SPECIAL ISSUE

Pediatrics

SEPTEMBER 2016 SUPPLEMENT

Asthma’s Perfect Storm: Bacteria, Vitamin D, Stress, and Inflammation

Probiotics for Infant Colic & Kids’ IBS

Green Spaces Improve Quality of Life and BMI

Iron Supplementation in Pregnancy and Infancy

IBS and Probiotic Treatment in Pediatric Patients

Does Homeopathy Prevent Flu?

Presents

October 13-16, Hyatt Regency Tamaya Resort & Spa Albuquerque (Santa Ana Pueblo), New Mexico

The BUSINESS of Better Medicine

Tina Kaczor, ND Dickson Thom, ND Dan Kalish, DC Leandra FishmanConsultant

Lorne BrownBSc, CPA

Tieraona Low Dog, MD Joseph Pizzorno, ND Mimi Guarneri, MD

Keynote Speakers

Session & Workshop Speakers

Julia Zaslow, NC Miriam Zacharias MS, LPSN

Rebecca Hunton, MD Paul Anderson, NMD

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SPECIAL ISSUE PEDIATRICSSEPTEMBER 2016 VOL 8, NO. 91 (SUPPL)

Contents

Copyright © 2016 by the Natural Medicine Journal. All rights reserved.

PEER-REVIEWED ARTICLE

6 Asthma’s Perfect Storm

SPONSORED PODCAST

16 Efficacy of Probiotics for Infant Colic ABSTRACTS & COMMENTARY

18 Usable Green Spaces Can Affect Children’s Health-Related Quality of Life and BMI

20 Parental Sleep and Reported Sleep Quality of Children

24 Iron Supplementation in Pregnancy and Infancy

26 IBS and Probiotic Treatment in Pediatric Patients

30 Does Homeopathy Prevent Flu?

http://eepurl.com/d6zXbWANT TO GET NATURAL MEDICINE JOURNAL IN YOUR INBOX EACH MONTH? SUBSCRIBE FOR FREE!

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email:drkurt@earthlink.net

LILIAN AU, ND, has been a part of Para-celsus Natural Family Health Center in Pasa-dena, California, for the past 7 years. She is a graduate of Southwest College of Natu-ropathic Medicine in Tempe, Arizona, and completed 3 years of residency through the National College of Natural Medicine based in Portland, Oregon. She received her bach-

elor’s degrees in biology and chemistry from Indiana Univer-sity – Bloomington. Before medical school she was a research associate in the Child Health Research Program at Children’s Memorial Hospital and helped to conduct studies on clinical and public health issues that affect children’s health. Au is also clinical adjunct faculty at Bastyr University California and currently serves as the secretary on the board of directors for the California Naturopathic Doctors Association. She is also a member of the Pediatric Association of Naturopathic Physi-cians. Au’s focus is in pediatrics and family practice, working particularly with women, infants, and children.

MATTHEW BARAL, ND, received his naturopathic medical degree from Bastyr University, Kenmore, Washington, in 2000. He is chair of the Department of Pedi-atric Medicine at the Southwest College of Naturopathic Medicine and Health Sciences (SCNM), Tempe, Arizona, where he teaches pediatrics in the classroom

and supervises student clinicians on clinical rotations. Baral designed the first naturopathic pediatric residency program in naturopathic medicine and serves as its director at SCNM. He is also the founding and current president of the Pediatric Association of Naturopathic Physicians.

KURT BEIL, ND, LAc, MPH, is a natu-ropathic and Chinese medicine practitioner in New York’s Hudson Valley region, as well as adjunct assistant research professor at the Helfgott Research Institute of the National College of Natural Medicine in Portland, Oregon. His research focuses on biomarker and psychometric assess-

ment of the restorative and therapeutic effect of natural envi-ronments. He is the founding cochair of the Health & Nature subcommittee of the Intertwine Alliance, a 150+ member coalition of nonprofits, governmental agencies, and private businesses promoting the parks, trails, and natural areas of the Portland Metro region. Beil maintains a research data-base related to the health benefits of contact with nature and speaks widely on this topic. He can be reached via email or at www. hudsonvalleynaturalhealth.com.

ERIN PSOTA, ND, completed her medical studies at the Canadian College of Natu-ropathic Medicine (CCNM) in 2005 after obtaining her bachelor of science degree from the University of Waterloo. In 2010, her passion for pediatric medicine led her to the Southwest College of Naturopathic Medicine in Arizona to pursue a pediatric residency.

In addition to maintaining a private practice in downtown Toronto, Psota is a clinical supervisor at CCNM and is actively involved with the College of Naturopaths of Ontario, the provincial regulatory body for naturopathic medicine.

PAUL RICHARD SAUNDERS, PhD, ND, DHANP, CCH, completed his docotorate in forest ecology at Duke University, his naturo-pathic degree at Canadian College of Natu-ropathic Medicine, and his homeopathic residency at National College of Naturopathic Medicine, Portland, Oregon, where he also earned a second naturopathic degree. He is professor of materia medica and clinical

medicine at the Canadian College of Naturopathic Medicine; senior naturopathic doctor, Beaumont Health System, Troy Hospital, Michigan; and adjunct professor of integrative medi-cine, Oakland University William Beaumont Medical School and has a private practice in Dundas, Ontario. Saunders was a member of the transition team that formed the Office of Natural Health Products, served as a natural health expert to the Directorate, and has served on several expert panels for Health Canada. He has conducted clinical research, super-vised students and residents, and published widely.

JACOB SCHOR, ND, FABNO, is a grad-uate of National College of Naturopathic Medicine, Portland, Oregon, and now prac-tices in Denver, Colorado. He served as president to the Colorado Association of Naturopathic Physicians and is on the board of directors of both the Oncology Association of Naturopathic Physicians and the Amer-ican Association of Naturopathic Physicians.

He is recognized as a fellow by the American Board of Natu-ropathic Oncology. He serves on the editorial board for the International Journal of Naturopathic Medicine, Naturopathic Doctor News and Review (NDNR), and Integrative Medicine: A Clinician’s Journal. In 2008, he was awarded the Vis Award by the American Association of Naturopathic Physicians. His writing appears regularly in NDNR, the Townsend Letter, and Natural Medicine Journal, where he is the Abstracts & Commentary Editor.

Contributors

Erin Psota, NDLilian Au, ND

Matthew Baral, ND

Kurt Beil, ND, LAc, MPH

Paul Richard Saunders, PhD, ND, DHANP, CCH

Jacob Schor, ND, FABNO

NMJ, SEPTEMBER 2016 SUPPLEMENT—VOL. 8, NO. 91 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. 5

MESSAGE FROM THE PUBLISHER

The Lifelong Impact of Integrative Pediatrics

Every medical specialty has its share of challenges and rewards. Pediatrics is no different. The pediatrician is often the very first doctor we are exposed to and that first encounter can stick with us for years after. A skilled pediatrician has the ability to relate to children and adolescents but also must address the information needs of the parents as well.

Pediatricians and family practitioners navigate a complex journey with their young patients, which includes constant movement through key growth stages. It’s an area of medicine in which integrative and naturopathic physicians can thrive.

While it is always a bit challenging to pick what gets to run in our special issues, our guest editor Matthew Baral, ND, did an outstanding job guiding this process. In addition, he also contributed this issue’s peer-reviewed paper on the complex topic of asthma and what integrative practitioners can do to help prevent and treat it.

This special issue is relevant not just to pediatricians, but to anyone who sees chil-dren in their practice. Our Abstracts & Commentary cover clinically relevant and diverse topics such as nature, prenatal sleep, iron supplementation, homeopathy, and probiotics. Our sponsored podcast is also on the topic of probiotics.

We hope you enjoy this special issue on pediatrics. Please share it with your colleagues and let us know what you think. Feel free to email me directly at Karolyn@IMPACThealthmedia.com. Thank you for your support of the Natural Medicine Journal!

Karolyn A. GazellaPublisher, Natural Medicine Journal

Copyright © 2016 by the Natural Medicine Journal. All rights reserved.

EDITOR IN CHIEFTina Kaczor, ND, FABNO

GUEST EDITORMatthew Baral, ND

ABSTRACTS & COMMENTARY EDITORJacob Schor, ND, FABNO

PUBLISHERKarolyn A. Gazella

ASSOCIATE PUBLISHERKathi Magee

VP, CONTENT & COMMUNICATIONSDeirdre Shevlin Bell

DESIGNKaren Sperry

PUBLISHED BYIMPACT Health Media, Inc.Boulder, Colorado

Natural Medicine Journal (ISSN 2157-6769) is published 14 times per year by IMPACT Health Media, Inc. Copyright © 2016 by IMPACT Health Media, Inc. All rights reserved. No part of this publication may be reproduced in whole or in part without written permission from the publisher. The statements and opinions in the articles in this publication are the responsibility of the authors; IMPACT Health Media, Inc. assumes no liability for any infor-mation published herein. Adver-tisements in this publication do not indicate endorsement or approval of the products or services by the editors or authors of this publica-tion. IMPACT Health Media, Inc. is not liable for any injury or harm to persons or property resulting from statements made or products or services referred to in the articles or advertisements.

6 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, SEPTEMBER 2016 SUPPLEMENT—VOL. 8, NO. 91 (SUPPL)

PEER-REVIEWED ARTICLE

Asthma’s Perfect Storm Bacteria, vitamin D, stress, and inflammation

ABSTRACTAsthma affects approximately 24 million Americans, and 6.3 million of those are under 18 years of age. The reli-ance on asthma medication as the only treatment for this widespread condition has had virtually no effect on asthma rates, which have continually increased since the 1980s. It is therefore imperative that the medical commu-nity at large start to commit to prevention as an equally important measure when considering asthma as a condi-tion. A holistic perspective should take into account all the factors affecting asthma prevalence and expose the connections between them.

INTRODUCTIONAsthma is one of the most common chronic diseases in childhood, second only to dental caries.1 Like many chronic conditions seen in both children and adults, asthma may be preventable and treatable with lifestyle changes and environ-mental improvements. Historically, the predominant medical approach to asthma management has been through the use of medications such as corticosteroids, beta-agonists, leukot-riene modifiers, anticholinergics, mast-cell stabilizers, meth-ylxanthines, and anti-IgE monoclonal antibodies.2 These medications are unquestionably effective at curbing or elim-inating the symptoms of asthma and saving lives. So effec-tive, in fact, that little else has the same immediate treatment response. That consequently lessens the perceived need of preventive and nutritional maintenance measures. However, asthma medications are not without adverse effects. Associa-tions between decreased bone mineral density and exposure to inhaled corticosteroids (ICS) have been reported.3-5 Most recently, ICS use for more than 6 months before 6 years of age proved to be a significant risk factor for decreased bone mineral density.6 Monoclonal antibody treatments, used in patients with severe and/or steroid-resistant asthma, have concerning adverse effects as well, including increased risk of cardiovas-cular and cerebrovascular events.7,8 Regardless, the FDA has approved 2 new monoclonal antibody treatments in the past year, one of which lists anaphylaxis and cancer as potential adverse effects.9,10 The leukotriene inhibitor montelukast has also been linked to neuropsychiatric events, including suicide

and depression,11 although there may be contributing factors to this risk, which will be discussed later in this paper.

Ignoring the research on potential roots of inflammation and aggravation of symptoms in asthmatic patients may be detrimental to the efforts of the National Heart, Lung, and Blood Institute’s National Asthma Education and Prevention Program (NAEP). Remarkably, since its creation in 1991 there has not been a decline in emergency room visits, hospi-talizations, or deaths in children with asthma.12,13 Despite the fact that asthma deaths overall have decreased,14 a trending increase in deaths due to asthma in children aged 0 to 4 years was seen from 1999 to 2009,14 implying that additional measures must be considered in the standards of asthma care. Additionally, asthma prevalence in children also trended upward in this same time period, plateauing after 2009 and followed by a modest decline in 2013 to 8.3%; however, the rate rose again to 8.6% in 2014.15,16

Parents are often told that their children will likely grow out of asthma, but according to a recent study by Andersson and colleagues, this may occur in only 21% of patients; women, severe asthmatics, and those with animal allergies have the lowest remission rates.17 Thus, since the majority of asthma patients do not have full resolution in their lifetime, more focus should be on preventive measures that are simple and noninvasive. Evidence shows that the most opportune times for preventive treatments are the prenatal and perinatal periods, through modification of diet and lifestyle factors.

THE MICROBIOMEThe microbiome has received considerable attention in medical communities in recent years, reflected by a large volume of published research on the subject. The intestinal flora plays a substantial role in directing immune system development in infants, including but not limited to improved thymus devel-opment and antibody response to vaccination.18 The intestinal milieu is an integral factor in asthma development through several mechanisms, including mucosal immunity,19 produc-tion of immunoglobulins E (IgE) and A (IgA),20 and modu-lation of allergic reactions to antigens.21 Lactic acid–forming

By Matthew Baral, ND

(continued on page 8)

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PEER-REVIEWED ARTICLE

bacteria specifically induce production of interluekin-10 (IL-10),22 an anti-inflammatory mediator, illustrating their role in asthma prevention. Interestingly, this is also a mechanism of corticosteroid therapy for alleviating asthma symptoms.23,24

Disrupting the internal microbial environment of preg-nant women often results in increased asthma risk in their offspring. A study of 39,907 mothers in China revealed that treatment of mothers with either penicillin or chloram-phenicol during pregnancy was associated with childhood asthma in their children, especially if treatment occurred during the first trimester.25 Metsala in Sweden showed that prenatal cephalosporin exposure, as well as infant exposure during the first year to cephalosporins, sulfonamides, trim-ethoprim, macrolides, and amoxicillin, was associated with an increased risk of asthma.26 Postnatal antibiotic exposure in infants seems to have similar effects in other areas of atopy; in a Swedish birth cohort of 4,051 children, antibiotic intake in the first year of life increased allergic rhinitis risk, while living on a farm decreased the risk.27 These findings are consistent with the hygiene hypothesis. However, another recent study questioned whether some of the data supporting the hygiene hypothesis is due to reverse causation. The correlation of asthma and antibiotic use during fetal and early life was only shown when antibiotics were used for respiratory infections and not for urinary tract or skin infections.28 Frequent respi-ratory infections are a known risk factor for asthma develop-ment. An earlier large meta-analysis of 21 research articles showed that probiotic administration during fetal and early life did not decrease asthma risk but did decrease atopic sensi-tization risk and total IgE levels in children.29 It is important to note here that studies showing an insignificant influence of probiotics on the development of asthma or atopy may be due to the limitations of investigating single-strain effects; measuring total microbial diversity and quantity seems to be a more reliable technique for determining the influence of the microbiome on the development of atopy.30,31

VITAMIN D: PRENATAL AND POSTNATALLike the microbiome, vitamin D has garnered consideration for its role in many conditions that have inflammation as a vital part of their pathophysiology. Vitamin D deficiency

[defined as 25-hydroxyvitamin D (25-OH vitamin D) level <20 ng/mL] during pregnancy can have significant inverse effects on asthma development and lung function.32 A 2014 study by Zosky showed that prenatal deficiency of vitamin D was related to increased asthma incidence at 6 years of age in boys, while girls showed a decrease in forced expiratory volume (FEV). When data was collected again at 14 years, girls whose mothers were vitamin D–deficient in pregnancy had adversely impacted FEV1/FVC (forced vital capacity) ratios. This pattern reflects existing data on asthma rates by gender, which show that males younger than 18 years have a 16% higher asthma rate than females the same age.33 Inter-estingly, several studies show gender differences with respect to lung development and asthma. In animal models, males have a stronger immune response when exposed to allergens, with higher rates of both eosinophil and neutrophil produc-tion compared to females.34 In humans and animals, there are also gender disparities in lung surfactant production, occur-ring earlier in female neonates than male.35 Vitamin D is intri-cately involved with maturation of the surfactant system.36 These influences of prenatal deficiency on asthma and lung function may be strongest if the mother is deficient between 16 and 20 weeks gestation, a time period when the majority of lung cell differentiation occurs.37 Furthermore, concerns have been expressed over earlier findings that supplementa-tion in late pregnancy may increase childhood asthma and eczema risk,38 but more recent research did not demonstrate any significant associations with development of any atopic conditions, including asthma.39

After birth, vitamin D supplementation in the infant can also play a critical role in asthma prevention and treatment. In the first in vivo study on vitamin D and its relationship to lung function and structural changes, Gupta et al discovered that children with moderate and steroid-resistant asthma were affected significantly by their vitamin D levels; asthma exac-erbations and steroid use were inversely related to vitamin D serum concentrations.40 Airway smooth muscle mass was also increased with lower vitamin D levels, but only in the steroid-resistant asthmatics in that study. This increase in mass may be a result of chronic inflammation, a phenomenon also seen

(continued on page 10)

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in those with chronic allergic rhinitis and subsequent turbi-nate hypertrophy. Gupta et al additionally reported a direct relationship between vitamin D levels and positive perfor-mance on the Asthma Control Test, a self-administered tool for identifying patients 4 to 11 years old with poorly controlled asthma.41 Reverse causation should also be considered; multiple studies show that vitamin D levels can be depressed as a result of systemic inflammation for up to 3 months afterwards.42-44

In 2008, the American Academy of Pediatrics (AAP) published guidelines for infant vitamin D intake at 400 IU daily,45 in order to maintain 25-OH vitamin D levels >20 ng/mL.46 However, the recommended daily intake for infants of 400 IU as stated in 2011 by the Institute of Medicine reveals that this would maintain a 25-OH vitamin D level of only 16 to 20 ng/mL.47 Considering that levels less than 20 ng/mL represent deficiency, and 20 to 32 ng/mL represents insufficiency,48,49,50 these recommendations will likely be inadequate for achieving necessary concentrations for many people. The AAP recom-mendations for breast-fed infants include continuation of supplementation unless an infant is additionally consuming at least 1 liter per day of vitamin D–fortified formula or 1 quart per day of fortified whole milk.47 Concerns expressed about vitamin D toxicity may be overestimated, as daily supplemen-tation in infants up to 1,600 IU per day does not appear to result in hypercalcemia.51-54 The standard recommendation for vitamin D intake during pregnancy is 400 to 600 IU per day. However, in the first study that tested the current prenatal upper limit of 4,000 IU per day, this dose produced sufficient levels in both the mother and neonate without any adverse effects, while the standard recommendation of 400 to 600 IU per day did not.55 Therefore, this author proposes that vitamin D intake guidelines should be revisited, at least for pregnant and breast-feeding women as well as infants.

Inverse relationships have been reported between vitamin D concentration and IgE levels, eosinophil count, hospitaliza-tions for asthma, lung function, and use of asthma medica-tions such as ICS and leukotriene inhibitors.56-58 Furthermore, Goleva et al found inverse relationships between vitamin D levels and both ICS use and IgE levels in asthma.59 Searing et al had similar findings and also discovered that vitamin

D in vitro increased corticosteroid effectiveness, evidenced by enhanced IL-10 production by CD4+ T cells.60 Previ-ously, Xystrakis et al found that CD4+ T cells of steroid-resistant asthmatics were unresponsive to dexamethasone by not producing IL-10, whereas cells from steroid-sensitive asthmatics did produce IL-10. Subsequently adding vitamin D to these steroid-resistant cells enhanced dexamethasone effectiveness by increasing IL-10 production to levels seen in steroid-sensitive cells.61 It has been postulated that corti-costeroid upregulation of renal 25-hydroxyvitamin D(3)-24-hydroxylase activity, which degrades vitamin D metabolites, is the mechanism responsible for reduced vitamin D levels in patients taking ICS.62,63 Vitamin D supplementation also attenuated the severity of atopic dermatitis, often a precursor to asthma, by regulating the balance of type 1 and type 2 T helper (Th1 and Th2) cells,64 which is skewed in asthmatics as well.

DIETARY AVOIDANCEThe effect of maternal diet during breastfeeding on atopic development has been extensively studied, with conflicting results. A study of primarily atopic mothers found that maternal cow’s milk avoidance while breast-feeding may increase risk of cow’s milk allergy in the infant.65 Avoidance in study participants resulted in lower cow’s milk–specific IgA in their breast milk. Subsequently, those infants who did develop cow’s milk allergy had much lower casein-specific IgA compared to control infants, as well as lower beta-lactoglob-ulin–specific and casein-specific IgG4 levels. The researchers demonstrated that breast milk low in cow’s milk–specific IgA reduced the antigen trafficking in vitro. The presence of secre-tory IgA would otherwise decrease this trafficking and there-fore reduce immune system exposure to those allergens at the mucosal barrier.66 Considering that most of the mothers and siblings of the infants in this study were atopic, more research is needed to determine whether these findings are applicable to the general population. Other research has confirmed that limiting the diet of a pregnant mother or a breastfeeding mother as well as the infant may not decrease risk of atopy or food-related allergies such as wheat and egg.67,68

(continued on page 12)

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PEER-REVIEWED ARTICLE

EMOTIONS AND ASTHMA The emotional link to asthma exists on several levels. Consis-tent feelings of shortness of breath or even the anticipation of an exacerbation can induce anxiety and depression, 2 commonly occurring comorbidities found in asthmatics as well as patients with chronic disease.69,70 To compound this scenario, chronic stress is a known precursor to decreased lung function as well as the fraction of exhaled nitric oxide, a marker for airway inflammation.71,72 As mentioned previously, asthma treatments such as montelukast may increase the risk for depression, but this may not be solely due to medication effects. Systemic inflammation can induce depression,73,74 and those with major depressive disorder show elevations in pro-inflammatory cytokines such as IL-6 and inflammatory marker C-reactive protein were not due to another existing condition.75,76 Interluekin-6 and tumor necrosis factor (TNF)-alpha are commonly elevated in asthmatics and are also associated with symptoms of depression.77,78 This asso-ciation may be explained through several factors; TNF-alpha can affect serotonin metabolism by activating indoleamine 2,3-dioxygenase, leading to a peripheral tryptophan deple-tion. Therefore supplementation may be of benefit and IL-1, IL-6, and TNF-alpha, pro-inflammatory mediators abundant in asthmatics, can stimulate hypothalamic-pituitary-adrenal (HPA) axis activity, as does acute stress.79,80 Conversely, an overactive HPA axis may be due to reduced sensitivity to endogenous (cortisol) and exogenous corticosteroids and thus the negative feedback they provide. One of the consequences of this blunted immune-suppressive action is higher TNF-alpha production demonstrated in asthma patients.81,82 This decreased response to corticosteroids has been identified in depressed patients as well.83-85

OXIDATIVE STRESS Increased oxidative stress plays a significant role and is a common finding in asthma.86 In fact, exhaled volatile organic compounds (VOCs), a marker of lipid peroxidation induced by reactive oxygen species, can help predict asthma exacerbations in children.87,88 During the inflammatory process, immune cells release reactive oxygen species that further increase the inflammatory response.89,90 In animal models exposed to

allergens, S-adenosylmethionine treatment decreased airway inflammation through suppression of pro-inflammatory cyto-kines, likely by reducing oxidative stress through its participa-tion in the methylation cycle.91 Relatedly, reduced eosinophil methylation activity was seen in asthma patients with high IgE levels, and to a lesser extent asthmatics without elevated IgE levels, when compared to controls.92 Another consider-ation is that reactive oxygen species can impair mitochondrial function, which can further reduce their ability to prevent oxidative stress, leading to airway inflammation, smooth muscle remodeling, and increased smooth muscle mass93 seen in both chronic obstructive pulmonary disease (COPD) and asthma.94,95 Other findings show that asthma symptoms were inversely related to serum selenium concentrations and directly associated with glutathione reductase activity in men.96 Guo et al additionally found that an antioxidant vitamin supple-ment can also attenuate oxidative stress and hence improve asthma control scores.97

CONCLUSIONThe existing volume of research on many aspects of asthma pathogenesis exposes the obvious connections between them. The use of pharmaceutical medication as the only approach to treat asthma has revealed that it is simply not sustainable. Without considering the measures stated here, we can expect asthma rates to remain unchanged or, more likely, to increase. Nevertheless, it is clear that asthma medications are neces-sary for the safe treatment of patients with asthma. However, stressing the importance of diet, vitamin D supplementa-tion, the microbiome, and emotions in all stages of life could diminish the tempest that is asthma and potentiate the change all physicians hope to see for this condition.

REFERENCES1 American Academy of Pediatric Dentistry. Early Childhood Caries. American Academy

of Pediatric Dentistry website. http://www.mychildrensteeth.org/assets/2/7/ECCstats.pdf. Accessed August 15, 2016.

2 National Asthma Education and Prevention Program. Expert Panel Report (EPR-3): Guidelines for the Diagnosis and Management of Asthma Guidelines for the Diagnosis and Management of Asthma. J Allergy Clin Immunol. 2007;120(5 Suppl):S94-S138.

3 Kelly HW, Van Natta ML, Covar RA, Tonascia J, Green P, Strunk RC, CAMP Research Group. Effect of long-term corticosteroid use on bone mineral density in children: a prospective longitudinal assessment in the childhood asthma management program (CAMP) study. Pediatrics. 2008;122:53-61.

(continued on page 14)

NMJ, SEPTEMBER 2016 SUPPLEMENT—VOL. 8, NO. 91 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. 13

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4 Allen HD, Thong IG, Clifton-Bligh P, Holmes S, Nery L, Wilson KB. Effects of high-dose inhaled corticosteroids on bone metabolism in prepubertal children with asthma. Pediatr Pulmonol. 2000;29:188-193.

5 Turpeinen M, Pelkonen AS, Nikander K, et al. Bone mineral density in children treated with daily or periodical inhaled budesonide: the Helsinki early intervention childhood asthma study. Pediatr Res. 2010;68:169-173.

6 Sidoroff VH, Ylinen MK, Kröger LM, Kröger HP, Korppi MO. Inhaled corticosteroids and bone mineral density at school age: a follow-up study after early childhood wheezing. Pediatr Pulmonol. 2015;50(1):1-7.

7 FDA Drug Safety Communication: FDA approves label changes for asthma drug Xolair (omalizumab), including describing slightly higher risk of heart and brain adverse events. Baltimore, MD: Johns Hopkins Office of Communications and Public Affairs; September 26, 2014. http://www.fda.gov/Drugs/DrugSafety/ucm414911.htm. Accessed August 15, 2016.

8 American Academy of Pediatrics. FDA warns of increased risks of asthma drug Xolair. AAP News. http://www.aappublications.org/content/early/2014/09/26/aapnews.20140926-1. Published September 26, 2014. Accessed August 15, 2016.

9 FDA approves Nucala to treat severe asthma [news release]. Baltimore, MD: Johns Hopkins Office of Communications and Public Affairs; November 4, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm471031.htm. Accessed August 15, 2016.

10 FDA approves Cinqair to treat severe asthma [news release]. Baltimore, MD: Johns Hopkins Office of Communications and Public Affairs; March 23, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm491980.htm. Accessed August 15, 2006.

11 Food and Drug Administration Office of Pediatric Therapeutics and Division of Pediatric and Maternal Health. Neuropsychiatric events linked to asthma medication. AAP News. 2015;36(4):18.

12 Weinberger M. Seventeen years of asthma guidelines: why hasn’t the outcome improved for children? J Pediatr. 2009;154(6):786-788.

13 Akinbami LJ. The State of Childhood Asthma, United States, 1980-2005. Hyattsville, MD: National Center for Health Statistics. Advance Data from Vital and Health Statistics. 2006;381. Available at http://www.cdc.gov/nchs/data/ad/ad381.pdf. Accessed August 16, 2016.

14 American Lung Association Epidemiology and Statistics Unit, Research and Health Education Division. Trends in Asthma Morbidity and Mortality. http://www.lung.org/assets/documents/research/asthma-trend-report.pdf. Published September, 2012. Accessed August 15, 2016.

15 Akinbami LJ, Simon AE, Rossen LM. Changing Trends in Asthma Prevalence Among Children. Pediatrics. 2016;137(1).

16 Centers for Disease Control and Prevention. Most Recent Asthma Data. http://www.cdc.gov/asthma/most_recent_data.htm#modalIdString_CDCTable_0. Updated March, 2016. Accessed August 15, 2016.

17 Andersson M, Hedman L, Bjerg A, Forsberg B, Lundbäck B, Rönmark E. Remission and persistence of asthma followed from 7 to 19 years of age. Pediatrics. 2013;132:e435-e442.

18 Huda MN, Lewis Z2, Kalanetra KM, et al. Stool microbiota and vaccine responses of infants. Pediatrics. 2014;134(2):e362-372.

19 Glück U, Gebbers JO. Ingested probiotics reduce nasal colonization with pathogenic bacteria (Staphylococcus aureus, Streptococcus pneumoniae, and beta-hemolytic streptococci). Am J Clin Nutr. 2003;77(2):517-520.

20 Erickson KL, Hubbard NE. Probiotic immunomodulation in health and disease. J Nutr. 2000;130(2S Suppl):403S-409S.

21 Matsuzaki T, Chin J. Modulating immune responses with probiotic bacteria. Immunol Cell Biol. 2000;78(1):67-73.

22 Miettinen M, Vuopio-Varkila J, Varkila K. Production of human tumor necrosis factor alpha, interleukin-6, and interleukin-10 is induced by lactic acid bacteria. Infect Immun. 1996;64(12):5403-5405.

23 Barnes PJ, Adcock IM. How do corticosteroids work in asthma? Ann Intern Med. 2003;139(5 Pt 1):359-370.

24 Umland SP, Schleimer RP, Johnston SL. Review of the molecular and cellular mechanisms of action of glucocorticoids for use in asthma. Pulm Pharmacol Ther. 2002;15(1):35-50.

25 Chu S, Yu H, Chen Y, Chen Q, Wang B, Zhang J. Periconceptional and gestational exposure to antibiotics and childhood asthma. PLoS One. 2015;10(10):e0140443.

26 Metsälä J, Lundqvist A, Virta LJ, Kaila M, Gissler M, Virtanen SM. Prenatal and post-natal exposure to antibiotics and risk of asthma in childhood. Clin Exp Allergy. 2015;45(1):137-145.

27 Alm B, Goksör E, Pettersson R, et al. Antibiotics in the first week of life is a risk factor for allergic rhinitis at school age. Pediatr Allergy Immunol. 2014;25(5):468-472.

28 Örtqvist AK, Lundholm C, Kieler H, et al. Antibiotics in fetal and early life and subse-quent childhood asthma: nationwide population based study with sibling analysis. BMJ. 2014;349:g6979.

29 Elazab N, Mendy A, Gasana J, Vieira ER, Quizon A, Forno E. Probiotic administra-tion in early life, atopy, and asthma: a meta-analysis of clinical trials. Pediatrics. 2013;132(3):e666-e676.

30 Abrahamsson TR, Jakobsson HE, Andersson AF, Björkstén B, Engstrand L, Jenmalm MC. Low gut microbiota diversity in early infancy precedes asthma at school age. Clin Exp Allergy. 2014;44(6):842-850.

31 Karvonen AM, Hyvärinen A, Rintala H, et al. Quantity and diversity of environmental microbial exposure and development of asthma: a birth cohort study. Allergy. 2014;69(8):1092-1101.

32 Zosky GR, Berry LJ, Elliot JG, James AL, Gorman S, Hart PH. Vitamin D deficiency causes deficits in lung function and alters lung structure. Am J Respir Crit Care Med. 2011;183(10):1336-1343.

33 American Lung Association. Trends in asthma morbidity and mortality, September 2012. http://www.lungusa.org/finding-cures/our-research/trend-reports/asthma-trend-report.pdf.

34 Gorman S, Weeden CE, Tan DHW, et al. Reversible control by vitamin D of granulo-cytes and bacteria in the lungs of mice: an ovalbumin-induced model of allergic airway disease. PLoS One. 2013;8:e67823.

35 Carey MA, Card JW, Voltz JW, et al. It’s all about sex: gender, lung development and lung disease. Trends Endocrinol Metab. 2007;18:308–313.

36 Nguyen M, Trubert CL, Rizk-Rabin M, et al.1,25-Dihydroxyvitamin D3 and fetal lung maturation: immunogold detection of VDR expression in pneumocytes type II cells and effect on fructose 1,6 bisphosphatase. J Steroid Biochem Mol Biol. 2004;89-90:93–97.

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38 Gale CR, Robinson SM, Harvey NC, et al. Maternal vitamin D status during pregnancy and child outcomes. Eur J Clin Nutr. 2008;62(1):68–77.

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40 Gupta A, Sjoukes A, Richards D, et al. Relationship between serum vitamin D, disease severity, and airway remodeling in children with asthma. Am J Respir Crit Care Med. 2011;184(12):1342-1349.

41 Liu AH, Zeiger R, Sorkness C, et al. Development and cross-sectional validation of the Childhood Asthma Control Test. J Allergy Clin Immunol. 2007;119(4):817-825.

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46 Wagner CL, Hulsey TC, Fanning D, Ebeling M, Hollis BW. High dose vitamin D3 supple-mentation in a cohort of breast- feeding mothers and their infants: a six-month follow-up pilot study. Breastfeed Med. 2006;1(2):59-70.

47 Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Dietary Reference Intakes for Calcium and Vitamin D. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. Washington, DC: The National Academies Press; 2001.

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

49 Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.50 Hollis BW, Wagner CL, Drezner MK, Binkley NC. Circulating vitamin D3 and 25-hydroxyvi-

tamin D in humans: an important tool to define adequate nutritional vitamin D status. J Steroid Biochem Mol Biol. 2007;103(3-5):631-634.

51 Grant CC, Stewart AW, Scragg R et al. Vitamin D during pregnancy and infancy and infant serum 25-hydroxyvitamin D concentration. Pediatrics. 2014;133(1):e143-153.

52 Gallo S, Comeau K, Vanstone C, et al. Effect of different dosages of oral vitamin D supplementation on vitamin D status in healthy, breastfed infants: a randomized trial. JAMA. 2013;309(17):1785-1792.

53 Holmlund-Suila E, Viljakainen H, Hytinantti T, Lamberg-Allardt C, Andersson S, Mäkitie O. High-dose vitamin D intervention in infants—effects on vitamin D status, calcium homeostasis, and bone strength. J Clin Endocrinol Metab. 2012;97(11):4139-4147.

54 Dawodu A, Saadi HF, Bekdache G, Javed Y, Altaye M, Hollis BW. Randomized controlled trial (RCT) of vitamin D supplementation in pregnancy in a population with endemic vitamin D deficiency. J Clin Endocrinol Metab. 2013;98(6):2337-2346.

55 Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res. 2011;26(10):2341-2357.

56 Wu AC, Tantisira K, Li L, Fuhlbrigge AL, Weiss ST, Litonjua A. Effect of vitamin D and inhaled corticosteroid treatment on lung function in children. Am J Respir Crit Care Med. 2012;186(6):508-513.

57 Brehm JM, Celedon JC, Soto-Quiros ME, et al. Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med. 2009;179:765-771.

58 Brehm JM, Schuemann B, Fuhlbrigge AL et al. Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. J Allergy Clin Immunol. 2010;126:52-58.

59 Goleva E, Searing DA, Jackson LP, Richers BN, Leung DY. Steroid requirements and immune associations with vitamin D are stronger in children than adults with asthma. J Allergy Clin Immunol. 2012;129(5):1243-1251.

60 Searing DA, Zhang Y, Murphy JR, Hauk PJ, Goleva E, Leung DY. Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use. J Allergy Clin Immunol. 2010;125(5):995-1000.

61 Xystrakis E, Kusumakar S, Boswell S, et al. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest. 2006;116(1):146-155.

62 Dhawan P, Christakos S. Novel regulation of 25-hydroxyvitamin D3 24-hydroxylase (24(OH)ase) transcription by glucocorticoids: cooperative effects of the glucocorticoid receptor, C/EBP beta, and the Vitamin D receptor in 24(OH)ase transcription. J Cell Biochem. 2010;110(6):1314-1323.

63 Akeno N, Matsunuma A, Maeda T, Kawane T, Horiuchi N. Regulation of vitamin D-1 alpha-hydroxylase and -24-hydroxylase expression by dexamethasone in mouse kidney. J Endocrinol. 2000;164(3):339-348.

64 Di Filippo P, Scaparrotta A, Rapino D, et al. Vitamin D supplementation modulates the immune system and improves atopic dermatitis in children. Int Arch Allergy Immunol. 2015;166(2):91-96.

65 Järvinen KM, Westfall JE, Seppo MS, et al. Role of maternal elimination diets and human milk IgA in development of cow’s milk allergy in the infants. Clin Exp Allergy. 2014;44(1): 69-78.

66 Renz H, Brandtzaeg P, Hornef M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nat Rev Immunol. 201;12(1):9-23.

67 Palmer DJ, Metcalfe J, Makrides M, et al. Early regular egg exposure in infants with eczema: a randomized controlled trial. J Allergy Clin Immunol. 2013;132(2):387-392.

68 Greer FR, Sicherer SH, Burks AW; American Academy of Pediatrics Committee on Nutrition; American Academy of Pediatrics Section on Allergy and Immunology. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics. 2008;121(1):183-191.

69 Ciprandi G, Schiavetti I, Rindone E, Ricciardolo FL. The impact of anxiety and depres-sion on outpatients with asthma. Ann Allergy Asthma Immunol. 2015;115(5):408-414.

70 Ferro MA. Major depressive disorder, suicidal behaviour, bipolar disorder, and gener-alised anxiety disorder among emerging adults with and without chronic health condi-tions. Epidemiol Psychiatr Sci. 2015;8:1-13.

71 Ritz T, Ayala ES, Trueba AF, Vance CD, Auchus RJ. Acute stress-induced increases in exhaled nitric oxide in asthma and their association with endogenous cortisol. Am J Respir Crit Care Med. 2011;183(1):26-30.

72 Kullowatz A, Rosenfield D, Dahme B, Magnussen H, Kanniess F, Ritz T. Stress effects on lung function in asthma are mediated by changes in airway inflammation. Psychosom Med. 2008;70(4):468-475.

73 Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the patho-genesis of depression. Trends Immunol. 2006;27(1):24-31.

74 Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD. Inflammation causes mood changes through alterations in subgenual cingulate activity and meso-limbic connectivity. Biol Psychiatry. 2009;66(5):407-414.

75 Zorrilla EP, Luborsky L, Mckay JR, et al. The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun. 2001;15(3):199-226.

76 Miller GE, Stetler CA, Carney RM, Freedland KE, Banks WA. Clinical depression and inflammatory risk markers for coronary heart disease. Am J Cardiol. 2002;90(12):1279-1283.

77 Bluthé RM, Pawlowski M, Suarez S, et al. Synergy between tumor necrosis factor alpha and interleukin-1 in the induction of sickness behavior in mice. Psychoneuroendocri-nology. 1994;19(2):197-207.

78 Wichers M, Maes M. The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. Int J Neuropsychopharmacol. 2002;5(4):375-388.

79 Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev. 2000;21:55-89.

80 Whelan R, Kim C, Chen M, Leiter J, Grunstein MM, Hakonarson H. Role and regulation of interleukin-1 molecules in pro-asthmatic sensitised airway smooth muscle. Eur Respir J. 2004;24(4):559-567.

81 Rosenkranz MA, Busse WW, Johnstone T, et al. Neural circuitry underlying the interac-tion between emotion and asthma symptom exacerbation. Proc Natl Acad Sci USA. 2005;102(37):13319-13324.

82 Webster JC, Oakley RH, Jewell CM, Cidlowski JA. Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resis-tance. Proc Natl Acad Sci USA. 2001;98(12):6865-6870.

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87 Robroeks CM, van Berkel JJ, Jöbsis Q, et al. Exhaled volatile organic compounds predict exacerbations of childhood asthma in a 1-year prospective study. Eur Respir J. 2013;42(1):98-106.

88 Van Berkel JJ, Dallinga JW, Moller GM, et al. Development of accurate classification method based on the analysis of volatile organic compounds from human exhaled air. J Chromatogr B Analyt Technol Biomed Life Sci. 2008;861:101–107.

89 Barnes PJ. The cytokine network in asthma and chronic obstructive pulmonary disease. J Clin Invest. 2008;118:3546-3556.

90 Kirkham P, Rahman I. Oxidative stress in asthma and COPD: antioxidants as a thera-peutic strategy. Pharmacol Ther. 2006;111:476-494.

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REFERENCEKim JH, Lee C, Sohn W. Urban natural environments, obesity, and health-related quality of life among Hispanic children living in inner-city neighborhoods. Int J Envir Res Public Health. 2016;13(1):121-136.

DESIGN AND PARTICIPANTSThis cross-sectional study collected data from children (N=92, 9-11 years old) who attended elementary school in the East End district of Houston, Texas. This area was chosen because of racial/ethnic and socioeconomic demographics. All participants were of Hispanic background, could speak and read in either English or Spanish, and had no major medical conditions. The quality of their natural environ-ment was assessed using landscape data generated by geographic information systems (GIS) and remote sensing.

OUTCOME MEASURESParticipants were assessed for their health-related quality of life (HRQOL) using the Pediatric Quality of Life Inventory (PedsQL), a validated and reliable QOL instrument for children. This self-report measure is filled out simultaneously by both child and parent to assess the child’s subjective internal states (child) and their objec-tive external behaviors (parents). Control variables collected included each child’s sociodemographic information (ie, parents’ income and education level), obesity status (BMI), physical activity level (PAQ-C), hours watching TV, and environmental perceptions of their neighbor-hood (ie, accessibility, safety, comfort, attractiveness, satisfaction).

Landscape GIS information was obtained from the Texas Natural Resources Information System and organized based on 40 recog-nized spatial land-use patterns. Comparisons of this information to each participant’s data were made for quarter-mile airline (QA) and half-mile airline (HA) buffers surrounding each participant’s house.

KEY FINDINGSMultivariate regression analysis detected statistically significant asso-ciations between landscape spatial patterns and HRQOL, with land-scape accounting for approximately 43% of the variance of HRQOL in both QA and HA radius buffer models.

After controlling for sociodemographic, BMI, PAQ-C, and envi-ronmental perception variables, specific sub-analyses of the land-scape patterns showed that green space percentage of buffer area (P=0.023/P=0.069), number of patches of trees (P=0.016/P=0.020), and mean distance between tree patches (P=0.001/P=0.004) were all significant predictors of HRQOL using both HA and QA models (respectively).

Data analysis also found statistically significant predictive associations between children’s HRQOL and BMI (P=0.010/P=0.008), weekend PAQ-C (P=0.000/P=0.000), and hours of TV (P=0.015/P=0.005).

PRACTICE IMPLICATIONSThis is one of the first studies in the growing body of green space and health literature to use children as a population of interest.1,2 Children are a critical popula-tion to consider, and not only because of the epidemic of childhood obesity that is currently plaguing our health-care system with physical and mental health effects.3,4 It is also vital that children be exposed to nature as early as possible to instill an ethic of environmental steward-ship; studies have shown that children who don’t get this exposure are less creative, less empathetic, and less likely to care about the environment as adults. In this era of “screen time vs green time,” there is growing concern that the next generation will not be able to provide enough capable, eco-minded leaders to solve the massive environment-related health problems that are coming our way.5-7

In addition, this study is one of the first to use a broad measure of health rather than investigating a specific biomarker or pathologic condition.8 HRQOL is an important metric in healthcare because it focuses on qualitative aspects of well-being rather than traditional quantitative metrics like disease prevalence or mortality rates. It also assesses the holistic, “multidimensional” aspects of life and considers how health affects all aspects of life.9 It is useful to remember that “health” itself is a holistic condition as defined by the World Health Organization (WHO). According to WHO, health is “a state of physical, mental, and social well-being and not merely the absence of disease or infirmity...[Health is] a resource for everyday life, not the objective of living…[Health is] a positive concept emphasizing social and personal resources, as well as physical capacities.”10,11 In an era in which so much of the medical system takes a pathocentric (disease-focused) approach to healthcare, it is nice to know that some interventions do have a salu-togenic (health-promoting) effect.12

For the practitioner, this study emphasizes that envi-ronmental factors may act as enhancers or barriers to achieving health. There are many things in a patient’s

ABSTRACT & COMMENTARY

Usable Green Spaces Can Affect Children’s Health-Related Quality of Life and BMIEvidence supports the benefits of the great outdoors By Kurt Beil, ND, LAc, MPH

NMJ, SEPTEMBER 2016 SUPPLEMENT—VOL. 8, NO. 91 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. 19

life that may influence health beyond what can be prescribed, or what may even come up, in a clinical visit. When a patient’s condition seems to be resistant to treatment, we must look past the condition itself and consider how the patient func-tions in the context of their greater life.

These findings also suggest the value of taking a proactive approach to getting kids outside. The positive associations between activity level and quality of life and negative asso-ciations between hours of TV and quality of life demon-strate how vital it is to encourage movement and decrease sedentary behavior in children. Increasingly, more conven-tional physicians are organizing and creating standardized “Vitamin N” (for “nature”) prescription-writing programs. Under the umbrella program of ParkRx in conjunction with the National Park Service, the National Recreation and Park Association, and the Institute at the Golden Gate, doctors are learning their role in promoting children’s use of the “natural medicine” a nearby park can provide.

REFERENCES1 Hartig T, Mitchell R, de Vries S, Frumkin H. Nature and health. Annu Rev Public Health.

2014;35:207-208.2 Kuo FE. Parks and Other Green Environments: Essential Components of a Healthy

Human Habitat. Ashburn, VA: National Recreation and Park Association; 2010.3 Williams J, Wake M, Hesketh K, Maher E, Waters E. Health-related quality of life of

overweight and obese children. JAMA. 2005;293(1):70-–76.4 Banis HT, Varni JW, Wallander JL, et al. Psychological and social adjustment of obese

children and their families. Child Care Health Dev. 1988;14(3):157-–173.5 Bragg R, Wood C, Barton J, Pretty J. Measuring connection to nature in children: a

robust methodology for the RSPB. University of Essex: Essex Sustainability Institute and School of Biological Sciences; 2013.

6 Pergams OR, Zaradic PA. Is love of nature in the US becoming love of electronic media? 16-year downtrend in national park visits explained by watching movies, playing video games, internet use, and oil prices. J Environ Manage. 2006;80(4):387–-393.

7 Zaradic PA, Pergams OR, Kareiva P. The impact of nature experience on willing-ness to support conservation. PLoS One. 2009;4(10):e7367. doi: 10.1371/journal.pone.0007367.

8 van den Berg M, Wendel-Vos W, van Poppel M, Kemper H, van Mechelen W, Maas J. Health benefits of green spaces in the living environment: a systematic review of epide-miological studies. Urban For Urban Gree. 2015;14(4):806-–816.

9 US Department of Health and Human Services. Health-related quality of life and well-being. In Healthy People 2020. Washington, DC: US Dept of Health and Human Services. Office of Disease Prevention and Health Promotion. https://www.healthy-people.gov/2020/topics-objectives/topic/health-related-quality-of-life-well-being. Updated June 10, 2016. Accessed June 13, 2016.

10 World Health Organization. WHO Definition of Health. Preamble to the Constitution of the World Health Organization as adopted by the International Health Conference, New York, June 19. July 22, 1946; signed on July 22, 1946.

11 World Health Organization. Ottawa Charter for Health Promotion. Health Promot Int; 1986:1(4):405. doi:10.1093/heapro/1.4.405-a.

12 Thompson CW, Aspinall P, Roe J. Access to green space in disadvantaged urban communities: evidence of salutogenic effects based on biomarker and self-report measures of wellbeing. Procedia Soc Behav Sci. 2014;153:10-22.

ABSTRACT & COMMENTARY

The positive associations between activity

level and quality of life and negative

associations between hours of TV and

quality of life demonstrate how vital it is to

encourage movement and decrease sedentary

behavior in children.

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REFERENCERönnlund H, Elovainio M, Virtanen I, Matomäki J, Lapinleimu H. Poor parental sleep and the reported sleep quality of their children. Pediatrics. 2016;137(4);e20153425.

DESIGNA cross-sectional, observational study

OBJECTIVETo assess the association of parental sleep quality with the reported sleep quality of their children

PARTICIPANTSIn this study, parents and their biological children aged 2 to 6 years were recruited from 16 daycare centers in Finland. A total of 108 children were enrolled and evaluated between January 2014 and February 2015. The mean age of the children was 4 years and the sex distribution was even. The sample included mainly Caucasian, highly educated families.

OUTCOME MEASURESParents completed questionnaires re gard ing socioeconomic status, their own well-being, and their child’s well-being and illnesses.

An actigraphy bracelet was provided for the child to wear on their nondominant hand for a period of 7 days. Parents were instructed to press the event button on the bracelet when the child went to sleep and when they woke up. While the actigraph does not differentiate between stages of sleep, it does estimate periods of sleep using a threshold for lack of movement. With consideration for the restless nature of children’s sleep, studies indicate that the actigraph shows good sensitivity (the ability to detect sleep), but poorer specificity (the ability to detect wake) in pediatric populations.1,2 However, the authors note that the accuracy can be enhanced using an appropriate algorithm.

Parents kept a sleep diary for the duration of the time that the child wore the actigraphy bracelet, which included the details of when and why the actigraphy bracelet was removed during this period.

Along with the sleep diaries, parents also completed the Sleep Disturbance Scale for Children (SDSC) which, in addition to the total score, evaluates 6 different sleep domains: disorders of initiating and maintaining sleep; sleep breathing disorders; disorders of arousal; sleep-wake transition disorders; disorders of excessive somnolence; and sleep hyperhidrosis.

With respect to their own health, parents completed both the Jenkins’ sleep scale and a 12-item General Health Questionnaire in order to assess parental sleep quality as well parental psychiatric symptoms, including anxiety and depression.

KEY FINDINGSThe authors found that parents who reported having sleep difficulties themselves were more likely to experience their children as having more sleep difficulties. Furthermore, they found that this association was not supported by the study’s objective measure, the acti-graph, indicating that the child’s sleep may not actually be as poor as parents perceived. The perception of children’s sleep difficulties was not explained by the child’s age, sex, number of siblings, chronic illness, or medication, nor was it related to parental psychiatric symptoms, education, socioeconomic status, marital status, or time of year.

ABSTRACT & COMMENTARY

Parental Sleep and Reported Sleep Quality of ChildrenIntervention for sleep problems should address the entire family unit By Erin Psota, ND

COMMENTARYMany factors influence children’s sleep, including social and cultural environ-ments, parental knowledge, and the child’s pre-existing medical conditions. Poor sleep and sleep disorders can have detrimental effects on a child’s anxiety level, mood, behavior, physical development, and weight, as well as academic competence.3 Thus, there is a need for screening and early inter-vention in sleep disorders. However, sleep screening and intervention may not be occurring as frequently and as effectively as one would hope.

Large epidemiological studies reveal that approximately 30% of children suffer from sleep problems.4 Despite this prevalence, the rates of screening and management of these concerns are low. Both primary care providers and parents frequently have gaps in knowl-edge when it comes to the topic of sleep in the pediatric population.5

Children depend on their parents’ understanding of their sleep needs in order to foster a healthy sleep regimen that is developmentally appropriate. In turn, parents rely on their healthcare providers to inquire about a child’s sleep habits routinely, identify problems, and provide education on the subject. Parental education is often the first line of intervention, and increasingly clini-cians are recognizing that parental knowledge impacts child sleep behavior. However, primary care providers receive minimal training

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about sleep. This may result in missed opportunities for discussion during visits, unless parents are reporting prob-lems or asking questions pertaining to sleep.3

Studies indicate that sleep disorders are more prevalent in single-parent families, and/or those with low parent educa-tion. This means there is more need for practitioner inquiry and education in patient visits where these conditions exist.4

When assessing sleep, there are 4 dimensions to consider: amount, quality, timing, and state of mind. BEARS is a useful acronym to use when asking parents and care providers about children’s sleep: (B) bedtime resistance (sleep onset delay); (E) excessive daytime sleepiness; (A) awakening at night (parasomnias); (R) regularity, patterns, and duration; and (S) snoring and other symptoms.4,6

While there are many pediatric sleep disturbances, among the most common is pediatric insomnia, which affects approximately 6% of typical children and as many as 75% of children with developmental impairments. In cases of pediatric insomnia, it is frequently the parent rather than the child who is frustrated, and the parent is often the one experiencing negative effects on daytime performance and increased stress levels.6

It is easy to see how, especially in cases such as these, parental emotions may influence prescribing behaviors of providers. The National Ambulatory Medical Care Survey demon-strated that, in visits involving sleep difficulties, 81% of children leave with a prescription compared to 48% of

adults. What is particularly concerning about this statistic is that there are currently no medications on the market that are FDA-approved for treating sleep problems in chil-dren.6 While integrative practitioners would be unlikely to suggest prescription sleep aids, it would be interesting to know whether a similar percentage would give children homeopathic, botanical, or nutritional supplements for sleep. Of course, when multiple behavioral interventions fail, both naturopathic and prescription treatments may be appropriate; however, a sedated sleep does not equate with a normal restorative sleep.7

As a naturopathic doctor, this study reminds me of 2 core principles we uphold: tolle causam (find the cause) and docere (teach). In addition, the therapeutic order for all patients is to remove disturbing factors and institute a healthful regime before interventions of any kind. In cases of pediatric sleep concerns, we should be addressing the entire family unit and ensuring that there are no unnecessary interventions, that carry the possibility of harm. We must consider that parents may be over-reporting their children’s sleep distur-bances because of their own sleep disorders. In addition to this, we must discuss the expectations that parents and care-givers have for their children’s sleep, in comparison with the developmental norms for their respective age groups. This leads to a natural segue to provide education surrounding these norms, including sleep requirements and good habits, understanding the signs of sleep problems, and suggestions on how to improve sleep for the whole family.

Parents with greater knowledge about sleep are more likely to establish better sleep hygiene routines for their children, including a regular, early bedtime, regular wake times, falling asleep without an adult, and no TV in the bedtime routine.3

Instead of simply relying solely on parental reporting of sleep disturbances and immediately treating children with seda-tive, nervine, and adaptogenic botanicals, or supplements such as melatonin, it may have a greater impact on the family unit to assess and treat the parents’ sleep. Addressing healthy sleep hygiene with the whole family will only have a positive impact. While parents generally recognize the importance of

The authors found that parents who

reported having sleep difficulties

themselves were more likely to

experience their children as having more

sleep difficulties.

ABSTRACT & COMMENTARY

22 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, SEPTEMBER 2016 SUPPLEMENT—VOL. 8, NO. 91 (SUPPL)

ABSTRACT & COMMENTARY

a bedtime routine for their children, we may need to remind them that an established routine is essential for their sleep and health as well.

Further studies on preconception and perinatal sleep habits and sleep quality of parents may also prove to be of interest. While the assumption is that parents who were sleeping poorly in the preconception and perinatal periods are over-reporting sleep disturbances in their children, it is equally possible that parents who were good sleepers before they had children are the ones who have poorer sleep after having children. These “good sleepers” may feel more “interrupted” compared to parents who were already used to poorer quality sleep. This is an unknown, and further research is warranted to investigate whether children with sleep disturbances have parents with historically poor sleep or good sleep. This may also inform us about whether sleep disturbances are influenced by genetic or learned behaviors.

REFERENCES1 Meltzer LJ, Wong P, Biggs SN, et al. Validation of actigraphy in middle childhood.

Sleep. 2016;39(6):1219-1224.2 Phillips LR, Parfitt G, Rowlands AV. Calibration of the GENEA accelerometer for assess-

ment of physical activity intensity in children. J Sci Med Sport. 2013;16(2):124-128.3 McDowall PS, Galland BC, Campbell AJ, Elder DE. Parent knowledge of children’s

sleep: a systematic review [published online ahead of print January 14, 2016]. Sleep Med Rev.

4 Martins AL, Chaves P, Papoila AL, Loureiro HC. The family role in children’s sleep disturbances: results from a cross-sectional study in a Portuguese Urban pediatric population. Sleep Sci. 2015; 8(3):108-114.

5 Honaker SM, Meltzer LJ. Sleep in pediatric primary care: a review of the literature. Sleep Med Rev. 2016;25:31-39.

6 Troester MM, Pelayo, R. Pediatric sleep pharmacology: a primer. Semin Pediatr Neurol. 2015;22(2):135-147.

7 Pelayo R, Dubik M. Pediatric sleep pharmacology. Semin Pediatr Neurol. 2008;15(2):79-90.

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PRACTICE IMPLICATIONS This study is one of many to show how the benefits of iron supplemen-tation during early infancy can affect the developmental outcomes of growing infants. Overall, there was a positive effect on gross motor and neurological development for the infants supplemented with iron from early infancy as well as infants whose mothers received supplementa-tion during pregnancy. Thus, this study confirms the importance of supporting potential nutritional deficiencies in early infancy—the period of most rapid growth and changes in motor development.1

The study supports the assertion that iron supplementation during infancy significantly improves gross motor skills during a child’s first year of life. The infants receiving iron supplementation during this rapid period of growth performed better on developmental milestones such as sitting upright, crawling, standing with lateral progression, and transitions from sitting to standing than the group who received no supplementation. Existing research shows a strong connection between iron deficiency and a child’s cognitive, social-emotional, and gross and fine motor development.2 In these studies, iron-deficient infants exhibited slower progression, delayed milestones, withdrawal, and lower spontaneous activity. Because areas of the brain mature at different times, it is critical to initiate iron supplementation during the earliest developmental periods and consider prenatal support as well.3

Iron deficiency is the most prevalent nutritional deficiency in the late infancy/toddler period.4 Notably, the study period focused on the specific ages (between 6 weeks and 9 months) when an infant’s brain matures most rapidly and iron is needed most in the formation of the brain’s neural network. The significant growth of the complex brain areas within the first year of life relies on iron and is most vulnerable to iron deficiencies or insufficiencies through the breast milk, diet, or during growth and development in the perinatal period.5 Periods of peak development and metabolic activity in the brain are sensitive to substrates that support metabolism, such as iron and thyroid hormone. This time period is characterized by peak hippocampal and cortical regional development, as well as proper myelin and synapse formation and oligodendrocyte function in the brain.

Recent studies have shown a relationship between perinatal iron defi-ciency and negative effects on the developing hippocampus in infants as young as 2 months. Infants who showed consistent and sufficient iron levels had greater auditory recognition memory when compared

ABSTRACT & COMMENTARY

Iron Supplementation in Pregnancy and InfancyIron sufficiency is critical for optimal development By Lilian Au, ND

REFERENCEAngulo-Barroso RM, Li M, Santos DC, et al. Iron supplementation in pregnancy or infancy and motor development: a randomized controlled trial. Pediatrics. 2016;137(4).

OBJECTIVETo assess the effects of iron supplementation in pregnancy and/or infancy on motor development at 9 months

DESIGNThe study was a randomized controlled trial (RCT) of iron supplementation in early infancy; the results were linked to an RCT of prenatal iron supplementa-tion (conducted in Hebei, China) to compare effects of prenatal vs postnatal supplementation.

PARTICIPANTSThe studies included a total of 2,371 women with single uncomplicated pregnancies and 1,482 infants. Infants were randomly assigned to receive either supplemental iron (n=752) or placebo (n=730) from 6 weeks to 9 months. Maternal and infant iron status and infant growth outcomes were considered in the criteria. The infants with cord ferritin levels suggesting brain iron deficiency (<35 ug/L) were excluded from the study. Develop-mental testing for the infants at 9 months occurred at the Peking University Maternity and Child Health Care Center.

OUTCOME MEASURES Investigators used the Peabody Developmental Motor Scale to assess gross motor development (primary outcome) and neurologic integrity and motor quality (secondary outcomes).

KEY FINDINGSThe authors compared the effects of iron/folate supplementation for prenatal patients and iron supplementation for infants from ages 6 weeks to 9 months. Iron supplementation in infancy, with or without iron supplementation in pregnancy, improved gross motor test scores at 9 months. There was improvement in gross motor scores: overall, P<0.001; reflexes, P=0.03; stationary, P<0.001; and locomotion, P<0.001. Iron supple-mentation in infancy improved motor scores by 0.3 SD compared with no supplementation or supple-mentation during pregnancy alone.

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to infants who had fetal-neonatal iron deficiency.6 Results from a 2016 study of iron deficiency and its effects on thyroid development and function in neonates (Hu et al) support the strong relationship between maternal iron levels and thyroid peroxidase synthesis, which is key to neonatal neurodevelopment because it depends so heavily on healthy perinatal iron levels and optimal thyroid function.7 Iron defi-ciency has a direct effect on sensory input which, combined with cognitive, motor, and affective changes, may adversely affect the infant’s interactions with the physical and social environment. Treating and resolving iron deficiencies in early infancy and childhood has been shown to decrease the likelihood of long-lasting neural and behavioral effects.8

Insufficient iron levels for optimal fetal and infant devel-opment are a concern during pregnancy and infancy with lasting effects into childhood.9 Despite the results of this study on iron supplementation in the prenatal period and its effect on motor development in infancy, other research shows a solid connection between the mother’s dietary and nutritional status during fetal development and the child’s overall growth and development. Although this current study of pregnant women in China did not show greater benefits in the child’s motor development with the addition of iron and folate supplementation, it is still important to support the critical nutritional needs for both mother and child.10

Previous trials in China exploring prenatal iron supplemen-tation and its effects on both mother and child found that supplementation had a positive response in reducing anemia overall, but iron deficiency still exists in more than 45% of children and about 70% of mothers despite supplementa-tion.11 In contrast, a study of prenatal iron supplementation in pregnant women in the United States revealed that only about 18% of women who did not receive supplementation experienced iron deficiency.12,13 Therefore, we should consider other factors that may account for the results of studies from rural China, such as whether or not poor nutrition or environ-mental toxicities can affect the study participants in the long term. For example, deficiencies of essential nutrients, such as iron, calcium, and zinc, may increase the absorption of lead. These nutritional deficiencies are likely to be more prevalent

in vulnerable groups such as low-income or minority popula-tions.14 According to the study by Jain et al on lead intoxica-tion, there is considerable research regarding the effects of lead toxicity on iron absorption and iron-deficiency anemia.15 Thus, the research supports the importance of supplementing iron for women in China during the prenatal period and preventing the deficiencies in early infancy and childhood.

Overall, the results of this study from Angulo-Barroso et al confirm the developmental benefits of iron supplementation early in infancy and indicate that supplementation should be an important part of routine care for all infants and mothers, espe-cially those with demonstrated iron deficiency, as well as popula-tions at risk for malnutrition and nutritional deficiencies.16

REFERENCES1 Georgieff M. The role of iron in neurodevelopment: fetal iron deficiency and the devel-

oping hippocampus. Biochem Soc Trans. 2008; 36 (6):1267-1271.2 Grantham-McGregor S, Baker-Henningham H. Iron deficiency in childhood: causes and

consequences for childhood development. Annales Nestle. 2010;68(3):105-119. 3 Lozoff B. Iron deficiency and child development. Food Nutr Bull. 2007;28(4

Suppl):S560-571.4 Wang M. Iron deficiency and other types of anemia in infants and children. Am Fam

Physician. 2016;93(4):270-278.5 Lozoff B, Georgieff MK. Iron deficiency and brain development. Semin Pediatr Neurol.

2006;13(3):158-165. 6 Geng F, Mai X, Zhan J, et al. Impact of fetal-neonatal iron deficiency on recognition

memory at 2 months of age. J Pediatr. 2015;167(6):1226-1232. 7 Hu X, Wang R, Shan Z, et al. Perinatal iron deficiency-induced hypothyroxinemia impairs

early brain development regardless of normal iron levels in the neonatal brain. Thyroid. [published on line ahead of print May 27, 2016].

8 Lozoff B, Beard J, Connor J, Felt B, Georgieff M, Schallert T. Long-lasting neural and behavioral effects of iron deficiency in infancy. Nutr Rev. 2006;64(5 Pt2):S34–S43.

9 Szajewska H, Ruszczynski M, Chmielewska A. Effects of iron supplementation in nonanemic pregnant women, infants, and young children on the mental performance and psychomotor development of children: a systematic review of randomized controlled trials. Am J Clin Nutr. 2010;9(6)1684-1690.

10 Saintand SE, Frick JE. Prenatal supplementation and its effects on early childhood cogni-tive outcome. In: Wallace TC, ed. Dietary Supplements in Health Promotion. Boca Raton, FL: Taylor and Francis Group; 2015:75-104.

11 Zhao G, Xu G, Zhou M, et al. Prenatal iron supplementation reduces maternal anemia, iron deficiency, and iron deficiency anemia in a randomized clinical trial in rural China, but iron deficiency remains widespread in mothers and neonates. J Nutr. 2015;145(8):1916-1923.

12 Mei Z, Cogswell ME, Looker AC, et al. Assessment of iron status in US pregnant women from the National Health and Nutrition Examination Survey (NHANES), 1999-2006. Am J Clin Nutr. 2011;93(6):1312-1320.

13 McDonagh M, Cantor A, Bougatsos C, Dana T, Blazina I. Routine Iron Supplementation and Screening for Iron Deficiency Anemia in Pregnant Women: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation. Rockville, MD: Agency for Healthcare Research and Quality (US); 2015.

14 Qiu J, Wang K, Wu X, et al. Blood lead levels in children aged 0–6 years old in Hunan Province, China from 2009-2013. PLoS One. 10(4):e0122710.

15 Jain A, Wolfe LC, Jain G. Impact of lead intoxication in children with iron deficiency anemia in low- and middle-income countries. Blood. 2013;122(13):2288-2289.

16 Janus J, Moerschel SK. Evaluation of anemia in children. Am Fam Physician. 2010;81(12):1462-1471.

ABSTRACT & COMMENTARY

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ABSTRACT & COMMENTARY

IBS and Probiotic Treatment in Pediatric PatientsEffects of Lactobacillus rhamnosus GG on pain and function

By Paul Richard Saunders, PhD, ND, DHANP

COMMENTARYThis was a well-designed study, but the lack of reporting all outcome measures as well as the statistical analysis weakened it considerably. The functional Liker scale was not presented, so that data is not avail-able to evaluate. The significant P values reported as 0.00 are either errors, typos, or otherwise incorrect. The lack of significant change in stool habit is disappointing but not uncommon in IBS studies. The short length of this study may be a factor; in clinical, practice stool consistency changes can occur over the long-term.

Lactobacillus rhamnosus is naturally found in the gastrointestinal tract and the healthy female genitourinary tract. It also is used in yogurt and other fermented dairy, as well as semi-hard cheeses. Sherwood Gorbach and Barry Goldin isolated this species in 1983 from the intestinal tract of a healthy human. They sought a beneficial bacteria that would colonize, survive an acid envi-ronment, and out-compete pathogenic bacteria. On April 17, 1985, they filed for a patent of Lactobacillus acidophilus GG (from the first letter of their surnames) as ATCC 53103 (American Type Culture Collection). It was later reclassified as Lactobacillus rhamnosus GG (ATCC 53103). It is considered the world’s most studied probiotic bacteria.1 It can survive the acid and bile of the stomach and small intestine to colonize the digestive tract,2 stop peanut allergic reactions in most chil-dren,3 prevent rotavirus diarrhea in chil-dren,4 and reduce abdominal pain in children.5 It also has the potential to stop respiratory tract infections in children at daycare.6

REFERENCEKianifar H, Jafari SA, Kiani M, et al. Probiotic for irritable bowel syndrome in pediatric patients: a randomized controlled clinical trial. Electron Physician. 2015;7(5):1255-1260.

DESIGNRandomized, double-blind, placebo-controlled trial

PARTICIPANTSFifty-two children, 4-18 years old (25 female, 27 male) all had active abdominal pain for at least 2 weeks before entering the study. All participants were diagnosed by a pediatric gastroenterologist using Rome III Criteria for irritable bowel syndrome (IBS) with other differential diagnoses excluded by laboratory, abdominal ultrasound, radiographic imaging, endoscopy, and hydrogen breath test as required. Exclusion criteria included any medication use and any underlying diseases

OUTCOME MEASURESSeverity of pain; functional changes (eg, disruption of social activities, need to see a doctor, use of medications, days absent from school); and variables that could induce abdominal pain (eg, gastroenteritis, abdominal pathologies, life events) were primary outcomes. A validated scale (Likert scale) was used to specify severity of the pain from 0 to 5, with 5 being most severe. A 3-point Likert scale was used to assess function changes (1-decrease, 2-no change, 3-increase). Secondary outcomes were changes of the functional scale, stool patterns, and associated problems (eg, headache, limb pain, sleep problems).

INTERVENTIONLactobacillus rhamnosus GG at 1x1010 CFU/mL or placebo of inulin (also in treat-ment capsule), 1 capsule twice daily for 4 weeks. Capsules were the same size, color, and taste.

RESULTSThere were 52 evaluable participants at the study conclusion. Of the 60 initial partici-pants, none discontinued due to reaction to treatment or placebo. The mean age of the children evaluated was 7.1 years old. Their most common type of IBS was alternating constipation and diarrhea, experienced by 16 children in the placebo group and 15 in the treatment group. Of the remainder, 6 in the placebo group and 6 in the treatment group had mostly constipation, and 4 in the placebo group and 6 in the treatment group had mostly diarrhea.

Pain severity decreased significantly in the treatment group versus the placebo group after 1, 2, 3, and 4 weeks of treatment (P=0.01, 0.00, 0.00, 0.00, respec-tively). There was significant improvement in the functional scale after 2 weeks in the treatment group (P<0.00). There was no significant change in stool consistency or associated problems over the 4 weeks (P>0.1).

FINDINGSThis study demonstrated that Lactobacillus GG 1x1010 CFU/mL twice daily can significantly reduce pain in pediatric IBS after 1 week and improve functional ability after 2 weeks, but the probiotic had no significant effect on stool consistency or associated health problems at the end of 4 weeks.

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Russian Nobel laureate Ilya Ilyich (Elie) Metchnikoff, professor at the Pasteur Institute in Paris, proposed in 1906 that one could modify the gut flora, replacing harmful bacteria with beneficial bacteria.7 He further proposed that the aging process resulted from the activity of putrefactive or proteolytic bacteria that produced toxins in the large bowel. The compound produced by this activity caused autointoxi-fication and the physical changes associated with aging. His work sparked both controversy and research into the role of gut microbes and human health.

The controversy surrounding probiotics and their clinical effects is closely tied to the diverse species tested and the dosage used. A medium-size study (N=362) of encapsulated Bifidobacterium infantis 35624 compared 1x106, 1x108, 1x1010

CFU/mL in women with IBS over 4 weeks. The middle dose, 1x108, was significantly effective for abdominal pain, bloating, bowel dysfunction, incomplete evacuation, straining, and flatulence reduction.8 The other 2 doses were no better than placebo, and the largest dose had formulation issues. No adverse events were recorded. The authors concluded that the dose and dosage form were features of probiotic use that still needed clinical data and resolution.

A study of 141 children with IBS in 9 centers over 8 weeks used Lactobacillus rhamnosus GG or placebo for pain control. There was significant reduction in pain frequency (P<0.01) and pain intensity (P<0.01). These results were still signifi-cant at 12 weeks. When the trial began, 59% of the children had abnormal intestinal permeability. At the end of the trial the treatment group had a significant reduction (P<0.03) in intestinal permeability.5

A current review article argues that since up to 50% of orally ingested strains survive gastric passage, ingested bacteria can impact resident communities by trophic interactions such as competition for substrate; a direct alteration of fitness (eg, competitive exclusion, physical displacement, vitamin production); or an indirect alteration of fitness (eg, altered production of host-derived molecules, bile salt alteration).9 Alteration of bile salts determines the fitness of the bowel, the expression of some bacteria, and the risk for some diseases.

Some studies show increased short-chain fatty acids that coin-cide with increased lactic acid bacteria and/or Bifidobacterium species. Supplementation with Bifidobacterium can directly stimulate butyrate producers that utilize acetate or lactate. Decreased butyrate production and the subsequent bloom of proteobacteria is associated with IBS, inflammatory bowel disease (IBD), and type 2 diabetes.9

There is a need for studies that identify specific probiotic-induced changes in the gut. Giving Lactobacillus rhamnosus GG, and L Casei Shirota can increase Bifidobacterium popu-lations.10 Administration of 1x109 CFU/mL Lactobacillus rhamnosus GG from birth to 6 month increased Lactobacil-laceae and Bifidobacteriaceae. It also resulted in more commu-nity “evenness,” a greater diversity of species, and less risk of developing allergic disease. Starting with a healthier bowel may reduce the risk for IBS, IBD, and other microbial dysbi-otic conditions.

Another study of pediatric IBS based on Rome III criteria in children 4 to 18 years old (66 boys, 137 girls) used Symbi-oflor® 2 (SF2). SF2 consists of both living and non-living Escherichia coli, 1.5-4.5x107 CFU/mL.11 The dose was 10 drops for those ages 4 to 11 and 30 drops for those ages 12 to 18 for 40 to 50 days (mean=43 days). Clinical benefits were significant improvements in abdominal pain, stool frequency, bloating, mucous, blood in stool, need for straining, and urge to defecate. The study lacked a control group, so a random-ized, placebo-controlled trial is required to verify clinical effect. These results do suggest that there is more than one probiotic approach to treating IBS.

ABSTRACT & COMMENTARY

Study finds Lactobacillus rhamnosus GG

significantly reduces pain severity after

one week and significantly improves

functional ability after two weeks in

children 4 to 18 years old.

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ABSTRACT & COMMENTARY

CLINICAL IMPLICATIONSLactobacillus rhamnosus GG has been shown in a random-ized, double-blind, placebo-controlled clinical trial to lessen abdominal pain and improve functional ability in children 4 to 18 years old with Rome III–defined IBS. The dose was 1x1010 CFU/mL twice daily. The unknowns for clinicians are how the subjects’ gut microbes were altered to achieve this effect and how L rhamnosus GG compares to other probiotic species or species combinations. The unfortunate finding is the lack of change in stool consistency at the end of the 4-week trial. Given the risk/benefit analysis easily tips the scale in favor of the intervention, it may only be through time and trial that clinicians learn if this treatment warrants endorsement.

REFERENCES1 Silva M, Jacobus NV, Deneke C, Gorbach SL. Antimicrobial substance from a human

Lactobacillus strain. Antimicrob Agents Chemother.1987;31(8):1231-1233.2 Conway PL, Gorbach SL, Goldin BR. Survival of lactic acid bacteria in the human

stomach and adhesion to intestinal cells. J Dairy Sci. 1987;70(1):1-12.3 Tang ML, Pnosonby AL, Orsini F, et al. Administration of a probiotic with peanut oral

immunotherapy: a randomized trial. J Allergy Clin Immunol. 2015;135(3):737-744.4 Canaani RB, Cirillo P, Terrin G, et al. Probiotics for treatment of acute diarrhea in chil-

dren: a randomised trial of five different preparations. BMJ. 2007;335(7615):340.5 Francavilla R, Miniello V, Magista AM, et al. A randomized controlled trial of Lactobacillus

GG in children with functional abdominal pain. Pediatrics. 2010;126(6):e1445-1452.6 Hojsak I, Snovak N, Abdovic S, Szajewska H, Misak Z, Kolacek S. Lactobacillus GG

in the prevention of gastrointestinal and respiratory tract infections in children who attend day care centers: a randomized, double-blind, placebo controlled trial. Clin Nutr. 2010;29(3):312-316.

7 Metchnikoff II. The Prolongation of Life: Optimistic Studies. 1906. English translation by PC Mitchell 1908. Putnam Books. New York.

8 Whorwell PJ, Altringe L, Morel J, et al. Efficacy of an encapsulated probiotic Bifido-bacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol. 2006;101(7):1581-1590.

9. Derrien M, van Hylckama Vlieg JET. Fate, activity, and impact of ingested bacteria within the human gut microbiota. Trends Microbiol. 2015;23(6):354-366.

10. Sanders ME. Impact of probiotics on colonizing microbiota of the gut. J Clin Gastroen-terol. 2011;45(3):S115-S119.

11. Martens U, Enck P, Zieseniss. Probiotic treatment of irritable bowel syndrome in chil-dren. Ger Med Sci. 2010;8:1-15.

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REFERENCESiqueira CM, Homsani F, da Veiga VF, et al. Homeopathic medicines for prevention of influenza and acute respiratory tract infections in chil-dren: blind, randomized, placebo-controlled clinical trial. Homeopathy. 2016;105(1):71-77.

DESIGNThis parallel clinical trial was a randomized, triple-blind, placebo-controlled study. It was conducted between April 2009 and March 2010.

PARTICIPANTSStudy included 600 children (ages 1-5 years) from the Brazilian Public Health System in Petropolis (BPHSP), Rio de Janeiro. The inclusion criteria were: male or female patients with no apparent disease. Children who lived in geographical areas that were difficult to monitor and those with the following characteristics were excluded: history of wheezing and asthma, HIV infection, immunodeficiency, type I diabetes, malignancies, cortico-steroid treatment, congenital anomalies, liver disease, history of at least 1 episode of respiratory infection in the previous 30 days.

STUDY MEDICATION AND DOSAGEThe children were randomized into 3 intervention groups with 200 patients in each group: homeopathic complex, placebo, and InfluBio.

The InfluBio solution was prepared by serially diluting a sample of puri-fied influenza virus [A/Victoria/3/75 (H3N2)] in 1:10 ratio with sterile water to a 30x dilution according to the Brazilian Homeopathic Pharmacopea employing mechanical succession 100 times between each dilution.

The homeopathic complex used was composed of bacterial strains (Strep-tococcus and Staphylococcus) and inactivated influenza virus, prepared following the same homeopathic procedures of serial dilution and succes-sion to a 30x dilution. This medicine is used routinely in Brazil for the prophylaxis and treatment of upper respiratory tract infections. The placebo consisted of 30% alcohol in a sterile water solution, which was the same composition used to dilute the homeopathic agents prepared in this study.

The child’s tutor administered the test solutions twice a day for 30 days.

During the study, neither the families nor the healthcare providers knew which solution was being given to each child.

OUTCOME MEASURESThe number of episodes of flu and acute respiratory infection during a 1-year period, as well as the duration of flu or acute respiratory infection, was tracked using a standardized questionnaire.

To characterize the number of flu and acute respiratory infection episodes, at least 2 of the following symptoms had to be present: fever (temperature > 37.8°C), nasal discharge, prostration, myalgia, headache, and cough.

ABSTRACT & COMMENTARY

Does Homeopathy Prevent Flu?Perspective on a recent high-profile study Jacob Schor, ND, FABNO

KEY FINDINGSOf the 600 children selected, 445 (74.17%) children completed the study (149: homeopathic complex; 151: placebo; 145: InfluBio) and 155 (25.83%) chil-dren dropped out during the research period. Of the children who completed the entire study period, the mean age was 2.4 years without differences among groups.

Most of the children were classified as Caucasian or mixed-race living in the urban area. In the year before the study, most children had at least 1 episode of either flu or acute respiratory infection. In general, the number of flu and acute respiratory infections detected was low. The incidence of flu and acute respi-ratory infection episodes in the group that received placebo was higher compared to the groups that received homeopathic medications. The difference between homeopathic and placebo groups was statis-tically significant (P<0.001), whereas the difference between the homeopathic medicine groups was not (P=0.99).

In the first year post-intervention, 46 of 151 children (30.5%) in the placebo group developed 3 or more flu and acute respiratory infection episodes, while there was no episode out of 149 children who used homeo-pathic complex and only 1 out of 145 (1%) in chil-dren who received InfluBio.

PRACTICE IMPLICATIONSThe results reported by Siqueira et al in this paper are incredible, but as in the true meaning of the word, unbelievable. They seem just too good to be true.

Our belief as naturopathic physicians in the efficacy of homeopathic medicines in which the active agent employed has been diluted to the point of extinction contradicts logic and generally accepted scientific understanding. Despite the logic-defying premise of homeopathy, experience of apparent clinical efficacy

(continued on page 32)

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leaves many of us in a quandary. How does one justify the use of a medical practice that in the opinion of most scien-tists should not work? As a result we are particularly atten-tive to scientific research that supports the use of this type of medicine.

It has been 2 decades since David Reilly’s Lancet articles, which showed homeopathic preparations of airborne allergens had significant impact on allergy symptoms, which prompted the editors of the Lancet to write “either there is something amiss with the clinical trial as conventionally conducted, or the effects of homoeopathic immunotherapy differ from those of placebo … carefully done work of this sort should not be denied the attention of Lancet readers.”1,2

Homeopathy was incorporated into Brazil’s Public Health Service in 2006. Petropolis was one of the first cities in Brazil to actively implement homeopathy. Petropolis was also the home of Roberto Costa and the Roberto Costa Institute.

The homeopathic medicines used in this study are some-what unique. Roberto Costa, a homeopathic physician from Petropolis, developed a method of preparing nosodes using living organisms and reported they produced dramatic results compared to standard nosodes that are prepared from dead organisms.3 Costa’s reported results prompted an in vitro study published in 2013, which demonstrated that living nosodes prepared from influenza A virus had measurable effects—in particular stimulating macrophage cells and inducing an increase in tumor necrosis factor-alpha.4 These results moti-vated the present clinical trial to be conducted in the Brazilian Public Health System. These living nosodes are designated as “RC nosodes” after Roberto Costa.

These results seem too good. While almost a third of the chil-dren in the placebo group had 3 or more episodes of flu per year, use of either one of the homeopathic preparations tested in this study reduced episodes dramatically to just 1 episode in almost 300 children.

The timing of the study is another detail that makes the results seem implausible. This study was conducted during a year when Brazil was in the midst of the worldwide H1N1 flu

pandemic. The pandemic reached Brazil between 2009 and 2010, but did so unevenly. The positive outcomes reported in this study occurred during a time when increased infection rates should have been expected.

We are thus obliged to look hard for potential errors in meth-odology that might account for misleading data.

Two states (out of a total of 23) were responsible for 73% of all influenza cases reported in Brazil that year.5 Could the children who received placebo have lived in an area of higher infection rates than those receiving the homeopathic medicines? The authors state that the treatment groups were randomized so that geographic location would not confound the data.

The most obvious weakness in this study was that there was no actual laboratory examination of ill patients to confirm influ-enza infection. It would be more accurate to say that the chil-dren had something similar to an upper respiratory infection (URI) or influenza-like illness (ILI). It would be presumptive to state that these children actually had legitimate influenza infections based only on their questionnaires.

This lack of laboratory confirmation is shared by many complementary and alternative medicine trials and has been listed as a prime methodological consideration for investi-gating homeopathic treatment of influenza. Unless laboratory testing is employed to confirm the nature of a reported illness, the term ILI should have been used instead of influenza in discussing findings.

ABSTRACT & COMMENTARY

Siquerira et al are not just proposing

homeopathic prophylaxis lowered

risk of infection, but that it prevented

99% of the expected cases. In

contrast, the CDC reports that this

year’s flu vaccine (2016) has been

“highly effective” at a 59% reduction.

NMJ, SEPTEMBER 2016 SUPPLEMENT—VOL. 8, NO. 91 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. 33

ABSTRACT & COMMENTARY

According to Paul Herscu, ND, DHANP, MPH, of the New England School of Homeopathy, studies are easily discredited when they claim to be about influenza but rely only on symptoms for diagnosis. This kind of criticism may sink a paper’s credibility.6,7 Whichever terms are ulti-mately chosen, the reader is nevertheless left with the fact that the treatment groups experienced far fewer episodes of apparent illness.

Another weakness in this Brazilian study is that it was depen-dent on, and may be weakened by, recall bias for the inclusion criterion, as well as recall bias during the actual trial. This is important since the actual time period during which the trial was conducted coincided with the 2009 H1N1 epidemic, a time when there would have been increased surveillance and increased reported incidence, not less.

Another factor that possibly affected recall bias is the Hawthorne Effect. The Hawthorne Effect is the positive change in the performance of a group taking part in an exper-iment or study due to their perception of being singled out for special consideration. Given the young age of the study participants, we might assume they would be far less sensi-tive to this effect, but perhaps their family or care providers who reported on symptoms of illness were influenced. Even so, this study was well blinded: Neither children, family, teachers, doctors, nor pharmacists knew whether the partici-pant was singled out to received active homeopathic medica-tion or placebo medication.

Rates of actual influenza and illnesses are incredibly hetero-geneous in Brazil, with a great deal of moveable pieces and fluctuating demographic changes to illnesses, making a trial difficult to understand, which is why we hope for labora-tory confirmation.

In another paper describing the 2009 Brazilian flu epidemic, Oliveira et al reported, “There were 2,651 (45.6 % of 5,817 acute febrile illness patients) ILI cases with a mean annual incidence of 60 cases/1,000 population (95% CI 58-62). Risk of ILI was highest among 5–9 year olds with an annual inci-dence of 105 cases/1,000 population in 2009.”8

In Siquerira’s homeopathy study, 46 of the 151 children who had received placebo developed 3 or more flu or acute respira-tory infection episodes. If this were only 1 episode per child, the incidence would equal 305 cases per 1,000. This would still be nearly 3 times the highest rate, or 7 times the average rate of illness that Oliveira et al report. These numbers are so far above the general infection rates reported elsewhere that it raises questions and cause for concern.

If the children in the homeopathic treatment groups were to have become ill at the same rate as those who received placebo, there should have been approximately 90 children who became ill (0.305 x 294=90), but apparently only 1 did. Siquerira et al are not just proposing homeopathic prophy-laxis lowered risk of infection, but that it prevented 99% of the expected cases.

In contrast, the CDC reports that this year’s flu vaccine (2016) has been “highly effective” at a 59% reduction.9

Even applying Oliveira’s reported incidence rate of 105 cases out of 1,000 to the 294 children who received homeopathic treatment and completed the study, we would extrapolate that 31 should have fallen ill during the year. Again, reporting that only 1 child became ill seems incredible.

Siqueira et al do not report vaccination rates among their study participants and whether rates varied among treatment versus placebo groups. More than 89 millions doses of H1N1 vaccine were administered during the course of this study in Brazil.10 While one assumes that randomization created subgroups that were equally vaccinated, this missing informa-tion raises the possibility that lower vaccination rates among

Science, good or bad, rarely stands in the

way of public belief, and we will likely

see this paper being used as justification

for homeopathic influenza prophylaxis

treatments this coming winter.

34 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, SEPTEMBER 2016 SUPPLEMENT—VOL. 8, NO. 91 (SUPPL)

the placebo group might be linked with higher incidence of infectious episodes.

The nature of the questionnaire Siqueira et al used to measure the effectiveness of the homeopathic interventions allowed for tracking frequency of perceived illness but not severity. It is typical to report these 2 measures together as a way to judge the effectiveness of an intervention. One way to do so is by reporting the number of severe acute respira-tory infections (SARIs), as in the paper cited below. Missing this more quantifiable measure of illness leaves the door open for conjecture; for example, is it possible that those individuals treated with homeopathic medicine had fewer episodes but that each episode was more severe or life threat-ening? Another possibility is that the placebo group had more frequent illnesses but of less severity.11 The authors did report that the children receiving the homeopathic prepa-ration were more likely to have mild flulike symptoms in the month following initial treatment, while those children receiving placebo were more likely to have flulike symptoms about 3 months after treatment and then repeatedly. One might argue that this was a “homeopathic proving” or an immunological response to the treatments. If the latter, it would be curious to have looked for changes in viral anti-body titers pre- and post-interventions.

Future trials like this would benefit from tracking symptoms and illness severity—and using lab testing to confirm flu infection.

Science, good or bad, rarely stands in the way of public belief, and we will likely see this paper being used as justification for homeopathic influenza prophylaxis treatments this coming winter. Given the low side effect risk of these medicines, there is little reason to dissuade people from engaging in such prac-tices. Whether these Roberto Costa (RC) nosodes become available in North America is another question. Perhaps as we gain clinical experience using these products, my initial doubts about these incredible results will change.

REFERENCES1 Reilly D, Taylor MA, Beattie NG, Campbell JH, McSharry C, Aitchison TC, Carter R, et

al. Is evidence for homoeopathy reproducible? Lancet. 1994;344(8937):1601-1606.2 Taylor MA, Reilly D, Llewellyn-Jones RH, McSharry C, Aitchison TC. Randomised

controlled trial of homoeopathy versus placebo in perennial allergic rhinitis with overview of four trial series. BMJ. 2000 Aug 19; 321(7259): 471–476.

3 Costa RA. Nosodios Vivos. 1st edn. Rio de Janeiro: Farmacia Homeopatica Atomo Ltda., 2002.

4 Siqueira CM, Costa B, Amorim AM, et al. H3N2 homeopathic influenza virus solution modifies cellular and biochemical aspects of MDCK and J774G8 cell lines. Homeop-athy. 2013;102:31e40.

5 Codeço CT, Cordeiro JD, Lima AW, et al. The epidemic wave of influenza A (H1N1) in Brazil. Cadernos de Saúde Pública. 2009;28(7):1325-1336.

6 Kirkby R, Calabrese C, Kaltman L, Monnier J, Herscu P. Methodological considerations for future controlled influenza treatment trials in complementary and alternative medi-cine. J Altern Complement Med. 2010;16(3):275-283.

7 Kirkby R, Herscu P. Homeopathic trial design in influenza treatment. Homeopathy. 2010;99(1):69-75.

8 Oliveira CR, Costa GSR, Paploski IAD, et al. Influenza-like illness in an urban community of Salvador, Brazil: incidence, seasonality and risk factors. BMC Infectious Diseases. 2016;16:125.

9 Centers for Disease Control and Prevention. Flu vaccine nearly 60 percent effective. http://www.cdc.gov/media/releases/2016/flu-vaccine-60-percent.html. Accessed August 29, 2016.

10 Domingues CM, de Oliveira WK; Brazilian andemic Influenza Vaccination Evaluation Team. Uptake of pandemic influenza (H1N1)-2009 vaccines in Brazil, 2010. Vaccine. 2012;30(32):4744-4751.

11 Oliveira W, Carmo E, Penna G, et al. Pandemic H1N1 influenza in Brazil: analysis of the first 34,506 notified cases of influenza-like illness with severe acute respiratory infection (SARI). Euro Surveill. 2009;14(42).

ABSTRACT & COMMENTARY

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