestock. Such agricultural practices provide additional benefit to the soil and the various soil organisms such as earthworms and the microorganisms of the soil; this 30 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

microbiome forms the foundation of all agriculture and is susceptible to damage from pesticides and herbicides. To make matters worse, pesticides, at least most of them, act as neurotoxins, which we believe should be avoided at all costs.

I recommended for Patient G that approximately 50% of his food be consumed in the raw, uncooked state, whereas 50% should be cooked. Researchers such as the late Edward Howell proposed that raw food contains all the vitamins, minerals, and trace elements in a completely undamaged, and usually more accessible, form than does cooked food.10 In addition, Howell pointed out that every cell, whether from a plant or animal, contains hundreds of different enzymes as part of the cell’s normal metabolic machinery. These enzymes, Howell maintained, based on his clinical and laboratory studies, could be absorbed like a vitamin or mineral to assist in various metabolic reactions and help in the repair and rebuilding of damaged tissue.

However, these “food enzymes,” as Howell called them, denature and deactivate above 117°F so even mild cooking will render them useless as beneficial nutrients. Because of this finding, Howell became a great proponent of raw food therapeutic diets, projecting him into the role of grandfather of the current “raw foods” movement.

Though Kelley acknowledged the benefits of raw food, he also learned, through his extensive clinical experience, that some patients did best with mostly cooked food. For those who might have been ravaged by cancer and aggressive conventional treatments such as chemotherapy and radiation, Kelley found their digestion to be so inefficient they could not tolerate an excess of raw food. Though cooking does neutralize certain nutrients such as folic acid and vitamin C, make certain minerals such calcium less available, and inactive the “food enzymes,” the process does break down cell walls and membranes in plant and animal food products respectively, in a sense “predigesting” the food, thereby making it more easily assimilated. To make up for any nutrient loss in the cooking process, Kelley would always prescribe—as we do today—large doses of accessory nutrients and an enzyme product developed by Dr Howell himself. In any event, we find balanced metabolizers particularly, such as Patient G, do best with a diet equally proportioned between cooked and raw.

In terms of specific food types, the diet prescribed Patient G allowed all the different vegetables, encouraging the intake of at least 3 to 4 servings per day with a mix of both cooked vegetables and raw vegetables in salads and freshly made juice, with no limit whatsoever on serving size or frequency. The diet did recommend frequent servings from the cruciferous family that have an anticancer effect, as well as dark leafy greens, which provide a significant amount of magnesium and a sympathetic-suppressing effect, ideally suited for a patient such as G who fell, if only mildly, on the sympathetic dominant side.

The prescribed diet also included a glass of freshly made carrot juice daily, which we find provides a host of useful nutrients and enzymes. We find that, in a patient such as this Gonzalez—Insulin-dependent Diabetes

with a strong SNS and what we consider an “insulin deficient” form of diabetes, the sugar content in a single glass of carrot juice does not affect the blood glucose to any great extent; the benefit, we believe, far exceeds any small risk.

Despite current recommendations in some camps that diabetics of any ilk should avoid all fruit, Patient G was allowed as much whole as desired, but restricted fruit juice and dried fruit whose concentrated sugar content would be initially excessive. In addition, Balanced Vegetarian Metabolizers diagnosed with diabetes tolerate grains, even gluten, well, as long as they consume non-GMO organic forms, preferably sprouted such as the Ezekiel line of breads and grain products.

Such grain foods tend to be not only more nutritious as the sprouting process increases the enzyme content, but also less allergenic. In any event, we do not find that these foods significantly and negatively affect blood glucose levels in this specific group of patients as long as they stick to the organic, non-GMO, preferably sprouted forms.

The diet also allowed as much, or as little of the nuts, seeds, and bean categories as Patient G might wish to consume, though again emphasizing organic non-GMO varieties in all cases, while forbidding peanuts and soy.

Peanuts, technically a legume, can grow the Aspergillus mold, which produces the liver toxin, aflatoxin. Though there remains ongoing debate about the potential problem this is in US-grown peanuts, we err on the side of caution. And we forbid for all our patients soy products, even though they are widely promoted as a “health food,” for 2 reasons. First, a regular intake of soy will, in time, block thyroid function, eventually leading to hypothyroidism. Second, soy contains the protein Bowman-Birk inhibitor, named for the scientists who isolated it, that interferes with the action of trypsin, the main pancreatic proteolytic enzyme so important in our anticancer programs.

Though Patient G tended toward the sympathetic dominant side, because he fell close to balance, I did allow in his diet a fair amount of animal protein, including 2 organic eggs daily, cooked anyway he preferred, and raw milk to drink as well as raw milk cheese, yogurt, and butter. Evidence dating back to the famed cat studies of Francis Pottenger Jr, son of the previously mentioned neuroscientist Pottenger, that he conducted in the course of 10 years beginning in 1932 rather forcefully documented the dangers of cooked milk and as opposed to the health-promoting qualities of raw milk.11 Today, the current industry practice of heating milk to 230°F, separating, recombining, and homogenizing the fat and watery liquid effectively destroys all the important enzymes and many other nutrients as well. Kurt Oster of Bridgeport, Connecticut, long argued that the cherished process of homogenization changed the milk into an atherosclerosisprovoking food.12 Of course, most states forbid the retail sale of raw milk, but even in those locales patients can often obtain raw milk from local farmers’ or buyer’s groups.

I also recommended 2 to 3 servings of seafood weekly.

We fully recognize the increasing problems of pollution of our major and minor waterways, which affects the quality of Gonzalez—Insulin-dependent Diabetes

the fish living in these waters. But there are still areas, as in the Alaskan inlets and waterways and in the North Atlantic, that provide clean fish, or as clean as one can find in this day and age. For all our patients, we do forbid the large predatory fish such as tuna and swordfish that accumulate mercury in time, as well as farm raised fish, much of which now comes from South Asia and China, where there are lax environmental regulations and questionable growing methods.

The diet allowed 2 to 3 servings of organically raised poultry per week and 2 to 4 servings of grass-fed fatty red meat. For the fish, poultry and red meat, I prescribed a specific frequency per week, but in all cases left the actual serving size up the patient. I learned a long time ago from Dr Kelley that a patient’s brain will be a far more accurate guide in determining appropriate serving sizes than some preconceived arbitrary rule.

I thought, based on my experience, that the weekly servings of acid-forming, sympathetic stimulating red meat were necessary in this case to help achieve balance in the autonomic branches. A diet too heavy in fruits and vegetables in a patient like this, and lacking sufficient animal foods, would in our experience push him too strongly into parasympathetic dominance, excessive production of insulin, and down the road, an insulin resistance type of diabetes. We find that the recommended servings of animal products in a slightly sympathetic dominant patient keep the pendulum from swinging too far into the parasympathetic realm, preventing a whole other set of problems.

The supplement protocol I designed for Patient G totaled 26 capsules with breakfast and dinner, and 37 with lunch. His program included what we call the “Moderate Vegetarian Multi Min” providing those minerals and trace metals such as magnesium, potassium, chromium, and manganese that we find suppress the SNS and activate the PNS. A separate supplement, the “Moderate Vegetarian Multi Vit,” as it is called, contains those vitamins we find similarly suppress the SNS while increasing parasympathetic tone, such as β-carotene; the B vitamins thiamine, riboflavin, niacin, folate, and pyridoxine; and vitamin C and vitamin D. In addition, I included a “Glucose Tolerance Factor” supplement consisting of chromium and associated nutrients that have been documented to help regulate sugar metabolism, and which we find particularly useful for our sympathetic dominant patients. For added benefit, Patient G’s program included the antioxidant α-lipoic acid and the amino acid N-acetylcysteine, a duo that together increases levels of glutathione in the body and, like chromium, assists in glucose regulation. For all patients, we also recommend a probiotic, most commonly “Vital 10” from Klaire Labs (ProThera, Inc, Reno, Nevada, USA). In addition, in Patient G’s particular case I also added a capsule of Saccharomyces boulardii, a specific bacteria found useful in those patients recovering from Clostridium difficile infection.

Patient G’s supplement protocol provided a number of “glandular” products in capsule form including adrenal medulla, hypothalamus, liver, and orchic (testicle), derived ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 31

from animals and made for us in New Zealand by exacting technology. Such supplements we believe provide certain growth factors that target like tissues, enhancing repair and regeneration of damaged cells. With each meal, I also prescribed 6 capsules of our pancreas enzyme product, which contains the various digestive enzymes but also homeopathic doses of insulin. In the whole pancreas glandular concentrate, we find that the insulin seems to be absorbed active into the blood stream, in contrast to purified preparations of insulin which denature in the stomach when taken orally. In the 1920s, before the wide availability of manufactured insulin, physicians at times would prescribe whole pancreas supplements that seemed to keep the disease in check.

As part of the third component of G’s treatment regimen, the detoxification routines I prescribed included daily coffee enemas, which we believe are as important to treatment success as the recommended diet and supplement protocols.

We find that as a patient’s body repairs and rebuilds, regardless of the underlying problem, large amounts of toxic debris will be released from stored sites within the various cells. These wastes include sequestered toxic chemicals from environmental sources such as heavy metals, pesticides, hydrocarbons, etc, that sit in the cells waiting to cause genetic and cytoplasmic damage. In addition, wastes from normal cellular metabolism can also accumulate, adding to the deleterious load. In our program, with all the good nutrition provided, it appears that the various cells get the signal to begin molecular “house cleaning,” gradually dumping the stored toxins and metabolic wastes into the blood stream for eventual processing and excretion primarily through the liver, and secondarily through the kidneys. Because of inefficiency in our natural detoxification systems due to chronic overexposure to environmental chemicals and processed food, we find adjunctive “detoxification” a critical component of the therapy.

The mainstay of the detoxification routines remains for all patients the daily coffee enemas, which have long been belittled by the conventional medical world. However, I have found few physicians aware that esteemed medical texts, including the Merck Manual,13 and many conventional nursing texts, recommended coffee enemas as a treatment modality for decades during the 20th century. In addition, there exist dozens of papers from the academic peerreviewed literature beginning in the 1920s documenting the effective use of coffee and other forms of enemas in syndromes as variable as septic shock and arthritis to bipolar illness. One memorable paper from the New England Journal of Medicine14 in 1932 reports the successful treatment of hospitalized psychiatric patients with a variety of “colonic irrigations.”

We believe that the coffee enemas, through activation of a parasympathetic reflex, stimulate both phase 1 and phase 2 detoxification systems in the liver, whose efficient function is so important in the treatment of just about any disease. For Patient G, I also prescribed other procedures such as a liver flush and a colon cleanse, to be alternated on a monthly basis.

For most of our patients we usually recommend any of a 32 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

number of juice fasts, but in this patient’s case, because of the unstable blood sugar picture, I thought any juice fast would be too strenuous early on in the treatment process.

Because of G’s terrible chronic insomnia, I prescribed the “blue light blocking glasses” (Photonic Developments, Walton Hills, OH, USA). This intervention is based on the discovery that all light, whether natural sunlight in origin or artificial from light bulbs, television screens, computers, smart phone screens, etc, contains a blue wave length, which is most commonly invisible to the eye. This particular light wavelength stimulates the alert centers in the brain as a survival benefit to keep us awake and aware in daylight. Like any daytime creature, our circadian rhythms dictate that we should be alert during daylight, and sleepy at night, when under natural conditions with the setting of the sun, the stimulating blue light wavelength disappears. But we creative humans with our synthetic lights and electronic devices expose our brain to an ongoing barrage of blue wavelength light that keeps us in an “unnatural” state of vigilance in preparation for activity, even well into late night. An outcome of disrupted sleep cycles and chronic insomnia often follows.

My patient’s research group designed eyeglasses, akin to sunglasses, with a rose colored lens that blocks specifically and only the blue light, in effect tricking the brain into thinking it is pitch dark even when surrounded by light. With the activating centers of the brain turned off, we can fall asleep normally, even if living in a light-rich environment and continuing our activities, such as television watching or computer work—as long as we wear the blue light blocking glasses. In clinical trials, the glasses worked well, bringing on sleepiness quickly, often in the most hardened of insomniacs.

For years, I have been prescribing the blue light blocking glasses for patients with a history of insomnia, usually with satisfying outcomes.

During the second 2-hour session with Patient G and his wife, I reviewed in great detail the various aspects of the prescribed protocol. By the end of that meeting, when he expressed his gratitude that I was willing to take him on as a patient, I suspected he would be compliant with all aspects of the treatment. As we parted, after the second part of the consultation, the patient expressed understanding of the treatment and was encouraged to call with any questions he might have, also suggesting, because he lived fairly close to New York City, that he return for an office visit in 3 months.

PATIENT G’S PROGRESS ON THE THERAPY For all my patients, wherever they may live, we require that they return for an extended re-evaluation every 6 months. More local patients like G, I like to monitor initially closely, usually every 3 months, but after our initial 2 sessions together, Patient G disappeared for an extended time. In the months that followed, our initial sessions together not once did he call with a question. There was no contact until he sent a Christmas card in late December, 2011, adding to the printed message, “Thank you for getting my life back in order.” I assumed he must be doing well, but I Gonzalez—Insulin-dependent Diabetes

would not hear from him again until he came in for an appointment in mid-June 2012—a year after he had first consulted with me.

At that time, he walked in, again with his wife, looking like a completely different individual from a year earlier. First of all he was smiling, in stark contrast to his pained visage during our first sessions and he had what might be best described as a “glow” of good health. He expressed gratefully that “the program has changed my life.” He apologized for not coming in sooner as I had recommended, but he had been out of work until recently, so money had been tight. But he was pleased to inform me that now he had a good job he enjoyed and his newfound excellent energy, stamina, and concentration he attributed to the nutritional regimen allowed him now to work long hours under stress without any difficulty.

During the previous 12 months, Patient G had been vigilantly compliant with all aspects of the prescribed nutritional program, including the diet, supplements, and detoxification routines. When we talked about his apparent good compliance, he had a very simple answer—I had told him what he needed to do, and he just went ahead and did it all, without complaint or need for constant support from me.

My note from the day sums up his current situation: He said that he is doing so much better. He said that when he walked in here he could barely function. He said that his functionality is extraordinary. He has been extremely compliant with all aspects of the program. … He does the whole program.

In addition, he is on insulin lispro, which he takes 3 times a day. He varies the dose according to his blood sugars. He is also on insulin glargine and down to about 25 to 30 units at bedtime. He was on 50 units when he first came in. … He is off the duloxetine.

He basically emphasized that the program has changed his life …

He is enjoying his work and working long hours.

He said that when he came in here one year ago he could not exercise at all. He is exercising regularly. He is going to the gym. He is lifting weights …

He said that he is enjoying his life. He is enjoying his children.

He said that it is just wonderful to be alive. He said that the program has made “an unbelievable difference” in his life. His energy is substantially improved. He is able to enjoy life, go out, and be with his children. He said that he could not do that one year ago when he came in here because he was so weak, exhausted, tired, and sick. He is using much less insulin. His endocrinologist, who knows he sees me, is extremely happy with how he is doing …

He said that for so long he was not exercising but he is now feeling so good that he can exercise. He does not need the duloxetine anymore for the muscle pain.

The blue light blocking glasses helped enormously with his sleep. He said that they were “miraculous.” He is sleeping soundly and sleeping well.

His energy is “unbelievable.” Stamina is “great.”

Concentration is “very good.”

His kidneys are fine. They did kidney function tests 3 months ago that were perfect, as if he had never been sick.

Nephrologist has discharged him as he does not need to see him anymore.

Gonzalez—Insulin-dependent Diabetes

In addition, Patient G’s periodontal disease had completely resolved, he had not experienced any further episodes of pancreatitis, his gastrointestinal function was now completely normal, and he rarely felt hypoglycemic.

Based on my testing, my experience, and his excellent clinical situation, no changes were made to his prescribed diet, and only very minor alterations in his supplement protocol. He was to continue the detoxification routines as before.

Subsequently, Patient G continued as a “low maintenance” patient. For the next 6 months, he did not call once with a question or problem, and I would not hear from him again until he and his wife returned to my office in mid-December, 2012, some 18 months after his first beginning treatment with me.

Again he looked well, reported feeling well, and remained very compliant with his nutritional regimen. My note from the session recorded his situation at the time: He looks great. He said that he is feeling great. His job is going well. … He is busy and he is doing well financially. When he first came in here, as he said today, he did not have a job and he said that he could not work. He had lost his job because he could not function …

He said that he is really doing fine. He continues on the insulin lispro but is adjusting the dose downward. He does not need as much. . . . He is really exercising quite vigorously …

He said that his stamina is “fantastic.” Energy is “fantastic. …”

He is sleeping well. He said that the blue light blocking glasses really changed his sleep …

The only doctor he is seeing at this point is his endocrinologist. … He has not done blood work so I suggested that we need to do that. He agreed. He said that he just does not want to see any other doctors other than me. His endocrinologist … is just monitoring his blood sugars. His hemoglobin A1C last time was 12 …

Although I had given him an order for extensive blood testing at our December, 2012, meeting, he would not have the test performed until late June, 2013, in preparation for his upcoming re-evaluation scheduled for the second week of July, 2013—now 2 years since he had begun treatment with me. At that time, his blood sugars seemed less controlled, coming in at 328 mg/dL with a significantly elevated hemoglobin A1C at 14% (normal 4.8%–5.6%). His TSH was also elevated at 6.24 mIU/L (normal 0.45–4.50 mIU/L).

Though he had remained on levothyroxine, clearly he needed more thyroid replacement, or a different form of medication.

Upon follow up, he looked well, seemed as before completely compliant with the therapy, and expressed, once again, his heartfelt gratitude for the treatment. He informed me that he felt so well he had taken on a second full-time job because of his family’s financial needs but felt terrific despite the added workload. I thought it a sign of great progress that he could manage 2 stressful jobs successfully, because when he had first consulted me, he could not work at all. He also explained that he, his wife, and his children had just returned from a 2-week vacation out west, including a trip to the Grand Canyon, which he had enjoyed immensely. As my ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 33

note recorded, “He said that it was really very relaxing and he really enjoyed it.”

Regarding blood sugar instability, he reported that his daily blood sugar monitoring generally indicated a level no higher than 200 mg/dL. Based on clinical experience, it was suspected that the problem might be stress brought on by his second job. Compliance with diet and the prescribed supplements did not seem to be an issue, since he appeared to be as dedicated as ever to the treatment. But he did acknowledge recent significant additional stresses in his life.

As my note from the visit reported: He has been under a lot of stress, and I could tell from the metabolic report. He took a second job. He is a salesman for medical products. … They are completely different products so he is able to do that without a conflict of interest. He is working anywhere from 10 to 16 hours a day. His territory … goes from Washington, DC, up to New Hampshire.

He said that he just needed the extra money with his 3 kids. … It is a lot of stress. He said that the miracle is that he is able to do it. He is able to work 12- to 16-hour days. He has good energy, stamina, and endurance. We talked at length about the fact that this is really too much considering where he came from as he was really burnt out when he first walked into my office. He said that he really feels “great.”

His blood sugars at home range around 200 mg/dL. He has been working out 3 to 5 times a week. He said that the miracle is that when he first came in [sic] could not work at all. … His energy, he said, is great. Stamina is “great.”

Concentration is good. He is sleeping great. He said that the blue light blocking glasses really made a difference.

Because of his high TSH, I increased his kelp supplement, a good source of iodine, and the thyroid glandular we use with patients experiencing hypothyroidism. Because he was due to see his endocrinologist in 2 weeks, adjustments to levothyroxine dose were deferred.

It was not surprising, based on increased work stress, that his blood sugar picture had become a problem; as patients improve on our therapy and start feeling truly well after long periods of severe ill health, they may take on more activities and responsibilities than I would normally recommend.

Particularly with Patient G’s autonomic profile, increased stress was almost guaranteed, at least at this still early point in his therapy with me, to worsen his blood sugars. Stress in any form in a patient such as this with a dominant SNS, whether it be physical, psychological, spiritual, or, as in this case, workrelated, turns on the sympathetic system more strongly, turns off the parasympathetic system, and reduces insulin synthesis and secretion.

In preparation for Patient G’s next visit with me in midJanuary 2014—2.5 years after his first consultation—blood testing indicated some improvement, with his blood sugar down to 280 mg/dL and hemoglobin A1C at 12.4%. His TSH had actually worsened to 8.43 mIU/L. Despite these results, when he was examined, he looked well, remained compliant with all aspects of his therapy, and reported that he was “doing great.” After seeing me in July, 2013, and despite his 34 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

misgivings, he had consulted again with his endocrinologist who had doubled his levothyroxin dose to 200 mg daily.

Fortunately, he had quit the more demanding of his 2 jobs, the one which required considerable travel, which he did not enjoy, and which he admitted had affected his sense of well-being. Instead, he had taken on another second fulltime job, but one that required only local travel and which he found more intellectually stimulating while at the same time less stressful. As I wrote in my note, “… he is very happy with his job and felt my advice was really very useful.”

He continued his regular strenuous workouts, which he acknowledged did help control his blood sugar levels, enabling him to reduce his insulin dosing still further. He also remarked that through trial and error he realized that when his blood sugar went below 120 mg/dL, he did not feel well at all, observing that a level between 120 and 150 mg/dL seemed most suitable, leaving him feeling most energetic and alert. We do find that our sympathetic-dominant patients in general, and our sympathetic-diabetic patients in particular, not only tolerate what would be considered higher than normal blood sugars, but, as in this case, feel best with moderately elevated blood glucose and feel terrible with sugars in the so-called optimal range.

My note described his continuing good health: Overall his energy is excellent. Stamina is good. He gets through the day fine. He is sleeping “great.” He does not even have to use the blue light blocking glasses anymore as sleep as improved so much. Concentration is good.

After discussing his worsening TSH result, I decided to up his dose of our nonprescription thyroid support supplement, to 2 at breakfast, 2 at dinner, and 1 at lunch.

When I next saw Patient G in mid-July, 2014, he had completed 3 years of treatment with me, remained compliant, and continued improving. Again he reported that the therapy “has changed my life.”

Though he had not gone for the blood testing I had requested for the visit, he reported that with increasing vigorous exercise, during the past 6 months his blood sugars had further stabilized, rarely going below 120 or above 150 mg/dL. The levels tended to be highest in the morning then improved throughout the day. As before, with these levels he seemed to feel clinically the best.

His assessment in comparison to his original set of health problems was as follows: He has had no recurrences of any of the diarrhea or pseudomembranous colitis type symptoms. He said his gut is “fine.”

He has been to his dentist and his gums and teeth are fine.

He has been to his ophthalmologist and there is no damage at all to his retina. His ophthalmologist is very pleased.

He has very rare hypoglycemic symptoms. He knows how to manage them well …

He has also had no further recurrences of any of his pancreatitis type symptoms. … He is really doing very well.

He has had no blood work done the last 6 months. … We will get some blood work done.

Gonzalez—Insulin-dependent Diabetes

I last saw Patient G in my office in mid-July, 2015, more than 4 years after his first visit. Patient G remains fully compliant with his therapy, continues doing well, and continues enjoying his work, his life, and his family. He remains grateful to the therapy we offer. His blood sugars had been falling steadily in the range of 120 mg/dL in the mornings, ideal for him, rising only slightly throughout the day. He was on the lowest doses of insulin since starting treatment with me.

He described his 2-job routine as demanding, but he felt so well he had no problem meeting his responsibilities. His career, in fact, seemed to be going quite well, better than ever.

He and his wife had purchased a new larger home, but even the stress of selling his old house and moving he handled without difficulty. I doubt in this particular case that Patient G will ever be free of all supplemental insulin.

However, I have learned not to underestimate the ability of any organ to regenerate at least to some extent. In any event, Patient G continues experimenting with lowering his insulin dose, with ongoing success in improving his blood sugar regulation. As a final note to Patient G’s complex history before his doctors finally diagnosed diabetes, repeated extensive blood testing did not show elevated blood sugars for 2.5 years.

REFERENCES 1. Gonzalez NJ, Isaacs LL. The Trophoblast and the Origins of Cancer. One Solution to the Medical Enigma of our Time. New York, NY: New Spring Press; 2009.

2. Ross CA. The trophoblast model of cancer. Nutr Cancer. 2015;67(1):61-67.

3. Gonzalez NJ, Isaacs LL. Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas with nutrition and detoxification support. Nutr Cancer. 1999;33(2):117-24.

4. Chabot JA, Tsai WY, Fine RL, et al. Pancreatic proteolytic enzyme therapy compared with gemcitabine-based chemotherapy for the treatment of pancreatic cancer. J Clin Oncol. 2010;28(12):2058-2063.

5. Gonzalez NJ. What Went Wrong. The Truth Behind the Clinical Trial of the Enzyme Treatment of Cancer. New York, NY: New Spring Press; 2012.

6. Ross CA. Methodological flaws in the Chabot trial of pancreatic enzymes for pancreatic cancer. Int J Cancer Prev Res. 2015;1:1-4.

7. Pottenger FM. Symptoms of Visceral Disease—A Study of the Vegetative Nervous System in Its Relationship to Clinical Medicine. New York, NY: CV Mosby; 1922.

8. Gellhorn E. Autonomic Imbalance and the Hypothalamus: Implications for Physiology, Medicine, Psychology, and Neuropsychiatry. Minneapolis, MN: University of Minnesota Press; 1957.

9. Gonzalez NJ. One Man Alone. An Investigation of Nutrition, Cancer, and William Donald Kelley. New York, NY: New Spring Press; 2010.

10. Howell E. Enzyme Nutrition. New York, NY: Avery Publishing Group; 1995.

11. Pottenger, FM Jr. Pottenger’s Cats: A Study in Nutrition. 2nd ed. Lemon Grove, CA: Price Pottenger Nutrition Foundation; 2012.

12. Oster K. Homogenized Milk and Atherosclerosis. Lawrence, KS: Sunflower Publishing; 1970.

13. Merck. The Merck Manual of Diagnosis and Therapy. 19th ed. Rahway, NJ: Merck Publishing, 2011.

14. Marshall JK, Thompson CE. Colon irrigation in the treatment of mental disease.

N Engl J Med. 1932;206:454-457.

CONCLUSION Patient G provides an interesting example of how a precisely targeted, precisely prescribed diet designed according to a patient’s autonomic state can lead to substantial improvement in serious illnesses other than cancer. In this case, in contradiction to current recommendations in both the conventional and more alternative medical worlds, Patient G’s specific diet recommended a considerable daily intake of carbohydrates, though mostly complex, always as part of a whole food, and always from organic sources. In this way, along with the complementary supplement protocol, we were able—at least in our model of physiology—to reduce his sympathetic tone, increase parasympathetic firing, increase β-cell activation and his own insulin production with resulting significant improvement not only in his blood sugars but also in his overall health. Even if my protocol had no effect on his pancreas, and even if it did not contribute to the stabilization of his blood glucose levels and a reduction in his insulin requirement, it was certainly associated with a remarkable improvement in health, life satisfaction, and function at work, at home and in the gym. I observe similar levels of wellness in my cancer patients, who are disease-free on repeat MRI, more than a decade out from initiating my treatment. I therefore think that such a nutritional protocol should be considered for a wide range of patients with debilitating illnesses, including those on chemotherapy.

My goal in this paper has not been to prove anything scientifically. It has been to provide enough detail on my nutritional protocol, and the rationale for it, that grantfunded researchers could begin to study it.

Gonzalez—Insulin-dependent Diabetes

ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 35

ORIGINAL RESEARCH

Improvement of QOL and Immunological Function With Lentinula Edodes Mycelia in Patients Undergoing Cancer Immunotherapy: An Open Pilot Study Keishi Tanigawa, MD, PhD; Yusuke Itoh, BS; Yasunobu Kobayashi, PhD ABSTRACT Context • Combined treatment with an extract of Lentinula edodes mycelia (LEM) and chemotherapy has been reported to improve quality of life (QOL) and immunological function in cancer patients. However, those effects have not been elucidated for patients receiving cancer immunotherapy.

Objective • The present study intended to investigate the effects of oral LEM on QOL and immunological function in cancer patients receiving immunotherapy.

Design • The research team designed an open-label, single-armed pilot study.

Setting • The study took place at Bio-Thera Clinic, a facility associated with Tokyo Women’s Medical University in Tokyo, Japan.

Participants • The participants were 10 cancer patients undergoing cancer immunotherapy at Bio-Thera Clinic.

Intervention • The participants received either dendritic cell (DC)-based cancer vaccine therapy or CD3-activated T-lymphocyte (CAT) therapy as immunotherapy. They received the immunotherapy only for the first 4 wk of the study, and then oral LEM (1800 mg/d) was added for the next 4 wk.

Keishi Tanigawa MD, PhD, is director of the Bio-Thera Clinic, Shinjuku-ku, and a lecturer in the Department of Gastroenterological Surgery, Tokyo Women’s Medical University, in Tokyo, Japan. Yusuke Itoh, BS, is a researcher, and Yasunobu Kobayashi, PhD, is a senior researcher, both at Bio-Thera Clinic, Shinjuku-ku, in Tokyo.

Corresponding author: Keishi Tanigawa, MD, PhD E-mail address: tangiawa@bio-c.jp

36 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

Outcome Measures • Preintervention and at 4 and 8 wk after the start of the study, participants completed a QOL survey, and immunological parameters were measured.

Results • Participants’ QOL symptom scores increased (ie, worsened) by 5.1 ± 1.7 during the first 4 wk of treatment when they were receiving immunotherapy only, but it decreased (ie, improved) by -2.5 ± 1.6 during the next 4 wk when the immunotherapy was combined with the LEM, P < .05. The measurement of the immunological parameters during the 4 wk of immunotherapy combined with LEM showed that the amount of interferon-γ (IFN-γ) produced in the peripheral blood tended to increase as compared with that during the first 4 wk of immunotherapy only. The rise in IFN-γ was correlated with changes in several regulatory T cells (Tregs) (ie, forkhead box P3 [FOXP3]+/cluster of differentiation 4 [CD4]+ and transforming growth factor beta [TGF-β]).

Conclusions • The findings suggest that a combined treatment of LEM and immunotherapy might improve QOL and immunological function in cancer patients.

(Altern Ther Health Med. 2016;22(4):36-42.)

T

he Shiitake mushroom (ie, Lentinula edodes) is an edible mushroom that has long been used in East Asia for better health. Lentinan, a neutral polysaccharide of high molecular weight that is extracted from the fruiting body of Shiitake mushrooms, is reported to produce antitumor activity and immunoregulatory effects. Lentinan was approved as an anticancer drug in Japan in 1985.

The mycelial extract of Shiitake mushrooms (ie, the extract Lentinula edodes mycelia [LEM]), is a hot-water extract obtained after production of a solid culture of Shiitake mycelia. In cell transplantation models for melanoma and colon cancer in mice, LEM has been reported to inhibit the increases in regulatory T cells (Tregs) and transforming growth factor beta (TGF-β) in peripheral blood that are associated with tumor proliferation and to restore the activity of cancer-specific cytotoxic T lymphocytes (CTLs).1,2 Tanigawa—Improvement of QOL and Immunological Function

Moreover, when combined Table 1. Demographics of Participants with cancer vaccine therapy, LEM is reported to reduce immunoAge Status Prior to suppression and enhance the (y) Gender Primary Cancer Immunotherapy Immunotherapy antitumor effects of the therapy.3 CAT 76 Female Biliary tract cancer After radical operation Therefore, LEM is promising for use DC 80 Female Biliary tract cancer After radical operation as an oral adjuvant in cancer CAT 58 Female Breast cancer After radical operation immunotherapy.

Tregs were discovered by CAT 48 Male Colorectal cancer Advanced cancer Sakaguchi et al4 in 1995 and are DC 58 Male Colorectal cancer Advanced cancer involved in immunological tolerance.

DC 52 Male Gastric cancer Advanced cancer Tregs also were later found to CAT 83 Male Lung cancer Advanced cancer suppress tumor immunity. For induction of antitumor immunity, DC 65 Male Lung cancer Recurrent cancer 2 approaches are required: (1) the DC 57 Male Pancreatic cancer Advanced cancer effective induction of tumor-specific DC 60 Female Pancreatic cancer Advanced cancer CTLs and (2) the reversal of immunosuppression mechanisms such as Tregs.

Abbreviations: CAT, CD3-activated T lymphocyte therapy; DC, dendritic cell-based For the former approach, in cancer vaccine therapy. addition to cancer vaccine therapy, interest has focused on CAR-T-cell therapy using artificial METHODS T cells. For the latter approach, immune checkpoint antibodies Participants have been developed to reverse the inhibition of CTLs directly From December 2009 to August 2011, the patients were and to restore the activation of CTLs. Immunotherapy drugs recruited at Bio-Thera Clinic (Tokyo, Japan) and the study based on those 2 types of mechanisms have shown promise as management physician chose 10 patients based on the being effective for various types of cancers. criteria for patient inclusion of this study. The current study However, mechanisms of immunosuppression are was conducted with the 10 patients—6 patients undergoing complicated. The effectiveness of any single drug may be dendritic cell (DC)-based cancer vaccine therapy and limited and, therefore, immunotherapy regimens using a 4 patients undergoing CD3 activated T lymphocyte (CAT) combination of treatment approaches as well as drugs are therapy—both immunotherapies, at Bio-Thera Clinic (Table 1).

The immunotherapy, which each patient received, was being developed.

LEM has been used clinically in combination with decided by the study physician based on the subject’s postoperative adjuvant chemotherapy in breast cancer (BC) condition before they were recruited for this study. The patients to improve quality of life (QOL) during chemotherapy selection and treatment processes were not blinded. The and to produce greater decreases in NK-cell activity.5 LEM clinic is a facility associated with Tokyo Women’s Medical used in combination with chemotherapy has also been University (Tokyo, Japan). The study received the approval of reported to improve QOL and NK-cell activity in patients the ethics committee of the International Research and with gastrointestinal (GI) cancer.6,7 In addition, LEM in Educational Institute for Integrated Medical Sciences at combination with postoperative hormonal therapy in BC has Tokyo Women’s Medical University and of the ethics been reported to improve QOL and the production of committee of the Japanese Society for Complementary and Alternative Medicine. Before the initiation of the study, the interferon-γ (IFN-γ) in peripheral blood.8 Thus, LEM may improve QOL and immunological patients were given sufficient explanations from the study function in cancer patients, but its effectiveness in patients physician about the purpose and methods of this study and receiving cancer immunotherapy has not previously been other necessary aspects regarding the protection of the investigated. Further, a few clinical studies have examined subjects’ human rights, and they provided written consent of the effectiveness of mushrooms other than Shiitake in cancer their own free will. patients (eg, Ganoderma lucidum) has been reported to improve fatigue and immunological function in cancer Procedures CAT Therapy. A total of 30 mL of peripheral blood was patients.9 Those studies have also targeted BC in patients on obtained from the participants, and the peripheral blood hormonal therapy. mononuclear cells (PBMCs) were isolated, which was Therefore, in the present study, the research team followed by stimulation with an anti-CD3 antibody and investigated the effects of oral LEM on QOL and cultivation for 2 weeks.

Cultivated lymphocytes, immunological function in patients receiving cancer approximately 107 cells, were reinfused into the participants immunotherapy, primarily cancer vaccine therapy. through an intravenous drip every 2 weeks.

Tanigawa—Improvement of QOL and Immunological Function

ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 37

DC Therapy. Fifty to 100 million peripheral monocytes were obtained through apheresis. The obtained monocytes were cultured through stimulation with granulocytemacrophage colony-stimulating factor (GM-CSF) for 1 week to induce dendritic cells. The dendritic cells were stimulated by tumor antigen peptide or tumor lysate that was selected for each participant and were reinfused into the participant every other week. Patients receiving DC therapy also received CAT therapy at the same time.

LEM Extract. The LEM was provided by the Kobayashi Pharmaceutical Co, Ltd (Osaka, Japan). The manufacturing method was as follows.10 First, the LEM strain NITE SD 0043, which had been registered at the National Institute of Technology and Evaluation, was inoculated onto a solid medium consisting of sugar-cane bagasse and rice bran, and it was cultured until the mycelia were spread in the solid medium. Second, a brownish-red powder was extracted from the medium with hot water; it was considered to be the LEM. Third, the LEM (600 mg) was mixed with several excipients— cornstarch, trehalose, and granulated sugar—and was compressed to 3000 mg of granulated powder per pack. Each participant consumed 3 packs per day. The composition of the drug is shown in Table 2.

It has been reported that arabinoxylan, syringic acid, and vanillic acid are active components of LEM and that LEM has an arabinoxylan content of more than 2.2% (as total amount of arabinose and xylose),11 a syringic acid content of 0.45 mg/g,10 and a vanillic acid content of 0.37 mg/g.10 For quality control, the current research team confirmed that the LEM used in the study had an arabinoxylan content of more than 2.5%, a syringic acid content of more than 0.45 mg/g, and a vanillic acid content of 0.4 mg/g.

Interventions Figure 1 shows the schedule for the treatments.

Immunotherapies. For participants in the DC group, the therapy was performed weekly during the 8 weeks of the study—4 times during the first course of treatment during the first 4 weeks of the study and 4 times during the second course of treatment during the second 4 weeks of the study.

For participants in the CAT group, the therapy was performed biweekly during the 8 weeks of the study—2 times during the first course of treatment during the first 4 weeks of the study and 2 times during the second course of treatment during the second 4 weeks of the study.

LEM Extract. All patients took 1800 mg of oral LEM every day for the last 4 weeks of the 8-week study.

Outcome Measures QOL Survey. The QOL survey was conducted 3 times: (1) at week 0, (2) at week 4, and (3) at week 8. The survey was conducted using the EORTC Quality of Life Questionnaire (QLQ)-C30, a questionnaire with 4 scales: (1) a global scale (a higher score represents a higher better level of global health status); (2) a functional scale that measures physical, role, emotional, cognitive, and social functioning, including an 38 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

Table 2. Components of the Drug per Pack of Granulated Powder Components LEM Cornstarch Trehalose Granulated sugar Total

Quantity Per Dose 600 mg 1882 mg 150 mg 368 mg 3000 mg

Note: Three times per day, the participants took a 600 mg/dose of the granular LEM with the added excipients cornstarch, trehalose, and granulated sugar, all compressed to 3000 mg of granulated powder per pack.

Abbreviation: LEM, extract of Lentinula edodes mycelia.

Figure 1. Treatment Schedule LEM Administration 1800 mg/d PO (on consecutive days) First course DC therapy weekly or CAT therapy (biweekly)

Second course DC therapy weekly or CAT therapy (biweekly)

0

4 8 Week Note: Each participant took 2 courses of their assigned immunotherapy: 1 in the first 4 weeks and 1 in the second 4 weeks of the study. All participants orally ingested the LEM at a dose of 1800 mg/day continuously for the last 4 weeks of the study.

Abbreviations: DC, dendritic cell; CAT, CD3-activated T-lymphocyte; LEM, Lentinula edodes mycelia; PO, by mouth. overall total score (a higher score represents a better level of each functioning); (3) a symptom scale that measures levels of fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea, including an overall total score (a higher score represents a worse level of each symptoms); and (4) a financial difficulties scale (a higher score represents a worse level of financial difficulties). All of the scales and single-item measures range in score from 0 to 100.

The questionnaire was field tested in a cross-cultural sample of cancer patients in 13 countries to confirm the hypothesized scale structure, to establish reliability, and to evaluate validity.12 Immunological Parameters. Participants’ peripheral blood was collected in heparin tubes for cytokine assay at weeks 0, 4, and 8. PBMCs were then isolated by centrifugal separation of blood in blood-draw (BD) Vacutainer cell preparation tubes (CPTs) (Becton, Dickinson and Company, Franklin Lakes, NJ, USA).

Tanigawa—Improvement of QOL and Immunological Function

Figure 2A. A Representative Flow Cytometric Profile of the Assay of NK-cell Activity

For the NK-cell assay, the prepared PBMCs were used as effector cells. The percentage of NK cells in the effector-cell populations was determined by calculation of the percentage of CD56positive and CD3-negative cells, using a flow cytometer (Epics XL, Beckman Coulter, Brea, CA, USA). Cells of the K562 myeloid-leukemia cell line that were obtained from Riken BRC (Tsukuba, Ibaragi, Japan) were used as target cells in the assay.

The NK-cell activity was examined using the LIVE/DEAD Cell-Mediated Cytotoxicity Kit (Molecular Note: The NK-cell activity was calculated based on the % specific cell death = (% DiO + PI + Probes, Eugene, OR, USA).

Prior to the assay, the K562 cells − % spontaneous DiO + PI + cells) × 100. cells were labeled with Abbreviations: NK, natural killer; DiO, 3.3’-dioctadecyloxacarbocyanine; PI, propidium iodide; 3.3’-dioctadecyloxacarbocyanine (DiO). The cells PBMC, peripheral-blood mononuclear cell. were then cocultured in a 96-well microplate with freshly isolated PBMC in Figure 2B. A Representative Flow Cytometry Profile of Tregs the presence of propidium iodide (PI). After 2 hours of incubation, the percentage of cytotoxicity of various ratios of effector to target cells was determined using flow cytometric analysis, and the data were analyzed using the Coulter EXPO 32 analysis software (Brea, CA, USA). The NK-cell activity (effector to target, 20:1) was calculated using the following formula: % specific cell death = (% DiO + PI + cells − % spontaneous DiO + PI + cells) × 100

Note: The percentage of Tregs was calculated by measuring the ratio of FOXP3-positive and CD25-positive cells to CD4-positive cells in PBMC. Abbreviations: Tregs, regulatory T cells; FOXP3, forkhead box P3; CD, cluster of differentiation; PBMC, peripheral-blood mononuclear cell.

Tanigawa—Improvement of QOL and Immunological Function

A representative flow cytometric profile is shown in Figure 2A. Flow cytometric analysis of Tregs was performed using the One Step Staining Human Treg Flow Kit (Biolegend, San Diego, CA, USA).

Briefly, freshly isolated PBMCs were fixed, permeabilized, and then stained with a cocktail of Alexa Fluor 488 antihuman FOXP3/CD25 PE/CD4 PerCP antibody (Biolegend, San Diego, CA, USA), in accordance with the manufacturer’s instructions. An antibody cocktail containing the Alexa Fluor 488 Mouse immunoglobulin G1 (IgG1), isotype control/CD25 PE/CD4 PerCP was used as a control. A representative flow cytometric profile is shown in Figure 2B. The ability of peripheral blood to produce cytokines was analyzed by the method of

ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 39

Heriot et al8,13 and was measured as follows. First, 1000 μL of RPMI1640 medium (Sigma-Aldrich Japan, Tokyo, Japan) was added to 250 μL of whole peripheral blood collected in heparin tubes and cultured for 24 hours at 37°C under 5% CO2 with lipopolysaccharide (LPS) from Sigma-Aldrich Japan (Tokyo, Japan). IFN-γ and interleukin 10 (IL-10) in the cultured supernatant were then quantified using enzyme-linked immunosorbent assay (ELISA) kits (Life Technologies Japan, Tokyo, Japan). The TGF-β1 and the alpha chain of the soluble interleukin-2 receptor (sIL-2R) (ie, sIL-2R, CD25) in that cultures supernatant were quantified using ELISA kits (Affymetrix Japan, Tokyo, Japan).

Statistical Analysis The measurement values are presented as means ± standard errors of the mean (SEMs) for the QOL scores and as means ± standard deviations (SDs) for the immunological parameters. Changes in individual parameters at each time point of measurement were evaluated using a paired t test.

SPSS version 12 (SPSS Japan, Tokyo, Japan) was used for all statistical analyses, with a 2-sided, 5% significance level.

RESULTS QOL Score Changes in the QOL during the study are shown in Table 3.

For all participants, the mean total score on the symptom scale increased by 5.1 ± 1.7 in the first 4 weeks when only immunotherapy was performed, indicating an exacerbation of the symptoms. However, that total score at 4 weeks after the start of concomitant use of LEM and immunotherapy was significantly decreased, with a change of -2.5 ± 1.6, versus the change in the first 4 weeks, P < .05. The global score for the QOL also displayed a tendency to improve in the second 4 weeks with concomitant use of LEM and immunotherapy.

Immunological Parameters The changes in immunological parameters during the study are shown in Table 4. No significant changes were observed in any of the parameters in the first 4 weeks when only immunotherapy was performed. However, a tendency existed for improved IFN-γ production for all participants in the peripheral blood at approximately 4 weeks after the start of concomitant use of LEM and immunotherapy, showing an increase from 69 ± 110 pg/mL to 124 ± 178 pg/mL, P < .1.

Those changes occurred in 7 of the 10 participants. For those 7 participants, no changes in immunological parameters other than in IFN-γ occurred from pre- to postintervention.

On the other hand, in the remaining 3 participants whose IFN-γ production did not increase during those 4 weeks, the percentage levels of Tregs significantly increased during the period, moving from 4.1 ± 2.5 to 7.4 ± 3.6, P < .05. Further, during that period, the ratio of NK cells to lymphocytes decreased from 12.8 ± 1.9 to 11.0 ± 2.0, P < .05, and TGF-β1 production tended to increase, moving from 56.3 ± 31.8 pg/mL to 68.1 ± 42.8 pg/mL, P < .1, in those 3 participants.

40 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

Table 3. QOL Scores

Global Scale Functional Scale Total Physical functioning Role Emotional Cognitive Social Symptom Scale Total Fatigue Nausea and vomiting Pain Dyspnea Insomnia Appetite loss Constipation Diarrhea Financial Difficulties

Change After 4 Change Over Weeks of LEM Pre-LEM Period Ingestion Week 4 vs Week 0 Week 8 vs Week 4 Mean ± SEM Mean ± SEM P Value -6.5 ± 5.7 4.6 ± 4.4 <.1 -3.1 ± 1.8 0.0 ± 1.1 -1.9 ± 4.9 -2.8 ± 4.2 -1.9 ± 3.2 -9.3 ± 6.5

0.6 ± 0.6 0.0 ± 1.1 0.0 ± 2.6 -0.9 ± 2.8 1.9 ± 1.8 1.9 ± 4.9

ns ns ns ns ns ns

5.1 ± 1.7 0.0 ± 3.0 3.7 ± 2.3 0.0 ± 5.3 0.0 ± 0.0 11.1 ± 7.5 7.4 ± 7.0 7.4 ± 8.8 11.1 ± 7.5 0.0 ± 5.3

-2.5 ± 1.6 -1.2 ± 2.1 -1.9 ± 1.8 5.6 ± 7.5 0.0 ± 0.0 -7.4 ± 4.6 -7.4 ± 11.5 -7.4 ± 7.0 0.0 ± 5.3 -7.4 ± 4.6

<.05 ns ns ns ns ns ns ns ns ns

Notes: The comparison of each subtracted value (ie, week 4 vs week 0 and week 8 vs week 4, was tested using a paired t test).

Abbreviations: QOL, quality of life; LEM, extract of Lentinula edodes mycelia; SEM, standard error of the mean; ns, not significant.

DISCUSSION During the first 4 weeks of the current study, the patients received immunotherapy only. During that first period, the participants’ scores on the functional scale either decreased or remained unchanged; their scores on the symptom scale either worsened or were unchanged; and the scores on the global scale, as an indicator of overall QOL, also decreased.

Although DC and CAT immunotherapy are generally not thought to have an adverse effect on QOL, the QOL in the current study did decrease. The reason is probably the fact that 7 of the 10 patients in the study had advanced cancer.

Therefore, the decreased QOL was probably due to cancer progression rather than the effects of the immunotherapy.

During the latter 4-week period of the current 8-week study, the patients received oral LEM together with immunotherapy. After that period, their scores on the functional scale and the symptom scale improved. The total scores on the symptom scale during the latter 4 weeks significantly improved compared with the first 4 weeks. The study is the first to report improved QOL using oral LEM in combination with cancer immunotherapy.

Oral LEM in combination with chemotherapy in BC and GI cancer patients has been reported to improve the physical score on the QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs (QOL-ACD) questionnaire.14 In Tanigawa—Improvement of QOL and Immunological Function

Table 4. Immunological Parameters (n = 10)

Participants All Participants NK cells/lymphocytes NK cell activity Tregs (FOXP3+/CD4+) IFN-γ production IL-10 production TGF-β1 production sIL-2R production 7 Participants NK cells/lymphocytes NK cell activity Tregs (FOXP3+/CD4+) IFN-γ production IL-10 production TGF-β1 production sIL-2R production 3 Participants NK cells/lymphocytes NK cell activity Tregs (FOXP3+/CD4+) IFN-γ production IL-10 production TGF-β1 production sIL-2R production

Week 0 Mean ± SD

Week 4 Mean ± SD

P Value Week 8 P Value (Week 0 vs Week 4) Mean ± SD (Week 4 vs Week 8)

% % % pg/mL pg/mL pg/mL ng/mL

Total Total Total Total Total Total Total

14.4 ± 6.4 5.6 ± 7.9 3.9 ± 4.1 56 ± 67 352 ± 390 51.0 ± 41.9 2.1 ± 5.6

16.4 ± 5.2 7.3 ± 7.1 3.3 ± 1.5 69 ± 110 385 ± 337 46.5 ± 27.3 1.9 ± 5.0

ns ns ns ns ns ns ns

17.0 ± 7.1 7.1 ± 6.2 4.5 ± 3.0 124 ± 175 326 ± 316 44.1 ± 37.6 1.8 ± 4.4

ns ns ns <.1 ns ns ns

% % % pg/mL pg/mL pg/mL ng/mL

Increase Increase Increase Increase Increase Increase Increase

16.3 ± 6.3 10.6 ± 8.6 2.1 ± 1.0 72 ± 74 325 ± 412 48.0 ± 28.7 0.3 ± 0.1

16.5 ± 5.9 12.2 ± 6.6 2.6 ± 0.8 86 ± 130 381 ± 410 42.3 ± 26.6 0.3 ± 0.1

ns ns ns ns ns ns ns

17.0 ± 7.9 9.3 ± 6.5 2.7 ± 1.0 171 ± 194 373 ± 372 33.7 ± 33.1 0.5 ± 0.3

ns ns ns <.05 ns ns ns

% % % pg/mL pg/mL pg/mL ng/mL

Decrease Decrease Decrease Decrease Decrease Decrease Decrease

9.9 ± 4.9 5.2 ± 5.0 6.6v 7.2 17 ± 14 413 ± 409 58.0 ± 72.9 6.2 ± 10.1

12.8 ± 1.9 2.5 ± 0.9 4.1 ± 2.5 29 ± 19 342 ± 167 56.3 ± 31.8 5.7 ± 9.1

ns ns ns ns ns ns ns

11.0 ± 2.0 2.7 ± 1.4 7.4 ± 3.6 15 ± 10 268 ± 91 68.1 ± 42.8 5.0 ± 8.1

<.05 ns <.05 ns ns <.1 ns

Note: The table shows the comparison of each measurement between 2 points, which was tested using a paired t test. The top set of data is the data for all 10 participants. The middle set is the data for the 7 participants who showed an increase in IFN-γ production after LEM administration. The bottom set is the data for the 3 participants who did not showed an increase in IFN-γ production after LEM administration.

Abbreviations: SD, standard deviation; NK, natural killer; ns, not significant; Tregs, regulatory T cells; FOXP3, forkhead box P3; IFN-γ, interferon-γ; IL-10, interleukin 10; TGF-β1, transforming growth factor beta-1; sIL-2R, soluble interleukin-2 receptor; LEM, an extract of Lentinula edodes mycelia. addition, oral LEM in combination with hormonal therapy has been shown to improve the total and vitality scores on the short form 36 (SF-36)15 health survey in BC patients.8 The current study assessed QOL using the EORTC QLQ-C30 questionnaire and, therefore, a direct comparison with results of studies that used the QOL-ACD and SF-36 is difficult.

However, the QOL-ACD physical score mainly assesses physical condition, fatigue, appetite, and vomiting, and the SF-36 vitality score mainly assesses fatigue and energy. The measures on the symptom scale used in the current study closely reflect the items assessed by the QOL-ACD physical score and are partially correlated with the SF-36 vitality score.

Therefore, the improvement in QOL with LEM in cancer patients in the current study, rather than being a direct effect of the concomitant use of LEM and cancer chemotherapy, hormonal therapy, or immunotherapy, is mainly due to an overall QOL effect on the participants’ well-being.

After the second 4 weeks of the current study in which participants received the combined treatment of LEM and immunotherapy, IFN-γ production in the peripheral blood tended to increase. The production of immunosuppressive cytokines, such as TGF-β1, IL-10, and sIL-2R, was also Tanigawa—Improvement of QOL and Immunological Function

measured in the current study, but no changes occurred in their production. In the 7 of the 10 participants with an increased production of IFN-γ, no changes occurred in the production of other cytokines. However, among the immunosuppressive cytokines, the production of TGF-β1 tended to increase in the 3 participants who showed a decrease in IFN-γ production. Those 3 participants also displayed a significant increase in Treg cells.

TGF-E is a key cytokine in Treg induction.16 The progression of immunosuppression, with an increase in TGF-E1, is associated with deterioration in a patient’s overall status, including the progression of inflammation in the cancer-bearing host and worsening nutritional status.16-18 Therefore, immunological status affects physical QOL in cancer-bearing patients.

In an in vivo model of colon cancer transplantation, oral LEM inhibited the production of TGF-E in serum and lymph-node T cells, and the production of IL-6, an indicator of cachexia, was also reduced.2 In the current study, although LEM had no pronounced effect on immunological function, LEM did reduce the progression of immunosuppression that is associated with an increase in Tregs and TGF-E1, which ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 41

may have provided the ability to improve the patientsâ&#x20AC;&#x2122; overall statuses. In addition, IL-6 is an immunosuppressive cytokine that induces myeloid-derived suppressor cells (MDSCs),19,20 which are closely associated with cancer cachexia.21 However, at present, there is no answer on how oral LEM affects MDSCs in cancer-bearing patients. Further studies should investigate the effects of LEM on IL-6 and MDSCs. The small sample size observed in this study represents its primary limitation. Further large-scale investigations of these immunotherapies are necessary to demonstrate adequate power for broad application.

CONCLUSIONS Many patients undergoing cancer immunotherapy are considered to have advanced cancer as was the case with participants in the current study, and a suppression of the deterioration in QOL that occurs with cancer progression and continuation of the treatment for a prolonged period are significantly beneficial for the patients. The results of the study have suggested that oral intake of LEM can provide those benefits to cancer patients. A future study using a greater number of patients is necessary to confirm those findings.

12. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-376.

13. Heriot AG, Marriott JB, Cookson S, Kumar D, Dalgleish AG. Reduction in cytokine production in colorectal cancer patients: Association with stage and reversal by resection. Br J Cancer. 2000;82(5):1009-1012.

14. Kurihara M, Shimizu H, Tsuboi K, et al. Development of quality of life questionnaire in Japan: Quality of life assessment of cancer patients receiving chemotherapy. Psychooncology. 1999;8(4):355-363.

15. McHorney CA, Ware JE Jr, Lu JF, Sherbourne CD. The MOS 36-item Short-Form Health Survey (SF-36), III: Tests of data quality, scaling assumptions, and reliability across diverse patient groups. Med Care. 1994;32(1):40-66.

16. Coe D, Addey C, White M, Simpson E, Dyson J, Chai JG. The roles of antigenspecificity, responsiveness to transforming growth factor-beta and antigenpresenting cell subsets in tumor-induced expansion of regulatory T cells.

Immunology. 2010;131(4):556-569.

17. Donkor MK, Sarkar A, Li MO. Tgf-beta1 produced by activated CD4(+) T cells antagonizes T cell surveillance of tumor development. Oncoimmunology.

2012;1(2):162-171.

18. Tsai VW, Husaini Y, Manandhar R, et al. Anorexia/cachexia of chronic diseases: A role for the TGF-beta family cytokine MIC-1/GDF15. J Cachexia Sarcopenia Muscle. 2012;3(4):239-243.

19. Cuenca AG, Cuenca AL, Winfield RD, et al. Novel role for tumor-induced expansion of myeloid-derived cells in cancer cachexia. J Immunol.

2014;192(12):6111-6119.

20. Yazawa T, Shibata M, Gonda K, et al. Increased IL-17 production correlates with immunosuppression involving myeloid-derived suppressor cells and nutritional impairment in patients with various gastrointestinal cancers. Mol Clin Oncol.

2013;1(4):675-679.

21. Bunt SK, Yang L, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res. 2007;67(20):10019-10026.

ACKNOWLEDGEMENTS The research team thanks the Kobayashi Pharmaceutical Co Ltd for the grant that funded the study.

AUTHOR DISCLOSURE STATEMENT The study was funded by a grant from Kobayashi Pharmaceutical Co Ltd.

REFERENCES 1. Tanaka K, Ishikawa S, Matsui Y, Tamesada M, Harashima N, Harada M. Oral ingestion of Lentinula edodes mycelia extract inhibits B16 melanoma growth via mitigation of regulatory T cell-mediated immunosuppression. Cancer Sci. 2011;102(3):516-521.

2. Tanaka K, Matsui Y, Ishikawa S, Kawanishi T, Harada M. Oral ingestion of Lentinula edodes mycelia extract can restore the antitumor T cell response of mice inoculated with colon-26 cells into the subserosal space of the cecum. Oncol Rep. 2012;27(2):325-332.

3. Tanaka K, Ishikawa S, Matsui Y, et al. Combining a peptide vaccine with oral ingestion of Lentinula edodes mycelia extract enhances anti-tumor activity in B16 melanoma-bearing mice. Cancer Immunol Immunother. 2012;61(11):2143-2152.

4. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic selftolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25): Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155(3):1151-1164.

5. Nagashima Y, Maeda N, Yamamoto S, Yoshino S, Oka M. Evaluation of host quality of life and immune function in breast cancer patients treated with combination of adjuvant chemotherapy and oral administration of Lentinula edodes mycelia extract. Onco Targets Ther. July 2013;6:853-859.

6. Yamaguchi Y, Miyahara E, Hihara J. Efficacy and safety of orally administered Lentinula edodes mycelia extract for patients undergoing cancer chemotherapy: A pilot study. Am J Chin Med. 2011;39(3):451-459.

7. Okuno K, Uno K. Efficacy of orally administered Lentinula edodes mycelia extract for advanced gastrointestinal cancer patients undergoing cancer chemotherapy: A pilot study. Asian Pac J Cancer Prev. 2011;12(7):1671-1674.

8. Suzuki N, Takimoto Y, Suzuki R, et al. Efficacy of oral administration of Lentinula eododes mycelia extract for breast cancer patients undergoing postoperative hormone therapy. Asian Pac J Cancer Prev. 2013;14(6):3469-3472.

9. Zhao H, Zhang Q, Zhao L, Huang X, Wang J, Kang X. Spore powder of Ganoderma lucidum improves cancer-related fatigue in breast cancer patients undergoing endocrine therapy: A pilot clinical trial. Evid Based Complement Alternat Med. 2012;2012:809614.

10. Itoh A, Isoda K, Kondoh M, et al. Hepatoprotective effect of syringic acid and vanillic acid on concanavalin a-induced liver injury. Biol Pharm Bull.

2009;32(7):1215-1219.

11. Kojima H, Akaki J, Nakajima S, Kamei K, Tamesada M. Structural analysis of glycogen-like polysaccharides having macrophage-activating activity in extracts of Lentinula edodes mycelia. J Nat Med. 2010;64(1):16-23.

42 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

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ORIGINAL RESEARCH

The Effects of Ozonated Olive Oil and Clotrimazole Cream for Treatment of Vulvovaginal Candidiasis Fatemeh Tara, MD; Ziba Zand-Kargar, MD; Omid Rajabi, PharmD, PhD; Fariba Berenji, MD, PhD; Farideh Akhlaghi, MD; Mohammad Taghi Shakeri, PhD; Hoda Azizi, MD, PhD

ABSTRACT Context • Vulvovaginal candidiasis is the most common infection of the vulvovagina, which manifests with itching, a burning sensation, and leucorrhea. Some infections have been reported to be tolerant to conventional treatments, especially in immunosuppressed patients. New studies have suggested that ozone, which is the allotropic form of oxygen, may have antifungal effects.

Objective • The study intended to compare the effects of ozononated olive oil and clotrimazole in the treatment of vulvovaginal candidiasis.

Design • Patients were randomly assigned either to an ozone group or to a clotrimazole group in a randomized, controlled trial.

Setting • The study took place in the Department of Gynecology of the School of Medicine at Mashhad University of Medical Sciences in Mashhad, Iran.

Participants • Participants were 100 female patients who had been referred to the women’s gynecology clinic at the Omolbanin and Ghaem Hospitals and who had confirmed vulvovaginal candidiasis.

Intervention • Patients in the ozone group were treated with ozonated olive oil or those in the clotrimazole group were treated with clotrimazole for 7 d.

Fatemeh Tara, MD, is an associate professor, and Farideh Akhlaghi, MD, is an associate professor; both are located in the Department of Gynecology. Omid Rajabi, PharmD, PhD, is an associate professor in the Department of Medicinal Chemistry, School of Pharmacy; and Fariba Berenji, MD, PhD, is a professor in the Department of Parasitology and Mycology. All are based in the School of Medicine at Mashhad University of Medical Sciences in Mashhad, Iran.

Ziba Zand-Kargar, MD, is a gynecologist in the Department of Gynecology at Razavi Hospital in Mashhad, Iran.

Mohammad Taghi Shakeri, PhD, is a professor in the Department of Biostatistics, School of Health at Mashhad University of Medical Sciences. Hoda Azizi, MD, PhD, is an 44 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

Outcome Measures • Patients were evaluated through an interview and a paraclinical examination at baseline and postintervention. The study measured changes in itching, burning, and leucorrhea using a questionnaire that patients completed at the end of the study and determined the presence of an infection with vaginal candidiasis through a culture both before acceptance into the study and after the treatments, if accepted.

Results • Ozone and clotrimazole both reduced symptoms significantly and led to a negative culture for vaginal candidiasis (P < .05). No significant differences existed between the 2 groups in their effects on the symptom of itching and leucorrhea and on the results of the culture (P > .05). However, clotrimazole decreased the burning sensation significantly more than did ozone (P < .05).

Conclusions • Considering the potential efficacy of ozonated olive oil in the improvement of the clinical and paraclinical aspects of treatment of patients with vulvovaginal candidiasis, the research team suggests that the treatment can be an effective topical treatment for those patients. (Altern Ther Health Med. 2016;22(4):4449.)

assistant professor at the Addiction Research Center and an assistant professor in the Department of Chinese and Complementary Medicine at the School of Traditional and Complementary Medicine, Mashhad University of Medical Sciences.

Corresponding author: Ziba Zand-Kargar, MD E-mail address: zandkargar.md@gmail.com

Tara—Olive Oil and Clotrimazole Cream for Vulvovaginal Candidiasis

V

ulvovaginal infections caused by different types of Candida are the most common infections of women’s genital systems. Cases of it have frequently been observed to be tolerant of its conventional treatments.

Seventy-five percent of women experience an infection with vulvovaginal candidiasis at least 1 time in their lives, and 45% of women experience it 2 times or more.1 Because of the prolonged treatment required for Candida and its drug tolerance, offering a treatment for removing the fungal infection that (a) is low in cost, (b) has no side effects, and (c) significantly affects the infection can have benefits for a society’s health.

Recently, in new studies, evidence of the benefits and efficacy of ozone has been observed for treatment of different infections and inflammations. Ozone therapy has been suggested since 1995 in the United States as a complementary medicine for treatment of the infection.

Moreover, ozone has been shown to have effects on the treatment of infections because it causes oxygen to reach the tissues and also decreases inflammation. Because the cost of treatment for the infections has been increasing in various societies, and because the drug tolerance of the infection is increasing, ozone therapy has received considerable notice because not only does it have a definite effect but also the infection does not tolerate it.2 In 1995, Rodriguez et al3 reported at a Cuban congress that ozonated oil was able to treat vulvovaginal candidiasis.

Also, De Las et al4 and Morris et al5 showed positive effects for ozone on the treatment of vulvovaginitis. A study in 2006 compared ozonated olive and sunflower oils chemically and microbiologically. It showed that the antimicrobial activity was similar for both ozonized oils, except for a minimum bacterial concentration of Pseudomona aeruginosa, where sunflower oil at low peroxide value had better antimicrobial activity, whereas ozonized olive oil was better to high peroxide value. The composition of the fatty acids in both of the ozonized oils showed a gradual decrease in the unsaturated fatty acids.6 The results of a study performed in 2010 at Mashhad University of Medical Sciences (MUMS) in Mashhad, Iran, showed that ozonated olive oil had a prohibitive effect on 3 types of Candida. The effects were dependent on the concentration, with those effects being observed in a shorter time at a higher concentration. The types of Candida most sensitive to the ozonated olive oil were Candida krusei, Candida glabrata, and Candida albicans.7 In a study performed in 2008 at MUMS, the efficacies of an ozonated gel and of metronidazole were compared for the treatment of trichomoniasis vulvovaginitis. The effects of the ozone were found to be better than the oral tablet of metronidazole for improving the symptoms and culture smears of the patients with that infection.8 Because the antifungal effects of ozone and its cost effectiveness and lack of side effects had been reported in the previous studies, the research team performed the current study with the aim of comparing the efficacies of ozonated olive oil and clotrimazole cream for treatment of vulvovaginal candidiasis.

Tara—Olive Oil and Clotrimazole Cream for Vulvovaginal Candidiasis

METHODS Participants The research team had calculated that the study required 82 patients who had had a positive culture for vaginal candidiasis, 41 patients in each group, according to the formula: n=

(P1 [1 - P1] + P2 [1 - P2])(Z1 - - Z1 - β)2 a 2

(P1 - P2)

2

P1 = 64%, α = .05 Z1 - = 1.96 a 2

P2 = 92%, β = .2 Z1 - β = .84 P1 and P2 values were based on the results of previous studies.

To be assured of sufficient power, the team determined that it needed 50 women in each group (ie, a total of 100 patients).

Potential participants were women who had been referred to the women’s gynecology clinic at the Omolbanin and Ghaem Hospitals. Candidates were interviewed and given a paraclinical examination by the corresponding author, who also reviewed the women’s medical charts. The first author determined whether or not each candidate met the inclusion criteria. A total of 200 women were interviewed.

Among them, 150 were eligible clinically and underwent culture. Of those candidates, 50 were negative for Candida or showed other or mixed infection.

To be included, the women had to (1) be of fertile age, (2) have received a clinical diagnosis of vaginal candidiasis, (3) have had a positive culture for vaginal candidiasis upon testing at baseline, (4) be willing to avoid intercourse during the treatment period, and (5) be willing to avoid taking a vaginal bath during the study. Patients were excluded if they (1) were currently using drugs for treatment of Candida; (2) had diabetes, vascular collagen diseases, or immunosuppressive diseases; (3) were using corticosteroids or antibiotics; (4) were using antifungal treatments from 1 week before the study; (6) had taken a vaginal bath during the week prior to the start of the study; and (7) were pregnant or breastfeeding.

The study was conducted according to the Declaration of Helsinki and was approved by the Ethics Committee of MUMS. Written informed consent was obtained from all patients.

Procedures Ozonated olive oil is an ivory-colored viscous jelly that remains unchanged at room temperature for 3 years. It keeps its ozone content even after melting. The medicated ozone used in the current study was produced in the research laboratory of the Pharmacy School at MUMS using an ozone-producing machine that had the capacity of making 13.6 g/hour of ozone. The machine conducts ozone bubbles ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 45

through the olive oil for 72 hours. It changes the liquid olive oil to solid. Glycozone, a superoxide, is released, and trepan gases are trapped inside the olive oil, which oxidizes it to peroxide O-O-H.9 The oxidative power of the ozonated olive oil was determined using iodometry with sodium thiosulfate.

After explaining the conditions of the study to the potential participants and obtaining informed consent, the research team obtained a vaginal culture for vaginal candidiasis. Women with a positive culture for vaginal candidiasis at baseline were included in the study. Participants were asked to visit the clinic on the tenth day after the start of treatment (ie, 3 days after the treatment ended) to allow the research team to evaluate the treatment. The patients underwent a clinical examination and a culture for vaginal candidiasis. At the end of the study, participants were also asked to record any changes in the symptoms of itching, burning, and leucorrhea, using a questionnaire.

Intervention The women with a positive culture at baseline were randomly divided into 2 groups: (1) one that received treatments of ozonated olive oil, applied using a vaginal applicator containing 5 g of the treatment (ozone group); and (2) one that used clotrimazole cream, applied using a vaginal applicator containing 5 g of the drug (clotrimazole group). The participants applied the treatments themselves, with 1 applicator used every night for 1 week.

Outcome Measures The study’s outcomes were (1) measures of the changes in the clinical symptoms of itching, burning, and leucorrhea that were obtained using a questionnaire; and (2) the results of a culture for vaginal candidiasis.

Questionnaire. The questions about itching, burning, and leucorrhea each asked participants to classify their symptoms as to their degrees of severity, which were (1) none, (2) mild, (3) moderate, (4) severe, and (5) very severe.

Culture for Vaginal Candidiasis. The culture medium was sabouraud dextrose agar with chloramphenicol in the laboratory temperature of 22°C to 25°C. The waiting time for culture was at least 72 hours and at most 10 days.

Statistical Analysis Data were analyzed using the SPSS software, version 17 (SPSS Inc, Armonk, NY, USA). A Student’s t test was used for quantitative variables, and χ2 and Fisher tests were used for qualitative variables. The Mann-Whitney U test, Wilcoxon signed-rank test, and logistic regression were used for analyzing the data.

RESULTS The current study enrolled 100 women, all with cultures that had confirmed the presence of an infection with vaginal candidiasis. All 100 women who started the study also completed it. Before treatment, the demographics of the 46 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

2 groups of participants were not significantly different (Table 1).

Table 2 shows data for the 2 groups for the severity of itching at baseline and postintervention. No significant differences existed between the ozone and the clotrimazole groups, either at baseline (P = .82) or postintervention (P = .74) using Mann-Whitney U test . The drugs were comparable in their treatment of the itching.

The study also compared the changes in the severity of itching from baseline to postintervention for each group. For the ozone group, the changes from baseline to postintervention were as follows: (1) none—from 2 women (4%) to 38 women (76%), (2) mild—from 17 women (34%) to 11 women (22%), (3) moderate—from 12 women (24%) to 1 woman (2%), (4) severe—from 10 women (20%) to no women (0%), and (5) very severe—from 9 women (18%) to no women (0%).

For all categories of the severity of itching, a significant difference was observed in terms of the reduction in the severity of itching for the ozone group (P = .0001).

The changes in the severity of itching between baseline and postintervention were also compared for the clotrimazole group, and for all categories of severity, results similar to those of the ozone group were found (P = .0001).

Table 3 shows data for the 2 groups for the severity of burning at baseline and postintervention. Significant differences were observed between the 2 groups at baseline (P = .041) and postintervention (P = .032). The ozone decreased the burning sensation significantly more than did clotrimazole (ie, the 2 drugs were not similar in their efficacies in decreasing the severity of burning).

The study also evaluated the changes in the severity of burning from baseline to postintervention for each group.

For the ozone group, the changes from baseline to postintervention were as follows: (1) none—from 15 women (30%) to 47 women (94%), (2) mild—from 14 women (28%) to 2 women (4%), (3) moderate—from 8 women (16%) to 1 woman (2%), (4) severe—from 10 women (20%) to no women (0%), and (5) very severe—from 3 women (6%) to no women (0%). For all categories of the severity of burning, a significant difference was observed in terms of the reduction in the severity of burning for the ozone group (P = .0001).

The changes in the severity of burning were also compared for the clotrimazole group, and for all categories of severity, results similar to those of the ozone group were found (P = .0001).

Table 4 shows data for the 2 groups for the severity of leucorrhea at baseline and postintervention. The 2 groups were not significantly different at baseline (P = .14) or postintervention (P = .75). The efficacies of the 2 drugs were similar in decreasing the severity of leucorrhea.

The study also evaluated the changes in the severity of the leucorrhea from baseline to postintervention for each group. For the ozone group, the changes from baseline to postintervention were as follows: (1) none—from 4 women (8%) to 42 women (84%), (2) mild—from 9 women (18%) to 7 women (14%), (3) moderate—from 13 women (26%) to Tara—Olive Oil and Clotrimazole Cream for Vulvovaginal Candidiasis

Table 1. Baseline Characteristics of Participants

Characteristics Age, mean ± SD, y Having recurrences of vaginal infections in the year prior to the study Using contraceptive methods Using antifungal drugs in the month prior to the study

Ozone Group n (%) 34.1 ± 7.9 13 (26) 8 (16) 8 (16)

Clotrimazole Group n (%) 34.4 ± 8.1a 15 (30)b 11 (22.9)b 6 (12)b

a

P > .05 using a t test.

P > .05 using the χ2 test.

b

Abbreviation: SD, standard deviation.

Table 2. Comparison of the Severity of Itching Pre- and Postintervention for the Groups (n = 50 in Each Group)

Itching None Mild Moderate Severe Very severe

Ozone Group Preintervention Postintervention n (%) n (%) 2 (4) 38 (76) 17 (34) 11 (22) 12 (24) 1 (2) 10 (20) 0 (0) 9 (18) (0)

Clotrimazole Group Preintervention Postintervention n (%) n (%) 5 (10) 37 (74) 14 (28) 10 (20) 9 (18) 2 (4) 10 (20) 0 (0) 12 (24) 1 (2)

Note: No significant differences existed between the ozone and the clotrimazole groups in the severity of itching, either at baseline (P = .82) or postintervention (P = .74) using the Mann-Whitney U test. Within-group analysis showed a significant difference in the severity of itching before and after the treatment with ozone, using the Wilcoxon signed-rank test (P = .0001). Within-group analysis showed a significant difference in the severity of itching before and after the treatment with clotrimazole, using the Wilcoxon signed-rank test (P = .0001). There was no significant difference between the 2 groups in the severity of itching before and after the study using logistic regression (P = .89).

Table 3. Comparison of the Severity of Burning Pre- and Postintervention for the Groups (n = 50 in Each Group)

Burning None Mild Moderate Severe Very severe

Ozone Group Preintervention Postintervention n (%) n (%) 15 (30) 47 (94) 14 (28) 2 (4) 8 (16) 1 (2) 10 (20) 0 (0) 3 (6) 0 (0)

Clotrimazole Group Preintervention Postintervention n (%) n (%) 10 (20) 42 (84) 11 (22) 6 (12) 6 (12) 1 (2) 14 (28) 0 (0) 9 (18) 1 (2)

Note: Significant differences existed between the ozone and the clotrimazole groups in the severity of burning at baseline (P = .04) or postintervention (P = .11) using the Mann-Whitney U test. Within-group analysis showed a significant difference in the severity of burning before and after the treatment with ozone, using the Wilcoxon signed-rank test (P = .0001). Withingroup analysis showed a significant difference in the severity of burning before and after the treatment with clotrimazole, using the Wilcoxon signed-rank test (P = .0001). There was a significant difference between the 2 groups in the severity of burning before and after the study using logistic regression (P = .032).

Tara—Olive Oil and Clotrimazole Cream for Vulvovaginal Candidiasis

ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 47

Table 4. Comparison of the Severity of Leukorrhea Pre- and Postintervention for the Groups (n = 50 in Each Group)

Leukorrhea None Mild Moderate Severe Very severe

Ozone Group Preintervention Postintervention n (%) n (%) 4 (8) 42 (84) 9 (18) 7 (14) 13 (26) 1 (2) 20 (40) 0 (0) 4 (8) 0 (0)

Clotrimazole Group Preintervention Postintervention n (%) n (%) 6 (12) 33 (66) 13 (26) 13 (26) 12 (24) 2 (4) 17 (34) 2 (4) 2 (4) 0 (0)

Note: No significant differences existed between the ozone and the clotrimazole groups in the severity of leukorrhea at baseline (P = .14) but significant difference was seen postintervention (P = .03) using the Mann-Whitney U test. Within-group analysis showed a significant difference in the severity of leukorrhea before and after the treatment with ozone, using the Wilcoxon signed-rank test (P = .0001). Within-group analysis showed a significant difference in the severity of leukorrhea before and after the treatment with clotrimazole, using the Wilcoxon signed-rank test (P = .0001). There was no significant difference between 2 groups in the severity of leukorrhea before and after the study using logistic regression (P = .75).

1 woman (2%), (4) severe—from 20 women (40%) to no women (0%), and (5) very severe—from 4 women (8%) to no women (0%). For all categories of the severity of leucorrhea, a significant difference was observed in terms of the reduction in the severity of in the ozone group (P = .0001).

The changes in the severity of leucorrhea were also compared for the clotrimazole group, and for all categories of severity, A significant difference in the severity of leukorrhea before and after the treatment with clotrimazole was found, using Wilcoxon signed-rank test (P = .0001).

Table 5 shows the results for the cultures performed after treatment for the 2 groups. No significant difference existed between the 2 groups in terms of the results for the culture postintervention (P = .62).

DISCUSSION The current study was performed to compare the efficacies of ozonated olive oil and clotrimazole cream for treatment of vulvovaginal candidiasis. Before treatment, the 2 groups were similar in terms of ages, recurrences of the infection, contraceptive methods, and use of antifungal drugs. The changes in patients’ symptoms (ie, in the severity of burning, itching, and leucorrhea) and in the results of the cultures for vaginal candidiasis were considered to be the outcomes for the study.

The present study has shown that the 3 symptoms significantly improved after treatment for the group receiving the ozonated olive oil, with P = .0001 for all measures. The ozone was as effective as clotrimazole in reducing the severity of both the itching (P = .89) and leucorrhea (P = .75), as well as reducing the number of women with a positive culture for Candida; however, the ozone decreased the burning sensation significantly more than did the clotrimazole (P = .032) (ie, the 2 drugs were not similar in their efficacies in decreasing the severity of burning). No side effects occurred during the study for either group.

The results of the current study confirmed the findings of a study performed by Minoocheher7 in 2010 that evaluated 48 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

Table 5. Results of Cultures for Vaginal Candidiasis Postintervention for the Groups (n = 50 in Each Group)

Results

Ozone Group n (%)

Clotrimazole Group n (%)

Positive

9 (18%)

13 (26)

Negative

41 (82%)

37 (74)

the fungal-removing effects of ozonated olive oil for 3 types of Candida. Also, the results of the current study are comparable to a study performed by Rajabi8 in 2007 that compared the effects of ozonated olive oil and clotrimazole cream on trichomoniasis infections and showed that 100% of the patients treated with ozone had improved symptoms. In that study, the 2 groups were not significantly different in terms of clinical symptoms after treatment, but in terms of the laboratory tests, the rate of negative smears was significantly higher for the ozone group than for the clotrimazole group. Rajabi’s study was very similar to the current study because it evaluated the treatment of vulvovaginitis and its symptoms using ozone. The reduction in symptoms by ozone in Rajabi’s study was similar to that in the current study, but the results in terms of the laboratory testing were different, because the present study showed that the treatments received by the ozone and clotrimazole groups were not significantly different in terms of obtaining a negative culture postintervention.

The results of the current study were in accordance with a study by Rodriguez et al3 in 1995. For 5 days, the researchers treated 12 patients with Candida vulvovaginitis that was tolerant to conventional treatments with ozonated oil and repeated the treatments for 2 additional cycles of 5 days.

Candida vulvovaginitis was completely removed in all patients. The researchers evaluated the infection recurrence during an 18-month follow-up, and in only 1 case was the Tara—Olive Oil and Clotrimazole Cream for Vulvovaginal Candidiasis

recurrence of symptoms observed, without confirmation of a Candida infection.3 In a study performed by De Las et al4 in Cuba, 60 patients with vulvovaginitis were placed in 3 treatment groups: (1) ozonated flower seed oil, (2) a conventional treatment, and (3) flower seed oil without ozone as a placebo group. Positive results were observed for 100% of the patients in the ozone group within 5 to 7 days. No changes occurred for the placebo group, and for the group receiving the conventional treatment, the changes were smaller and occurred later than in the ozone group.4 Bailey has indicated that the reaction of ozone with vegetable oils such as olive or sunflower oils occurs exclusively within the carbon-carbon double bonds that are present in unsaturated fatty acid.10 That reaction produces several oxygenated compounds, including hydroperoxides, ozonides, aldehydes, peroxides, deperoxides, and polyperoxides. Those oxygenated compounds also could be responsible for the wide biological activity of ozonized vegetable oils.

The yield of oxygenated compounds from unsaturated oils depends on the reaction conditions, such as the type of medium where the reaction takes place, the presence of additives, the reaction temperature, the type of reactor, the agitation of the reaction mixture, and the applied ozone doses.6,10,11 A study by Sadowska et al12 confirmed Bailey’s10 findings that the reaction of ozone with vegetable oils occurs almost exclusively with the carbon-carbon double bounds present in unsaturated fatty chains. The viscosity measurements in that study showed that viscosity is a function of the dimension and orientation of molecules. The decrease in the degree of unsaturation and the increase in the molar mass both contributed to the increase in viscosity of the ozonated oils.

Because ozone itself does not penetrate cells but immediately reacts with polyunsaturated fatty acids, its effects should be the result of oxidative reaction. For that reason, ozonated oils could be a way to deliver ozone messengers to tissue. Valacchi et al13 concluded that treatment with moderately ozonated sesame oil provided faster rate of wound closure in the first 7 days than did treatment with an oil containing either a lower or a higher peroxide value and even provided a faster rate than did the controls.

The limitations of the present study are technical problems related to maintaining the ozonated olive oil in a cold place, not having placebo group, and not making the study blinded. The current research team recommends the performance of a study to evaluate the rate and time of infection after treatment with ozone and to evaluate the side effects accurately. Repeating the current study with a placebo group could help to determine the efficacy of ozone in the treatment of candida vaginitis more accurately. Further, the research team recommends the performance of a new study that repeats the culture for vaginal candidiasis at several, frequent, consecutive points after starting the treatment, to determine better the required period for treatment with ozone. Moreover, the team also suggests the performance of a study about the efficacy of ozone for patients with an Tara—Olive Oil and Clotrimazole Cream for Vulvovaginal Candidiasis

infection that is tolerant to antifungal treatments, both oral and local.

Moureu et al14 found that the antibacterial activity of oils ozonized with water was better than the one with the oils ozonized alone. The current research team also suggests that future studies use water within ozonated oil to determine whether it enhances the antifungal activity.

CONCLUSIONS Ozone appears to be as effective as clotrimazole for treatment of Candida vulvovaginitis both clinically (ie, resulting in reduced symptoms) and in terms of a laboratory culture. Because the efficacy of ozone has been confirmed in the current study, because recent reports have indicated the tolerance of the infection to new antifungal drugs, because ozone is a common drug that is widely used in most developed countries, and because no side effects have been recorded so far, the current research team suggests the introduction of ozone as an alternative and cost-effective treatment.

REFERENCES 1. Berek JS. Berek & Novak’s Gynecology. 15th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011.

2. Shaschova NM, Kachalina TS, Nevmjatullin AL. Application of ozone therapy in complex treatment of inner female genital inflammatory diseases. In: Proceedings from the 12th World Congress of the International Ozone Association; May 15-18, 1995; Lille, France.

3. Rodriguez BR, Valdés L, Menéndez S, Gómez M. Application of ozonized oil as a treatment of vulvovaginitis in patients intolerant to carbohydrates. In: Proceedings of the 1st Iberolatinoamerican Congress on Ozone Applications; October 31-November 3, 1990; Havana, Cuba.

4. De las Cagigas T, Bestard V, Menéndez S, Gómez M, Eng L. Use of the ozonized oil on patients with vulvovaginitis. In: Proceedings of the 1st Iberolatinoamerican Congress on Ozone Applications; October 31-November 3, 1990; Havana, Cuba.

5. Morris G, Gómez M, Menéndez S, Correa M, Pérez N, Fernández LA. Treatment with ozone in gynecology. In: Proceedings of the 1st Iberolatinoamerican Congress on Ozone Applications; October 31-November 3, 1990; Havana, Cuba.

6. Díaz MF, Hernández R, Martínez G, et al. Comparative study of ozonized olive oil and ozonized sunflower oil. J Braz Chem Soc. 2006;17(2):403-407.

7. Minouchehr N. A Comparison of Ozonated Olive Oil and Clotrimazole Cream on Three Candida Species (Albicans, Glabrata and Krusei) on the Culture Medium [dissertation]. Mashhad, Iran: Mashhad University of Medical Sciences; 2010.

8. Rajabi R. A Comparative Study on Ozonated Gel and Metronidazole in the Treatment of Trichomonas Vaginitis [dissertation]. Mashhad, Iran: Mashhad University of Medical Sciences; 2008.

9. Marckland C. The Therapeutical Applications of Hydrozone and Glycozone.

18th ed. New York, NY: Walter Gortz; 1904:183-186.

10. Bailey PS. Ozonolysis of olefins: Introduction, initial ozone attack and adduct, the peroxidase products. In: Bailey PS, ed. Ozonation in Organic Chemistry: Olefinic Compounds. New York, NY: Academic Press; 1978.

11. Pryor WA, Wu M. Ozonation of methyl oleate in hexane, in a thin film, in SDS micelles, and in distearoylphosphatidylcholine liposomes: Yields and properties of the Criegee ozonide. Chem Res Toxicol. 1992:5(4):505-511.

12. Sadowska J, Johansson B, Johannessen E, Friman R, Broniarz-Press L, Rosenholm JB. Characterization of ozonated vegetable oils by spectroscopic and chromatographic methods. Chem Phys Lipids. 2008;151(2):85-91.

13. Valacchi G, Lim Y, Belmonte G, et al. Ozonated sesame oil enhances cutaneous wound healing in SKH1 mice. Wound Repair Regen. 2011;19(1):107-115.

14. Moureu S, Violleau F, Ali Haimoud-Lekhal D, Calmon A. Ozonation of sunflower oils: Impact of experimental conditions on the composition and the antibacterial activity of ozonized oils. Chem Phys Lipids. February 2015;186:79-85.

ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 49

ORIGINAL RESEARCH

Effects of Balsamodendron mukul Gum Resin Extract on Articular Cartilage in Papain-induced Osteoarthritis Jayanand Manjhi, PhD; Maneesh Gupta, PhD; Anvesha Sinha, PhD; Beena Rawat, MPhil; Durg V. Rai, PhD

ABSTRACT Context • Osteoarthritis (OA) is one of the most prevalent chronic diseases of the musculoskeleton, causing functional disability among older adults. Management of OA includes conventional pharmacological treatments consisting primarily of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, physiotherapy, and surgical procedures. The medications are not ideal therapeutic agents; NSAIDs in particular can cause serious side effects.

Objective • The study was conducted to investigate the effects of Balsamodendron mukul (BDM) gum resin extract on cartilage damage and microstructural changes in the subchondral bone of rats with papain-induced, osteoarthritic knee joints.

Design • The authors designed a parallel randomized, controlled study to examine the effects of 3 concentrations of BDM on OA in a murine model.

Setting • The present study was undertaken at the research laboratory, Faculty of Biological Engineering, Shobhit University (Modipuram, Meerut, India).

Intervention • OA was induced by intra-articular injections of 0.2 mL of 4% papain solution and 0.1 mL of 0.03 M cysteine through the patellar ligament using a 26-gauge, 1.27-cm needle. The rats in the sham group received same volume of isotonic sodium chloride solution. The rats were divided into 6 groups : (1) control group—fresh rats, with ages and genders similar to those of the other groups but with no induction of OA and no treatments; (2) sham group—rats receiving a sham

Jayanand Manjhi, PhD, is an associate professor; Anvesha Sinha, PhD, is a scholar; Beena Rawat, MPhil, is an assistant professor; and Durg V. Rai, PhD, is professor; all are in the Faculty of Biological Engineering at Shobhit University in Modipuram, Meerut, India. Maneesh Gupta, PhD, is an assistant professor in the Department of Botany at Vardhaman College in Bijnor, Uttar Pradesh, India.

50 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

induction of OA using an intra-articular injection of saline of the same volume as the papain given to all OA rats but no treatments; (3) OA group—rats induced with OA but receiving no treatments; (4) OA + BDM (10%) group—rats induced with OA that received a 10% dose of BDM; (5) OA + BDM (20%) group—rats induced with OA that received a 20% dose of BDM; and (6) OA + BDM (40%) group—rats induced with OA that received a 40% dose of BDM. Rats in the treatment groups were fed their respective doses of BDM extract for 30 d.

Outcome Measures • The articular cartilages from the knee joints and epiphyseal bones of the femur and tibia were extracted from the right- and left-side limbs to perform the biochemical, microarchitectural, and histological analyses.

Results • The total protein and collagen content of the articular cartilage of the knees were significantly higher in all treated groups when compared with the OA group of rats. The histological analysis revealed a thicker cartilage and a higher trabecular density of the subchondral bone (epiphyseal bone) in BDM-treated rats.

Conclusions • The oral dose of BDM gum resin extract was shown to relieve OA pain, regenerate the cartilaginous matrix, and increase the subchondral bone components.

On the basis of the findings, the research team suggests that the BDM gum resin extract may be used for therapeutic interventions for reversal of OA and reduction in its related inflammatory pain. (Altern Ther Health Med. 2016;22(4):50-58.)

Corresponding author: Jayanand Manjhi, PhD E-mail address: jayanand@shobhituniversity.ac.in

Manjhi—Therapeutic Activity of BDM in Osteoarthritis

O

steoarthritis (OA) is one of the most prevalent chronic diseases of the musculoskeleton, causing functional disability among older adults. The current concept holds that OA involves the entire joint organ, including the subchondral bone, menisci, ligaments, periarticular muscle, capsule, and synovium.1 Its most prominent feature is the progressive destruction of articular cartilage, which results in impaired joint motion, severe pain, and structural and functional failure of synovial joints.2 The onset and progression of the disease depends on various factors, such as obesity, joint injury, metabolic diseases, bone and joint malformation, genetic factors, and nutritional factors.3-6 In individuals older than 55 years, the incidence of OA is higher among women than men. The incidence ratio for OA of the knee joint of females to males is 1.7:1, and the erosive OA ratio is approximately 12:1.7 OA is characterized by a progressive loss of articular cartilage, leading to inflammation, subchondral bone formation, and development of osteophytes at the joint margins. A prominent histological feature of cartilage in OA is a decrease in the number of chondrocytes, which are normally responsible for repair and regeneration of articular cartilage.8,9 Moreover, a number of studies have demonstrated that the integrin-mediated interaction between chondrocytes and collagen architecture is vital for cartilage formation.10,11 In OA, a direct relationship exists between the level of active collagenase and the collagen present in the articular cartilage, and collagen release and collagenase activity are driven by matrix metalloproteinase (MMP) 1, MMP8, and MMP13.12,13 The development of OA is highly dependent on the antioxidant system. MMPs and reactive oxygen species (ROS) are the main causative agents of cartilage disintegration.

Articular chondrocytes express collagenase—MMP1, MMP8, MMP13, and MMP14—and cathepsin K, a cysteine protease, all of which are capable of breaking the triple-helical region of type 2 collagen at specific and distinct sites.14-18 Management of OA includes conventional pharmacological treatments consisting primarily of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, physiotherapy, and surgical procedures.

Although the medications often relieve symptoms, they are not ideal therapeutic agents. NSAIDs in particular can cause serious side effects, including peptic ulcers and hepatic or renal failure. Neither of the classes of medication prevents or delays the progression of OA.19,20 However, to date, no disease-modifying drugs with low side effects are available for the treatment of OA, which represents a major hole in the support of clinical needs. It is the current research team’s objective to address the need for alternatives and to propose an herbal therapeutic intervention for OA that is natural and cost effective, without any side effects.

Commiphora mukul (or Commiphora wightii) is a small tree of the Burseraceae family that is indigenous to India.

C mukul grows wild in the semiarid Indian states of Rajasthan, Gujarat, Karnataka, Rajasthan, and Mysore and in Afghanistan, Arabia, and northeast Africa in rocky, dry Manjhi—Therapeutic Activity of BDM in Osteoarthritis

areas.21-24 It has been used to cure several ailments, including hypercholesterolemia, atherosclerosis, rheumatism, and obesity, for several thousands of years and is mentioned in the Vedas, the holy scriptures of India for treating human illnesses.25 Gum guggul (resin) is the oleoresin of the plant C mukul.

Crude gum guggul has been found to contain 2% guggulsterones (GUGs). GUG has been used in Ayurvedic medicine for centuries to treat a variety of ailments.26 Moreover, an oral dose of the Balsamodendron mukul (BDM) gum resin extract has the potential to relieve osteoarthritic pain, regenerate the cartilaginous matrix, and increase subchondral bone components.27 Among the various animal models that are available for OA studies in rats are an ideal animal model that are tractable, inexpensive, and easy to house and manage and large enough to allow multiple analyses. Moreover, they provide a similar physiology to humans.28 The present work was primarily focused on the evaluation of a plant product that is capable of preventing, slowing, or reversing the structural and pathological alterations in osteoarthritic joints. The study aimed to evaluate the chondroprotective effects of the BMD gum resin extract, a purified compound of C mukul, against papain-induced knee arthritis in rats.

METHODS Animals To carry out the present investigation, 30 albino male Wistar rats of 200 to 250 g were procured from the Central Animal House of Shobhit University (Modipuram, Meerut, India) and randomly segregated in 6 groups, namely control, sham, OA, OA + BDM (10%), OA + BDM (20%), and OA + BDM (40%). The animals were kept in polypropylene cages with 5 animals per cage. For acclimatization before and during the experimental period, they were maintained under standard laboratory conditions at 26 ± 2°C and 44% to 56% relative humidity, with a light and dark cycle of 10 and 14 hours, respectively, for 5 days. The animals were provided with a standard pellet diet for rodents (Aashirwad, Meerut, Uttar Pradesh, India), and the food was withdrawn 18 hours before the experiment, although water was allowed ad libitum.

All experiments were performed in the morning according to the current guidelines for the care of laboratory animals and the institutional ethical guidelines for investigations of experimental pain in conscious animals.29All protocols for the animal procedures were reviewed and approved by the institutional animal ethics committee, approval letter No. 46/1219/ac/Su/IAEC/2012, of Shobhit University and followed by the Committee for the Purpose of Control and Supervision on Experiments on Animals in India.

Procedures Induction of OA. OA was induced in both knee joints of the rats by an intra-articular injection of a solution of 0.2 mL of 4% papain (Shri Ganesh Industrial Enzymes, Burhanpur, ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 51

Madhya Pradesh, India), with 0.1 mL of 0.03 M cysteine (Merck, Kenilworth, NJ, USA) used as an activator. Injections were given through the patellar ligament of both knees using a 26-gauge, 1.27-cm needle. The intra-articular injections were repeated on the fourth and seventh days.30 The general health of the animals was monitored as per the ethical guidelines of the research team’s institution.

Pellet Formation. The pellets containing the treatments were made by kneading 10 g of the BDM gum resin extract into wheat flour, using a Soxhlet apparatus (Perfit India, Ambala, Haryana, India), with the total weight of the mixture being 100 g. The kneaded flour was divided into 100 pellets, with each pellet 1 g in weight with 0.1 g of the gum resin. The rats in groups other than the intervention groups were fed with same number of wheat flour pellets of the same weights but without the BMD. Sample Preparation. Rats in all groups were sacrificed on day 50 by decapitation under deep-ether anesthesia. Then the lower-limb bones (ie, the femurs and tibias with intact joints) were freed from the soft tissues on both sides.

Thereafter, the bones were kept in solution of 10% formaldehyde and stored at -20°C for further analysis.

Biochemical Cartilage Sample Preparation. The epiphyseal and articular cartilages were extracted from the knee joints and from the articulated femur and tibia bones on the right side. The extracted cartilage samples were freezedried and milled down for biochemical assays (ie, totalprotein estimation and type 2 collagen).

Histological Bone Sample Preparation. The left limb joints were dissected, with all soft tissues, and fixed with paraformaldehyde/lysine/periodate (PLP) fixative, a 2% paraformaldehyde solution containing 0.075 M of lysine and 0.01 M of sodium periodate, pH 7.4, and stored at 4°C for 24 hours for the histological assays.

Interventions In the delivery of the BDM intervention, 3 regimens were used: 10%, 20%, and 40% of the BDM gum resin extract. The rats in the 10% group received 1 pellet with 0.1 g of the gum resin and those in the 20% group were given 2 pellets with 0.1 g in each pellet. Similarly, those in the 40% group received 4 pellets containing 0.1 g of gum resin in each pellet. Rats in the intervention groups were fed their respective doses of BDM extract for 30 days.

The rats were divided into 6 groups: (1) control group— fresh rats, with ages and genders similar to those of the other groups but with no induction of OA and no treatments; (2) sham group—rats receiving a sham induction of OA using an intra-articular injection of saline of the same volume as the papain given to all OA rats but no treatments; (3) OA group—rats induced with OA but receiving no treatments; (4) OA + BDM (10%) group—rats induced with OA that received the 10% dose of BDM; (5) OA + BDM (20%) group—rats induced with OA that received the 20% dose of BDM; and (6) OA + BDM (40%) group—rats induced with OA that received the 40% dose of BDM. 52 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

Outcome Measures Biochemical Analysis in Knee Joints Cartilages. The protein content was measured to analyze the extracellularmatrix formation and resorption after induction of OA with papain and cysteine. For protein estimation, 1 mL of chilled 1-M acetic acid was added to the tissue samples of the lyophilized cartilage for each 50 mg of the samples, yielding a final pH of 3.6 to 4.2. The mixture was shaken vigorously and allowed to stand on ice for 2 hours. The sample was then centrifuged at 600× g for 10 minutes, and the supernatant was removed by pipette and stored. The precipitate was then resuspended into fresh 1 M of acetic acid and centrifuged as was previously done to obtain the supernatant.

The 2 supernatants were combined and precipitated with 2.6 M of ammonium chloride (NH4Cl), pH 7.4, by stirring for 24 hours and then centrifuged at 15 000 g for 45 minutes.

The collected precipitates were then frozen at -20°C and stored at 4°C. Thereafter, the protein estimation was carried out by the Lowry’s method.31 Bovine serum albumin (BSA) was used as a standard for preparation of the standard graph with concentrations in a range from 0 μg to 100 μg; the 0 μg served as a blank. The concentrations of protein were calculated by an equation that was obtained from the standard curve (R2 = 0.980). The absorbance was read at 660 nm on an ultraviolet (UV) spectrophotometer (Shimadzu UV-1800, Shimadzu Analytical Pvt Ltd, New Delhi, India).

Biochemical Analysis of Collagen. The estimation of collagen was done to analyze the collagenous microstructural changes in diseased as well as the treatment stages. The extraction of the collagen from the lyophilized cartilage powder was done with 25%-saturated ammonium sulfate ([NH4]2SO4), using constant agitation in the presence of a proteinase inhibitor for 24 hours at 4°C. The solution was subjected to centrifugation at 15 000 g for 45 minutes, and the collagen precipitates were dissolved in 2 mL of 0.5-M acetic acid to make stock solution of each test sample. Then collagen standards were made with purified collagen from rat tail tendons (Sigma-Aldrich, Bengaluru, Karnataka, India). One-hundred mL of a solution of 1% Sirius Red (Direct Red 80, Sigma-Aldrich) was prepared in 0.5 M of acetic acid and was preserved for preparation of standard solutions and test samples.

The calibration graph was prepared using aliquots of a standard solution of collagen, and absorbance of the elution was determined by spectrophotometer (Shimadzu UV-1800, Shimadzu Analytical Pvt Ltd) at a 540-nm wavelength. The obtained optical densities were interpolated in a curve of absorbance. The concentration of collagen was calculated in test samples, with the help of an equation obtained by the calibrated graph (R2 = 0.99).32 Histological Analysis of Knee Joints. Histological assessment of OA is one of the prime facets for determining presence, extent, and severity of OA. As mentioned earlier, the left limb joints were dissected out with all soft tissues and fixed for histological assays.33 Manjhi—Therapeutic Activity of BDM in Osteoarthritis

Manjhi—Therapeutic Activity of BDM in Osteoarthritis

Abbreviations: BDM, Balsamodendron mukul; OA, osteoarthritis; ANOVA, analysis of variance.

The P values of the differences between the groups of animals (ie, control group vs sham group, control group vs OA group, control group vs OA + BDM [10%] group, control group vs OA + BDM [20%] group, and control group vs OA + BDM [40%] group) were calculated using 1-way ANOVA.

a

.0013 .012 .061 16.1 ± 0.89 Total collagen

16.86 ± 1.14

10.58 ± 1.40

12.22 ± 0.75

12.88 ± 0.76

14.63 ± 1.23

.27

7.38 × 10-5

.05

4.82 × 10-5 .0007 .03 .93 .004 .77 217.71 ± 4.7 211.02 ± 6.27 201.83 ± 7.96 189.93 ± 6.25 217.13 ± 13.92 Total protein

219.53 ± 0.79

OA vs 40% BDM OA vs 20% BDM OA vs 10% BDM Control vs 40% BDM

P Valuesa

Control vs OA Control vs Sham OA + 40% BDM OA + 20% BDM OA + 10% BDM OA Sham

Total Protein Estimation For the OA + BDM (10%), OA + BDM (20%), and OA + BDM (40%) groups, the protein contents were 201.83 ± 7.96 μg/mg, 211.02 ± 6.27 μg/mg, and 217.02 ± 4.79 μg/mg, respectively, versus those for the OA group at 189.93 ± 6.25 μg/mg (Table 1 and Figure 1). The protein concentration in the articulating joint had increased significantly for all intervention groups after treatment with BDM gum resin extract for 30 days as compared with that of the OA group: OA + BDM (10%), P = .03; OA + BDM (20%), P = .0007; and OA + BDM (40%), P = 4.82 × 10-5. The protein content in the articulating joint of the OA group was significantly lower (P = .004) than that of the control group at 217.13 ± 13.92 μg/mg. No significant differences existed between the control group and the OA + BDM (40%) group or between the control group and the sham group at 219.53 ± 0.79.

Control

RESULTS For the rats in the OA groups, the induction of OA caused a significant discrepancy in locomotion leading to a progressive, accelerated loss of mobility.

Measures

Statistical Analyses The resulting values were analyzed statistically by mean ± standard deviation (SD) or median with range and 1-way analysis of variance (ANOVA) method, which demonstrated the relative variations in the P values of the treatment groups with respect to OA group and control group.

Table 1.Effects of BDM Gum Resin Extract on Total Protein and Total Collagen in Femurs and Tibias

Decalcification of Bone Samples. OA is commonly associated with the significant loss of calcium from the osteoarthritic bones. It is primarily due to this reason the decalcification status of bones was investigated.

After fixation, the samples were washed for 12 hours at 4°C in each of the following series of 0.01-M phosphate-buffered saline (PBS), pH 7.5, that contained different concentrations of glycerol (5%, 10%, and 15%). The samples were then decalcified in a 10% formic acid in the ratio of 1:20 (v/v) for 6 to 8 days. To remove the formic acid, the decalcified tissues were then washed at 4°C for 12 hours in successive solutions of 15% sucrose and 15% glycerol in PBS, 20% sucrose and 10% glycerol in PBS, 20% sucrose and 5% glycerol in PBS, 20% sucrose in PBS, 10% sucrose in PBS, 5% sucrose in PBS, and 100% PBS. Synovial-joint Morphology. OA has been known to severely affect the histopathology of the synovial joints. The knee-joint samples were dehydrated in graded ethanol, cleared in chloroform, and embedded in a paraffin block. The blocks were then placed in a microtome, and 5-μm longitudinal sections were obtained. Tissue sections were then floated in a water bath at 48°C and collected on glass slides that had been precoated with poly-L-lysine. Sections were stained with hematoxylin and eosin to determine the morphological features of the synovial joints.

Histochemical Demonstration of Collagen. The histochemical status of collagen was determined to visualize the microstructural modifications of cartilage in diseased and treated bone samples. The decalcified, paraffinencased bone sections were dewaxed and stained with picrosirius red (ie, in a solution of 1% Sirius Red) (Sigma-Aldrich) or Direct Red 80 in a saturated aqueous solution of picric acid. After that process, they were washed twice with acidified water. The water was then physically removed from the slides by blotting with filter paper and air drying. Then the bone sections were again dehydrated 3 times with 100% ethanol, cleared in xylene, and mounted in a resinous medium. Those slides were observed under bright-field microscopy.

ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 53

Figure 1. Protein Content (μg/mg) of Articulated Femur and Tibia Bones 250

Figure 2. Collagen Content (mg) of Articulated Femur and Tibia Bones 250

c

c

b b a

b

200 Control

150

Sham OA

100

OA + BDM (10%) OA + BDM (20%)

50

Collagen Content (mg)

Protein Content (μg/mg)

200

OA + BDM (40%)

b a

Control 150

Sham OA

100

OA + BDM (10%) OA + BDM (20%)

50

0

OA + BDM (40%)

0 Groups

Groups

a

Statistically significant reduction in protein content for the OA group as compared with the control group. b Statistically significant increases in protein content for the intervention groups as compared with the OA group. c No significant difference in protein content for the OA + BDM (40%) group as compared with the control group.

a

Abbreviations: OA, osteoarthritis; BDM, Balsamodendron mukul.

Abbreviations: OA, osteoarthritis; BDM, Balsamodendron mukul.

Collagen Estimation For the OA + BDM (10%), OA + BDM (20%), and OA + BDM (40%) groups, the collagen content were 12.22 ± 0.75 mg/g, 12.88 ± 0.76 mg/g, and 14.63 ± 1.23 mg/g, respectively, versus that of the OA group at 10.58 ± 1.40 mg/g (Table 1 and Figure 2). The collagen concentration in the articulating joint had decreased significantly for all intervention groups after treatment with BDM gum resin extract for 30 days as compared with that of the OA group: OA + BDM (10%), P = .05; OA + BDM (20%), P = .012; and OA + BDM (40%), P = .0013. The collagen content in the articulating joint of the OA group was significantly lower (P = .7.38 × 10-5) than that of the control group at 16.1 ± 0.89 mg collagen. No significant differences existed between the control group and the OA + BDM (40%) group or between the control group and the sham group at 16.86 ± 1.14.

histological status of the articulating bone as compared with the sham group. The effects of BDM (40%) restored the initial appearance of the articulating bone, as observed in the control group (Figure 3).

Histological images of the articulating joint in the control group showed a thick hyaline-cartilage lining, which was little attenuated in the sham group but was totally damaged in the OA group. Moreover, the OA group showed fragmentation in the hypophyseal zone of the femur bone.

The BDM treatment demonstrated the reversal of OA. The OA + BDM (10%) group showed the development of a thin lining between the articulating bones, which was even more connected and thick in the case of the OA + BDM (20%) group. In the OA + BDM (40%) group, the lining was as good as that of the control group (Figure 4).

Immunohistochemical Analysis of the Joint Histological images of the joints in the control group showed a well-defined margin of articulating bone and a good arrangement of cancellous bones. On the other hand, the OA group’s joints showed a high amount of damage in the articulating bones. The cancellous bone of the femur hypophysis shows resorption of cancellous bone as well as of the lining cartilage.

The epiphysis of the tibia was also damaged, and shrinkage of the articulating bone part took place.

BDM induced the reversal of joint damage at the articulating area of the bone. The OA + BDM (10%) group showed a small increase in the cancellous bone and cartilage lining of both the adjoining part of the bone, whereas the OA + BDM (20%) and OA + BDM (40%) groups showed an enhancement of the cancellous bone development and of the 54 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

Statistically significant reduction in collagen content for the OA group as compared with the control group. b Statistically significant decreases in collagen content for the intervention groups as compared with the OA group. c No significant difference in collagen content for the OA + BDM (40%) group as compared with the control group.

Immunohistochemical Analysis of Collagen The structural information obtained from the picrosiriusred-stained section displayed a heterogeneous structure with a surface defect. In the sham group, the collagen staining exhibited the damage to cartilage in the surface covering of the articulating femur and tibia bones, with the gap between the bones increasing upon the laminar resorption of the interbone cartilage, whereas in the bones of the control and sham groups, the collagen fiber was well distributed throughout the fret as well as on the covering cartilage. The damage was almost reversed in the OA + BDM (40 %) group’s treatment (Figure 5).

Immune-histopathological, zoomed images using picrosirius revealed the dissolution of the cartilage lining in the laminar region as well as the subchondral mesenchymal part of the bone. The lamina and the tibial hypophyseal lining Manjhi—Therapeutic Activity of BDM in Osteoarthritis

Figure 3. Photomicrographs Using an HE Stain That Show Rats’ Knee Joints at a 1000-μm Resolution

Figure 4. Photomicrographs Using an HE Stain That Show Rats’ Knee Joints at a 100-μm Resolution

A. Control

B. Sham

C. OA

A. Control

B. Sham

C. OA

D. OA + BDM (10%)

E. OA + BDM (20%)

F. OA + BDM (40%)

D. OA + BDM (10%)

E. OA + BDM (20%)

F. OA + BDM (40%)

Note: Figure 3C shows the damage in the articulating joint margin and in the cancellous bone of a rat in the OA group, whereas the bone was reformed after treatment for a rat in the OA + BDM (40%) group (Figure 3F).

Note: Figure 4C shows the damage in the thick hyaline cartilage lining of a rat in the OA group, whereas the lining was reformed after treatment for a rat in the OA + BDM (40%) group (Figure 4F).

Abbreviations: HE, hematoxylin and eosin; OA, osteoarthritis; BDM, Balsamodendron mukul.

Abbreviations: HE, hematoxylin and eosin; OA, osteoarthritis; BDM, Balsamodendron mukul.

Figure 5. Photomicrographs Using a Sirius Stain That Shows Rats’ Knee Joints at a 1000-μm Resolution

Figure 6. Photomicrographs Using a Sirius Stain that Show Rats’ Knee Joints at a 100-μm Resolution

A. Control

B. Sham

C. OA

A. Control

B. Sham

C. OA

D. OA + BDM (10%)

E. OA + BDM (20%)

F. OA + BDM (40%)

D. OA + BDM (10%)

E. OA + BDM (20%)

F. OA + BDM (40%)

Note: Figure 5C shows the damage to cartilage in the surface covering of the articulating femur and tibia of a rat in the OA group, whereas the cartilage was reformed after treatment for a rat in the OA + BDM (40%) group (Figure 5F).

Note: Figure 6C shows the damage to the cartilage lining in the laminar region as well as in the subchondral mesenchymal part of the bone in a rat in the OA group, whereas the lining was reformed after treatment for a rat in the OA + BDM (40%) group (Figure 6F).

Abbreviations: OA, osteoarthritis; BDM, Balsamodendron mukul.

Abbreviations: OA, osteoarthritis; BDM, Balsamodendron mukul.

in the OA group were completely absent. Collagen fibers were very prominent in the control and sham groups. A reversal of OA by formation of collagen in the lamina and in the articulating part of the bone (femur and tibia) was found due to BDM treatment. In the OA + BDM (10%) group, it appeared in a small amount, but in the OA + BDM (40%) group, the collagen deposition in the lamina as well in the cancellous part of the articulating bone was much more prominent (Figure 6).

DISCUSSION The present study was proposed to investigate the therapeutic efficiencies of a BDM extract in a papain-induced animal model for OA. The study found that the induction of OA caused a significant discrepancy in locomotion leading to a progressive, accelerated loss of mobility.

The study further aimed to ascertain the expediency of using a BDM gum resin extract to treat the detrimental damages to OA knee joints. It has been used in Ayurvedic medicine for more than 2000 years to heal arthritic inflammation and to

Manjhi—Therapeutic Activity of BDM in Osteoarthritis

ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 55

support the antioxidant defense system.34-36 It has been reported that the gum extract of C mukul is GUG,37 which has been shown to have significant antioxidant properties that inhibit the formation of reactive oxygen species (ROS).38 Earlier studies have revealed that GUG has striking effects on the interleukin (IL) β-activated, matrix metalloprotein in synoviocytes. Those studies have shown the inhibition ability of GUG in IL-1β-mediated production of matrix metalloproteinase.39,40 Chander et al38 and Lee et al40 collectively have suggested that GUG is a useful inhibitor of OA progression. It has been recently shown to antagonize the farnesoid X receptor and to decrease the expression of bile, acid-activated genes.

Because activation of nuclear factor κ-light-chainenhancer of activated B (NF-κB) cells has been closely linked to inflammatory diseases and is affected by GUG, the BDM extract may have a significant therapeutic role as a drug that modifies osteoarthritic disease.41,42 With those plausible revelations in mind, the current research team fed the osteoarthritic rats a BDM-gum-extract pellet for 30 days and observed the biochemical and histological modifications.

The current research team has evaluated the efficacy of the BMD extract on papain-induced arthritis by measuring total protein. Scientists have found an important link between the total protein of joint cartilage matrix and OA. They have observed that the total protein declines during development of OA.43 The development of OA through papain induces structural changes in joints because of its proteolytic nature, and histopathologically, the OA is similar to human OA.44-48 According to the team’s observations, the progressive deterioration of cartilage was found in the OA group, and the total protein content was significantly lower in that group compared with the control group. After treatment with the BDM gum resin extract, the total protein content was highest in the OA + BDM (40%) group of rats, with all intervention groups— OA + BDM (10%), OA + BDM (20%), and OA + BDM (40%)— showing significant increments in protein content.

After induction of inflammatory OA by papain, the current research analyzed the biochemical and histochemical properties of the knee joints, in which a significant, detrimental decrease in type 2 collagen to 10.58 ± 1.40 mg/g in the OA group was observed compared with the results for the control group at 16.1 ± 0.89 mg/g (P = 7.38 × 10-5). Type 2 collagen is the major structural component of the articular cartilage, and it is composed of 3 identical α chains that form the collagen fibril. The mechanical property and tensile strength of cartilage depend on the amount of type 2 collagen and on the integrity of the fibril with orientation.49 The type 2 collagen content at the joint cartilage was also found to be increased significantly in the 3 intervention groups as compared with the OA group. The results are in agreement with Sumantran et al,50 who observed that the Triphala guggul extract has a collagenase-type-2 inhibitory activity. Those researchers have also found hyaluronidase and gelatinase inhibitory activity for the Triphala formulation that contains C mukul resin, finding it promising for cartilage retrieval.

56 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

The musculoskeletal modifications in the rats’ joints, after OA induction and treatment, were monitored by histological analyses. Figure 3C shows the loss in articular cartilage and subchondral bone in the OA group of rats. It also shows the cancellous bone loss in the hypophyseal part of the femur and the epiphyseal part of the tibia. An increasing concentration of BDM gum extract showed the progressively enhancing, therapeutic effect on the histological architect (Figure 3D, Figure 3F).

In addition to improving cancellous bone and cartilage, the BDM extract expedited the regeneration of hyaline cartilage onto the articulating joint bone. Articular cartilage contains 5% chondrocytes by volume, and the remaining cartilage is occupied by an extensive extracellular matrix. The structural backbone of the matrix is collagen fiber, of which the chief component is type 2 collagen,51 for which the cleavage by matrix MMP results in the onset of the disease.

GUG has a positive effect through interleukin and suppresses the proteolytic nature of the enzyme.

The present findings thus open the door to evaluating the effectiveness of an herbal compound with negligible side effects in preventing the increased development of an existing ailment or new cases for OA. With the ongoing aging of the population worldwide, OA is a disease that will affect increasing numbers of people, leading to an increasing personal as well as socioeconomic burden. Until now, the only nonsurgical measures that are available to treat OA-related symptoms have been pain medication and physical therapy.52 If those conservative measures prove to be insufficient, the only remaining possibility to restore joint function and relieve pain is joint-replacement surgery.

Pharmaceutical treatment is limited by the inability of prescribed medications to alter the disease’s outcome.

Moreover, the prescribed NSAIDs have limited efficacy and are associated with a number of potentially serious toxicities, including gastrointestinal bleeding and increased incidence of ischemic cardiovascular events. Further, the use of natural products and nutraceuticals in treatment of OA is common.

Various papers have reviewed the application of different nutraceuticals, including glucosamine, chondroitin, and collagen hydrolysate, for the disease modification of OA.53-55 However, the uses of those natural products are not standardized with respect to symptomatic and structural alterations.

The histological images from the study show the loss in articular cartilage, damage to subchondral bone joints, and cancellous bone loss in the hypophyseal part of the femur and in the epiphyseal part of tibia. The current research team has found that treatment of OA with BDM gum resin extract seems to be very promising, because with an increasing concentration of the gum resin extract, the previously mentioned parameters were restored. The BDM (40%) resin extract proved to possess anabolic activity in reformation of the cartilaginous, extracellular matrix with a significant decrease in pathogenic pain after oral intervention. The subchondral bone is closely associated with cartilage Manjhi—Therapeutic Activity of BDM in Osteoarthritis

formation, and it provides a cushioning effect on the bone covering of joint. When cartilage gets degenerated in OA, the change affects the cancellous bone of the joint as well. In the current study, it was observed that the cancellous bone formation had increased and the compactness was enhanced, thereby decreasing porosity.

Identification of new therapeutic agents that reverse, slow down, or stabilize the pathologic changes is an important area in OA research. The current study searched for an existing remedial measure for OA that is cost effective, uses indigenous herbals, and has no side effects from the intervention. The current therapeutic approach of OA is to alleviate the symptoms and preserve function. The present study demonstrated an antiosteoarthritic effect for the BDM gum resin extract.

The current study strongly advocates the application of BDM extract as an effective therapeutic substitute of the commercially available medication; nevertheless the status of a preclinical investigation limits the colossal appliance of the herb for OA reversal, which needs further clinical research and development of suitable drug formulation using BDM extract.

CONCLUSIONS The oral dose of BDM gum resin extract was shown to relieve OA pain, regenerate the cartilaginous matrix, and increase the subchondral bone components. The current research team concludes that the results indicate that an enormous possibility exists to exploit the therapeutic efficacies and potentialities of BDM gum resin extract for OA treatment.

The current work was confined to preclinical observations, which can serve as a base for future clinical research that might lead to more advanced and accurate, dose-dependent effects for BDM gum resin extract on OA, paving the way for an effective, natural intervention for OA treatment.

ACKNOWLEDGEMENTS The research team offers thanks to Shobhit University (Meerut, India) for providing all the necessary laboratory facilities.

AUTHOR DISCLOSURE STATEMENT The research team declares that no competing interests exist.

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Manjhi—Therapeutic Activity of BDM in Osteoarthritis

ORIGINAL RESEARCH

Smartphone-based Music Listening to Reduce Pain and Anxiety Before Coronarography: A Focus on Sex Differences Stéphane Guétin, PhD; Luc Brun, MD; Maelle Deniaud; Jean-Michel Clerc, MD; Julian F. Thayer, PhD; Julian Koenig, DrScHum

ABSTRACT Background • Music Care is a smartphone-based application providing a musical intervention for the management of pain and anxiety in a clinical setting.

Coronarography is a medical procedure frequently associated with examination anxiety.

Objectives • The study intended to perform an initial evaluation of the application for use with patients undergoing a coronarography.

Design • The research team performed an uncontrolled, observational study.

Setting • The study took place at Nouméa General Hospital in Nouméa, New Caledonia, France.

Participants • Participants were 35 patients, 17 women and 18 men, who were undergoing a coronarography between November 2010 and April 2011 at the Nouméa General Hospital.

Intervention • Participants listened to a standardized musical sequence of adjustable length by choosing a preferred style of music (eg, classic rock or folk music) from a variety of choices that the research team had chosen to include in the application.

Stéphane Guétin, PhD, is a researcher in the Department of Neurology, Centre Mémoire de Ressources et de Recherches, Montpellier University Hospital, in Montpellier, France; a researcher for the Association for Music Therapy Applications and Clinical Research, in Paris, France; and a researcher in the Department of Psychologie, Université Paris 5–Renée Descartes, in Paris, France. Luc Brun, MD, is doctor in in the Pain Unit Center, Nouméa General Hospital (NGH), in Nouméa, New Caledonia, France. Maelle Deniaud is a psychologist in the Pain Unit Center at NGH. Jean-Michel Clerc, MD, is a doctor in the Department of Cardiology at NGH. Julian F. Thayer, PhD, is the Ohio Eminent Scholar Professor in Health Psychology in the Department of Psychology at the Ohio State University (OSU) in Columbus, Ohio. Julian Koenig, DrScHum, is a researcher at OSU. 60 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

Outcome Measures • Before and after listening to the music, all participants were asked to rate their anxiety and pain on an 11-item, visual analogue scale and to complete a questionnaire on their satisfaction with use of the application.

Results • The paired sample t test revealed a significant reduction in participants’ anxiety (t33 = 4.12, P < .0001) after they had listened to the music. No significant reduction in self-reported pain occurred; however, only a few participants reported pain associated with the procedure. No significant sex differences existed. Women and men both showed reduced anxiety after listening to music as well as reported a high level of satisfaction in using the Music Care application.

Conclusions • The smartphone-based Music Care application is an easy-to-use tool to reduce anxiety in patients undergoing coronarography. Future large-scale, controlled trials are necessary to compare its effectiveness with other interventions. Both women and men can benefit from the use of the application. (Altern Ther Health Med. 2016;22(4):60-63.)

Corresponding author: Stéphane Guétin, PhD E-mail address: s.guetin@music-care.com

P

atients undergoing coronarography may exhibit anxiety and have pain prior to and during the procedure. Reducing that anxiety and discomfort could increase compliance and improve outcomes. Musicbased interventions are widely used to distract patients during medical procedures and to reduce their pain and discomfort. For example, music has been used for pediatric1-3 and adult4-6 patients with burn injuries during changes to burn dressings or during the processes of burn debridement.

Listening to music has been shown to reduce pain and discomfort in patients undergoing the placement of a femoral Guétin—Music Care During Coronarography

nerve block7 and to reduce anxiety in adolescents receiving a colposcopy.8 Other studies have shown that patient-controlled music listening can reduce procedural pain and anxiety during a coronary angiography.9,10 Recent technological developments (ie, handheld devices) allow a patient or caregiver to control the use of music at a bedside within a large variety of clinical applications and settings. The Music Care program (Music Care, Paris, France) in the current study is a smartphone-based application that allows patients to listen to a variety of professionally prerecorded pieces of a preferred style of music (eg, classic rock or folk music) from a variety of choices.

The application has previously been evaluated in patients with chronic pain11,12; Alzheimer’s-type dementia13; acute pain in intensive care units14; and mechanic, inflammatory, fibromyalgia, and neurological pain.15 Within the current uncontrolled observational study, the research team aimed to assess the pain- and anxiety-reducing effects of the Music Care application in patients undergoing coronarography.

Given that some evidence has supported sex differences for preprocedural anxiety,16,17 the current research team aimed to explore further whether the effects of music listening were comparable among the women and men in the study.

METHODS Participants All patients undergoing coronarography from November 2010 to April 2011 at Nouméa General Hospital in Nouméa, New Caledonia, France, were offered the use of the Music Care application before their coronarography.

Procedures The Music Care application is a receptive musical intervention, allowing a patient to listen to a standardized musical sequence of adjustable length by choosing a preferred style of music (eg, classic rock or folk music) from a variety of choices that the research team had programmed into the application. All of the musical pieces were recorded in highquality recording studios with professional musicians to meet the demands for use in the application and to provide its clinical benefits.

Details on the compositional technique that was used when recording the musical pieces (ie, the U-shape technique) and on the application in general are published elsewhere.3,5-7 All participants listened to the music using high-quality headphones that were provided by the research team. Patients were enabled to use the application at hospital within an examination room. Patients were instructed to lie down flat in a comfortable position, with their eyes masked, while they listened to the music via high-quality headphones, which were provided.

Intervention The Music Care enables the patient-controlled therapeutic use of music within various settings. The client can freely choose from a variety of 20 musical styles (eg, classical: piano, Guétin—Music Care During Coronarography

violin, flute, etc; jazz: trumpet, saxophone, trombone, etc; world music: India, Andes, Africa, etc). All musical pieces are 20 minutes in length and have been recorded in high-quality recording studios with professional musicians to meet the demands of the application and its clinical use. Each standardized music session of 20 minutes is broken down into several phases, which gradually help the patient to relax, according to the so-called U sequence. The effect of this technique is achieved first through a reduction in musical tempo, orchestral size, frequencies, and volume (descending arm of the U), reaching a phase of maximum relaxation (bottom of the U) before a redynamizing phase (ascending arm of the U). All the musical sequences constructed for the U technique were specially composed and recorded by the music publication company Music Care. The music has solely been recorded for the use within the application, to ensure that patients are not familiar with the music, avoiding potential memory effects or later conditioning. In this regard and given the large variety of musical pieces that patients can choose from, the Music Care application is distinguished from other forms of music medicine interventions using prerecorded music from commercial compact discs and other formats.

Outcome Measures All participants who had agreed to participate in the study and who had provided informed consent were asked to complete self-report questionnaires in the course of the study. Before and after use of the application, they were asked to rate their current pain intensity on a visual analogue scale that was integrated within the application, with anchors at 0 = no pain and 10 = most intense pain.

Ratings of anxiety were obtained in the same manner, before and after the musical intervention, based on an 11-point scale from 0 = no anxiety to 10 = most intense anxiety. Satisfaction with the intervention was rated after the session, with the application providing 4 categorical responses: very satisfied, satisfied, unsatisfied, and very unsatisfied.

Statistical Analyses Descriptive statistics on ratings of pain intensity and anxiety at baseline and postintervention were expressed as means and standard deviations. Differences between those measures were analyzed using a paired Student’s t test.

Further, data were analyzed using a response criterion of a 33% reduction in pain intensity and anxiety (ie, a clinically relevant change) with patients being classified as responders, who met the criterion, versus nonresponders, who did not.

Differences between responders and nonresponders on baseline ratings and ratings of satisfaction were analyzed using the χ2 test or Fisher’s exact F test for categorical variables (ie, satisfaction) and independent t tests for continues variables (ie, pain and anxiety ratings). All tests were 2-sided, with the level of significance set at .05.

Statistical analyses were performed using SPSS version 21.0 (IBM, Armonk, NY, USA).

ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 61

Table 1. Changes in Primary Outcome Measures Preintervention

Postintervention

t Statistics

Response

Responders

Mean ± SD Min Max Mean ± SD Min Max

df

t

P

Mean (%)

n (%)

Pain

0.11 ± 0.53

0

3

0.3 ± 1.7

0

1

34

1.00

.324

-2.94

1 (2.9)

Anxiety

2.63 ± 2.67

0

8

1.74 ± 2.20

0

7

33a

4.12

<.0001

-23.25

8 (22.9)

Pain

0.24 ± 0.75

0

3

0.06 ± 0.24

0

1

16

1.00

.332

-6.25

1 (5.9)

Anxiety

3.12 ± 2.87

0

8

2.18 ± 2.51

0

7

16

2.63

.018

-20.96

3 (17.6)

0.0 ± 0.0

0

0

0.0 ± 0.0

0

0

-

-

-

0.00

0 (0.0)

2.12 ± 2.52

0

7

1.29 ± 1.86

0

5

16

3.35

.004

-25.41

5 (27.8)

Total

Women

Men Pain Anxiety a

One participant did not complete the postintervention assessment.

Note: Pain and anxiety were rated on a visual analogue scale from 0 to 10. The mean % represents the mean reduction as a percentage in the comparison from pre- to postintervention. Responders were participants with a reduction greater than 33% on ratings of pain and anxiety.

Abbreviations: SD, standard deviation; df, degrees of freedom (t statistics).

Figure 1. Percentage Reduction in Pain and Anxiety After Use of the Music Care Application in Women and Men Undergoing Coronarography

20

0

0 -2

0 -4

0 -6

-8

0

Outcome Pain Anxiety

Women Men

Reduction (%)

Note: The error bars indicate a 95% confidence interval.

62 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

RESULTS A total of 35 patients, 17 women and 18 men with a mean age of 61.26 ± 11.64 years, agreed to participate in the study and provided informed consent. The women and men did not differ significantly on age (t33 = 0.449, P = .656). The selection of musical styles differed widely, with the majority of patients selecting Andean instrumental music (n = 7, 20%), Indian music (n = 6, 17.1%), or instrumental jazz music (n = 5, 14.3%). The selection of musical style did not differ significantly as a function of gender (χ212 = 12.467, P = .409).

The mean ratings of pain intensity and anxiety before and after listening to music with the application are given in Table 1. The ratings of pain (t33 = 1.328, P = .193) and anxiety (t33 = 1.055, P = .299) before the procedure did not differ significantly between women and men. After the participants listened to music, their ratings on pain (t33 = 1.030, P = .311) and anxiety (t32 = 1.165, P = .253) also did not differ as a function of gender.

The paired t test revealed a significant reduction in anxiety (t33 = 4.12, P < .0001) when comparing ratings obtained before and after the intervention for the total group of participants, as illustrated in Figure 1. However, no significant differences were found from pre- to postintervention for the pain ratings (t34 = 1.00, P = .324) for the total group.

Guétin—Music Care During Coronarography

Similar patterns for the application’s anxiety-reducing effects were found for women (t16 = 2.63, P = .018) and men (t16 = 3.35, P = .004). The mean reductions for pain (t32 = 1.063, P = .296) and anxiety (t31 = 0.363, P = .719) as percentages did not differ significantly between women and men.

Also, the number of responders related to reductions in anxiety (χ21 = 0.654, P = .419) and pain (χ21 = 1.090, P = .296) was similarly distributed in women and men. The majority of participants was satisfied (n = 17) or very satisfied (n = 17) with the music-listening intervention, and no sex differences occurred for satisfaction with the application (χ22 = 3.916, P = .141).

DISCUSSION The present study of 35 patients undergoing a coronarography aimed to evaluate a smartphone-based intervention using music listening to reduce pain and anxiety.

In line with previous controlled studies on the effectiveness of the application,11,13-15 the current 20-minute intervention significantly reduced anxiety. Patients in the study and, in particular, men in the study exhibited no to very low pain in association with the procedure. Thus, the research team was not able to perform an analysis on the intervention’s painreducing effects in men.

For the women in the study, the comparison of the subjective ratings of pain intensity before and after listening to music showed no significant effects. The effect size (ES) for anxiety reduction (ie, ES = 0.75, given a zero-order correlation of 0.890 between the pre- and postintervention measures) was sizeable, representing a medium-to large-effect. However, the preintervention ratings of anxiety were quite low within the study’s participants. Nevertheless, responder rates of 22.9% indicate a clinically significant effect by the application at least for 8 patients who experienced a clinically relevant reduction in anxiety.

5. Tan X, Yowler CJ, Super DM, Fratianne RB. The efficacy of music therapy protocols for decreasing pain, anxiety, and muscle tension levels during burn dressing changes: a prospective randomized crossover trial. J Burn Care Res. 2010;31(4):590-597.

6. Prensner JD, Yowler CJ, Smith LF, Steele AL, Fratianne RB. Music therapy for assistance with pain and anxiety management in burn treatment. J Burn Care Rehabil. 2001;22(1):83-88.

7. Nikolajsen L, Lyndgaard K, Schriver NB, Moller JF. Does audiovisual stimulation with music and nature sights (MuViCure) reduce pain and discomfort during placement of a femoral nerve block? J Perianesth Nurs. 2009;24(1):14-18.

8. Rickert VI, Kozlowski KJ, Warren AM, Hendon A, Davis P. Adolescents and colposcopy: The use of different procedures to reduce anxiety. Am J Obstet Gynecol. 1994;170(2):504-508.

9. Bally K, Campbell D, Chesnick K, Tranmer JE. Effects of patient-controlled music therapy during coronary angiography on procedural pain and anxiety distress syndrome. Crit Care Nurse. 2003;23(2):50-58.

10. Doğan MV, Şenturan L. The effect of music therapy on the level of anxiety in the patients undergoing coronary angiography. Open J Nurs. 2012;2(3):165-169.

11. Guétin S, Coudeyre E, Picot MC, et al. Effect of music therapy among hospitalized patients with chronic low back pain: A controlled, randomized trial [in French]. Ann Readapt Med Phys. 2005;48(5):217-224.

12. Guétin S, de Diego E, Mohy F, Alphonse C, Hoareau G, Touchon J, Thayer JF, Koenig J. A patient-controlled, smartphone-based music intervention to reduce pain—A multi-center observational study of patients with chronic pain. Euro J Integrat Med. In press.

13. Guétin S, Portet F, Picot MC, et al. Effect of music therapy on anxiety and depression in patients with Alzheimer’s type dementia: Randomised, controlled study. Dement Geriatr Cogn Disord. 2009;28(1):36-46.

14. Jaber S, Bahloul H, Guétin S, Chanques G, Sebbane M, Eledjam JJ. Effects of music therapy in intensive care unit without sedation in weaning patients versus non-ventilated patients [in French]. Ann Fr Anesth Reanim. 2007;26(1):30-38.

15. Guétin S, Giniès P, Siou DK, Picot MC, et al. The effects of music intervention in the management of chronic pain: a single-blind, randomized, controlled trial.

Clin J Pain. 2012;28(4):329-337.

16. Auerbach SM, Kendall PC. Sex differences in anxiety response and adjustment to dental surgery: effects of general vs. specific preoperative information. J Clin Psychol. 1978;34(2):309-313.

17. Sghaireen MG, Zwiri AM, Alzoubi IA, Qodceih SM, AL-Omiri MK. Anxiety due to dental treatment and procedures among university students and its correlation with their gender and field of study. Int J Dent. 2013;2013:647436.

CONCLUSIONS The Music Care application appears to provide an adjuvant tool for the management of anxiety for patients undergoing a coronarography. Further, the research team found no gender differences in the results for use of the application. Overall, the use of the Music Care application within the setting proved good feasibility for use of the application. Future large-scaled and well-controlled studies are necessary to further test the effectiveness of the intervention compared with other methods of distraction.

AUTHOR DISCLOSURE STATEMENT The research team received no external funding for the study.

REFERENCES 1. Whitehead-Pleaux AM, Baryza MJ, Sheridan RL. The effects of music therapy on pediatric patients’ pain and anxiety during donor site dressing change. J Music Ther. 2006;43(2):136-153.

2. Whitehead-Pleaux AM, Zebrowski N, Baryza MJ, Sheridan RL. Exploring the effects of music therapy on pediatric pain: Phase 1. J Music Ther. 2007;44(3):217-241.

3. Fratianne RB, Prensner JD, Huston MJ, Super DM, Yowler CJ, Standley JM. The effect of music-based imagery and musical alternate engagement on the burn debridement process. J Burn Care Rehabil. 2001;22(1):47-53.

4. Son JT, Kim SH. The effects of self-selected music on anxiety and pain during burn dressing changes [in Korean]. Taehan Kanho Hakhoe Chi. 2006;36(1):159-168.

Guétin—Music Care During Coronarography

ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 63

REVIEW ARTICLE

Profiling the Australian Consumer of Complementary and Alternative Medicine: A Secondary Analysis of National Health Survey Data Matthew J. Leach, RN, BN (Hons), ND, DipClinNutr, PhD

ABSTRACT Background • Consumers’ interest in complementary and alternative medicine (CAM) has escalated in the past few decades. Some observers argue that the changing needs and expectations of consumers are driving the surge.

Although some studies support that notion, much of the research has been limited methodologically. Profiling can provide important insights into the distinct needs of CAM consumers.

Objective • The study intended to profile consumers of CAM in Australia.

Design • The study was a secondary analysis of 5 Australian National Health Surveys conducted between 1989 and 2008.

Outcome Measures • The study measured the differences between CAM users and nonusers in terms of: (1) predisposing factors (ie, the prevailing conditions that predispose an individual to use a health service, such as age); (2) enabling factors (ie, circumstances that facilitate or hinder health service use, such as income); (3) need factors (ie, an actual or perceived need for health services, such as poor health); and (4) personal health practices (ie, behaviors that influence health status, such as alcohol consumption).

Matthew J. Leach, RN, BN (Hons), ND, DipClinNutr, PhD, is a senior research fellow and research degree coordinator at the School of Nursing & Midwifery, Sansom Institute, University of South Australia, in Adelaide, South Australia, Australia.

Corresponding author: Matthew J. Leach,

RN, BN (Hons), ND,

DipClinNutr, PhD

E-mail address: matthew.leach@unisa.edu.au

64 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

Results • The 5 surveys provided data for 181 549 Australian adults and children. Predisposing factors associated with CAM use were (1) being aged >40 y, (2) being female, (3) being married, and (4) holding a postsecondary school qualification. Significant enablers of CAM use were (1) high income, (2) private health insurance, and (3) employment. As for personal health practices, CAM users had significantly higher odds of (1) being physically active, (2) being a nonsmoker, and (3) meeting national recommendations for intake of fruits and vegetables. The prevalence of chronic disease and the use of pharmaceutical agents and health services were comparatively high among CAM users.

Conclusions • CAM consumers reported relatively healthier lifestyles compared with nonusers, although some data indicated that CAM users might have greater health care needs. The use of CAM in this high-need population suggests that the present health care system may be inadequate in addressing the needs of these consumers and that CAM may play an important role in servicing these unmet demands. (Altern Ther Health Med. 2016;22(4):64-72.)

T

he past few decades have witnessed a surge of interest in complementary and alternative medicine (CAM), which includes a large and diverse range of therapeutic preparations or practices that are not regarded as a core part of conventional medicine. The escalating frequency of CAM articles in the mass print media,1,2 the growth in CAM research,3,4 and the increasing expressed demand for CAM services across the globe5-10 are all testament to that surge.

The prevalence of CAM use varies across most developed countries, with relatively high rates of use of CAM products and services in the 12 months prior to survey administration being reported in Australia—69% and 44%, respectively11; in the United States—62% and 16%, respectively5,12; and in Canada—60% and 12%, respectively.13,14 Natural products, specifically nutritional and herbal supplements, are the most Leach—Profile of the CAM Consumer

frequently used CAM therapies across most developed countries,11,12 trailed by massage therapy in Australia15 and Canada16 and relaxation therapies in the United States.12 Many descriptions have been given to explain the rising interest in CAM. Dissatisfaction with Western medicine, once claimed to be the leading motivation for people turning to CAM,17 is now considered to be a minor contributing factor.18,19 It now seems that the changing needs and expectations of health consumers are driving the increasing interest in CAM, including an aspiration for active participation in health care, greater disease chronicity and severity, holistic health care beliefs, and an increase in health awareness behaviors.20-23 Other observers have adopted a different view of CAM users. Those individuals posit that CAM consumers are a population of gullible,24,25 misguided26 consumers. Some even characterize CAM users as nothing more than rich hippies and spa-obsessed suburbanites.15 Regardless of the position taken, a presumption exists that CAM users differ from nonusers. Findings from numerous surveys support that notion, at least for factors such as age, gender, education, and income.6,11,12,27,28 Notwithstanding those findings, those surveys have several limitations. For example, most population-based surveys exploring the use of CAM exclude children,11,12,27-30 and most report data from a single point in time.6,11,12,28,30 Some surveys are also limited by low participation rates11,30 and small sample sizes relative to the national population.11,30 Those limitations highlight the need for additional work in the area.

Profiling, or the description and analysis of the fundamental characteristics of a defined population or setting, is becoming an increasingly important element in health policy development and clinical practice improvement.

In the United States, profiling has been used to address rural shortages in the primary care workforce by development of an understanding of the types of health care providers that are more likely to practice and remain in the rural sector.31 Similarly, profiling has provided new insights into the needs of patients requiring cataract surgery in the United Kingdom to improve health services planning.32 The need to understand the CAM user better is no exception.

Building a profile of the CAM consumer is important for several reasons: (1) it challenges misconceptions about CAM users, which potentially affect providers’ attitudes and quality of care; (2) it assists clinicians in identifying the patients most likely to be using or seeking CAM to recognize those at risk of CAM-drug interactions; and (3) it helps in identifying the characteristics of CAM users to understand the distinct health care needs of that subpopulation, knowledge of which may generate new ideas about how health care might better serve the needs of those consumers.

In recognizing the implications of health consumer profiling and the limitations of previous work in the area, a clear need exists to understand the CAM consumer further.

The research described in the current article addresses that need by profiling a large Australian population.

Leach—Profile of the CAM Consumer

METHODS Procedures The purpose of the current study was to characterize users and nonusers of CAM in Australia. The Andersen behavioral model of health service use33 provided an overarching framework for the study. That model proposes that the individual determinants of CAM use can be divided into 4 broad categories: (1) predisposing factors (ie, the prevailing conditions that predispose an individual to use a health service, such as age); (2) enabling factors (ie, circumstances that facilitate or hinder health-service use, such as income); (3) need factors (ie, actual or perceived need for health services, such as poor health); and (4) personal health practices (ie, behaviors that influence health status, such as alcohol consumption).33 Using the model, the current study set out to understand what, if any, predisposing, enabling, and need factors and personal health practices differentiated CAM consumers from nonusers.

Answers to those questions were determined through the secondary analysis of Australian National Health Survey (ANHS) data. The ANHS is a cross-sectional survey that has been conducted every 3 years since 2001 and every 6 years prior to 2001 by the Australian Bureau of Statistics. The survey captures detailed information about health status and health service usage of randomly selected Australians, using face-to-face interviews and stratified, multistage area sampling. Data on children aged 0 to 15 years are collected by proxy, whereas children aged 15 to 17 years are interviewed directly if parental consent is provided. Other strengths include (1) high response rates (ie, >89%); (2) large sample sizes (ie, >20 000 participants per survey); and (3) inclusion of adults aged 18+ years and children aged 0 to 17 years across all states and territories in Australia (Table 1). A more detailed description of the methodology of each survey has been reported elsewhere.34-38 Only those surveys for which complete individual-level data on CAM use could be obtained were used; this included data from the 1989–1990, 1995, 2001, 2004–2005, and 2007–2008 surveys. A CAM user was defined as someone who had reported using any of the following services in the 2 weeks prior to the survey, or in the case of the 2007–2008 survey, in the prior 12 months: (1) an acupuncturist, excluding 2001; (2) a chiropractor; (3) an osteopath, excluding 2001 onward; or (5) an herbalist, excluding 2001 onward, and/or a naturopath.

Users were also defined as individuals who had reported using a vitamin, mineral, or natural or herbal supplement for a national health-priority condition (ie, asthma, diabetes, cancer, arthritis, cardiovascular disease, osteoporosis, or mental illness) in the 2 weeks prior to the survey, or in the case of the 1989–1990 survey, in the prior 12 months.

Outcome Measures Participants’ characteristics of interest included the following factors: (1) predisposing factors (ie, age, gender, marital status, country of birth, highest postsecondary school qualification, and remoteness of area of the ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 65

Table 1. Description of Australian Bureau of Statistics’ National Health Surveys Conducted Between 1989 and 2008.

Year 1989–1990a 1995b 2001c 2004–2005d 2007–2008e

Sample Response Size Rate Sample 54 241 NR Every adult and child, where applicable, from each dwelling 53 751 91.5% Every adult and child, where applicable, from each dwelling 26 863 92% One adult aged 18+ years, one child aged 7–17 years, and all children aged 0–6 years from each dwelling 25 906 89.4% One adult aged 18+ years and one child, where applicable, from each dwelling 20 788 90.6% One adult aged 18+ years and one child, where applicable, from each dwelling

a

Australian Bureau of Statistics (1991)32 Australian Bureau of Statistics (1996)33 c Australian Bureau of Statistics (2003)34 d Australian Bureau of Statistics (2006)35 e Australian Bureau of Statistics (2009)36 b

Abbreviation: NR, not reported.

Note: Participants in all surveys were randomly selected residents of private dwellings across all states and territories in Australia.

All surveys were conducted using personal interviews. residence); (2) enabling factors (ie, employment status, hours worked per week, gross weekly income, private health insurance coverage, and use of government/concession card—or a card allowing low-income individuals to receive discounted health services/products); (3) need factors (ie, poor health and use of health products or services); and (4) personal health practices (ie, alcohol consumption, smoking status, level of physical activity, breastfeeding status, and intake of fruits and vegetables).

Statistical Analysis Data were first harmonized (ie, variable and value labels were adjusted to ensure that labels were consistent across surveys) to enable intersurvey comparisons. Apart from age and gender, the value labels of all variables had to be reduced to the lowest common denominator of detail that was fully comparable. Statistical analyses were performed using SPSS, version 21 (IBM Corp, Armonk, NY, USA).

Comparisons of categorical variables by CAM user status were conducted using χ2 tests. Unadjusted odds ratios (ORs) with 99% confidence intervals (CIs) were calculated for all variables demonstrating a statistically significant difference between CAM users and nonusers. The significance level was set at P < .001 due to the large sample size of each survey. ORs derived from each survey were then pooled, and a summary OR was calculated for each respective variable using a fixed-effect model and the Mantel-Haenszel test.

RESULTS Five national health surveys, implemented over a period of 19 years (1989–2008), had collected data from a total of 181 549 Australian adults and children. CAM users made up between 5.5% and 30.4% of the 5 survey samples; those users 66 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

included persons who had taken a vitamin, mineral, natural, or herbal supplement (56.0%–96.8%) and/or who had consulted a CAM practitioner (7.7%–48.0%) during the relevant periods.

Predisposing Factors Proportionally, more CAM consumers than nonusers (1) were female—pooled OR, 1.66; 99% CI, 1.61 to 1.71; P < .0001; (2) were married—pooled OR, 1.45; 99% CI, 1.41 to 1.49; P < .0001; and (3) held a postsecondary school qualification—pooled OR, 1.74; 99% CI, 1.68 to 1.80; P < .0001 (Table 2). A higher proportion of CAM consumers relative to nonusers were (1) aged ≥60 years—pooled OR, 1.55; 99% CI, 1.49 to 1.61; P < .0001; and (2) to a lesser extent, aged between 40 and 59 years—pooled OR, 1.50; 99% CI, 1.45 to 1.55; P < .0001. Relatively more CAM consumers (1) lived in a major city—pooled OR, 1.25; 99% CI, 1.21 to 1.29; P < .0001; or (2) were born overseas—pooled OR, 1.11; 99% CI, 1.07 to 1.15; P < .0001.

Enabling Factors More CAM consumers than nonusers (1) were employed—pooled OR, 1.43; 99% CI, 1.39 to 1.47; P < .0001; (2) worked 25 to 34 hours per week—pooled OR, 1.61; 99% CI, 1.50 to 1.73; P < .0001; (3) earned a gross weekly income in the 9th to 10th decile—pooled OR, 1.35; 99% CI, 1.30 to 1.40; P < .0001; and (4) had private health insurance—pooled OR, 1.89; 99% CI, 1.83 to 1.95; P < .0001 (Table 3). Also, more CAM users were government/concession card holders— pooled OR, 1.34; 99% CI, 1.29 to 1.38; P < .0001, compared with nonusers.

Leach—Profile of the CAM Consumer

Leach—Profile of the CAM Consumer

ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 67

<20 y 20–39 y 40–59 y ≥60 y Female Married Born overseas Had a postsecondary school qualification Had a bachelor’s degree qualification or higher Lived in a capital or major city 0.95 (0.91 to 1.00)

1.79 (1.61 to 1.99)

1.47 (1.33 to 1.62) 1.06 (1.00 to 1.12)

OR (99% CI) 0.47 (0.45 to 0.50) 1.23 (1.17 to 1.30) 1.50 (1.42 to 1.58) 1.20 (1.12 to 1.29) 1.63 (1.55 to 1.71) 1.34 (1.28 to 1.41) 1.06 (1.00 to 1.12) 1.60 (1.50 to 1.70)

OR (99% CI) 0.59 (0.55 to 0.62) 1.29 (1.22 to 1.36) 1.25 (1.18 to 1.33) 1.10 (1.02 to 1.18) 1.57 (1.49 to 1.66) 1.21 (1.15 to 1.28) 0.95 (0.89 to 1.01) 1.51 (1.43 to 1.59)

1.03 (0.89 to 1.19)

1.90 (1.58 to 2.28)

OR (99% CI) 0.24 (0.20 to 0.30) 2.10 (1.82 to 2.42) 1.45 (1.25 to 1.68) 1.08 (0.90 to 1.30) 2.33 (2.00 to 2.71) 2.15 (1.87 to 2.47) 1.12 (0.94 to 1.32) 2.17 (1.89 to 2.50)

2001

1995 OR (99% CI) 1.51 (1.44 to 1.59) 0.66 (0.63 to 0.69) 1.59 (1.47 to 1.73) 1.62 (1.44 to 1.83) 1.23 (1.17 to 1.29) 0.82 (0.77 to 0.88) 0.86 (0.80 to 0.92) 0.91 (0.85 to 0.97) 1.03 (0.97 to 1.10) 1.34 (1.26 to 1.43) 1.57 (1.47 to 1.67) 1.11 (1.05 to 1.18)

OR (99% CI) 0.03 (0.03 to 0.04) 0.99 (0.91 to 1.08) 1.95 (1.79 to 2.12) 2.70 (2.46 to 2.95) 1.55 (1.43 to 1.68) 2.15 (1.98 to 2.33) 1.34 (1.22 to 1.46) 2.37 (2.18 to 2.56)

2007–2008 Pooled OR (99% CI) 0.37 (0.36 to 0.39)a 1.18 (1.15 to 1.22)a 1.50 (1.45 to 1.55)a 1.55 (1.49 to 1.61)a 1.66 (1.61 to 1.71)a 1.45 (1.41 to 1.49)a 1.11 (1.07 to 1.15)a 1.74 (1.68 to 1.80)a

TOTAL (all surveys)

2001 OR (99% CI) 1.88 (1.64 to 2.17) 0.53 (0.46 to 0.61) 1.94 (1.60 to 2.34) 1.91 (1.43 to 2.56) 1.29 (1.11 to 1.49) 0.97 (0.80 to 1.17) 0.85 (0.70 to 1.03) 0.89 (0.74 to 1.08) 1.02 (0.84 to 1.22) 1.22 (1.02 to 1.46) 2.34 (2.03 to 2.69) 1.20 (1.03 to 1.39)

2004–2005 OR (99% CI) 1.13 (1.04 to 1.23) 0.88 (0.81 to 0.96) 1.23 (1.08 to 1.40) 1.44 (1.21 to 1.71) 0.96 (0.88 to 1.05) 1.33 (1.18 to 1.50) 2.02 (1.83 to 2.23) 1.33 (1.19 to 1.49) 1.14 (1.01 to 1.29) 1.10 (0.98 to 1.24) 2.04 (1.88 to 2.22) 2.39 (2.20 to 2.61)

2007–2008 OR (99% CI) 1.76 (1.62 to 1.91) 0.57 (0.53 to 0.62) 1.26 (1.11 to 1.43) 1.77 (1.50 to 2.10) 1.46 (1.34 to 1.58) 1.68 (1.50 to 1.87) 1.53 (1.37 to 1.71) 1.53 (1.37 to 1.71) 1.62 (1.45 to 1.80) 1.73 (1.56 to 1.93) 2.62 (2.42 to 2.84) 1.91 (1.76 to 2.08)

TOTAL (all surveys) Pooled OR (99% CI) 1.43 (1.39 to 1.47)a 0.70 (0.68 to 0.72)a 1.51 (1.44 to 1.58)a 1.61 (1.50 to 1.73)a 1.17 (1.13 to 1.20)a 0.95 (0.92 to 0.99)a 1.02 (0.98 to 1.06)a 1.02 (0.98 to 1.06)a 1.13 (1.08 to 1.17)a 1.35 (1.30 to 1.40)a 1.89 (1.83 to 1.95)a 1.34 (1.29 to 1.38)a

1.98 (1.82 to 2.15) 2.56 (2.35 to 2.77) 1.25 (1.21 to 1.29)a

1.46 (1.31 to 1.64) 1.69 (1.53 to 1.87) 1.62 (1.54 to 1.70)a

Abbreviations: OR, odds ratio; CAM, complementary and alternative medicine; CI, confidence interval.

P < .0001 for difference between CAM users and nonusers (Mantel-Haenszel test).

a

Employment status Employed Usual hours worked per week 0 hours 1–24 hours 25–34 hours ≥35 hours Gross weekly income 1st/2nd decile 3rd/4th decile 5th/6th decile 7th/8th decile 9th/10th decile Private health insurance Had private health insurance Government/concession card Government or concession card holder

1989–1990 OR (99% CI) 1.29 (1.22 to 1.36) 0.78 (0.74 to 0.82) 1.66 (1.51 to 1.82) 1.55 (1.34 to 1.79) 1.06 (1.01 to 1.12) 0.79 (0.73 to 0.86) 0.82 (0.77 to 0.88) 0.95 (0.89 to 1.01) 1.11 (1.04 to 1.18) 1.35 (1.27 to 1.43) 1.72 (1.62 to 1.84) 1.04 (0.97 to 1.11)

Table 3. Unadjusted ORs for Enabling Factors of CAM Use Versus Nonuse

2004–2005 OR (99% CI) 0.10 (0.09 to 0.12) 0.78 (0.71 to 0.86) 1.68 (1.54 to 1.84) 2.97 (2.71 to 3.26) 1.97 (1.81 to 2.15) 1.67 (1.54 to 1.82) 1.47 (1.33 to 1.61) 1.87 (1.72 to 2.03)

Abbreviations: OR, odds ratio; CAM, complementary and alternative medicine; CI, confidence interval.

P < .0001 for difference between CAM users and nonusers (Mantel-Haenszel test).

a

Remoteness of area

Gender Marital status Country of birth Postsecondary school qualification

Age

1995

1989–1990

Table 2. Unadjusted ORs for Predisposing Factors of CAM Use Versus Nonuse

Table 4. Unadjusted ORs for Need Factors (Morbidity) of CAM Use Versus Nonuse

Asthma Arthritis Cardiovascular disease Diabetes mellitus Mental illness

1989–1990

1995

2001

2004–2005

2007–2008

OR (99% CI) 1.55 (1.28 to 1.86) 1.69 (1.34 to 2.13) 1.90 (1.61 to 2.24) 2.24 (1.63 to 3.08) 1.51 (1.23 to 1.85)

OR (99% CI) 1.42 (1.26 to 1.61) 5.28 (4.76 to 5.86) 2.75 (2.48 to 3.05) 0.96 (0.76 to 1.21) 3.13 (2.74 to 3.58)

OR (99% CI) 1.20 (1.08 to 1.32) 5.95 (5.43 to 6.52) 2.92 (2.68 to 3.18) 2.02 (1.71 to 2.38) 2.41 (2.10 to 2.77)

OR (99% CI) 1.18 (1.08 to 1.29) 1.43 (1.33 to 1.55) 1.28 (1.20 to 1.38) 2.01 (1.75 to 2.31) 2.09 (1.86 to 2.35)

OR (99% CI) 1.18 (1.10 to 1.27) 1.62 (1.51 to 1.73) 1.57 (1.48 to 1.67)a 0.82 (0.69 to 0.97) 1.94 (1.76 to 2.15)

TOTAL (all surveys) Pooled OR (99% CI) 1.23 (1.18 to 1.29)b 2.35 (2.27 to 2.45)b 1.79 (1.72 to 1.85)b 1.46 (1.34 to 1.58)b 2.18 (2.06 to 2.31)b

a

Cardiovascular disease was presumed to be present if the participant reported the use of a prescribed medication for a cardiac or vascular condition. b P < .0001 for difference between CAM users and nonusers (Mantel-Haenszel test).

Abbreviations: OR, odds ratio; CAM, complementary and alternative medicine; CI, confidence interval.

Table 5. Unadjusted ORs for Need Factors (ie, Use of Health Products or Services) of CAM Use Versus Nonuse

2004–2005

2007–2008

OR (99% CI) OR (99% CI) OR (99% CI) 1.73 (1.63 to 1.83) 1.72 (1.64 to 1.81) 1.95 (1.68 to 2.25) 1.14 (0.99 to 1.31) 1.09 (0.96 to 1.24) 1.67 (1.22 to 2.30) 1.38 (1.29 to 1.46) 1.34 (1.26 to 1.41) 1.90 (1.65 to 2.20)

OR (99% CI) 3.94 (3.61 to 4.29) 1.40 (1.14 to 1.72) 2.08 (1.90 to 2.27)

OR (99% CI) 3.72 (3.42 to 4.06) NR 2.58 (2.36 to 2.83)

TOTAL (all surveys) Pooled OR (99% CI) 2.11 (2.05 to 2.18)a 1.18 (1.08 to 1.28)a 1.60 (1.55 to 1.65)a

1.12 (1.00 to 1.26) 1.24 (1.12 to 1.37) 1.24 (0.95 to 1.61) 0.84 (0.65 to 1.07) 0.84 (0.68 to 1.05) 1.43 (0.89 to 2.29) 1.72 (1.56 to 1.89) 1.74 (1.59 to 1.91) 2.02 (1.67 to 2.45)

1.29 (1.10 to 1.53) 1.10 (0.78 to 1.55) 2.23 (1.97 to 2.51)

NR 2.01 (1.63 to 2.47) 3.02 (2.78 to 3.29)

1.20 (1.13 to 1.29)a 1.16 (1.03 to 1.30)a 2.16 (2.06 to 2.26)a

1989–1990

Using a pharmaceutical agent Visiting a hospital/ED/OPD Visiting a GP/medical specialist Visiting a dentist Visiting a nurse Visiting an allied health provider a

1995

2001

P < .0001 for difference between CAM users and nonusers (Mantel-Haenszel test).

Abbreviations: OR, odds ratio; CAM, complementary and alternative medicine; CI, confidence interval; ED, emergency department; OPD, outpatient department; GP, general practitioner; NR, not reported.

Need Factors Higher odds of self-reported chronic disease were evident among CAM consumers, particularly for (1) arthritis—pooled OR, 2.35; 99% CI, 2.27 to 2.45; P < .0001; and (2) mental illness—pooled OR, 2.18; 99% CI, 2.06 to 2.31; P < .0001. Those findings were closely followed by (1) cardiovascular disease—pooled OR, 1.79; 99% CI, 1.72 to 1.85; P < .0001; (2) diabetes—pooled OR, 1.46; 99% CI, 1.34 to 1.58; P < .0001; and (2) asthma—pooled OR, 1.23; 99% CI, 1.18 to 1.29; P < .0001 (Table 4).

The odds of using a pharmaceutical agent were much higher among CAM consumers when compared with nonusers—pooled OR, 2.11; 99% CI, 2.05 to 2.18; P < .0001 (Table 5). Similarly, relative to nonusers, a larger proportion of CAM consumers had consulted a mainstream health professional in the 2 weeks prior to being surveyed. The odds were particularly high for visiting (1) an allied health professional (such as a physiotherapist, podiatrist, dietician)— pooled OR, 2.16; 99% CI, 2.06 to 2.26; P < .0001; or (2) a general practitioner or medical specialist—pooled OR, 1.60; 99% CI, 1.55 to 1.65; P < .0001; followed by visits to a 68 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

(3) dentist—pooled OR, 1.20; 99% CI, 1.13 to 1.29; P < .0001; (4) hospital or an emergency or outpatient department— pooled OR, 1.18; 99% CI, 1.08 to 1.28; P < .0001; and (5) nurse—pooled OR, 1.16; 99% CI, 1.03 to 1.30; P < .0001.

Personal Health Practices Compared with nonusers, CAM consumers had significantly higher odds of (1) exercising >210 minutes per week—pooled OR, 1.58; 99% CI, 1.53 to 1.63; P < .0001; (2) consuming ≥2 servings of fruit daily—pooled OR, 1.85; 99% CI, 1.76 to 1.96; P < .0001; (3) consuming ≥4 servings of vegetables daily—pooled OR, 1.75; 99% CI, 1.65 to 1.85; P < .0001; (4) breastfeeding their children—pooled OR, 1.38; 99% CI, 1.30 to 1.47; P < .0001; and (5) never smoking— pooled OR, 1.47; 99% CI, 1.43 to 1.52; P < .0001 (Table 6). By contrast, relatively fewer CAM users were nondrinkers— pooled OR, 0.64; 99% CI, 0.62 to 0.67; P < .0001, although no statistically significant difference existed between the 2 groups in the odds of drinking to excess (ie, >4 standard drinks daily)—pooled OR, 1.04; 95% CI, 0.98 to 1.11; P = .07.

Leach—Profile of the CAM Consumer

Table 6. Unadjusted ORs for Personal Health Practices of CAM Users Versus Nonusers

Daily alcohol consumption, standard drinks Smoking status Total time spent exercising in past wk, min Breastfeeding status Daily fruit intake, servings per day

0 drinks 1–4 drinks >4 drinks

Never smoked 0 min >0–150 min >150–210 min >210 min Breastfed children Does not eat fruit ≤1 servings 2+ servings Daily vegetable Does not eat intake, servvegetables ings per day ≤1 servings 2–3 servings 4+ servings

a

TOTAL (all surveys) Pooled OR OR (99% CI) OR (99% CI) OR (99% CI) OR (99% CI) OR (99% CI) (99% CI) 0.73 (0.70 to 0.77) 0.73 (0.69 to 0.77) 0.61 (0.53 to 0.70) 0.59 (0.54 to 0.64) 0.42 (0.39 to 0.45) 0.64 (0.62 to 0.67)a 1.41 (1.34 to 1.48) 1.43 (1.35 to 1.52) 1.65 (1.44 to 1.90) 1.75 (1.61 to 1.90) 2.26 (2.08 to 2.46) 1.58 (1.53 to 1.63)a 0.90 (0.80 to 1.01) 0.91 (0.77 to 1.07) 0.39 (0.01 to 15.33) 1.03 (0.91 to 1.16) 1.26 (1.13 to 1.39) 1.04 (0.98 to 1.11) 1989–1990

1995

2001

2004–2005

2007–2008

1.33 (1.26 to 1.40) 0.60 (0.57 to 0.63) 1.39 (1.29 to 1.50) 1.24 (1.10 to 1.40) 1.41 (1.34 to 1.49) 1.60 (1.43 to 1.78)

1.46 (1.39 to 1.54) 0.51 (0.49 to 0.54) 1.35 (1.26 to 1.45) 1.36 (1.22 to 1.52) 1.63 (1.55 to 1.72) 1.87 (1.73 to 2.02)

1.94 (1.69 to 2.23) 0.41 (0.35 to 0.48) 1.63 (1.36 to 1.95) 1.50 (1.13 to 1.99) 1.71 (1.49 to 1.97) 0.22 (0.14 to 0.36)

1.75 (1.61 to 1.90) 0.08 (0.06 to 0.10) 1.42 (1.30 to 1.56) 1.24 (1.07 to 1.43) 1.65 (1.52 to 1.80) 0.10 (0.06 to 0.16)

1.49 (1.38 to 1.61) 0.01 (0.01 to 0.02) 1.73 (1.58 to 1.88) 1.36 (1.18 to 1.58) 1.72 (1.59 to 1.86) NR

NR

NR

0.30 (0.24 to 0.37) 0.20 (0.17 to 0.23) 0.27 (0.23 to 0.32) 0.24 (0.22 to 0.27)a

NR NR NR

NR NR NR

1.11 (0.96 to 1.29) 0.97 (0.89 to 1.06) 0.99 (0.91 to 1.07) 0.99 (0.94 to 1.05)a 1.95 (1.70 to 2.24) 2.21 (2.03 to 2.40) 1.57 (1.45 to 1.69) 1.85 (1.76 to 1.96)a 0.24 (0.18 to 0.30) 0.10 (0.08 to 0.13) 0.04 (0.03 to 0.07) 0.11 (0.09 to 0.13)a

NR NR NR

NR NR NR

0.95 (0.78 to 1.15) 0.93 (0.83 to 1.04) 0.83 (0.76 to 0.91) 0.88 (0.82 to 0.94)a 1.35 (1.17 to 1.55) 1.23 (1.13 to 1.34) 1.28 (1.18 to 1.38) 1.27 (1.20 to 1.34)a 1.83 (1.58 to 2.12) 1.85 (1.69 to 2.01) 1.61 (1.46 to 1.77) 1.75 (1.65 to 1.85)a

1.47 (1.43 to 1.52)a 0.43 (0.42 to 0.45)a 1.45 (1.40 to 1.51)a 1.31 (1.23 to 1.40)a 1.58 (1.53 to 1.63)a 1.38 (1.30 to 1.47)a

P < .0001 for difference between CAM users and nonusers (Mantel-Haenszel test).

Abbreviations: OR, odds ratio; CAM, complementary and alternative medicine; CI, confidence interval; NR, not reported.

DISCUSSION The value of consumer profiling is well recognized in sectors unrelated to health; it is only recently that the health sector has appreciated the role of profiling in understanding patients’ needs, improving health service delivery and clinical practice, and informing health policy. The current study, the largest and most comprehensive CAM-consumer profiling study conducted in Australia to date, suggests that CAM users clearly differ from nonusers in terms of predisposing, enabling, and need factors and personal health practices.

Predisposing Factors In the current study, a number of predisposing factors were shown to be related to the use of CAM, with CAM consumers most likely to be married, well-educated, middleaged to older women residing in a capital or major city. Those findings are not surprising because well-educated, married, middle-aged women tend to access health care more frequently than men, unmarried women, and the younger and less educated.39 These characteristics also closely approximate those reported in earlier studies of CAM users,6,11,12,27,40 although that approximation seems to be the case only for Western populations.28,41 Comprehensive profiling of CAM consumers in non-Western countries may help to determine the origins of the geographical differences.

The findings also suggest the presence of regional variations in CAM use, with higher rates of use being observed in urban areas over rural or remote regions. The Leach—Profile of the CAM Consumer

reduced availability of CAM services in rural and remote regions may explain why the odds of CAM use were higher in urban areas; the finding is not dissimilar to that observed with conventional health service use39 or with CAM-service use in the United Kingdom and United States.6,12 The situation in Australia, however, is less clear, with an earlier Australian study by Robinson et al42 reporting similar 12-month, prevalence rates for CAM use among rural and urban respondents. Even though the poor representation of urban respondents in that study may have contributed to the disparate findings, it is probable that the limited scope of CAM in the current study, including the omission of 9 therapies demonstrating relatively greater usage in rural areas (ie, massage therapy, aromatherapy, reflexology, magnet therapy, Bowen therapy, Reiki, kinesiology, spiritual healing, and tai chi) could have skewed the results. In either case, the issue of regional variation warrants further investigation to ascertain whether access to CAM services is inequitable in rural or remote communities relative to urban locations.

Enabling Factors Most CAM products and services in Australia are paid for by consumers out of pocket. Thus, consumers wanting to access CAM must have sufficient disposable income to support its use. Alternatively, consumers must have access to private health insurance to rebate the cost of CAM use that is covered by insurance; of course, access to such insurance is dependent on adequate disposable income.

ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 69

In accordance with the findings of other Western studies,6,11,12,27,40 the current analysis has shown that CAM users have relatively higher incomes and are more likely to have private health insurance than nonusers. That finding lends support to the claim that income and private health insurance are key enablers of CAM use. Given that the cost of CAM may be out of the reach of underprivileged populations, those findings again raise the issue of inequitable access to CAM services in Australia.

An unexpected finding, which appears to contradict the previous discussion, was that CAM users were 34% more likely to possess a government/concession card than nonusers. That finding is unusual because government concessions are typically paid to low-income earners.

Notwithstanding, because the type of concession was indeterminate, it was not possible to distinguish low-income concessions from other types of government support, such as disability-support payments. It is possible that the inclusion of the latter may have confounded the results because CAM use is frequently reported by people with disabilities and by those with disabling chronic disease.43-45 Need Factors The prevalence of chronic disease was shown to be significantly higher among consumers of CAM when compared with nonusers. Although the association between chronic disease and CAM use is well documented,6,13,19,27,29,46,47 the reasons for that relationship have not been fully explored.

Recognizing the factors that contribute to the relationship may engender a better understanding of the needs of consumers with chronic disease.

The use of CAM by people with chronic disease appears to be driven by a myriad of push-and-pull factors. Some consumers are attracted to the holistic nature of CAM.21,22,48 For others, use of CAM provides an opportunity to take an active role in oneâ&#x20AC;&#x2122;s health and to exert greater control over disease.22,48,49 Another pull factor is the frustration of chronic illness, which often leads to feelings of desperation and the need to find an immediate solution to a persistent health problem.22 A frequently reported push factor is dissatisfaction with conventional medicine, including a perceived lack of the effectiveness of conventional treatment, concerns about the safety of conventional medicines, and difficulties communicating with medical providers.22,48,49 Those drivers suggest that the mainstream health system, in its present state, may be failing to meet the distinct needs of consumers with chronic diseases and that CAM may be addressing some of those unmet needs.

The high rate of chronic disease amongst consumers of CAM might explain why CAM users were more likely to use pharmaceutical agents and to access the services of mainstream health providers. That idea is supported by the mounting evidence that links multicomorbidity with higher rates of health service use in the general population.50,51 Notwithstanding that evidence, it is possible that the relationship between CAM use and use of mainstream health services could be reflective of other important, yet unknown, factors.

70 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

Because CAM consumers report higher rates of health service and pharmaceutical use relative to nonusers, the assumption that CAM use unnecessarily prevents or delays access to mainstream medical treatment is put into question.52 Although that question was not explicitly examined in the ANHS, preventing the assumption from being categorically refuted, the finding does lend support to a growing body of evidence demonstrating greater conventional health service use among CAM consumers.53,54 Further research in the area is clearly needed; in particular, a need exists to establish whether CAM use unnecessarily delays access to mainstream medical treatment and whether the consequence of such delays are or are not detrimental to a consumerâ&#x20AC;&#x2122;s health and well-being.

Personal Health Practices CAM consumers are clearly different from nonusers in terms of personal health practices. For instance, consumers of CAM were more likely to engage in physical activity at levels recommended by the Australian national guidelines for physical activity55; to meet daily recommendations for intake of fruit (ie, 2 servings/day) and vegetables (ie, 5 servings/day) as outlined in the Australian dietary guidelines56; to breastfeed; and to be nonsmokers. When the findings are compared to the few studies that have examined those variables in CAM users,27,40,47,57 the results consistent.

It is not entirely clear why CAM consumers are more likely to engage in healthy lifestyle behaviors than nonusers. One possibility is that these behaviors are a product of comorbidity, with people often adopting lifestyle changes in response to a chronic disease diagnosis.58 However, Newsom et al59 challenge that view, with an analysis of data from a US Health and Retirement Study revealing that most individuals diagnosed with a new chronic condition failed to adopt healthier behaviors at up to 14 years postdiagnosis. A factor almost certainly contributing to the adoption of healthy behaviors is the health beliefs of consumers, with CAM users more likely to support a holistic view of health, to be more active participants in their health care and to possess greater health awareness behaviors.20-22 It is also conceivable that consumers of CAM might be more receptive to health promotion messages, a notion also supported by Nahin et al.40 An intriguing finding was that users of CAM were more likely to consume alcohol when compared with nonusers, though not to excessive levels. One possible interpretation of that finding is that CAM users consume alcohol to reduce the burden of chronic disease, among other reasons.60,61 Alternatively, it may be that the higher level of alcohol consumption reported by CAM consumers correlates with the higher incidence of chronic disease and mental illness in the population, with sufferers of those chronic illnesses perhaps motivated to use alcohol for medicinal purposes, such as the relief of depression or anxiety.62 Given the level of uncertainty on the issue, the association between alcohol consumption and CAM use warrants further exploration.

Leachâ&#x20AC;&#x201D;Profile of the CAM Consumer

Limitations A few limitations to the current study warrant consideration. First, given that the study was not longitudinal but a series of distinct, cross-sectional surveys, any changes observed over time could be the result of sample variation rather than a product of time. Second, the range of CAM products and services captured by the ANHS was not comprehensive. Similarly, because most surveys asked only about CAM service use over the 2 weeks prior to the survey, any use of CAM outside of that period was not captured.

Both of those factors were likely to have underestimated the extent of CAM use.

The pooling of cross-sectional data also has its limitations, including potential sampling overlap, the loss of independence between time points, and the smoothing of estimates. On the other hand, pooling improves effective sample size and reduces sampling error.62 Other strengths of the study include the reporting of data at multiple time points and the sourcing of data from a large, nationally representative sample of adults and children.

Implications The current research has not only provided additional insights into the CAM consumer, it has also highlighted a number of areas needing attention. The first area relates to the ANHS itself. It is clear that the survey has some deficiencies, particularly around the scope of CAM. To improve our understanding of health service usage in Australia and to better inform policy and practice, a much broader range of CAM services needs to be included in future versions of the survey. The second area relates to the implications of the findings for clinical practice and research.

Specifically, how can knowledge of the CAM user profile be harnessed to facilitate clinical decision making? And how can health services better meet the needs of CAM consumers?

Answers to those questions will not only be valuable for health services planning but also assist in delivering better health outcomes for CAM consumers.

CONCLUSIONS The current analysis of 5 ANHSs furthers the understanding of the CAM consumer. It has shown that being a married, well-educated, middle-aged to older woman predisposes an individual to using CAM, which is enabled by income and private health insurance. It also reveals that CAM users have comparatively healthier lifestyles than nonusers but report higher rates of chronic disease, use of pharmaceutical medicines, and health service usage. That finding suggests that the mainstream health care system, in its present state, is perhaps failing to meet the needs of consumers with chronic disease and that CAM may be addressing some of those unmet demands. The first step to addressing those needs and delivering better health outcomes for CAM consumers is to explore in greater depth the reasons for the different characteristics of CAM users and nonusers.

Leach—Profile of the CAM Consumer

AUTHOR DISCLOSURE STATEMENT The author has no competing financial interests.

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29. Spinks J, Hollingsworth B. Policy implications of complementary and alternative medicine use in Australia: Data from the national health survey. J Altern Complement Med. 2012;18:371-378.

30. Yamashita H, Tsukayama H, Sugishita C. Popularity of complementary and alternative medicine in Japan: A telephone survey. Complement Ther Med. 2002;10:84-93.

31. McEllistrem-Evenson A. Informing rural primary care workforce policy: What does the evidence tell us? A review of rural health research center literature, 2000-2010.

Grand Forks, ND: University of North Dakota Center for Rural Health; 2011.

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32. Desai P, Reidy A, Minassian D. Profile of patients presenting for cataract surgery in the uk: National data collection. Brit J Opthalmol. 1999;83:893-896.

33. Andersen R, Davidson P. Improving access to care in America: Individual and contextual indicators. In: Andersen R, Rice T, Kominski E, eds. Changing the US Health Care System: Key Issues in Health Services, Policy, and Management. San Francisco, CA: Jossey-Bass; 2001.

34. Australian Bureau of Statistics. National Health Survey, 1989-90: User’s Guide.

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Canberra, ACT, Australia: Australian Bureau of Statistics; 2006.

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39. Babitsch B, Gohl D, von Lengerke T. Re-revisiting Andersen’s behavioral model of health services use: A systematic review of studies from 1998–2011. Psychosoc Med. 2012;9:1-15.

40. Nahin R, Dahlhamer J, Taylor B, et al. Health behaviors and risk factors in those who use complementary and alternative medicine. BMC Public Health.

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41. Hori S, Mihaylov I, Vasconcelos J, McCoubrie M. Patterns of complementary and alternative medicine use amongst outpatients in Tokyo, Japan. BMC Complement Altern Med. 2008;8:14.

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43. Carlson M, Krahn G. Use of complementary and alternative medicine practitioners by people with physical disabilities: Estimates from a national US survey. Disabil Rehabil. 2006;28:505-513.

44. Leong E, Semple S, Angley M, et al. Complementary and alternative medicines and dietary interventions in multiple sclerosis: What is being used in South Australia and why? Complement Ther Med. 2009;17:216-223.

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46. McCann L, Newell S. Survey of paediatric complementary and alternative medicine use in health and chronic illness. Arch Dis Child. 2006;91:173-174.

47. Simoes-Wust A, Rist L, Dettling M. Self-reported health characteristics and medication consumption by cam users and nonusers: A Swiss cross-sectional survey. J Altern Complement Med. 2014;20:40-47.

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49. Shirofi S. Complementary and alternative medicine (CAM) among hospitalised patients: Reported use of CAM and reasons for use, CAM preferred during hospitalisation, and the socio-demographic determinants of CAM users.

Complement Ther Clin Prac. 2011;17:199-205.

50. Hernandez C, Jansa M, Vidal M, et al. The burden of chronic disorders on hospital admissions prompts the need for new modalities of care: A crosssectional analysis in a tertiary hospital. QJM. 2009;102:193-202.

51. Nagl A, Witte J, Hodek J, Greiner W. Relationship between multimorbidity and direct healthcare costs in an advanced elderly population. Results of the priscus trial. Z Gerontol Geriatr. 2012;45:146-154.

52. Curtis P. Safety issues in complementary & alternative medicine. In: Gaylord S, Norton S, Curtis P, eds. The Convergence of Complementary, Alternative & Conventional Health Care: Educational Resources for Health Professionals. Chapel Hill, NC: University of North Carolina; 2004.

53. Davis M, West A, Weeks W, Sirovich B. Health behaviors and utilization among users of complementary and alternative medicine for treatment versus health promotion. Heath Serv Res. 2011;46:1402-1416.

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57. Steinsbekk A, Rise M, Johnsen R. Changes among male and female visitors to practitioners of complementary and alternative medicine in a large adult Norwegian population from 1997 to 2008 (the hunt studies). BMC Complement Altern Med. 2011;11:61.

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CAM Practitioner: Where alternative meets mainstream.

There are nearly 4 million articles in PubMed that respond to the search medical. But when you narrow it to complementary medicine the number of hits drops to just over 200,000. But even 200,000 are a lot of articles to sift through. CAM Practitioner is a new site to help target the most recent and most heavily researched topics within PubMed. CAM Practitioner is a valuable resource you can use to access leading research to guide your practice.

According to the National Institute of Health, more than 30 percent of adults and about 12 percent of children use health care approaches developed outside of mainstream Western, or conventional, medicine.

A recent survey found that the use of dietary supplements is the most popular complementary health approach.

The most frequently cited reasons for CAM use are general wellness, and pain management.

CAMPractitioner.com

CONVERSATIONS

Edwin Lee, MD: Treating the Cause and Teaching the Young Interview by Craig Gustafson Edwin Lee, MD, graduated from Medical College of Pennsylvania and then completed 2 fellowships—in critical care medicine and in endocrinology and metabolism—at the University of Pittsburgh. He has served as the team endocrinologist for the Cleveland Indians during their spring training in Florida, and he is an active member of the Age Management Medicine Group and the American Association of Clinical Endocrinology. (Altern Ther Health Med. 2016;22(4):74-76.)

Alternative Therapies in Health and Medicine (ATHM): How early in life do you remember being interested in medicine, and were there any events or people who influenced that?

Dr Lee: Well, I was not really a great student and my father doubted if I would even graduate high school. I remember when I was young, he would show me the Parade magazine and there were pictures of all these different occupations with their salaries. I remember he said, “Well, I think this is what you’ll be.” It was a picture of a clown. I was always the clown in class, never really focused well in elementary school.

Later in life, I started studying harder and got better grades and eventually did really well in high school, college and in medical school and moved on from there. I am not quite sure exactly when I actually had the inkling that I wanted to go into medicine. I did not want to announce that because even my father, who was a professor of political science, did not really have much faith in me when I was young, so I kind of kept it to myself. I would say, if I had to pick an age, it was in sixth or seventh grade when I thought, “maybe I can go into medicine.”

ATHM: As you became more interested in academic performance, was there something particular that drew your interest toward medicine?

Dr Lee: That is the big question during medical school interviews: “What brought you into medicine?” and “Who was your influence in medicine?” I cannot remember exactly the particular person for that, but I remember during my residency, one of my mentors—his name was Larry Merkle, MD. He actually was a pediatric/adult endocrinologist, a hormone 74 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

specialist. He really, profoundly, influenced a love for me to get into hormones and endocrinology.

We published a lot of papers, case reports, when we worked together. We had this wonderful relationship. He actually encouraged me to enter in a research contest among residents in Pennsylvania. I submitted a paper during my residency for this research project, looking at how many people actually got the PNEUMOVAX, or pneumococcal vaccine polyvalent, after a splenectomy. The interesting finding was if you were admitted on the surgical team, chances were 99% that you were going to get the PNEUMOVAX. If you were admitted on the medical team, chances were less than 50%. I got second place in the state championship. Dr Merkle really showed me the world of endocrinology and that really opened my eyes.

ATHM: As you found yourself drawn toward endocrinology and progressed through medical school, what shaped your interest in optimizing health rather than just treating disease?

Dr Lee: During my residency, I met Dr Merkle and he encouraged me to do a fellowship in endocrinology. But there was another person who also got me interested in critical care medicine. His name is Richard Snyder, MD, the director of our residency program, and he encouraged me to do a fellowship in critical care medicine. So I decided to do 2 fellowships after my 3 years of internal medicine. Critical care and endocrinology fellowships are opposite ends of the medical spectrum. One is really emergency or acute medicine.

The other one is all intellectual—understanding pathways. I did both my fellowships at the University of Pittsburgh.

After completing the fellowships, I decided to go only into endocrinology. My first position was at Gessler Clinic in Winter Haven, Florida. I happened to be the first endocrinologist in this town. I joined a large, multispecialty group and right away I became very busy doing conventional endocrinology. I would see about 30 patients a day and treat a lot of diabetics, thyroid problems, and other endocrine disorders—including growth hormone deficiency. During that process I saw the writing on the wall: The whole medical system is broken. I was realizing that there had to be a different way to treat people, rather than through our conventional insurance/medical system.

Conversations With Edwin Lee, MD

One day, I went to a conference of the Age Management Medicine Group, or AMMG, at Red Rock in Las Vegas. I wanted to see what antiaging meant—what this whole science was. I went there and sat in the very back. I was really impressed with those lectures and immediately saw the light at the end of the tunnel. I realized that this was the field of medicine I wanted to get into: nutritional medicine, functional medicine, and trying to figure out what the root cause is. When I got back from Las Vegas, I told my wife, “I really want to switch careers. I want to learn more about this.” I had started in 1998 in Winter Haven and in 2008 I decided to start my own practice in Orlando, Florida.

and you have to remove toxins. We live in such a toxic world.

It is so important to detoxify and reduce exposure. You can do genetic testing to see how well your liver can remove toxins. A lot of people have some minor SNPs, or single nucleotide polymorphisms, or genetic defects, in terms of removing toxins. Nutrition is a huge thing. A lot of people, even though they try to eat healthy, their bodies can benefit from better nutrition with intravenous nutrtion. Heavy metals are a big component. If you look at the autopsy reports, heavy metals are found in the thyroid. That is something that you have to check for and you have to treat.

ATHM: How do you draw heavy metals out of the thyroid?

ATHM: You mentioned that, when you were doing the conventional endocrinology role, you were seeing a lot of thyroid issues. Thyroid tends to be something that confounds a lot of conventional doctors and is something that integrative practitioners have been known for dealing with successfully.

Did that evolve into a core area of your practice or is that something that fell away as you transitioned?

Dr Lee: No, it has never fallen away. I still see it all day long.

A lot of people are affected with thyroid conditions, but now I see it differently. What I see in 2016 is very different from what I saw prior to 2008.

ATHM: Is that because of a shift in your perspective?

Dr Lee: Yes. I would say a lot of thyroid disease is involved with environmental toxins or heavy metals. The thyroid can easily be affected. It is like a canary in a coal mine. It is one of those things that now I know how to deal with. Not all the time, certainly, but I can reverse Hashimoto’s thyroiditis.

Before, I would have had no idea how to lower thyroid antibodies. It is a process. It is something that I am still reading about as much as I can and trying to learn as much as I can, because no one knows it all.

ATHM: How did your protocol for working with Hashimoto’s develop?

Dr Lee: Going to a lot of conferences, meeting other people, and reading a lot. It is all a part of the process. I was invited to write a chapter for a functional medicine book on the thyroid, specifically Hashimoto’s. It was an honor, but I have too much going on right now, so I had to say I could not do it with my family commitments.

ATHM: What do you find are the keys to address during treatment?

Dr Lee: I look at many different topics to help with Hashimoto’s. The first thing that I look for is leaky gut. If you have a leaky gut or a hole in your gut, you have to fix that.

That is a big source for people with thyroid conditions, especially Hashimoto’s. In most cases, you have to fix the gut Conversations With Edwin Lee, MD

Dr Lee: Heavy metals are not only in your thyroid, but in your brain, in the breast, in the testicles, and in every part of our body. How do you get heavy metals out? You have got to chelate.

ATHM: What do you find the most success with?

Dr Lee: It depends on which heavy metals they have. If there is a lot of lead, then I use EDTA; for mercury I use DMSA. I see a lot of lead and mercury in my patients.

ATHM: Your Web site mentions the importance of dealing with endocrine disruptors. Can you talk a little bit about the role they play in modern disease states?

Dr Lee: The endocrine disrupting agents are huge. What I see is younger and younger men with low testosterone. You see younger women, instead of being 12, having their first period at 9 or even 8 years old. There are so many xenoestrogens, or estrogen-like molecules, that are causing endocrine disruption. Bottled water contains bisphenol A and phthalates and personal care products contains parabens.

A lot of these industrial chemicals are not regulated and are poisoning our water, air, and food system. The environment is becoming more and more toxic. Even though we live in the United States, a lot of these chemicals are not regulated.

Unfortunately, a lot of these endocrine disrupting agents are also linked to cancer. It is one of those really important things: We have to detox. We have to remove toxins from our system. Not everyone is blessed when it comes to removing toxins from your system; some people are genetically cursed.

They have difficulties in doing it. That is why I offer some of my patients a genetic test, to detect a defect, in terms of removing toxins from their systems. If you do, then sometimes you may need to compensate by eating a lot of broccoli. Or you may need to take more methylated B vitamins to help your defective enzymes.

It is all about trying to keep your DNA healthy. Once you start damaging your DNA, then basically, chronic disease and everything else starts falling into place, including cancer. It is all about DNA protection.

ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 75

ATHM: You mentioned that early puberty is one of the ways that these endocrine disruptors are manifesting in youth. Are there any other signs that go along with that?

Dr Lee: Another sign is you can see is the rise in infertility.

There are more and more infertility clinics around the country. You are wondering, “Why? Over the past 40 years, why are we all of a sudden seeing all this?” You are seeing younger periods, but you are also seeing higher rates of infertility. Down the line, you are seeing younger and younger people with cancer. It rears its head in different ways.

It is not just, “Oh, look at that. Her period started at 9.” You can see 35-year-olds with breast cancer. Why? ATHM: Is there a link between endocrine disruptors and early obesity?

Dr Lee: Huge, definitely. A whole topic of insulin resistance and with obesity and with prediabetes leading to type 2 diabetes. It is all the junk food that is being put out there, which has all these chemicals in it, like Cheetos and Doritos.

For kids, they cannot stop eating them. They are full of chemicals. We do not have a chance. The food industry—it is a billion-dollar industry. How can you go against those commercials? No one is putting commercials on for broccoli or cauliflower or kale. We live in a society that wants convenience. They do not want to work hard at it. If it tastes good and smells good and it is made out of plastic, who cares? It is sad. It is not the terrorists who will kill our country, it is the decline in our health from all the toxins in our society.

ATHM: What gave you the idea to start writing books for kids?

Dr Lee: It is because of the whole issue we just talked about.

We have to educate our youth if we have any chance to make a difference in the next generation. We need to start at a younger age. I actually did research, looking for children’s books on health to help teach my kids on how to be healthy and found none that were educational and also entertaining.

My approach in writing these books was to make it fun and entertaining, and to keep it simple so that they can say, “Hey, there are 3 secrets that I need to do so I do not have a heart attack.” It does work in helping some kids in losing weight. I actually have read several of these books to different schools because I have 2 kids—one in seventh grade and one in sixth grade—but I still have connections to their old elementary school. I just wish more parents knew about these books.

One is about the brain and the other is about the heart. The one with the heart is called Your Amazing Heart1 and then there is Your Awesome Brain.2 Both of them show children and adults what happens in 10, 20, and 30 years to your heart and brain when you don’t take of your body. One shows what a heart attack is, and the other one shows 2 different types of stroke. Both of these 76 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

books have 3 secrets on how to keep brains and hearts healthy. For the 3 secrets of the heart, it is about exercising, eating more vegetables, and eating less. It is a really simple concept, but our youth have to understand why eating too much sugar is bad for your health.

ATHM: When you start talking about prevention and staying healthy, it really is something simple enough for children to understand. But it’s just that adults do not want to do it.

Dr Lee: The only real chance we have in making a difference in this world about improving our health and not being dependent on pharmaceutical medications is to educate our youth. That is the main reason I wrote these 2 books.

One reason that these books can make a make difference is that they teach why eating too much sugar over time leads to the top 2 causes of mortality: heart attacks and strokes. So many parents find it frustrating that they tell their child not to eat too much sugar like ice cream, candy, or soda, and the kids will ignore their advice, because it tastes good and they have no idea what will happen to them over time. Education is the key in this battle of chronic diseases. I have read those books to third-grade grade up to sixth-grade grade students when I volunteered at different schools. Once I was reading Your Amazing Heart to the fourth graders and one kid was eating candy. During the middle of the read, that kid stood up and threw her entire bag of candy in the trash can because she realized she wanted to be healthy. Once they understand that sugar is the devil and that it starts forming plaque or atherosclerosis, and that plaque can eventually rupture and cause an immediate blood clot, and results in a heart attack or a stroke, they can actually understand why eating too much sugar is bad. That is the beauty of these children’s books: They help kids and adults understand why eating too much sugar is bad for you and gives 3 simple secrets on how to be healthy. This is advice that we should have received when we were young.

REFERENCES

1. Lee E. Your Amazing Heart. Orlando, FL: IHB Publishing, LLC; 2013.

2. Lee E. Your Awesome Brain. Orlando, FL: IHB Publishing, LLC; 2015.

Conversations With Edwin Lee, MD

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CONFERENCE CALENDAR Re-examining the Oath: Reversing Nutrient Depletion and Iatrogenic Toxicity September 8-11, 2016—Toronto Marriott Downtown Eaton Center Hotel, Toronto, Ontario The International College of Integrative Medicine is a nonprofit medical association that has been organizing CME conferences in the Great Lakes region for more than 30 years. Join us in Toronto to re-examine current approaches to cardiology, pain, autoimmune disorders, psychiatric care, and endocrinology. Our speakers will guide you through the maze of side effects, nutrient depletion, and toxicity, and they will reinvigorate your practice of medicine with new ideas to address iatrogenic damage and achieve break-through healing for your patients. For more information, please visit http://www.IntegrativeMedicineConference.com/.

14th Annual International Restorative Medicine Conference September 16-18, 2016—Sonesta Resort, Hilton Head Island, South Carolina The 14th Annual International Restorative Medicine Conference is an extraordinary opportunity to hear expert speaker’s present emerging research and up-to-date protocols that empower you to effectively treat your patients. The annual conference consistently lives up to its reputation for providing innovative educational opportunities for practitioners. For more information, please visit http://restorativemedicine.org/aarm2016/.

American College for Advancement in Medicine Annual Conference September 15-18, 2016—Hilton El Conquistador, Tucson, Arizona ACAM will host its annual conference titled “What’s Next: An Interdisciplinary Approach to Advanced Prevention.” For more information, please visit http://www.acam.org/.

Applying Functional Medicine in Clinical Practice (AFMCP) September 19-23, 2016—Marriott Baltimore Waterfront, Baltimore, Maryland AFMCP teaches health care practitioners to more effectively integrate science, research, and clinical insights to treat and prevent disease and maintain health.

Established and emerging diagnostics, therapeutics, and prevention strategies are extensively covered. AFMCP integrates these approaches through the Functional Medicine Matrix Model (an innovative and practical assessment tool) and the emphasis on a therapeutic partnership between patient and practitioner. AFMCP is a well-orchestrated, comprehensive, patient-centered education program that helps you deepen your clinical understanding and practical application of the Functional Medicine Matrix Model. For more information, please visit https://www.functionalmedicine.org/.

The American Academy of Anti-Aging Medicine (A4M): BHRT Symposium September 21-24, 2016—Hyatt Regency Dallas, Dallas, Texas In this exclusive 3.5-day seminar, you will be able to analyze the medical evidence on BHRT, listen to experts who are actively practicing this specialty, and get the information needed to merge BHRT safely into your practice. The traditional medical view of aging is a process with inevitable complications such as cardiovascular disease, diabetes, cancer, dementia, and the general steady decline of quality of life. For more information, please visit http://www.a4m.com/anti-aging-conferences.html/.

7th Annual Integrative Medicine for Mental Health Conference September 29-October 2, 2016—Reston, Virginia This international conference will explore the field of integrative medicine in the treatment of mental health, autism, and related disorders. The current trial-and-error, polypharmacy approach to the treatment of psychiatric disorders may not work for everyone. Research studies have revealed that many disorders such as depression, bipolar disorder, anxiety, OCD, eating disorders, and autism spectrum disorders often have dietary and biological causes, which contribute to symptoms. Patients have better outcomes when these causes are successfully addressed and treated through a combination of specialized testing and nutritional therapies, even in combination with traditional approaches. For more information, please visit http://www.IMMH2016.com/.

78 ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4

Inflammation: Cooling the Heat September 30-October 1, 2016—Hilton Scottsdale Resort and Villas, Scottsdale, Arizona InnoVision Professional Media is sponsoring a unique health care symposium that will focus on inflammation. The event will combine the latest research and applications into a 2-day event with CMEs. Attendees will hear from leading healthcare thought leaders who will share their perspective on inflammation for your patient’s health. For more information, please visit http://innovisionhm.com/inflammation/.

11th Annual Cardiometabolic Health Congress October 5-8, 2016—Sheraton Boston Hotel, Boston, Massachusetts The Cardiometabolic Health Congress provides a one-of-a-kind opportunity to stay informed on the latest scientific and clinical developments in these overlapping disease areas through a comprehensive and integrated agenda.

The CMHC has grown to be the largest multidisciplinary conference addressing the prevention, diagnosis, and management of cardiometabolic diseases in the United States. CMHC offers new educational formats, 27+ credit hours, symposia and workshops, lively debates with ample time for Q&A, renowned faculty and Meet-the-Expert sessions, and an expanded exhibit hall showcasing technological innovations, products, and prevention tools to improve your practice. For more information, please visit http://www.cardiometabolichealth.org/2016/.

AAEM 2016 Annual Meeting October 6-9, 2016—Marriott San Diego La Jolla, La Jolla, California The goal of this conference is to present current data regarding mitochondria as a therapeutic target in many disease states. The information presented will better train primary care clinicians with the knowledge and skills needed to help prevent chronic disease in their patients, as well as identifying mitochondrial dysfunction and formulating a more comprehensive and effective approach to managing and even eliminating many modern complex chronic disease states. For more information, please visit http://aaemconference.com/fall/.

IVC & Cancer Symposium October 13-15, 2016—Hotel at Old Town, Wichita, Kansas Biannually, Riordan Clinic IVC Academy holds an IVC and Cancer Symposium in Wichita that offers doctors from around the world the opportunity to visit our facilities, learn more about high-dose IV vitamin C (IVC), listen to leading doctors in functional medicine, and learn how to use IVC in their offices. For more information, please visit https://riordanclinic.org/riordan-ivc-academy-symposium/.

American Meditation: The Heart and Science of Yoga October 25-29, 2016—Cranwell Resort and Spa, Lenox, Massachusetts Dr Jyothi Bhatt will lecture on the benefits of the ancient chakra system as a complementary diagnostic tool at the eighth annual mind/body medicine CME conference. Dr Bhatt will explain how a basic understanding and practical application of Ayurveda can be used alongside allopathic medicine in a complementary manner. For more information, please visit http://americanmeditation.org/portfolio/physicians-cme-conference/.

Functional Medicine Advanced Practice Modules (APMs) October 28-30, 2016—Hyatt Regency, Chicago, Illinois Join us for “GI—Restoring Gastrointestinal Equilibrium: Practical Applications for Understanding, Assessing, and Treating Gut Dysfunction.” This Advanced Practice Module takes a whole-systems approach to evaluating and treating not only local gastrointestinal disease, but many systemic diseases that are linked to gastrointestinal (GI) dysfunction. This course will supply you with the foundational background, insight, and in-depth clinical thinking to confidently work up and treat patients who may present with conditions, signs, and symptoms indicative of GI dysfunction. We will discuss in detail the important laboratory evaluations to be considered, the appropriate clinical connections that must be made, and the treatment approaches that should be used. For more information, please visit https://www.functionalmedicine.org/.

Conference Calendar

Functional Medicine Advanced Practice Modules (APMs) October 28-30, 2016—Hyatt Regency, Chicago, Illinois Join us for “Detox—Understanding Biotransformation and Recognizing Toxicity: Evaluation and Treatment in the Functional Medicine Model.” There is persuasive evidence that even low-level toxic exposures contribute to the development of a variety of chronic health conditions, including fatigue, endocrine disruption, and chronic degenerative diseases such as Parkinson’s.

Given the ubiquitous nature of chemicals in the environment, it is likely that the single exposure model of toxicology is more the exception than the rule.

It is therefore critical for clinicians to learn how to assess both exposures and total toxic load to appropriately assess and address each individual’s toxicological situation. Our expert faculty team will review the foundational biochemistry and genetics of biotransformation pathways, connect organ system dysfunctions to potential toxic exposures, and detail the available laboratory evaluations useful in working up a toxin-exposed patient. Once these important clinical connections are made, the team will detail specific treatment approaches. This program also uses a case-based, integrated approach to deliver effectively the tools necessary for clinicians to diagnose and treat the toxic component of their patients’ total health pictures. For more information, please visit https://www.functionalmedicine.org/.

Nutrition Pro 2016 Symposium: Personalizing Medical Nutrition Therapy Saturday, November 12, 2016—Hilton San Diego Resort, San Diego, California This clinical symposium will bring together experts on two very important and timely topics and is geared to all health professionals who utilize nutrition as a practice tool. Join us and add to your nutrition science knowledge and enhance your clinical skills. For more information, please visit http://www.nutritionspecialists.org/NutriPro2016/.

AIHM Annual Conference: People Planet, Purpose October 30-November 3, 2016—Paradise Point, San Diego, California Join the Academy of Integrative Health & Medicine annual conference and workshops. For more information, please visit https://www.aihm.org/.

The American Academy of Anti-Aging Medicine (A4M) 24th Annual Winter World Congress December 9-11, 2016—Venetian/Palazzo Hotel, Las Vegas, Nevada The American Academy of Anti-Aging Medicine (A4M) invites you to attend the 24th Annual World Congress on Anti-Aging, Regenerative, and Aesthetic Medicine. A4M is the largest antiaging and aesthetic event with more than 3000 health care practitioners, both domestic and international, attendees. This event will include board certification exams, fellowship modules, general conference activities, and exhibition. For more information, please visit http://www.a4m.com/.

GPL University Workshops by The Great Plains Laboratory, Inc November 5-6, 2016—Dallas, Texas Learn how to effectively integrate our comprehensive testing into your practice to enhance your bottom line and achieve greater outcomes for your patients.

Upcoming workshops include those on organic acids testing and genetic testing in San Jose, CA, and Dallas, TX. For all workshop details, including all dates and locations, and to register, go to www.GPLUniversity.com/.

13th International Conference of Society for Integrative Oncology November 6-8, 2016—Miami, Florida Multidisciplinary oncology practitioners from around the globe, including stakeholders from major cancer centers, convene at SIO annual international conferences to discuss the evolution of evidence-based integrative oncology in practice, the steadily growing science base, and its continued rise in popularity use as patients demand a whole-person approach to cancer care with mind, body, and spirit. For more information, please visit https://integrativeonc.org/.

The American College of Nutrition’s 57th Annual Conference— Translational Nutrition: The Science of Personalized Nutrition November 9-11, 2016—Hilton San Diego Resort, San Diego, California Nutrition is the single most important determinant of human health.

Personalization maximizes nutrition’s effect, and health care practitioners can now use the science of personalized nutrition to maximize their patient’s long-term health. This interactive educational event offers an understanding of the latest research and clinical applications of nutrigenetics and nutrigenomics. It will provide strategies for designing optimized interventions that improve health and well-being and prevent nutritionrelated diseases. Join us in San Diego for the nutrition science conference of the year! The ACN annual conference is a must-attend for anyone interested in the field of nutrition science and is a wonderful opportunity to connect with world-renowned researchers and clinicians to establish a network of like-minded professionals. Translate nutrition science into practice by exploring the science of personalized nutrition. For more information, please visit http://www.americancollegeofnutrition.org/conference/.

Gut-Brain Relationship Conference November 11-12, 2016—Marriott Marina del Rey, Marina del Rey, California InnoVision Professional Media is sponsoring a unique health care symposium that will focus on the unique relationship between the gut and the brain. The event will combine the latest research, testing techniques, and applications into a 2-day event with CMEs. Attendees will hear from leading health care thought leaders who will share their perspective on this important relationship for your patient’s health. For more information, please visit http://innovisionhm.com/gutbrain/.

2017 South Beach Symposium February 9-12, 2017—Loews Miami Beach Hotel, Miami Beach, Florida Attend the 15th Annual South Beach Symposium, February 9-12, at the Loews Miami Beach Hotel. This must-attend conference features cutting edge educational sessions with educational tracks featuring the Masters of Pediatric Dermatology Symposium, the South Beach Clinical Dermatology Symposium, the South Beach Aesthetics Symposium and the Practice Management Symposium. For more information, please visit http://www.southbeachsymposium.org/.

The Roots of Toxicity March 2-4, 2017—The Hyatt Regency, Savannah, Georgia Explore the connection between physicians and dentists at this joint meeting of the International Academy of Biological Dentistry & Medicine, International College of Integrative Medicine, American Academy of Environmental Medicine and International Academy of Oral Medicine and Toxicology. More than 500 dentists, physicians, and researchers are expected to attend. For more information, please visit https://iaomt.org/events/upcoming-meetings/.

2017 Joint American Homeopathic Conference (JAHC) March 31-April 2, 2017—Loews Atlanta Hotel, Atlanta, Georgia Join the Joint American Homeopathic Conference (JAHC) for its 12th annual conference. This special event is the largest gathering of the homeopathic community in the United States. Each year, the JAHC features some of the most well-known, experienced, successful homeopaths from around the globe. For more information, please visit http://www.homeopathycenter.org/.

For additional listings, please visit http://alternative-therapies.com/.

Conference Calendar

ALTERNATIVE THERAPIES, JUL/AUG 2016 VOL. 22 NO. 4 79

INFLAMMATION: COOLING THE HEAT

THE GUT-BRAIN RELATIONSHIP CONFERENCE

SEPTEMBER 30-OCTOBER 1, 2016 SCOTTSDALE, ARIZONA

NOVEMBER 11-12, 2016 MARINA DEL REY, CALIFORNIA

PRESENTED BY:

FOR MORE INFORMATION, VISIT HTTP://IVPMEDUCATION.COM

INFLAMMATION:

Cooling The Heat September 30-October 1, 2016 | Scottsdale, AZ Hilton Scottsdale Resort and Villas, Scottsdale, Arizona 6333 N Scottsdale Rd., Scottsdale, AZ 85250

innovisionhm.com/inï¬&#x201A;ammation 877/904.7951

GUT-BRAIN

RELATIONSHIP November 11-12, 2016 | Marina del Rey, CA Marina del Rey Marriott 4100 Admiralty Way, Marina del Rey, CA 90292

innovisionhm.com/gutbrain 877/904.7951

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