The Role of Nutrition in Children's Growth & Health

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The Role of Nutrition

in Children’s Growth & Health

Abdulmoein Al-Agha, FRCPCH (UK)

Professor & Head of Pediatric Endocrinology, King Abdulaziz University Hospital,

www.aagha.kau.edu.sa

Saturday, January 9, 2021

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Agenda

• Introduction.

• Factors affecting post natal growth.

• Nutrition during infancy & its importance for growth.

• Nutrition & growth faltering.

• Malnutrition has a negative effects on the growth.

• Effective intervention to restore growth.

• Importance of macronutrients & micronutrients for children’s growth.

• The rationale for novel ingredients in ONS: Arginine & Vitamin K2.

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Introduction

• Growth is a fundamental physiologic process that characterizes childhood.

• It should be closely monitored by paediatricians & families as an index of child’s health.

• Nutrition plays fundamental role in determining the growth of children.

• An appropriate growth progression is considered as indicator of adequate nutrient intake & good health.

• On the other hand, growth deceleration with / without short stature may indicate inadequate nutrition.

• Nutritional growth retardation is most prevalent in populations at risk of poverty.

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• Protein-energy malnutrition, in early life led to compromised growth &

cognitive functions in young children.

• Important nutrients for children’s growth include:

• Calcium strengthens bones.

• Proteins (amino acids e.g., Arginine)

• Carbohydrates provide energy.

• Iron is essential for tissue oxygenation & growth.

• Essential fatty acids help the body to absorb other vitamins.

• Vitamins e.g., vitamin D, K & folic acid…..etc.)

• Trace elements include zinc, copper, iodine & selenium.

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• The first 3 years of life are most crucial & vulnerable to the hazards of undernutrition.

• All efforts should be made so that preschool children are given a balanced nutritious home-based diet.

• It has been shown that it is not possible to meet 100% requirements of recommended dietary allowances (RDA's) of micronutrients from

dietary sources alone.

• Most preschool children need administration of oral nutritional supplements (ONS) to optimize their genetic potential for physical growth & mental development.

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Linear Growth in Children &

Role of Nutrition

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Factors affecting children’s growth

Intra uterine Growth factors

IGF2 Insulin

Nutrition

&Thyroid hormone Nutrition ,Thyroid &

Growth Hormone

Nutrition ,Thyroid

Growth & Sex Hormones

Birth

^1-2

years

Childhood

Puberty

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Postnatal linear growth can be described in three distinct phases:

1. Nutrition-dependent infancy phase.

2. Growth-hormone-dependent childhood phase.

3. Pubertal growth spurt during adolescence driven by sex steroids.

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Linear Growth is regulated by GH in childhood

• GH is very essential for linear growth:

✓ Directly by binding to its receptors in the growth plate (20%).

✓Indirectly (80%) via insulin-like growth factor (IGF-1).

• GH & IGF-1 concentration and

subsequently an increased growth velocity help determine the growth curve of each child.

References: Lindsey et al. Mol Cell Endocrinol. 2016 September 5; 432: 44–55.

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Linear Growth at the Epiphyseal growth plate

• Linear growth is determined by

the cell proliferation at the growth plates of long bones.

• The growth hormone/insulin-

like growth factor (GH/IGF) axis is critically important for the regulation of bone formation

& longitudinal bone growth.

The Role of Nutrition on Linear Growth and Catch-Up Growth

FRANCISCO J. ROSALES, M.D., SC.D.,

Medical Director, Abbott Nutrition, Scientific and Medical Affairs

SCIENTIFIC OVERVIEW

APPLYING TO YOUR PRACTICE KEY TAKEAWAYS

• Catch-up growth is aided by dietary counseling in addition to the use of a complete, balanced ONS in a child who can take nutritional requirements orally .

• In selecting an ONS, the nutritional value and child’ s taste preferences and tolerance are important. Choose an ONS formulated to reflect the reference values for macro- and micronutrients for a healthy population and a history of clinical efficacy.

• Dietary counseling and provision of ONS are key in restoring the gro wth potential of children at nutritional risk.

• Nutrition/undernutrition has a key role in the ra te of growth plate chondrogenesis.

• Growth monitoring of young children is important to determine their needs for catch-up growth, especially among those with weight-for -height < 25th percentile.

References:

1. Baron J. e t al. Nat. Rev. Endocrinol. 2015;11: 735–746 2. Gat-Yablonski & Phillip. Nutrients 2015, 7, 517-551 3. 6th Report on the World Nutrition Situation. United Nations System. Standing Committee on Nutrition. Underweight and stunting pg 42 4. Boerman & WIT. Endocrine Reviews 1997;18(5): 646–661. 5. Prader et al. JPediatric 1963; 62:646-59 6. Huynh et al. J Hum Nutr Diet. 2015 Dec;28(6):623-35

GROWTH &

NUTRITION

CHILDHOOD

E X P E R TS

Growth Plate Chondrogenesis

Linear growth, or height gain, is determined by the growth plate, the area of

cartilaginous tissue growing near the end of the long bones in children and adolescents. ¹ Each long bone has at least two growth plates, which determine the future length and shape of the mature bone through a process called chondrogenesis.¹

The rate of growth plate chondrogenesis (GPC) is regulated by many factors including hormonal mechanisms, and local intracellular and extracellular GPC ma trix factors.^1,2

Dysfunction of the GPC can be caused by a primar y defect in the growth plate, or a

secondary defect in which the growth plate is adversely affected by a disorder elsewhere in the body like undernutrition.¹

Nutritional Impacts on Growth Trajectories

Nutrition provides the required “building blocks” for optimal growth, including energy, proteins and micronutrients. Conversely, nutrient deficiencies are considered a leading cause of underweight and short stature (stunting) in children.³ The best example of how nutrition affects linear growth is the “catch-up growth” (CU) phenomenon..

Catch-up growth is the phase of rapid linear growth that allows a child to accelerate toward, and even resume his or her pre-illness growth curve. ⁴ Undernutrition can lead to reduced plasma levels of insulin, insulin-like growth factor-1, thyroid hormone, leptin and sex hormones, and increases in the level of glucocorticoids, all factors which can

negatively affect GPC.² With proper nutrition, the slowed senescent GPC shows a greater growth rate than expected for age, resulting in CU.⁵

Effects of a Nutritional Supplement on Catch-Up (CU) Growth

Clinical studies have shown CU in 4 to 8 weeks after providing complete, balanced Oral Nutritional Supplements (ONS) to young children with weight-for -height <25th percentile.⁶ For underweight and short stature children, early detection followed by nutritional counseling with ONS can restore their gro wth potential.

* p<0.0001, Compared to Baseline Point of Intervention with a ONS

BMI FOR AGE IN PERCENTILES

WEEKS 4 0

35 30 25 20 15 10 5 0

0 4 8 16 24 32 4 0 4 8

* *

* * *

BODY MASS INDEX (BMI=KG/M²) FOR AGE IN PERCENTILES Figure 3

Figure 2

TIME

SIZE

Bone age at the onset o f recovery

From Roselló-Díez & Joyner. Endocr Rev. 2015;36(6):646-80. Adapted from Huynh et al. J Hum Nutr Diet. 2015 Dec;28(6):623-35

A

B

TIME

Normal growth Impaired growth Type A catch-up gr owth Type B catch-up gr owth GROWTH TRAJECTORIES

Figure 1

RESTING ZONE

PROLIFERATIVE ZONE

PREHYPERTROPHIC ZONE

HYPERTROPHIC ZONE

TRABECULAR BONE

CHONDROGENESIS

JP-18358

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Nutrition & Growth during infancy

• Nutrition provides the required “building blocks” for optimal growth, including energy, proteins & micronutrients.

• Conversely, nutrient deficiencies are considered a leading cause of underweight & short stature (stunting) in children.

• Undernutrition can lead to reduced plasma levels of insulin, insulin-like growth factor-1, thyroid hormone, leptin and sex hormones.

• Nutrition in the first year most important as growth & development most rapid as:

• Birthweight doubles at 6 months of age & triples at 1yr.

• Height ↑from 50 cm at birth- 70-75 cm at 1 yr.

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Malnutrition & growth falttering

ENDOCRINE Lowers IGF-1 (Liver)

Lowers thyroid hormone Lowers androgens

Lowers estrogens

POOR NUTRITION

Calories Protein Vitamins Minerals

INFLAMMATION raises cytokines

sustains epithelial injury lowers appetite

stimulates glucocorticoids

Millward J. Nutr Res Rev (2017), 30, 50–72 Saturday, January 9, 2021

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Linear Growth at the Epiphyseal Growth Plate

• Undernutrition impairs the rate of longitudinal bone growth and length of the growth plate

o GH and IGF-1 can be impacted

• In states of growth restriction, the

growth plate conserve growth capacity until conditions improve- enabling

catch up growth to help achieve full growth potential.

References: Gat-Yablonski, G. Nutrients no. 7 (1):517-51.

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Breast-feeding

Stimulates Optimal Initial Growth

WHO: Breastfeeding exclusively for 6 months = 820,000 lives saved per year

https://www.unicef.org/publications/files/UNICEF_Breastfeeding_A_Mothers_Gift_for_Every_Child.pdf Saturday, January 9, 2021

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Nutrition plays key role for growth in early life

• The role of genetics on height growth from infancy to early childhood is relatively small.

• Nutrition is recognized as a key influential factor for height growth in early child growth.

48 58 68 78 88 98 108

0 1 2 3 4 5

Length or Height (cm)

Age (Years)

Pelotas, Brazil Accra, Ghana South Delhi, India Olso, Norway Muscat, Oman

Infants & young children with different ethnic

background grow in very similar speed when

environment is affluent and supportive

References: WHO Multicentre Growth Reference Study Group (2006). Acta Paediatr Suppl450: 56-65

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Rapid growth raises the risk of malnutrition

An infant / toddler’s rapid growth rate coupled with very high metabolic rate makes the risk of growth faltering

highest during the first 3 years.

Dietary energy is expended on:

1) basal metabolism.

2) functional activity.

3) requirements for growth, which varies by life stage and circumstances.

The basal metabolic rate corresponds to changes in growth velocity

Son’kin V, Tambovtseva R. Energy metabolism in children and adolescents. In, Bioenergetics, 2012. Ed, Dr. Kevin Clark. Intech Press. Chapter 5: 121-142Saturday, January 9, 2021

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Nutrition & Growth faltering

• Children at sub-optimal growth may not born to be small.

• Growth faltering usually

happens after breastfeeding is discontinued.

• Poor quality of

complementary/solid food.

References: Leroy et al., J. Nutr. 144: 1460–1466, 2014

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Poor

Dietary Intake

Serious Complications Family Concern

Physician Concern Weight < 5^th %

Height Slows

Height < 5^th % Energy/

Protein/

Vitamins/

Minerals Deficient

At-Risk?

FEEDING PROBLEMS

Murray RD. Pediatr Ann 2018;47:e465-e469Saturday, January 9, 2021

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Identify “Risks groups of poor growth

Medical & dietary history red flags:

• Infant/ toddler.

• Repeated infections.

• Food insecurity.

• Hospitalization.

• Chronic diseases.

• Neuro-physical disabilities.

• Prematurity/ IUGR.

• Stress /mental illness in the family.

• Poor diet quality/ picky eaters.

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Feeding history of picky eaters

• Difficult to feed.

• Parenting style more rigid.

• Mothers often were picky eaters too.

• Breastfeeding was limited.

• Early solid food introduction.

• Suspicious of new tastes, textures, colors.

• A lower enjoyment of food.

• A slow, disengaged eater.

• Prefers liquids to solids.

✓Limited variety of foods consumed

✓Limited vitamins & minerals

✓Lower diet quality at a critical time

✓May or may not be underweight

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Reference: Malnutrition: The Child At-Risk, Robert Murray MD, FAAP Professor of Pediatrics, The Ohio State University, March 2016

When to Intervene ?

A family’s concern about their child’s nutrition usually precedes a physician’s concern

LIMITED NUTRITION INTAKE NUTRITION DEPLETION

WEIGHT FALTERING NUTRIENT DEFIENCIES

HEIGHT FALTERING

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Nutritional management

Objectives:

improve energy & nutrient intake.

promote weight/height gain and enable catch-up growth.

correct nutritional deficiencies.

support parents to make the dietary changes.

1 2 3 4

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Important Nutrients for Optimal Growth Potential

• Arginine

• Vitamin K2

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Amino acids & Growth

• Based on growth & nitrogen balance, amino acids have been classified as essential (indispensable) or nonessential (dispensable) types.

• Essential amino acids are those whose carbon skeletons are not

synthesized by human cells and, must be provided from the diet (e.g., arginine, glycine, proline, and taurine).

• Essential amino acids (e.g., glutamine, glutamate, and arginine) play an important roles in multiple signalling pathways, thereby regulating gene expression, intracellular protein turnover, nutrient metabolism, and

oxidative defence mechanisms.

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Roles of amino acids in nutrition

& whole-body homeostasis.

Besides serving as building blocks for proteins.

AA have multiple regulatory functions in cells.

These nutrients are crucial for growth, development, and

health of animals and humans

Adv Nutr. 2010 Nov; 1(1): 31–37.

Published online 2010 Nov 16. doi: 10.3945/an.110.1008

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Arginine

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Serum Arginine levels are lower in stunted children

References: Semba, R. D.,2016. EBioMedicine 6:246-252.

74 76 78 80 82 84 86 88 90 92

Serum Arg concentration

Serum arginine in children (12-59 months) with and without stunting (N=313)

Stunted non-stunted

P=0.0003

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• Data collected from the Copenhagen School Child Intervention (n=261, age 7-13 y)

• Arginine intake was estimated via a 7-d food diary at baseline(2002) and 3-year follow-up(2005)

• The association between arginine intake and growth velocity were evaluated (adjusted for sex, age, baseline height, energy intake and puberty stage) at 7-year follow-up

Dietary Arginine consumption was associated with increased growth velocity in children

References: van Vught, Br J Nutr no. 109 (6):1031-9.

Children with an arginine intake between 2.8 and 3.2 g/d grew 0.33 cm/year faster compared to intake lower than 2.2 g/d (adjusted for confounding factors)

Incremental growth velocity (cm/year) per quintile of mean arginine intake

Mean Growth Velocity (cm/year)

Arginine Intake (g/d)

0 0.05 0.1 0.15 0.2 0.25 0.3 0.35

<2.2 2.2 –2.5 2.5 –2.8 2.8 –3.2 >3.2

Quintiles 1 2 3 4 5

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Malnutrition, Immunity & Arginine

• Undernutrition can compromise the immune system

• gut permeability, inflammatory cell in the intestine, B-cells and effector T-cells

• Arginine is reported to impacts immune response

• synthesis of NO and reactive oxygen species

• antimicrobial activity

• secretion of hormones that regulate the metabolism and activity of immunocytes

• maturation and proliferation of T-lymphocytes and B-lymphocytes

• production of cytokines and specific antibodies by T-lymphocytes and B-lymphocytes

• Children: Supplemental arginine (2 gram/ day) increased markers of immune system defense

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Role of micronutrients for physical growth &

cognitive function

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• It is estimated that, over 50% of apparently healthy-looking children have subclinical or biochemical deficiencies of vitamins A, K, B2, B6, folate and vitamin C.

• Over two-third of children have clinical evidences of iron deficiency

while deficiency of trace minerals like iodine and zinc is quite common in certain populations.

• Micronutrients are required for the integrity and optimal functioning of immune system.

• Several micronutrients are required for optimal physical growth and neuromotor development.

• Isolated deficiencies of micronutrients are rare in clinical practice and usually deficiencies of multiple micronutrients co-exist.

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Vitamin K

• A group of fat-soluble

molecules essential to human health

• Act as cofactors for several proteins.

• Two main biologically active forms: K1 & K2

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Vitamin Vitamin K1 Vitamin K2 (MK7)

Dietary sources Green leafy vegetables Certain fermented foods

Structure Short chain Long chain

Bioavailability Short half life (3-4 hours) Long half life (3-4 d)

Major uptake tissue Hepatic Hepatic and Extra hepatic

(e.g. bone)

K2 (MK7) could have a more pronounced impact on bone due to its longer half life and higher serum circulation level after ingestion

Vitamin K1 vs. Vitamin K2 (MK7)

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Osteocalcin

• The 2nd most abundant protein in bone tissue after collagen.

• Produced by osteoblasts and support bone building by facilitate calcium transportation to bone.

• Used as a marker for the bone formation process.

• Its synthesis is vitamin K dependent.

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K1 vs. K2(MK7): Metabolic difference in human

K2 (MK7) supplementation lead to higher and more stable serum vitamin K level (A) and induced more complete activation of

osteocalcin (B)

○: K1 supplementation

●: K2 supplementation

▲: no supplementation

References: Schurgers, L. Blood no. 109 (8):3279-83.2007.

Serum vitamin K (μg/L) difference from baseline

A

B

cOC/ucOCratio difference from baseline 8 6 4 2 0

Duration of treatment (days)

0 20 40

Duration of treatment (days)

0 20 40

1 2

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Vitamin K facilitates bone building

S u p p o r t b o n e

m i n e r a l i z a t i o n f o r s t r o n g b o n e s

ACTIVE OSTEOCALCIN

INACTIVE

OSTEOCALCIN K2

Natural Vitamin K2 : Mechanism of Action

• Vitamin K Activates Osteocalcin

• When osteocalcin is fully-activated, it attaches to calcium and transports it into bone

• Measure of circulating osteocalcin (active and inactive) is used as a biomarker for vitamin K status

ACTIVE OSTEOCALCIN bound to Ca

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Synergistic effect of Ca, Mg, Vitamin D & K2

Vitamin D Magnesium Vitamin K2

Magnesium

SMALL

INTESTINE BLOOD

Ca Ca BONE

Helps calcium absorption

Helps bone formation

Helps calcium retention

Ca

A B S O R B B U I L D

S T R E N G T H E N

Calcium from Diet

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Take Home Messages

• Undernutrition can have serious consequences for children, including stunting, wasting, poor cognitive development & illness.

• Addressing undernutrition early to reactivate the growth plate, helps a child reach their full growth potential.

• ONS may help improve nutrient intake and support absorption and utilization of nutrients to support growth (height and weight) in the child falling behind.

• Vitamin K2 (MK7) and arginine may further support healthy growth.

o Dietary arginine intake is associated with increased growth velocity in children.

o Vitamin K2 (MK7) is more bioavailable than typical K1 and it supports bone mineralization by facilitating the transport of calcium into bones.

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References

• Son’kin V, Tambovtseva R. Energy metabolism in children and adolescents. In, Bioenergetics, 2012. Ed, Dr. Kevin Clark. Intech Press.

Chapter 5: 121-142

• https://www.unicef.org/publications/files/UNICEF_Breastfeeding_A_Mothers_Gift_for_Every_Child.pdf

• WHO Multicenter Growth Reference Study Group (2006). Acta Paediatr Suppl 450: 56-65

• Leroy JL, Ruel M, Habicht JP, Frongillo EA. Linear growth deficit continues to accumulate beyond the first 1000 days in low- and middle-income countries: global evidence from 51 national surveys. J Nutr. 2014 Sep;144(9):1460-6. doi: 10.3945/jn.114.191981.

Epub 2014 Jun 18. PMID: 24944283.

• Robert Murray RD. Starting strong: Dietary, behavioral, and environmental factors that promote “strength” from conception to age 2 years. Pediatr Ann 2018;47:e465-e469

• Malnutrition: The Child At-Risk, Robert Murray MD, FAAP Professor of Pediatrics, The Ohio State University, March 2016

• Lindsey RC, Mohan S. Skeletal effects of growth hormone and insulin-like growth factor-I therapy. Mol Cell Endocrinol. 2016 Sep 5;432:44-55. doi: 10.1016/j.mce.2015.09.017. Epub 2015 Sep 25. PMID: 26408965; PMCID: PMC4808510.

• Millward DJ. Nutrition, infection and stunting: the roles of deficiencies of individual nutrients and foods, and of inflammation, as determinants of reduced linear growth of children. Nutr Res Rev. 2017 Jun;30(1):50-72. doi: 10.1017/S0954422416000238. Epub 2017 Jan 23. PMID: 28112064.

• Gat-Yablonski G, Phillip M. Nutritionally-induced catch-up growth. Nutrients. 2015 Jan 14;7(1):517-51. doi: 10.3390/nu7010517.

PMID: 25594438; PMCID: PMC4303852

• Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, Wei R, Curtin LR, Roche AF, Johnson CL. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11. 2002 May;(246):1-190. PMID: 12043359

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References

• Alarcon PA, et al. Effect of Oral Supplementation on Catch-Up Growth in Picky Eaters. Clin Pediatr. 2003;42:209-217

• Huynh et al, Longitudinal growth and health outcomes in nutritionally at‐risk children who received long‐term nutritional intervention. Journal of human nutrition and dietetics.

Volume28, Issue6. March 2015 https://doi.org/10.1111/jhn.12306.

• Dieu T. T. Huynh, Elvira Estorninos, Maria Rosario Capeding, Jeffery S. Oliver, Yen Ling Low, Francisco J. Rosales, Impact of long-term use of oral nutritional supplement on nutritional adequacy, dietary diversity, food intake and growth of Filipino preschool children, Journal of Nutritional Science, 10.1017/jns.2016.6, 5, (2016).

• Tapiero H, Mathé G, Couvreur P, Tew KD. I. Arginine. Biomed Pharmacother. 2002 Nov;56(9):439-45. doi: 10.1016/s0753-3322(02)00284-6. PMID: 12481980.

• Semba RD, Shardell M, Sakr Ashour FA, Moaddel R, Trehan I, Maleta KM, Ordiz MI, Kraemer K, Khadeer MA, Ferrucci L, Manary MJ. Child Stunting is Associated with Low Circulating Essential Amino Acids. EBioMedicine. 2016 Apr;6:246-252. doi: 10.1016/j.ebiom.2016.02.030. Epub 2016 Feb 19. PMID: 27211567; PMCID: PMC4856740.

• van Vught AJ, Dagnelie PC, Arts IC, Froberg K, Andersen LB, El-Naaman B, Bugge A, Nielsen BM, Heitman BL. Dietary arginine and linear growth: the Copenhagen School Child Intervention Study. Br J Nutr. 2013 Mar 28;109(6):1031-9. doi: 10.1017/S0007114512002942. Epub 2012 Oct 10. PMID: 23046689.

• Jiang MY, Cai DP. Oral arginine improves linear growth of long bones and the neuroendocrine mechanism. Neurosci Bull. 2011 Jun;27(3):156-62. doi: 10.1007/s12264-011-1051-3.

PMID: 21614098; PMCID: PMC5560364.

• Baligan, M., Giardina, A., Giovannini, G., Laghi, M. G., & Ambrosioni, G. (1997). [L-arginine and immunity. Study of pediatric subjects]. Minerva Pediatr, 49(11), 537-542.

• Karpinski, M. et al. 2017. J Am Coll Nutr no. 36 (5):399-412. doi: 10.1080/07315724.2017.1307791.

• van Summeren MJ, van Coeverden SC, Schurgers LJ, Braam LA, Noirt F, Uiterwaal CS, Kuis W, Vermeer C. Vitamin K status is associated with childhood bone mineral content. Br J Nutr. 2008 Oct;100(4):852-8. doi: 10.1017/S0007114508921760. Epub 2008 Feb 18. PMID: 18279558.

• Popko, J.; Karpiński, M.; Chojnowska, S.; Maresz, K.; Milewski, R.; Badmaev, V.; Schurgers, L.J. Decreased Levels of Circulating Carboxylated Osteocalcin in Children with Low Energy Fractures: A Pilot Study. Nutrients2018, 10, 734.

• Schurgers LJ, Teunissen KJ, Hamulyák K, Knapen MH, Vik H, Vermeer C. Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood. 2007 Apr 15;109(8):3279-83. doi: 10.1182/blood-2006-08-040709. Epub 2006 Dec 7. PMID:

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The Role of Nutrition in Children's Growth & Health