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Оценка композиционного состава тела детей и подростков с ожирением для совершенствования предикции метаболического риска
Тодиева А.М., Никитина И.Л., Каронова Т.Л., Буданова М.В. Оценка композиционного состава тела детей и подростков с ожирением для совершенствования предикции метаболического риска. Consilium Medicum. Педиатрия (Прил.). 2016; 3: 92–98.
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Todieva A.M., Karonova T.L., Budanova M.V., Nikitina I.L. Evaluation of body composition of children and adolescents with obesity to improve the prediction of metabolic risk. Consilium Medicum. Pediatrics (Suppl.). 2016; 3: 92–98.
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Аннотация
Актуальность. Широкое распространение ожирения и ассоциированных с ним метаболических расстройств – актуальная медико-социальная проблема. Жировая ткань является не только депо, но и активным эндокринным органом, продуцирующим адипокины и изменяющим механизмы взаимовлияния витамина D. Абсолютные значения индекса массы тела (ИМТ) высоко коррелируют с количеством жировой ткани, однако особенности организма детей и подростков в ряде случаев затрудняют использование ИМТ как метода диагностики ожирения, в связи с чем большое практическое значение представляют собой методы исследования композиционного состава тела и выделение в его структуре жирового компонента. Одним из таких методов является определение индекса массы жира (ИМЖ) с помощью двухэнергетической рентгеновской абсорбциометрии.
Цель – изучение особенностей композиционного состава тела у детей и подростков с первичным ожирением, а также установление возможных взаимосвязей ИМЖ с некоторыми предикторами метаболических расстройств.
Методы. Включены 34 ребенка школьного возраста с ожирением, у которых оценены ИМТ, ИМЖ, окружности талии и бедер, обеспеченность витамином D, уровни лептина и адипонектина. По значению ИМТ обследуемые были разделены на 2 группы сравнения: 1-я группа – стандартное отклонение (SDS – standard deviation score) ИМТ от +2 до +2,9; 2-я группа – SDS ИМТ≥+3.
Результаты. Медиана ИМЖ была высокой, составила 12,3 кг/м2 и у всех обследованных детей превышала 75-й перцентиль как для европейской, так и для американской популяции. Выявлена закономерно сильная положительная корреляция между ИМТ и ИМЖ у детей с ожирением (r=0,73, р<0,01). Содержание витамина D имело обратную корреляцию с общим количеством жира (r=-0,39, p<0,05), с количеством свободного жира (r=-0,44, p<0,05). Содержание лептина прямо коррелировало практически со всеми показателями жировой ткани и особенно сильно ассоциировано как с ИМЖ в целом (r=0,77, p<0,05), так и с ИМЖ в группе более тяжелой степени ожирения (SDS ИМТ>+3). Уровень адипонектина показал умеренную обратную корреляцию с количеством свободного жира (r=-0,41, p<0,05).
Выводы. Прогрессирование ожирения происходит в основном за счет возрастания количества жира преимущественно андроидной локализации. Независимым предиктором метаболического синдрома следует считать прямые корреляции лептина и обратные корреляции адипонектина с увеличением количества жировой ткани. Увеличение количества жировой ткани влияет на снижение уровня витамина D. Изучение композиционного состава тела и определение с его помощью жировой составляющей позволяют глубже охарактеризовать взаимосвязи между количеством и расположением жировой ткани, а также между изменениями уровня ассоциированных адипокинов и гормонов.
Ключевые слова: ожирение, дети и подростки, индекс массы жира, витамин D, адипонектин, лептин.
Цель – изучение особенностей композиционного состава тела у детей и подростков с первичным ожирением, а также установление возможных взаимосвязей ИМЖ с некоторыми предикторами метаболических расстройств.
Методы. Включены 34 ребенка школьного возраста с ожирением, у которых оценены ИМТ, ИМЖ, окружности талии и бедер, обеспеченность витамином D, уровни лептина и адипонектина. По значению ИМТ обследуемые были разделены на 2 группы сравнения: 1-я группа – стандартное отклонение (SDS – standard deviation score) ИМТ от +2 до +2,9; 2-я группа – SDS ИМТ≥+3.
Результаты. Медиана ИМЖ была высокой, составила 12,3 кг/м2 и у всех обследованных детей превышала 75-й перцентиль как для европейской, так и для американской популяции. Выявлена закономерно сильная положительная корреляция между ИМТ и ИМЖ у детей с ожирением (r=0,73, р<0,01). Содержание витамина D имело обратную корреляцию с общим количеством жира (r=-0,39, p<0,05), с количеством свободного жира (r=-0,44, p<0,05). Содержание лептина прямо коррелировало практически со всеми показателями жировой ткани и особенно сильно ассоциировано как с ИМЖ в целом (r=0,77, p<0,05), так и с ИМЖ в группе более тяжелой степени ожирения (SDS ИМТ>+3). Уровень адипонектина показал умеренную обратную корреляцию с количеством свободного жира (r=-0,41, p<0,05).
Выводы. Прогрессирование ожирения происходит в основном за счет возрастания количества жира преимущественно андроидной локализации. Независимым предиктором метаболического синдрома следует считать прямые корреляции лептина и обратные корреляции адипонектина с увеличением количества жировой ткани. Увеличение количества жировой ткани влияет на снижение уровня витамина D. Изучение композиционного состава тела и определение с его помощью жировой составляющей позволяют глубже охарактеризовать взаимосвязи между количеством и расположением жировой ткани, а также между изменениями уровня ассоциированных адипокинов и гормонов.
Ключевые слова: ожирение, дети и подростки, индекс массы жира, витамин D, адипонектин, лептин.
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Relevance. Widespread obesity and associated metabolic disorders are an urgent medical and social problem. Adipose tissue is not only a depot, but an active endocrine organ, producing adipokines and changing mechanisms of mutual influence of vitamin D. The absolute values of body mass index (BMI) is highly correlated with the amount of fatty tissue, but especially the organism of children and adolescents in some cases, make it difficult to use BMI as a method of obesity diagnosis, and therefore the research methods of body composition and allocation of the fat component in its structure are very important. One of these methods lies in determining the fat mass index (FMI) by dual energy X-ray absorptiometry.
The goal is to study the features of body composition in children and adolescents with primary obesity, as well as to establish possible links between FMI ans some predictors of metabolic disorders.
Methods. Included are 34 school-age children with obesity who have assessed BMI, waist and hips, security vitamin D, levels of leptin and adiponectin. According to BMI, the subjects were divided into two comparison groups: Group 1 – standard deviation (SDS – standard deviation score) BMI fr om +2 to +2.9; Group 2 – SDS IMT≥+3.
Results. FMI median was high, was 12.3 kg/m2 and all children surveyed exceeded the 75th percentile for both European and American population. The regularities of strong positive correlation between BMI and FMI in obese children (r=0.73, p<0.01)were also found. Vitamin D content was inversely correlated with total body fat (r=-0.39, p<0.05), with the amount of free fat (r=-0.44, p<0.05). Leptin directly correlated with almost all indicators of adipose tissue and especially strongly associated with both FMI as a whole (r=0.77, p<0.05), and with the group wh ere FMI was an indicator of a more severe obesity (SDS BMI>3). Moderate level of adiponectin showed an inverse correlation with the amount of free fat (r=-0.41, p<0.05).
Conclusions. The progression of obesity is mainly due to the increase in the amount of fat mostly Android-localization. Independent predictor of metabolic syndrome should be considered as the direct correlation of leptin and adiponectin inverse correlation with the increase in the amount of adipose tissue. Increasing the amount of adipose tissue influences the reduction of vitamin D. The study and body composition determination with the help of deep fat component allows to characterize the relationship between the number and arrangement of adipose tissue and associated changes in level between adipokines and hormones.
Key words: obesity, children and adolescents, fat mass index, vitamin D, adiponectin, leptin.
Полный текст
Список литературы
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2. Ng M, Fleming T et al. Global, regional and national prevalence of overweight and obesity in children and adults 1980–2013: A systematic analysis. Lancet 2014; 384 (9945): 766–81.
3. Hakim F, Kheirandish-Gozal L, Gozal D. Obesity and Altered Sleep: A Pathway to Metabolic Derangements in Children? Semin Pediatr Neurol 2015; 22 (2): 77–85.
4. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity and trends in body mass index among US children and adolescents. JAMA 2016; 315 (21): 2292–9.
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6. Петеркова В.А., Ремизов О.В. Ожирение в детском возрасте. Ожирение и метаболизм. 2004; 1: 17–23. / Peterkova V.A., Remizov O.V. Ozhirenie v detskom vozraste. Ozhirenie i metabolizm. 2004; 1: 17–23. [in Russian]
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8. Freedman DS, Mei ZG, Srinivasan SR et al. Cardiovascular risk factors and excess adiposity among overweight children and adolescents: The Bogalusa Heart Study. J Pediatr 2007; 150 (1): 12–7.
9. Raitakari OT, Juonala M, Kähönen M et al. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: The Cardiovascular Risk in Young Finns Study. JAMA 2003; 290: 2277–83.
10. Deshmukh-Taskar P, Nicklas TA, Morales M et al. Tracking of overweight status from childhood to young adulthood: the Bogalusa Heart Study. Eur J Clin Nutr 2006; 60: 48–57.
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12. August GP, Carpio S, Fennov I. Prevention and treatment of pediatric obesity: an endocrine society clinical practice guideline based on expert opinion. J Clin Endocrinol Metab 2008; 93 (12): 4576–99.
13. Дедов И.И., Петеркова В.А. Федеральные клинические рекомендации (протоколы) по ведению детей с эндокринными заболеваниями. М.: Практика, 2014. / Dedov I.I., Peterkova V.A. Federal'nye klinicheskie rekomendatsii (protokoly) po vedeniiu detei s endokrinnymi zabolevaniiami. M.: Praktika, 2014. [in Russian]
14. Dietz WH, Bellizzi MC. Introduction: the use of body mass index to assess obesity in children. Am J Clin Nutr 1999; 70 (1): 123–5.
15. Zimmet P, Alberti K, George MM et al. The metabolic syndrome in children and adolescents – an IDF consensus report. Pediatric Diabetes 2007; 8: 299–306.
16. Alberti KG. The metabolic syndrome – a new worldwide definition. Lancet 2005; 366 (9491): 1059–62.
17. Coelho M, Oliveira T, Fernandes R. Biochemistry of adipose tissue: an endocrine organ. Arch Med Sci 2013; 9 (2): 191–200.
18. Huang KC, Lue BH, Yen RF et al. Plasma adiponectin levels and metabolic factors in nondiabetic adolescents. Obes Res 2004; 12 (1): 119–24.
19. Panagopoulou P, Galli-Tsinopoulou A, Fleva A et al. Adiponectin and insulin resistance in childhood obesity. J Pediatr Gastroenterol Nutr 2008; 47 (3): 356–62.
20. Catli G, Anik A et al. The relation of leptin and soluble leptin receptor levels with metabolic and clinical parameters in obese and healthy children. Peptides 2014; 56: 72–6.
21. Holic MF, Binkley NC, Bischoff-Ferrari HA et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrin Metab 2011; 96 (7): 1911–30.
22. Каронова Т.Л., Гринева Е.Н., Никитина И.Л. и др. Распространенность дефицита витамина D в северо-западном регионе РФ среди жителей г. Санкт-Петербурга и г. Петрозаводска. Остеопороз и остеопатии. 2013; 3: 3–7. / Karonova T.L., Grineva E.N., Nikitina I.L. i dr. Rasprostranennost' defitsita vitamina D v severo-zapadnom regione RF sredi zhitelei g. Sankt-Peterburga i g. Petrozavodska. Osteoporoz i osteopatii. 2013; 3: 3–7. [in Russian]
23. Wortsman J, Matsuoka LY, Chen TC et al. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 2000; 72 (3): 690–3.
24. Rusconi RE, De Cosmi V, Gianluca G et al. Vitamin D insufficiency in obese children and relation with lipid profile. Int J Food Sci Nutr 2015; 66 (2): 132–4.
25. Walker GE, Rocotti R, Roccio M et al. Pediatric obesity and vitamin D deficiency: a proteomic approach identifies multimeric adiponectin as a key link between these conditions. PLoS One 2014; 9 (1): e83685.
26. Menezes AR, Lamb MC, Lavie CJ, DiNicolantonio JJ. Vitamin D and atherosclerosis. Curr Opin Cardiol 2014; 29 (6): 571–7.
27. Мартиросов Э.Г., Николаев Д.В., Руднев С.Г. Технологии и методы определения состава тела человека. М.: Наука, 2006. / Martirosov E.G., Nikolaev D.V., Rudnev S.G. Tekhnologii i metody opredeleniia sostava tela cheloveka. M.: Nauka, 2006. [in Russian]
28. Ellis KJ. Measuring body fatness in children and young adults: comparison of bioelectric impedance analysis, total body electrical conductivity, and dual-energy
X-ray absorptiometry. Int J Obes Relat Metab Disord 1996; 20 (9): 866–73.
29. Slaughter MH, Lohman TG, Boileau RA et al. Skinfold equations for estimation of body fatness in children and youth. Hum Biol 1988; 60 (5): 709–23.
30. Dezenberg CV, Nagy TR, Goweret BA et al. Predicting body composition from anthropometry in pre-adolescent children. Int J Obes 1999; 23 (3): 253–9.
31. Bray GA, DeLany JP, Harsha DW et al. Evaluation of body fat in fatter and leaner
10-y-old African American and white children: the Baton Rouge Children's Study. Am J Clin Nutr 2001; 73 (4): 687–702.
32. Kyle UG. Bioelectrical impedance analysis – part I: review of principles and methods. Clin Nutr 2004; 23 (5): 1226–43.
33. Kyle UG. Bioelectrical impedance analysis – part II: utilization in clinical practice. Clin Nutr 2004; 23 (6): 1430–53.
34. Bunc V. Prospects of body composition analysis by bioimpedance method in children. Cas Lek Cesk 2007; 146 (5): 492–6.
35. Rodríguez PN, Bermúdez EF, Rodríguez GS et al. Body composition by simple anthropometry, bioimpedance and DXA in preschool children: interrelationships among methods. Arch Argent Pediatr 2008; 106 (2): 102–9.
36. Kettaneh А, Heude В, Lommez А et al. Reliability of bioimpedance analysis compared with other adiposity measurements in children: the FLVS II Study. Diabetes Metab 2005; 31 (6): 534–41.
37. Ching S Wan. Bioelectrical impedance analysis to estimate body composition, and change in adiposity, in overweight and obese adolescents: comparison with dual-energy x-ray absorptiometry. BMC Pediatr 2014; 14: 249.
38. Hofsteenge GH. Fat-free mass prediction equations for bioelectric impedance analysis compared to dual energy X-ray absorptiometry in obese adolescents: a validation study. BMC Pediatr 2015; 15: 158.
39. Verney J. Bioelectrical impedance is an accurate method to assess body composition in obese but not severely obese adolescents. Nutr Res 2016; 36 (7): 663–70.
40. Hosking J. Validation of foot-to-foot bioelectrical impedance analysis with dual-energy X-ray absorptiometry in the assessment of body composition in young children: the EarlyBird cohort. Br J Nutr 2006; 96 (6): 1163–8.
41. Eisenkolbl J. Underestimation of percentage fat mass measured by bioelectrical impedance analysis compared to dual energy X-ray absorptiometry method in obese children. Eur J Clin Nutr 2001; 55 (6): 423–9.
42. Kelly TL, Berger N, Richardson TL. DXA body composition: theory and practice. Appl Radiat Isotopes 1998; 49 (5–6): 511–3.
43. Leslie WD, Morin S, Lix LM et al. Fracture risk assessment without bone density measurement in routine clinical practice. Osteoporosis International 2012; 23 (1): 75–85.
44. Margulies L. Reproducibility of pediatric whole body bone and body composition measures by dual-energy X-ray absorptiometry using the GE Lunar Prodigy. J Clin Densitom 2005; 8 (3): 298–304.
45. Kelly TL, Wilson KE, Heymsfield SB. Dual Energy X-Ray Absorptiometry Body Composition Reference Values from NHANES. PLoS ONE 2009; 4 (9): e7038.
46. VanItallie TB, Yang MU, Heymsfield SB et al. Height-normalized indices of the body's fat-free mass and fat mass: potentially useful indicators of nutritional status. Am J Clin Nutr 1990; 52 (6): 953–9.
47. Каронова Т.Л., Гринева Е.Н., Михеева Е.П. и др. Уровень витамина D и его взаимосвязь с количеством жировой ткани и содержанием адипоцитокинов у женщин репродуктивного возраста. Пробл. эндокринологии. 2012; 58 (6): 19–23. / Karonova T.L., Grineva E.N., Mikheeva E.P. i dr. Uroven' vitamina D i ego vzaimosviaz' s kolichestvom zhirovoi tkani i soderzhaniem adipotsitokinov u zhenshchin reproduktivnogo vozrasta. Probl. endokrinologii. 2012; 58 (6): 19–23. [in Russian]
48. Weber DR. Fat and lean BMI reference curves in children and adolescents and their utility in identifying excess adiposity compared with BMI and percentage body fat. Am J Clin Nutr 2013; 98 (1): 49–56.
49. Wells JC, Williams JE, Chomtho S et al. Body-composition reference data for simple and reference techniques and a 4-component model: a new UK reference child. Am J Clin Nutr 2012; 96 (6): 1316–26.
50. Demerathr EW, Johnson W. Pediatric body composition references: what’s missing? Am J Clin Nutr 2013; 98 (1): 1–3.
________________________________________________
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19. Panagopoulou P, Galli-Tsinopoulou A, Fleva A et al. Adiponectin and insulin resistance in childhood obesity. J Pediatr Gastroenterol Nutr 2008; 47 (3): 356–62.
20. Catli G, Anik A et al. The relation of leptin and soluble leptin receptor levels with metabolic and clinical parameters in obese and healthy children. Peptides 2014; 56: 72–6.
21. Holic MF, Binkley NC, Bischoff-Ferrari HA et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrin Metab 2011; 96 (7): 1911–30.
22. Karonova T.L., Grineva E.N., Nikitina I.L. i dr. Rasprostranennost' defitsita vitamina D v severo-zapadnom regione RF sredi zhitelei g. Sankt-Peterburga i g. Petrozavodska. Osteoporoz i osteopatii. 2013; 3: 3–7. [in Russian]
23. Wortsman J, Matsuoka LY, Chen TC et al. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 2000; 72 (3): 690–3.
24. Rusconi RE, De Cosmi V, Gianluca G et al. Vitamin D insufficiency in obese children and relation with lipid profile. Int J Food Sci Nutr 2015; 66 (2): 132–4.
25. Walker GE, Rocotti R, Roccio M et al. Pediatric obesity and vitamin D deficiency: a proteomic approach identifies multimeric adiponectin as a key link between these conditions. PLoS One 2014; 9 (1): e83685.
26. Menezes AR, Lamb MC, Lavie CJ, DiNicolantonio JJ. Vitamin D and atherosclerosis. Curr Opin Cardiol 2014; 29 (6): 571–7.
27. Martirosov E.G., Nikolaev D.V., Rudnev S.G. Tekhnologii i metody opredeleniia sostava tela cheloveka. M.: Nauka, 2006. [in Russian]
28. Ellis KJ. Measuring body fatness in children and young adults: comparison of bioelectric impedance analysis, total body electrical conductivity, and dual-energy
X-ray absorptiometry. Int J Obes Relat Metab Disord 1996; 20 (9): 866–73.
29. Slaughter MH, Lohman TG, Boileau RA et al. Skinfold equations for estimation of body fatness in children and youth. Hum Biol 1988; 60 (5): 709–23.
30. Dezenberg CV, Nagy TR, Goweret BA et al. Predicting body composition from anthropometry in pre-adolescent children. Int J Obes 1999; 23 (3): 253–9.
31. Bray GA, DeLany JP, Harsha DW et al. Evaluation of body fat in fatter and leaner
10-y-old African American and white children: the Baton Rouge Children's Study. Am J Clin Nutr 2001; 73 (4): 687–702.
32. Kyle UG. Bioelectrical impedance analysis – part I: review of principles and methods. Clin Nutr 2004; 23 (5): 1226–43.
33. Kyle UG. Bioelectrical impedance analysis – part II: utilization in clinical practice. Clin Nutr 2004; 23 (6): 1430–53.
34. Bunc V. Prospects of body composition analysis by bioimpedance method in children. Cas Lek Cesk 2007; 146 (5): 492–6.
35. Rodríguez PN, Bermúdez EF, Rodríguez GS et al. Body composition by simple anthropometry, bioimpedance and DXA in preschool children: interrelationships among methods. Arch Argent Pediatr 2008; 106 (2): 102–9.
36. Kettaneh А, Heude В, Lommez А et al. Reliability of bioimpedance analysis compared with other adiposity measurements in children: the FLVS II Study. Diabetes Metab 2005; 31 (6): 534–41.
37. Ching S Wan. Bioelectrical impedance analysis to estimate body composition, and change in adiposity, in overweight and obese adolescents: comparison with dual-energy x-ray absorptiometry. BMC Pediatr 2014; 14: 249.
38. Hofsteenge GH. Fat-free mass prediction equations for bioelectric impedance analysis compared to dual energy X-ray absorptiometry in obese adolescents: a validation study. BMC Pediatr 2015; 15: 158.
39. Verney J. Bioelectrical impedance is an accurate method to assess body composition in obese but not severely obese adolescents. Nutr Res 2016; 36 (7): 663–70.
40. Hosking J. Validation of foot-to-foot bioelectrical impedance analysis with dual-energy X-ray absorptiometry in the assessment of body composition in young children: the EarlyBird cohort. Br J Nutr 2006; 96 (6): 1163–8.
41. Eisenkolbl J. Underestimation of percentage fat mass measured by bioelectrical impedance analysis compared to dual energy X-ray absorptiometry method in obese children. Eur J Clin Nutr 2001; 55 (6): 423–9.
42. Kelly TL, Berger N, Richardson TL. DXA body composition: theory and practice. Appl Radiat Isotopes 1998; 49 (5–6): 511–3.
43. Leslie WD, Morin S, Lix LM et al. Fracture risk assessment without bone density measurement in routine clinical practice. Osteoporosis International 2012; 23 (1): 75–85.
44. Margulies L. Reproducibility of pediatric whole body bone and body composition measures by dual-energy X-ray absorptiometry using the GE Lunar Prodigy. J Clin Densitom 2005; 8 (3): 298–304.
45. Kelly TL, Wilson KE, Heymsfield SB. Dual Energy X-Ray Absorptiometry Body Composition Reference Values from NHANES. PLoS ONE 2009; 4 (9): e7038.
46. VanItallie TB, Yang MU, Heymsfield SB et al. Height-normalized indices of the body's fat-free mass and fat mass: potentially useful indicators of nutritional status. Am J Clin Nutr 1990; 52 (6): 953–9.
47. Karonova T.L., Grineva E.N., Mikheeva E.P. i dr. Uroven' vitamina D i ego vzaimosviaz' s kolichestvom zhirovoi tkani i soderzhaniem adipotsitokinov u zhenshchin reproduktivnogo vozrasta. Probl. endokrinologii. 2012; 58 (6): 19–23. [in Russian]
48. Weber DR. Fat and lean BMI reference curves in children and adolescents and their utility in identifying excess adiposity compared with BMI and percentage body fat. Am J Clin Nutr 2013; 98 (1): 49–56.
49. Wells JC, Williams JE, Chomtho S et al. Body-composition reference data for simple and reference techniques and a 4-component model: a new UK reference child. Am J Clin Nutr 2012; 96 (6): 1316–26.
50. Demerathr EW, Johnson W. Pediatric body composition references: what’s missing? Am J Clin Nutr 2013; 98 (1): 1–3.
Авторы
А.М.Тодиева*, И.Л.Никитина, Т.Л.Каронова, М.В.Буданова
ФГБУ Северо-Западный федеральный медицинский исследовательский центр им. В.А.Алмазова Минздрава России. 197341, Россия, Санкт-Петербург, ул. Аккуратова, д. 2
*kislorod83@gmail.com
ФГБУ Северо-Западный федеральный медицинский исследовательский центр им. В.А.Алмазова Минздрава России. 197341, Россия, Санкт-Петербург, ул. Аккуратова, д. 2
*kislorod83@gmail.com
________________________________________________
A.M.Todieva*, I.L.Nikitina, T.L.Karonova, M.V.Budanova
V.A.Almazov North-West Federal Medical Research Center of the Ministry of Health of the Russian Federation. 197341, Russian Federation, Saint Petersburg, ul. Akkuratova, d. 2
*kislorod83@gmail.com
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