Publications by authors named "Valentina Peterkova"

36 Publications

Parental Perceptions of Children's Weight Status in 22 Countries: The WHO European Childhood Obesity Surveillance Initiative: COSI 2015/2017.

Obes Facts 2021 Nov 5:1-17. Epub 2021 Nov 5.

Observatory of Nutrition and Study of Obesity, Spanish Agency for Food Safety & Nutrition, Ministry of Health, Madrid, Spain.

Introduction: Parents can act as important agents of change and support for healthy childhood growth and development. Studies have found that parents may not be able to accurately perceive their child's weight status. The purpose of this study was to measure parental perceptions of their child's weight status and to identify predictors of potential parental misperceptions.

Methods: We used data from the World Health Organization (WHO) European Childhood Obesity Surveillance Initiative and 22 countries. Parents were asked to identify their perceptions of their children's weight status as "underweight," "normal weight," "a little overweight," or "extremely overweight." We categorized children's (6-9 years; n = 124,296) body mass index (BMI) as BMI-for-age Z-scores based on the 2007 WHO-recommended growth references. For each country included in the analysis and pooled estimates (country level), we calculated the distribution of children according to the WHO weight status classification, distribution by parental perception of child's weight status, percentages of accurate, overestimating, or underestimating perceptions, misclassification levels, and predictors of parental misperceptions using a multilevel logistic regression analysis that included only children with overweight (including obesity). Statistical analyses were performed using Stata version 15 1.

Results: Overall, 64.1% of parents categorized their child's weight status accurately relative to the WHO growth charts. However, parents were more likely to underestimate their child's weight if the child had overweight (82.3%) or obesity (93.8%). Parents were more likely to underestimate their child's weight if the child was male (adjusted OR [adjOR]: 1.41; 95% confidence intervals [CI]: 1.28-1.55); the parent had a lower educational level (adjOR: 1.41; 95% CI: 1.26-1.57); the father was asked rather than the mother (adjOR: 1.14; 95% CI: 0.98-1.33); and the family lived in a rural area (adjOR: 1.10; 95% CI: 0.99-1.24). Overall, parents' BMI was not strongly associated with the underestimation of children's weight status, but there was a stronger association in some countries.

Discussion/conclusion: Our study supplements the current literature on factors that influence parental perceptions of their child's weight status. Public health interventions aimed at promoting healthy childhood growth and development should consider parents' knowledge and perceptions, as well as the sociocultural contexts in which children and families live.
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http://dx.doi.org/10.1159/000517586DOI Listing
November 2021

Methodology and implementation of the WHO European Childhood Obesity Surveillance Initiative (COSI).

Obes Rev 2021 Nov 4;22 Suppl 6:e13215. Epub 2021 Nov 4.

Department of Epidemiology and Public Health Sciensano, Brussels, Belgium.

Establishment of the WHO European Childhood Obesity Surveillance Initiative (COSI) has resulted in a surveillance system which provides regular, reliable, timely, and accurate data on children's weight status-through standardized measurement of bodyweight and height-in the WHO European Region. Additional data on dietary intake, physical activity, sedentary behavior, family background, and school environments are collected in several countries. In total, 45 countries in the European Region have participated in COSI. The first five data collection rounds, between 2007 and 2021, yielded measured anthropometric data on over 1.3 million children. In COSI, data are collected according to a common protocol, using standardized instruments and procedures. The systematic collection and analysis of these data enables intercountry comparisons and reveals differences in the prevalence of childhood thinness, overweight, normal weight, and obesity between and within populations. Furthermore, it facilitates investigation of the relationship between overweight, obesity, and potential risk or protective factors and improves the understanding of the development of overweight and obesity in European primary-school children in order to support appropriate and effective policy responses.
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http://dx.doi.org/10.1111/obr.13215DOI Listing
November 2021

Thinness, overweight, and obesity in 6- to 9-year-old children from 36 countries: The World Health Organization European Childhood Obesity Surveillance Initiative-COSI 2015-2017.

Obes Rev 2021 Nov 7;22 Suppl 6:e13214. Epub 2021 Jul 7.

Center for Health Ecology, Institute of Public Health, Podgorica, Montenegro.

In 2015-2017, the fourth round of the World Health Organization (WHO) European Childhood Obesity Surveillance Initiative (COSI) was conducted in 36 countries. National representative samples of children aged 6-9 (203,323) were measured by trained staff, with similar equipment and using a standardized protocol. This paper assesses the children's body weight status and compares the burden of childhood overweight, obesity, and thinness in Northern, Eastern, and Southern Europe and Central Asia. The results show great geographic variability in height, weight, and body mass index. On average, the children of Northern Europe were the tallest, those of Southern Europe the heaviest, and the children living in Central Asia the lightest and the shortest. Overall, 28.7% of boys and 26.5% of girls were overweight (including obesity) and 2.5% and 1.9%, respectively, were thin according to the WHO definitions. The prevalence of obesity varied from 1.8% of boys and 1.1% of girls in Tajikistan to 21.5% and 19.2%, respectively, in Cyprus, and tended to be higher for boys than for girls. Levels of thinness, stunting, and underweight were relatively low, except in Eastern Europe (for thinness) and in Central Asia. Despite the efforts to halt it, unhealthy weight status is still an important problem in the WHO European Region.
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http://dx.doi.org/10.1111/obr.13214DOI Listing
November 2021

Socioeconomic disparities in physical activity, sedentary behavior and sleep patterns among 6- to 9-year-old children from 24 countries in the WHO European region.

Obes Rev 2021 Nov 7;22 Suppl 6:e13209. Epub 2021 Jul 7.

Division of Noncommunicable Diseases and Promoting Health through the Life-Course, WHO Country Office for Tajikistan, Dushanbe, Tajikistan.

Physical activity, sedentary behavior, and sleep are important predictors of children's health. This paper aimed to investigate socioeconomic disparities in physical activity, sedentary behavior, and sleep across the WHO European region. This cross-sectional study used data on 124,700 children aged 6 to 9 years from 24 countries participating in the WHO European Childhood Obesity Surveillance Initiative between 2015 and 2017. Socioeconomic status (SES) was measured through parental education, parental employment status, and family perceived wealth. Overall, results showed different patterns in socioeconomic disparities in children's movement behaviors across countries. In general, high SES children were more likely to use motorized transportation. Low SES children were less likely to participate in sports clubs and more likely to have more than 2 h/day of screen time. Children with low parental education had a 2.24 [95% CI 1.94-2.58] times higher risk of practising sports for less than 2 h/week. In the pooled analysis, SES was not significantly related to active play. The relationship between SES and sleep varied by the SES indicator used. Importantly, results showed that low SES is not always associated with a higher prevalence of "less healthy" behaviors. There is a great diversity in SES patterns across countries which supports the need for country-specific, targeted public health interventions.
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http://dx.doi.org/10.1111/obr.13209DOI Listing
November 2021

Socioeconomic differences in food habits among 6- to 9-year-old children from 23 countries-WHO European Childhood Obesity Surveillance Initiative (COSI 2015/2017).

Obes Rev 2021 Nov 7;22 Suppl 6:e13211. Epub 2021 Jul 7.

World Health Organization (WHO) European Office for the Prevention and Control of Noncommunicable Diseases, Division of Country Health Programmes, WHO Regional Office for Europe, Moscow, Russian Federation.

Background: Socioeconomic differences in children's food habits are a key public health concern. In order to inform policy makers, cross-country surveillance studies of dietary patterns across socioeconomic groups are required. The purpose of this study was to examine associations between socioeconomic status (SES) and children's food habits.

Methods: The study was based on nationally representative data from children aged 6-9 years (n = 129,164) in 23 countries in the World Health Organization (WHO) European Region. Multivariate multilevel analyses were used to explore associations between children's food habits (consumption of fruit, vegetables, and sugar-containing soft drinks) and parental education, perceived family wealth and parental employment status.

Results: Overall, the present study suggests that unhealthy food habits are associated with lower SES, particularly as assessed by parental education and family perceived wealth, but not parental employment status. We found cross-national and regional variation in associations between SES and food habits and differences in the extent to which the respective indicators of SES were related to children's diet.

Conclusion: Socioeconomic differences in children's food habits exist in the majority of European and Asian countries examined in this study. The results are of relevance when addressing strategies, policy actions, and interventions targeting social inequalities in children's diets.
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http://dx.doi.org/10.1111/obr.13211DOI Listing
November 2021

Socioeconomic inequalities in overweight and obesity among 6- to 9-year-old children in 24 countries from the World Health Organization European region.

Obes Rev 2021 Nov 28;22 Suppl 6:e13213. Epub 2021 Jun 28.

Center for Health Ecology, Institute of Public Health, Podgorica, Montenegro.

Childhood overweight and obesity have significant short- and long-term negative impacts on children's health and well-being. These challenges are unequally distributed according to socioeconomic status (SES); however, previous studies have often lacked standardized and objectively measured data across national contexts to assess these differences. This study provides a cross-sectional picture of the association between SES and childhood overweight and obesity, based on data from 123,487 children aged 6-9 years in 24 countries in the World Health Organization (WHO) European region. Overall, associations were found between overweight/obesity and the three SES indicators used (parental education, parental employment status, and family-perceived wealth). Our results showed an inverse relationship between the prevalence of childhood overweight/obesity and parental education in high-income countries, whereas the opposite relationship was observed in most of the middle-income countries. The same applied to family-perceived wealth, although parental employment status appeared to be less associated with overweight and obesity or not associated at all. This paper highlights the need for close attention to context when designing interventions, as the association between SES and childhood overweight and obesity varies by country economic development. Population-based interventions have an important role to play, but policies that target specific SES groups are also needed to address inequalities.
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http://dx.doi.org/10.1111/obr.13213DOI Listing
November 2021

Physical Activity, Screen Time, and Sleep Duration of Children Aged 6-9 Years in 25 Countries: An Analysis within the WHO European Childhood Obesity Surveillance Initiative (COSI) 2015-2017.

Obes Facts 2021 22;14(1):32-44. Epub 2020 Dec 22.

National Institute of Health Dr Ricardo Jorge I.P., Lisbon, Portugal.

Background: Children are becoming less physically active as opportunities for safe active play, recreational activities, and active transport decrease. At the same time, sedentary screen-based activities both during school and leisure time are increasing.

Objectives: This study aimed to evaluate physical activity (PA), screen time, and sleep duration of girls and boys aged 6-9 years in Europe using data from the WHO European Childhood Obesity Surveillance Initiative (COSI).

Method: The fourth COSI data collection round was conducted in 2015-2017, using a standardized protocol that included a family form completed by parents with specific questions about their children's PA, screen time, and sleep duration.

Results: Nationally representative data from 25 countries was included and information on the PA behaviour, screen time, and sleep duration of 150,651 children was analysed. Pooled analysis showed that: 79.4% were actively playing for >1 h each day, 53.9% were not members of a sport or dancing club, 50.0% walked or cycled to school each day, 60.2% engaged in screen time for <2 h/day, and 84.9% slept for 9-11 h/night. Country-specific analyses of these behaviours showed pronounced differences, with national prevalences in the range of 61.7-98.3% actively playing for >1 h/day, 8.2-85.6% were not members of a sport or dancing club, 17.7-94.0% walked or cycled to school each day, 32.3-80.0% engaged in screen time for <2 h/day, and 50.0-95.8% slept for 9-11 h/night.

Conclusions: The prevalence of engagement in PA and the achievement of healthy screen time and sleep duration are heterogenous across the region. Policymakers and other stakeholders, including school administrators and parents, should increase opportunities for young people to participate in daily PA as well as explore solutions to address excessive screen time and short sleep duration to improve the overall physical and mental health and well-being of children.
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http://dx.doi.org/10.1159/000511263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983588PMC
July 2021

[Remote monitoring and treatment of children and adolescents with type 1 diabetes].

Probl Endokrinol (Mosk) 2020 09 28;66(4):50-60. Epub 2020 Sep 28.

Endocrinology Research Centre.

Rationale: Continuous subcutaneous insulin infusion (CSII) is an effective method for optimizing glycemic control in children with type 1 diabetes mellitus (DM1). However, the use of CSII does not always result in adequate glycemic control. Telehealth can be applied as one of the methods to improve the effectiveness of treatment.

Aims: To evaluate the use of remote medical support of children and adolescents with DM1 and its influence on glycemic control, quality of life, and incidence of acute complications of DM1.

Materials And Methods: We conducted a 24-week multi-institutional prospective open-label controlled clinical trial. 180 children and adolescents were included in this study and divided into the following categories: 1) age 8-18 years; 2) DM1 at least 1 year; 3) pump insulin therapy Medtronic Paradigm (Medtronic MiniMed, USA) at least 6 months; 4) self-monitoring of glycemia at least 4 times a day and replacement of the insulin pump infusion system at least once every 3 days; 5) inadequate glycemic control of DM1: the level of glycated hemoglobin (HbA1c) 7.5% or higher. Patients were assigned to a remote consultation group (RC; n=100) or a traditional control group (TC; n=80). All patients were trained on the basic principles of DM1 and CSII, and we measured initial HbA1c, then after 12 and 24 weeks, also registered and analyzed glycemic indicators and daily doses of insulin, evaluated and corrected the treatment. Patients or their parents in the RC group sent pump data via the Internet to the pump insulin therapy center at least once every 2 weeks at home and received treatment recommendations in response.

Results: The total number of patients included in the study in all institutions was 180 children at 8-18 years. Patients in both groups did not differ in age, gender, duration of DM1 and CSII, and HbA1c level. The total amount of remote consultations for all institutions was 949. The decrease in the level of HbA1c by the end of the study against the initial one was statistically significantly greater in the RC group: 1.17% compared to 0.59% in the TC group (p<0.05). The proportion of patients who reached the target level of HbA1c (<7.5%) was significantly higher in the RC group (32%) compared to the TC group (12.5%, p<0.05). During the study, the incidence of DKA and severe hypoglycemia in the RC group was statistically significantly lower.

Conclusions: Remote monitoring in children with DM1 resulted in significant improvements in glycemic control (HbA1c, glycemic variability, and hypoglycemic frequency). The accumulation of evidence on the effectiveness and safety of telehealth in DM should contribute to implementing this approach in practical health care.
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http://dx.doi.org/10.14341/probl12201DOI Listing
September 2020

[Assessment of autoantibodies against 21-hydroxylase in the diagnosis of primary autoimmune adrenal insufficiency].

Probl Endokrinol (Mosk) 2020 06 10;65(6):466-473. Epub 2020 Jun 10.

Endocrinology Research centre.

Primary adrenal insufficiency is manifested by a deficiency of adrenal cortex hormones and can lead to a life-threatening condition. Early diagnosis is key to patient survival. Auto-antibodies to one of the adrenal steroidogenesis enzymes, 21-hydroxylase, are an immunological marker of autoimmune adrenal insufficiency. On the one hand, the study of antibodies to 21-hydroxylase is a method that helps establish the etiology of the disease – the autoimmune genesis of adrenal gland damage. On the other hand, the determination of autoantibodies to 21-hydroxylase is the only prognostic factor of the risk of adrenal insufficiency, which makes it possible to prevent the development of acute adrenal crisis. The article provides a brief literature review on autoantibodies to 21-hydroxylase and the pathogenesis of autoimmune adrenal insufficiency, and a series of clinical cases that illustrates the significant role of autoantibodies to 21-hydroxylase in diagnosis of adrenal insufficiency.
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http://dx.doi.org/10.14341/probl12106DOI Listing
June 2020

[The efficacy of outpatient monitoring of children and adolescents with type 1 diabetes with regular use of professional continuous glucose monitoring].

Probl Endokrinol (Mosk) 2020 08 4;66(1):14-22. Epub 2020 Aug 4.

Regional Children Clinical Hospital named after N.V. Dmitrieva.

Background: According to research, only 38% of patients reach glycated hemoglobin targets. It is possible to improve the effectiveness of medical care for children with T1D using modern technologies, including continuous glucose monitoring (CGM).

Aims: To evaluate the effectiveness of outpatient monitoring of children and adolescents with T1D with regular use of professional continuous glucose monitoring.

Methods: The inclusion criteria: age 8−12 years; T1D at least 1 year; insulin therapy by multiple injections of insulin; inadequate glycemic control of T1D: НbА1с level of 7.5% and higher and / or children and adolescents with frequent episodes of hypoglycemia (usually 4 times a week) or with a history of severe hypoglycemia; signed informed consent. All patients initially and 12 weeks after inclusion in the study conducted a study of the level of НbА1с, and also performed CGM for 6 days. Based on the results of CGM, glycemia indicators and daily doses of insulin were recorded, treatment was evaluated and corrected, and recommendations for self-monitoring were made. Glucose monitoring was carried 120−144 hours using the blind method iPro2 (Medtronic, USA).

Results: In all, 99 children aged 8−18 years were included in the study in all centers. The decrease in the level of НbА1с by the end of the study was 0.72%, while the proportion of patients who reached the target level of НbА1с (defined as <7.5%) was statistically significantly higher at the end of the study (15.5% and 2%, respectively; p<0.05). During the study, patients showed a trend towards a decrease in the average level and variability of glycemia by the end of the study, however, statistical significance was achieved only in relation to the average level of glycemia (p=0.04). Conducted insulin therapy, determined by the average daily doses of long-acting and short-acting insulin, did not statistically significantly change at the end of the study. The frequency of DKA episodes and severe hypoglycemia did not statistically significantly differ from the initial level.

Conclusions: For children with poor glycemic control of T1D, the use of professional CGM is effective in terms of glycemic control and a safe method.
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http://dx.doi.org/10.14341/probl12200DOI Listing
August 2020

A Snapshot of European Children's Eating Habits: Results from the Fourth Round of the WHO European Childhood Obesity Surveillance Initiative (COSI).

Nutrients 2020 Aug 17;12(8). Epub 2020 Aug 17.

Department for Organization of Health Services to Children, Mothers, Adolescents and Family Planning, Ministry of Health and Social Protection of Population, 734025 Dushanbe, Tajikistan.

Consuming a healthy diet in childhood helps to protect against malnutrition and noncommunicable diseases (NCDs). This cross-sectional study described the diets of 132,489 children aged six to nine years from 23 countries participating in round four (2015-2017) of the WHO European Childhood Obesity Surveillance Initiative (COSI). Children's parents or caregivers were asked to complete a questionnaire that contained indicators of energy-balance-related behaviors (including diet). For each country, we calculated the percentage of children who consumed breakfast, fruit, vegetables, sweet snacks or soft drinks "every day", "most days (four to six days per week)", "some days (one to three days per week)", or "never or less than once a week". We reported these results stratified by country, sex, and region. On a daily basis, most children (78.5%) consumed breakfast, fewer than half (42.5%) consumed fruit, fewer than a quarter (22.6%) consumed fresh vegetables, and around one in ten consumed sweet snacks or soft drinks (10.3% and 9.4%, respectively); however, there were large between-country differences. This paper highlights an urgent need to create healthier food and drink environments, reinforce health systems to promote healthy diets, and continue to support child nutrition and obesity surveillance.
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http://dx.doi.org/10.3390/nu12082481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468747PMC
August 2020

Association between Characteristics at Birth, Breastfeeding and Obesity in 22 Countries: The WHO European Childhood Obesity Surveillance Initiative - COSI 2015/2017.

Obes Facts 2019 26;12(2):226-243. Epub 2019 Apr 26.

NCD Office, WHO European Office for Prevention and Control of Noncommunicable Diseases, Moscow, Russian Federation.

Background: In Europe, although the prevalence of childhood obesity seems to be plateauing in some countries, progress on tackling this important public health issue remains slow and inconsistent. Breastfeeding has been described as a protective factor, and the more exclusively and the longer children are breastfed, the greater their protection from obesity. Birth weight has been shown to have a positive association with later risk for obesity.

Objectives: It was the aim of this paper to investigate the association of early-life factors, namely breastfeeding, exclusive breastfeeding and birth weight, with obesity among children.

Method: Data from 22 participating countries in the WHO European COSI study (round 4: 2015/2017) were collected using cross-sectional, nationally representative samples of 6- to 9-year-olds (n = 100,583). The children's standardized weight and height measurements followed a common WHO protocol. Information on the children's birth weight and breastfeeding practice and duration was collected through a family record form. A multivariate multilevel logistic regression analysis regarding breastfeeding practice (both general and exclusive) and characteristics at birth was performed.

Results: The highest prevalence rates of obesity were observed in Spain (17.7%), Malta (17.2%) and Italy (16.8%). A wide between-country disparity in breastfeeding prevalence was found. Tajikistan had the highest percentage of children that were breastfed for ≥6 months (94.4%) and exclusively breastfed for ≥6 months (73.3%). In France, Ireland and Malta, only around 1 in 4 children was breastfed for ≥6 months. Italy and Malta showed the highest prevalence of obesity among children who have never been breastfed (21.2%), followed by Spain (21.0%). The pooled analysis showed that, compared to children who were breastfed for at least 6 months, the odds of being obese were higher among children never breastfed or breastfed for a shorter period, both in case of general (adjusted odds ratio [adjOR] [95% CI] 1.22 [1.16-1.28] and 1.12 [1.07-1.16], respectively) and exclusive breastfeeding (adjOR [95% CI] 1.25 [1.17-1.36] and 1.05 [0.99-1.12], respectively). Higher birth weight was associated with a higher risk of being overweight, which was reported in 11 out of the 22 countries. Bulgaria, Croatia, France, Italy, Poland and Romania showed that children who were preterm at birth had higher odds of being obese, compared to children who were full-term babies.

Conclusion: The present work confirms the beneficial effect of breastfeeding against obesity, which was highly increased if children had never been breastfed or had been breastfed for a shorter period. Nevertheless, adoption of exclusive breastfeeding is below global recommendations and far from the target endorsed by the WHO Member States at the World Health Assembly Global Targets for Nutrition of increasing the prevalence of exclusive breastfeeding in the first 6 months up to at least 50% by 2025.
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http://dx.doi.org/10.1159/000500425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547266PMC
February 2020

One-year recombinant growth hormone therapy does not improve hemoglobin state and morphology of erythrocytes in growth hormone deficient children.

Pathophysiology 2018 Mar 7;25(1):13-17. Epub 2017 Oct 7.

Endocrinology Research Centre, Department of Paediatric Endocrinology, Moscow, Russian Federation.

An increase in growth rates of children suffering from growth hormone deficiency (GHD) subjected to recombinant growth hormone treatment (rGHT) was shown to be accompanied by acceleration of metabolic processes that may stimulate oxygen consumption in various organs and tissues. Therefore, oxygen-transporting properties of RBC should undergo considerable changes during the rGHT. The aim of this study was to examine the effects of rGHT on erythrocyte shape and hemoglobin state in GHD children. The level of oxyhemoglobin (Oxy-Hb) in RBC was analyzed by Raman spectroscopy. The RBC count, mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV) and other parameters were calculated. The blood of eleven treatment-naive prepubertal children with GHD (aged 3-9, median 5.7 years) was examined and compared with control group (aged 5-7; median 6.0 years) at three time points: 0, 3 and 12 months of rGHT. Before rGHT, the MI in GHD children was higher (median 0.48 vs 0.14 p=0.0018) and the RBC count was lower (median 4.20 vs 4.96 10 cells/L p=0.0022) than in control group. After the treatment, cell count in GHD patients did not differ significantly from the control group, but Oxy-Hb level became higher (median 0.64 vs 0.41 p=0.0075). During rGHT, MCV decreased (median 80.3 vs 83.2μm p=0.0231). Morphological and functional characteristics of erythrocytes in GHD children were shown to differ significantly from the healthy control group. A twelve-month rGHT partially improved some of the studied parameters but Oxy-Hb level and echinocyte count remained high.
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http://dx.doi.org/10.1016/j.pathophys.2017.09.002DOI Listing
March 2018

Expanding the Phenotypic and Genotypic Landscape of Autoimmune Polyendocrine Syndrome Type 1.

J Clin Endocrinol Metab 2017 09;102(9):3546-3556

Department of Clinical Science, University of Bergen, Bergen 5020, Norway.

Context: Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene and characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. Comprehensive characterizations of large patient cohorts are rare.

Objective: To perform an extensive clinical, immunological, and genetic characterization of a large nationwide Russian APS-1 cohort.

Subjects And Methods: Clinical components were mapped by systematic investigations, sera were screened for autoantibodies associated with APS-1, and AIRE mutations were characterized by Sanger sequencing.

Results: We identified 112 patients with APS-1, which is, to the best of our knowledge, the largest cohort described to date. Careful phenotyping revealed several additional and uncommon phenotypes such as cerebellar ataxia with pseudotumor, ptosis, and retinitis pigmentosa. Neutralizing autoantibodies to interferon-ω were found in all patients except for one. The major Finnish mutation c.769C>T (p.R257*) was the most frequent and was present in 72% of the alleles. Altogether, 19 different mutations were found, of which 9 were unknown: c.38T>C (p.L13P), c.173C>T (p.A58V), c.280C>T (p.Q94*), c.554C>G (p.S185*), c.661A>T (p.K221*), c.821del (p.Gly274Afs*104), c.1195G>C (p.A399P), c.1302C>A (p.C434*), and c.1497del (p.A500Pfs*21).

Conclusions: The spectrum of phenotypes and AIRE mutation in APS-1 has been expanded. The Finnish major mutation is the most common mutation in Russia and is almost as common as in Finland. Assay of interferon antibodies is a robust screening tool for APS-1.
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http://dx.doi.org/10.1210/jc.2017-00139DOI Listing
September 2017

A glucokinase gene mutation in a young boy with diabetes mellitus, hyperinsulinemia, and insulin resistance.

Int Med Case Rep J 2017 7;10:77-80. Epub 2017 Mar 7.

Endocrinology Research Centre, Moscow, Russian Federation.

We report the case of a 12-year-old boy with a glucokinase () mutation, and diabetes with hyperinsulinemia and insulin resistance. For 4 years, the patient intermittently received insulin medications Actrapid HM and Protaphane HM (total dose 5 U/day), with glycated hemoglobin (HbA) levels of 6.6%-7.0%. After extensive screening the patient was found to carry a heterozygous mutation (p.E256K) in (MIM #138079, reference sequence NM_000162.3). Insulin therapy was replaced by metformin at 1,700 mg/day. One year later, his HbA level was 6.9%, postprandial glycemia at 120 min of oral glucose tolerance test was 15.4 mmol/L, hyperinsulinemia had increased to 508.9 mU/L, homeostasis model assessment index was 114.2 and the Matsuda index was 0.15. Insulin resistance was confirmed by a hyperinsulinemic euglycemic clamp test - M-index was 2.85 mg/kg/min. This observation is a rare case of one of the clinical variants of diabetes, which should be taken into account by a vigilant endocrinologist due to the need for nonstandard diagnostic and therapeutic approaches.
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http://dx.doi.org/10.2147/IMCRJ.S125103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348075PMC
March 2017

Long-Acting C-Terminal Peptide-Modified hGH (MOD-4023): Results of a Safety and Dose-Finding Study in GHD Children.

J Clin Endocrinol Metab 2017 05;102(5):1578-1587

OPKO Biologics, Kiryat Gat 8211804, Israel.

Context: Daily injections are required for growth hormone (GH) replacement therapy, which may cause low compliance as a result of inconvenience and distress in patients.

Objective: C-terminal peptide-modified human GH (MOD-4023) is developed for once-a-week dosing regimen in GH-deficient (GHD) adults and children. The present trial was a safety and dose-finding study for weekly MOD-4023 in GHD children.

Design: A multicenter, open-label, randomized, controlled phase 2 study in children with GHD, evaluating the safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy of three different weekly MOD-4023 doses, compared with daily recombinant human GH (r-hGH).

Setting: The trial was conducted in 14 endocrinology centers in Europe.

Patients: Fifty-three prepubertal children with GHD completed 12 months of treatment with either MOD-4023 (N = 42) or r-hGH (N = 11).

Interventions: C-terminal peptide-modified hGH (MOD-4023) was administered weekly at a dose of either 0.25, 0.48, or 0.66 mg/kg/wk and compared with daily hGH at a dose of 0.24 mg/kg/wk.

Results: MOD-4023 showed an estimated half-life approximately fivefold to 10-fold longer when compared with daily r-hGH. Insulin-like growth factor (IGF)-I and IGF-binding peptide 3 showed a dose-dependent increase during MOD-4023 treatment. IGF-I standard deviation score for MOD-4023 did not exceed +2. All MOD-4023 cohorts demonstrated adequate catch-up growth. The 0.66 mg/kg/wk dose demonstrated efficacy closest to daily r-hGH. No serious adverse events were observed during MOD-4023 treatment, and its tolerability was consistent with known properties of r-hGH.

Conclusions: This study confirms the long-acting properties of MOD-4023 and shows a promising safety and tolerability profile. This provides support for initiation of a phase 3 study in GHD children using a single weekly injection of MOD-4023.
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http://dx.doi.org/10.1210/jc.2016-3547DOI Listing
May 2017

A Randomized Phase 2 Study of Long-Acting TransCon GH vs Daily GH in Childhood GH Deficiency.

J Clin Endocrinol Metab 2017 05;102(5):1673-1682

Ascendis Pharma, 2900 Hellerup, Denmark.

Context: TransCon Growth Hormone (GH) (Ascendis Pharma) is a long-acting recombinant sustained-release human GH prodrug in development for children with GH deficiency (GHD).

Objective: To compare the pharmacokinetics, pharmacodynamics, safety, and efficacy of weekly TransCon GH to that of daily GH in prepubertal children with GHD.

Design: Randomized, open-label, active-controlled study of three doses of weekly TransCon GH versus daily Genotropin (Pfizer).

Setting: Thirty-eight centers in 14 European countries and Egypt.

Patients: Prepubertal male and female treatment-naïve children with GHD (n = 53).

Interventions: Subjects received one of three TransCon GH doses (0.14, 0.21, or 0.30 mg GH/kg/wk) or Genotropin 0.03 mg GH/kg/d for 26 weeks.

Main Outcome Measures: GH and insulinlike growth factor-1 (IGF-1) levels, growth, adverse events, and immunogenicity.

Results: Both GH maximum concentration and area under the curve were similar following TransCon GH or Genotropin administration at comparable doses. A dose response was observed, with IGF-1 standard deviation scores increasing into the normal range for all three TransCon GH doses. Annualized mean height velocity for the three TransCon GH doses ranged from 11.9 cm to 13.9 cm, which was not statistically different from 11.6 cm for Genotropin. Adverse events were mild to moderate, and most were unrelated to the study drug. Injection site tolerance was good. One TransCon GH subject developed a low-titer, nonneutralizing antibody response to GH.

Conclusions: The results suggest that long-acting TransCon GH is comparable to daily Genotropin for GH (pharmacokinetics) and IGF-1 (pharmacodynamics) levels, safety, and efficacy and support advancement into phase 3 development.
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http://dx.doi.org/10.1210/jc.2016-3776DOI Listing
May 2017

Development of Insulin Detemir/Insulin Aspart Cross-Reacting Antibodies Following Treatment with Insulin Detemir: 104-week Study in Children and Adolescents with Type 1 Diabetes Aged 2-16 Years.

Diabetes Ther 2016 Dec 6;7(4):713-724. Epub 2016 Sep 6.

Endocrinological Research Centre, Institute of Paediatric Endocrinology, Moscow, Russia.

Background: To study the long-term development (104 weeks) of insulin antibodies during treatment with insulin detemir (IDet) and insulin aspart (IAsp) in children with type 1 diabetes aged 2-16 years.

Methods: A 52-week, two-arm, randomized trial comparing IDet and neutral protamine Hagedorn insulin, both in combination with IAsp, was followed by a one-arm, 52-week extension trial of the IDet + IAsp arm. The present analysis was conducted in children who completed the randomized trial and entered into the extension trial.

Results: Of the 177 children randomized to IDet treatment, 146 entered the extension trial. IDet-IAsp cross-reacting antibodies peaked within the first 39 weeks of treatment before gradually declining. A similar pattern was seen for IDet-specific and IAsp-specific antibodies. At end of trial (EOT), no correlation was observed between the level of IDet-specific or IAsp-specific antibodies or IDet-IAsp cross-reacting antibodies and either glycated hemoglobin (HbA1c) or basal insulin dose. Mean HbA1c was stable during the treatment period, with a slight increase over time from 8.41% (68.4 mmol/mol) at baseline to 8.74% (72 mmol/mol) at EOT. Mean IDet dose increased from 0.43 U/kg at baseline to 0.66 U/kg at EOT. Mean IAsp dose increased from 0.46 U/kg to 0.51 U/kg at EOT.

Conclusion: Although treatment with IDet and IAsp is associated with development of specific and cross-reacting antibodies, no correlation between insulin antibodies and basal insulin dose or HbA1c was found.

Funding: Novo Nordisk A/S. ClinicalTrials.gov identifiers: NCT00435019 and NCT00623194.
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http://dx.doi.org/10.1007/s13300-016-0196-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118234PMC
December 2016

GH deficiency status combined with GH receptor polymorphism affects response to GH in children.

Eur J Endocrinol 2015 Dec 4;173(6):777-89. Epub 2015 Sep 4.

Merck Serono SAGeneva, SwitzerlandDépartement de PédiatrieHôpital Mère-Enfant, Université Claude Bernard, Lyon, FranceFederal State Institution 'Endocrinology Scientific Center of Russian Medical Technology'Moscow, RussiaEndocrine ServiceHospital de Pediatría Garrahan, Ciudad Autónoma de Buenos Aires, Buenos Aires, ArgentinaIRCCS Istituto Giannina Gaslini di GenovaClinica Pediatrica, Università di Genova, Genova, ItalyPediatra d.U. Azienda Ospedaliera Universitaria IntegrataUniversità di Verona, Verona, ItalyManchester Academic Health Sciences CentreRoyal Manchester Children's Hospital, 5th Floor, Oxford Road, Manchester M13 9WL, UK

Meta-analysis has shown a modest improvement in first-year growth response to recombinant human GH (r-hGH) for carriers of the exon 3-deleted GH receptor (GHRd3) polymorphism but with significant interstudy variability. The associations between GHRd3 and growth response to r-hGH over 3 years in relation to severity of GH deficiency (GHD) were investigated in patients from 14 countries. Treatment-naïve pre-pubertal children with GHD were enrolled from the PREDICT studies (NCT00256126 and NCT00699855), categorized by peak GH level (peak GH) during provocation test: ≤4 μg/l (severe GHD; n=45) and >4 to <10 μg/l mild GHD; n=49) and genotyped for the GHRd3 polymorphism (full length (fl/fl, fl/d3, d3/d3). Gene expression (GE) profiles were characterized at baseline. Changes in growth (height (cm) and SDS) over 3 years were measured. There was a dichotomous influence of GHRd3 polymorphism on response to r-hGH, dependent on peak GH level. GH peak level (higher vs lower) and GHRd3 (fl/fl vs d3 carriers) combined status was associated with height change over 3 years (P<0.05). GHRd3 carriers with lower peak GH had lower growth than subjects with fl/fl (median difference after 3 years -3.3 cm; -0.3 SDS). Conversely, GHRd3 carriers with higher peak GH had better growth (+2.7 cm; +0.2 SDS). Similar patterns were observed for GH-dependent biomarkers. GE profiles were significantly different between the groups, indicating that the interaction between GH status and GHRd3 carriage can be identified at a transcriptomic level. This study demonstrates that responses to r-hGH depend on the interaction between GHD severity and GHRd3 carriage.
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http://dx.doi.org/10.1530/EJE-15-0474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4623334PMC
December 2015

Imbalance in the blood antioxidant system in growth hormone-deficient children before and after 1 year of recombinant growth hormone therapy.

PeerJ 2015 25;3:e1055. Epub 2015 Jun 25.

Faculty of Biology, Department of Biophysics, Lomonosov Moscow State University , Moscow , Russian Federation.

The aim of our study was to examine the effects of 12-month therapy with recombinant growth hormone (rGH) on the blood antioxidant system in children with growth hormone deficiency (GHD). Total antioxidant capacity (TAC) of plasma was measured by FRAP (ferric reducing antioxidant power or ferric reducing ability of plasma); activities of superoxide dismutase (SOD) and catalase (CAT) in erythrocytes were assessed; non-protein thiols (NT) and ceruloplasmin (CP) levels were also measured. These parameters were determined before and after 12 month of rGH treatment. Eleven treatment-naive prepubertal children with growth hormone deficiency were included in the study. Another 11 prepubertal children comprised a control group. Before rGH treatment, TAC of plasma and NT level in the control group were significantly lower (726 ± 196 vs. 525 ± 166 µmol/L, P = 0.0182 and 0.92 ± 0.18 vs. 0.70 ± 0.22 µmol/ml, P = 0.0319, before and after the therapy, respectively). The only parameter that significantly (19.6 ± 4.7 vs. 14.5 ± 3.4 Units/g Hb, P = 0.0396) exceeded the same in the control group after rGH therapy was SOD activity. However, none of the measured parameters of antioxidant system in GHD children, except for TAC (525 ± 166 vs. 658 ± 115 µmol/L, P = 0.0205), exhibited significant improvement toward the end of the 12-month treatment period, although non-significant changes in CAT activity and CP level were also observed. This work has demonstrated that some parameters of the blood antioxidant system are out of balance and even impaired in GHD children. A 12-month treatment with rGH resulted in a partial improvement of the antioxidant system.
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http://dx.doi.org/10.7717/peerj.1055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485705PMC
July 2015

Studying progression from glucose intolerance to type 2 diabetes in obese children.

Diabetes Metab Syndr 2014 Jul-Sep;8(3):133-7. Epub 2014 Aug 7.

Department of Pediatrics, Endocrinology Research Center, Moscow, Russia.

Aim: Identification of metabolic and genetic factors capable to mediate progression from normal glucose tolerance (NGT) through impaired glucose tolerance (IGT) to type 2 diabetes (T2D) in childhood obesity.

Patients And Methods: Three groups of obese children with NGT (n=54), IGT (n=35), and T2D (n=62) were evaluated. A control group of non-obese normal children (n=210) was also studied. In obese patients, an oral glucose tolerance test (OGTT) was performed. Insulin resistance (IR) was assessed using HOMA-IR index. Insulin sensitivity (IS) was assessed according to the Matsuda formula. Genomic DNA from obese and control children was genotyped for genetic variants of PPARG, ADIPOQ, ADIPOR1, FTO, TCF7L2, and KCNJ11 using a real-time PCR strategy. The unpaired Student's t-test and Kruskal-Wallis one-way test were used to compare quantitative data in two and more groups. To assess the extent to which the various genetic variants were associated with pathology, ORs (odds ratios) and 95% CI (confidence interval) were estimated.

Results: In T2D children, HOMA-IR value (7.5±3.1) was significantly (P<0.001) higher than that in IGT (4.21±2.25) and NGT (4.1±2.4) subjects. The Matsuda IS index was significantly increased in normoglycemic patients compared to IGT individuals (2.8±1.75 vs. 2.33±1.2, P<0.05). The Pro12Ala polymorphism of PPARG was significantly associated with obesity (OR=1.74, 95% CI=1.19-2.55, P=0.004) and T2D in obesity (OR=2.01, 95% CI=1.24-3.26, P=0.004).

Conclusion: IR is a major risk factor that mediates progression from NGT to clinical T2D in Russian obese children. This progression may be genetically influenced by the Pro12Ala variant of PPARG.
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http://dx.doi.org/10.1016/j.dsx.2014.07.002DOI Listing
June 2015

24-month use of once-weekly GH, LB03002, in prepubertal children with GH deficiency.

J Clin Endocrinol Metab 2014 Jan 20;99(1):126-32. Epub 2013 Dec 20.

Department of Paediatric Endocrinology (V.K.), Jehangir Hospital, Pune 411004, India; Second Children's Hospital (K.A.R.), Minsk 220020, Belarus; Institute of Endocrinology and Metabolism (E.B.), Academy of Medical Sciences, Kiev 04114, Ukraine; Department of Endocrinology (R.K.), All India Institute of Medial Sciences, New Delhi 110029, India; Department of Pediatrics (M.E.K.), Ain Shams University, Cairo 12311, Egypt; Sir Hurkisondas Nurrotumdas Hospital and Research Centre (M.D.), Mumbai 400004, India; Endocrinological Scientific Center (V.P.), Russian Academy of Medical Sciences, Moscow 117036, Russia; Institute of Maternal and Child Research (V.M.), Santiago de Chile 8389100, Chile; Institute for Laboratory Medicine (J.K.), Leipzig 04103, Germany; Biopartners GmbH (E.C.S., D.M., P.L.), Baar 6340, Switzerland; LG Life Sciences Ltd (H.-J.J., Y.J.B., J.H.L.), Seoul 110-783, South Korea; and Department of Pediatrics (P.H.S.), Winthrop University Hospital, Mineola, New York 11501.

Background: Sustained-release GH formulations may provide a strategy for improving treatment compliance and persistence in GH-deficient patients.

Objective: The aim of the study was to examine efficacy and safety of LB03002, a sustained-release GH formulation for once-weekly administration.

Design: We conducted a phase III, 12-month, multinational, randomized, open-label, comparator-controlled trial with a 12-month uncontrolled extension.

Patients: Prepubertal GH treatment-naive GH-deficient children (mean age, 7.8 y) participated in the study.

Intervention: We administered once-weekly LB03002 (n=91) or daily GH (n=87) for 1 year, followed by once-weekly LB03002 for all patients for another year (LB03002 throughout, n=87; switched to LB03002, n=80).

Outcome Measures: Height, height velocity (HV), IGF-1, GH antibodies, and adverse events were determined throughout. Primary analysis was noninferiority of LB03002 vs daily GH at 1 year by analysis of covariance.

Results: Mean±SD HV during year 1 was 11.63±2.60 cm/y with LB03002, and 11.97±3.09 cm/y with daily GH, with increases from baseline of 8.94±2.91 and 9.04±3.19 cm/y, respectively. The least square mean HV difference for LB03002 - daily GH was -0.43 cm/y (99% confidence interval, -1.45 to 0.60 cm/y). Mean HV also remained above baseline in year 2 (8.33±1.92 cm/y in the LB03002 throughout group, and 7.28±2.34 cm/y in the switched to LB03002 group). Injection site reactions occurred more frequently in LB03002-treated patients but were considered mild to moderate in >90% of cases.

Conclusions: Growth response with once-weekly LB03002 in GH-deficient children is comparable to that with daily GH, achieving expected growth rates for 24 months. Once-weekly LB03002 is a strong candidate for long-term GH replacement in GH-deficient children.
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http://dx.doi.org/10.1210/jc.2013-2502DOI Listing
January 2014

Response of pure red cell aplasia to cyclophosphamide after failure of mycofenolate mofetil in a patient with polyglandular syndrome type I.

J Pediatr Hematol Oncol 2013 Nov;35(8):e338-40

*Endocrinology Research Centre, Institute of Pediatric Endocrinology †Federal Research Center for Pediatric Hematology, Oncology, and Immunology, Moscow, Russian Federation.

A 26-year-old female with the classic major and minor components of autoimmune polyglandular syndrome type 1 was diagnosed as having pure red cell aplasia. Treatment with 1.5 g/d mycofenolate mofetil for 3 months failed to restore erythroid production. Treatment with cyclosporine A produced a good partial response but led to renal toxicity and was therefore substituted with cyclophosphamide, which had a good partial effect and lasted for 18 months. The relapse of anemia was not observed during the 6-month follow-up period after the cessation of treatment.
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http://dx.doi.org/10.1097/MPH.0b013e3182755c52DOI Listing
November 2013

Mutations and pituitary morphology in a series of 82 patients with PROP1 gene defects.

Horm Res Paediatr 2011 18;76(5):348-54. Epub 2011 Oct 18.

Department of Pediatrics, Second Faculty of Medicine, Charles University, Prague, Czech Republic.

Background/aims: Defects of the PROP1 gene are the most prevalent genetic cause of combined pituitary hormone deficiency. Previous observations in affected patients have shown pituitary size ranging from hypoplasia to overt pituitary mass and evolution of size over the lifespan.

Methods: We evaluated pituitary size and morphology in PROP1-mutation carriers who originated from Central and Eastern Europe. We analyzed 112 pituitary magnetic resonance imaging (MRI) scans from 82 patients (42 males) aged 2.5-72.7 (median 16.6) years from 60 kindreds.

Results: Among the 120 independent PROP1 alleles, the most prevalent mutations were delGA301/302 (99 alleles) and delA150 (13 alleles). Median pituitary height at first MRI was 4.7 mm (range 1.0-20.7) and median volume was 127.6 mm(3) (range 7.5-3,087.0). Pituitary size did not differ between sexes and did not correlate with hormonal phenotype, but significantly decreased with increasing age. However, evaluation of individual values suggested a biphasic mode with increasing volume during childhood, peak in adolescence, and subsequent regression in adulthood.

Conclusion: Although pituitary size was increased in a number of PROP1-deficient patients, none of them suffered permanent damage from pituitary mass; therefore, any proposed surgery should be postponed as long as possible and ultimately may not be necessary due to the self-limiting nature of the pituitary enlargement.
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http://dx.doi.org/10.1159/000332693DOI Listing
March 2012

Treatment with insulin detemir or NPH insulin in children aged 2-5 yr with type 1 diabetes mellitus.

Pediatr Diabetes 2011 Nov 21;12(7):632-41. Epub 2011 Mar 21.

Jenny Lind Children's Department, Norfolk & Norwich University Hospital, Norwich, UK.

This randomised (1:1), multinational, open-labelled, parallel group trial compared insulin detemir (IDet) with neutral protamine Hagedorn (NPH) insulin, in combination with mealtime insulin aspart, over 1 yr in subjects aged 2-16 yr with type 1 diabetes mellitus. Of 348 randomised subjects, 82 (23.6%) were 2-5 yr (IDet: 42, NPH: 40). This article is a descriptive subgroup analysis of these young children. Baseline characteristics (IDet vs. NPH) were similar: mean age, 4.3 vs. 4.5 yr; diabetes duration, 2.2 vs. 2.1 yr; males, 42.9 vs. 52.5%. Mean haemoglobin A1c (HbA1c) was similar between groups at baseline (8.2 vs. 8.1%), and changed little over 1 yr (8.1 vs. 8.3%). Fasting plasma glucose (FPG) was similar at baseline (8.44 vs. 8.56 mmol/L) and decreased during the study (-1.0 vs. -0.45 mmol/L). A lower rate of hypoglycaemia was observed with IDet compared with NPH (24-h; 50.6 vs. 78.3 episodes per patient-year; nocturnal hypoglycaemia, 8.0 vs. 17.4 episodes per patient-year). No severe hypoglycaemic episodes occurred with IDet, while 3 subjects reported 6 episodes with NPH. Change in weight standard deviation score standardised by age and gender was -0.17 with IDet and +0.03 with NPH. A slightly lower proportion of subjects in this age group reported adverse events with IDet than with NPH (69.0 vs. 77.5%). Serious adverse events were few (5 with IDet, 7 with NPH). In conclusion, long-term treatment with IDet in children aged 2-5 yr suggested similar glycaemic control, greater reduction in FPG, lower rates of hypoglycaemia, no inappropriate weight gain, and fewer adverse events compared with NPH.
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http://dx.doi.org/10.1111/j.1399-5448.2010.00750.xDOI Listing
November 2011

Comparable efficacy and safety of insulin glulisine and insulin lispro when given as part of a Basal-bolus insulin regimen in a 26-week trial in pediatric patients with type 1 diabetes.

Diabetes Technol Ther 2011 Mar 3;13(3):327-34. Epub 2011 Feb 3.

University of Cape Town Diabetes Clinical Trials Unit, New Groote Schuur Hospital, Cape Town, South Africa.

Background: We compared the efficacy and safety of insulin glulisine with insulin lispro as part of a basal-bolus regimen in children and adolescents with type 1 diabetes.

Methods: Overall, 572 children and adolescents (4-17 years old) using insulin glargine or neutral protamine Hagedorn insulin as basal insulin were enrolled in a 26-week, multicenter, open, centrally randomized, parallel-group, noninferiority study. Subjects were randomized to receive glulisine (n = 277) or lispro (n= 295) 0-15 min premeal.

Results: Baseline-to-endpoint hemoglobin A1c changes were similar between the two insulins: adjusted mean change (glulisine vs. lispro), 0.10% versus 0.16%; between-treatment difference (glulisine-lispro), &minsu;0.06, 95% confidence interval (-0.24; 0.12); and prespecified noninferiority margin, 0.4%. Overall, for all age groups together, the percentage of patients achieving American Diabetes Association age-specific A1c targets at endpoint was significantly higher (P = 0.039) with glulisine (38.4%) versus lispro (32.0%). From Month 4 to endpoint, both "all" and "severe" symptomatic hypoglycemia rates were similar (3.10 vs. 2.91 and 0.06 vs. 0.07 events/patient-month, respectively). Frequency and type of adverse events, serious adverse events, or hypoglycemia reported as serious adverse events were similar between both groups.

Conclusions: Glulisine was as effective as lispro in baseline-to-endpoint A1c change, and both treatments were similarly well tolerated.
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http://dx.doi.org/10.1089/dia.2010.0072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3045789PMC
March 2011

The carriage of the type 1 diabetes-associated R262W variant of human LNK correlates with increased proliferation of peripheral blood monocytes in diabetic patients.

Pediatr Diabetes 2011 Mar;12(2):127-32

Department of Molecular Diagnostics, National Research Center GosNIIgenetika, Moscow, Russia.

Objective: Lymphocyte adaptor protein (LNK) plays a pivotal role as a suppressor of T-cell receptor-mediated immune signaling and negative regulator of lymphopoiesis and early hematopoiesis. Recently, association between the R262W (c.784T>C) variant of the SH2B3 gene (rs3184504) encoding human LNK and type 1 diabetes (T1D) was found in several populations. In this study, we aimed to check whether this marker is associated with T1D in a Russian population.

Methods: Using a Taqman allele discrimination assay, we genotyped 1062 unrelated Russian individuals with diabetes at childhood and adolescence onset and 1020 healthy controls. T-cell proliferation assay based on the measurement of incorporation of bromo-2'-deoxyuridine incorporation into newly synthesized DNA was used to evaluate whether carriage of SH2B3 784T>C correlates with T-cell proliferation in patients' peripheral mononuclear blood cells (PMBCs) stimulated with anti-CD28 and anti-CD3 antibodies.

Results: The allele 784C of SH2B3 was related to a higher risk of T1D (odds ratio of 1.52, p = 1.2 × 10(-12)). A correlation between the carriage of the predisposing C/C variant of LNK and increased proliferation of T lymphocytes was shown in PMBCs of both diabetic [C/C vs. C/T vs.T/T = optical density at 450 nm (OD(450)) 6.3 ± 0.8 vs. 4.4 ± 0.7 vs. 2.7 ± 0.5, p = 0.0007] and non-diabetic (C/C vs. C/T vs.T/T = OD(450) 2.9 ± 0.6 vs. 2.2 ± 0.4 vs. 1.7 ± 0.4, p = 0.022) patients.

Conclusions: The SH2B3 784T>C variant could contribute to the pathogenesis of T1D through impaired immune response that promotes activation and expansion of self-reactive lymphocytes in susceptible individuals.
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http://dx.doi.org/10.1111/j.1399-5448.2010.00656.xDOI Listing
March 2011

Autoimmune polyglandular syndrome type 1 in Russian patients: clinical variants and autoimmune regulator mutations.

Horm Res Paediatr 2010 20;73(6):449-57. Epub 2010 Apr 20.

Endocrinology Research Centre, Institute of Paediatric Endocrinology, Moscow, Russia. elizaveta.orlova @ mail.ru

Background: Autoimmune polyglandular syndrome type 1 (APS-1) (OMIM 240300) is a rare autosomal recessive disorder associated with three major manifestations: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. There are, however, multiple minor components of APS-1 that induce significant phenotype variability. Subsequently, the diagnosis of APS-1 during early stages is often challenging.

Aim: We aimed to provide clinical and mutational data for a large number of APS-1 patients in the Russian population.

Methods: We analyzed clinical variations and component prevalence in APS-1 patients. DNA screening for autoimmune regulator (AIRE) gene mutations was performed in established APS-1 patients and in patients with the single components of chronic mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency, or alopecia.

Results: We identified 46 patients from 42 families with APS-1. Eighteen different components were present in the patients, including very rare conditions - bone dysplasia and retinitis pigmentosa. We identified 10 different mutations, 3 of which were novel (M1T, E298K, c1053_1060del). The common Finnish mutation, R257X, was the most frequent in our population, present in 64/92 (70%) of the alleles.

Conclusion: We found that the R257X AIRE mutation is common in Russian APS-1 patients. The majority of children with hypoparathyroidism and chronic mucocutaneous candidiasis were carriers of the AIRE mutations.
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http://dx.doi.org/10.1159/000313585DOI Listing
July 2010

Biosimilars: controversies as illustrated by rhGH.

Curr Med Res Opin 2010 May;26(5):1219-29

Faculty of Pharmaceutical Sciences, KU Leuven, Leuven, Belgium.

Unlabelled: Abstract Background and scope: Similar biological medicinal products, also called 'biosimilars', are copies of biopharmaceutical products whose patent has expired. Whether biosimilars are truly comparable and interchangeable with their reference biopharmaceutical products in terms of quality, efficacy and tolerability, is still a matter of debate. This review discusses the controversies related to the criteria for regulatory approval of biosimilars. These concerns are illustrated using recombinant human growth hormone (rhGH) biosimilars as an example.

Methods: Publications on the regulatory approval of biosimilars in general and rhGH biosimilars in particular were searched in MEDLINE by exploding and combining the medical subject heading terms 'human growth hormone', 'efficacy' or 'safety' and the free-text words 'biosimilar', 'biopharmaceutical', 'similar biological medicinal product', 'follow-up biologic' or 'biogeneric'. Searches were limited to full-text English-language articles. The websites from the European Medicines Agency (EMA) and from the American Food and Drug Administration were also consulted. Regulatory status: To obtain regulatory approval of a biosimilar product by EMA, demonstration of comparability with an approved reference biopharmaceutical product in terms of quality, efficacy and tolerability is needed. Thus, comparative quality studies, non-clinical and clinical efficacy and tolerability studies are required. However, in contrast to the reference product, comparative non-clinical pharmacokinetics, safety pharmacology, reproduction toxicology, mutagenicity and carcinogenicity studies are not mandatory to obtain approval of a biosimilar. In addition, comparable efficacy and tolerability only needs to be established by one study in a single population during a limited time interval (12 months) and often allows extrapolation to all other approved indications of the reference product. Consequently, for the currently approved rhGH biosimilars, long-term efficacy and tolerability in all indications has not been proven to the same degree as for the reference products.

Conclusions: The validity of the current criteria for comparability and interchangeability of biosimilars and their reference products remains controversial. The authors conclude that long-term clinical investigations and systematic monitoring of the efficacy and tolerability of rhGH biosimilars in all indications are needed. In addition, the medico-economical environment should allow physicians to take a free and informed decision about the type of rhGH to be prescribed.
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http://dx.doi.org/10.1185/03007991003719642DOI Listing
May 2010

A randomized, double-blind study to assess the efficacy and safety of valtropin, a biosimilar growth hormone, in children with growth hormone deficiency.

Horm Res 2007 11;68(6):288-93. Epub 2007 Jul 11.

Endocrinological Scientific Centre, Russian Academy of Science, Moscow, Russia.

Valtropin is a recombinant human GH (rhGH) manufactured using a novel yeast expression system, classed as a 'biosimilar'. Valtropin was compared with Humatrope in children with GH deficiency (GHD). Treatment-naive, prepubertal children with GHD were randomized to Valtropin (n = 98) or Humatrope (n = 49) for 1 year. Standing height was measured 3-monthly and height velocity (HV) calculated. Serum IGF-I, IGFBP-3 and GH antibodies were determined centrally. HV at 1 year was 11.3 +/- 3.0 cm/year with Valtropin and 10.5 +/- 2.8 cm/year with Humatrope. Treatment difference was 0.09 cm/year with 95% confidence limits of -0.71, 0.90, within the preset non-inferiority limit of -2.0 cm/year. Height standard deviation (SD) scores were increased in both treatment arms with no acceleration of bone maturation. IGF-I and IGFBP-3 were increased comparably for both treatments. Adverse events showed no clinically relevant differences between treatment groups. Anti-GH antibodies were detected in 3 (3.1%) Valtropin and 1 (2.0%) Humatrope patients and the growth pattern was indistinguishable from the rest of the cohort. The 1-year efficacy and safety profile of Valtropin, a new biosimilar rhGH, are equivalent to the comparator rhGH, Humatrope. Valtropin can be used for the treatment of children with GHD and longer term data will fully establish its efficacy and safety profile.
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http://dx.doi.org/10.1159/000105494DOI Listing
December 2007
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