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Purpose Gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard for diagnosing central precocious puberty (CPP). However, intravenous GnRH is not always readily available. The aim of the present study was to evaluate the diagnostic accuracy of triptorelin-stimulated luteinizing hormone (LH) concentrations in the diagnosis of CPP among girls presenting with premature thelarche compared to the gold standard GnRH test. Methods A prospective, case-control (CPP vs isolated premature thelarche), clinical study evaluating the diagnostic accuracy of triptorelin-stimulated LH concentrations in 60 girls with premature thelarche was performed. All girls underwent stimulation with subcutaneous triptorelin injection and intravenous GnRH in a randomized order. During the stimulation test with triptorelin, LH and FSH were measured at time 0, 30, 60, 90, 120, and 180 min after the injection. Estradiol was sampled 24 h after the injection. During the GnRH test, LH and FSH were measured at time 0, 30, 45, and 60 min. Girls with peak GnRH-stimulated LH concentrations ≥5.0 IU/L were classified as having CPP. Area under the curve (AUC) for triptorelin-stimulated LH concentrations was assessed using the receiver operating characteristic (ROC) analysis. Results Triptorelin-stimulated LH concentrations were significantly higher in girls who had CPP according to the GnRH test (53.3%). LH peaked at 180 min after the triptorelin injection. The highest diagnostic accuracy for CPP (AUC = 0.973, sensitivity 96.9%, specificity 89.3%) at 180 min was at a LH concentration ≥3.4 IU/L. The 24 h estradiol concentration did not improve the predictive model. Conclusions Measuring LH concentrations 180 min after triptorelin injection with a cut-off value of ≥3.4 IU/L demonstrated a high diagnostic accuracy compared to the GnRH test. Thus, stimulation with triptorelin can be used as a reliable alternative for diagnosing CPP in girls with premature thelarche.

Despite significant strides from the beginning of the 20th century, there was no systematic or institutionalized reflection on photography in Serbian ethnology and anthropology until the 1980s. Until then, photography was mainly used as an additional technical tool for field recording, documenting, and presenting field materials in museums or scientific institutions. However, since the end of the 20th, and especially at the beginning of the 21st century, an increasing number of social scientists have included photography in their works, either through historical and theoretical reflection or through practical use in specific research. This step can be related to the institutionalization of the sub discipline of visual anthropology in Serbia. The paper presents the assumption that both flows are part of a broader process called the visual turn, and the associated flourishing of systematic thinking about visual culture. In this paper, we aim to reconstruct the main features of the visual turn in the local academic community and point out some of its consequences. In addition, our goal is to present the most important achievements related to the mentioned turn, and consider their impact on recent examples of thinking about photography, i.e. its use in ethnological and anthropological research in Serbia. This paper emphasizes the examples that are important in the theoretical, methodological, or applied-scientific framework. Key words: anthropology of photography, ethnology and anthropology of photography in Serbia, visual turn, visual culture, visual anthropology

Introduction/Aim: Spondylodysplastic Ehlers-Danlos Syndrome (sdEDS) is a rare genetic disorder of collagen synthesis, caused by a mutation in the B4GALT7, B3GALT6, or SLC39A13 gene. Features of this very rare disorder are short stature, hypotonia, hyperflexible joints, soft, thin, and overly stretchable skin, sparse hair and eyebrows, elderly face, wide forehead and prolonged wound healing. Molecular genetic analysis is needed for definite confirmation of the diagnosis. So far, only three case reports describing growth hormone treatment response in patients with sdEDS have been published. All of these patients had growth hormone (GH) deficiency. We present the first case report regarding growth hormone treatment response in a patient with sdEDS and normal GH secretion (without GH deficiency). Case report: Patient was a girl with short stature and normal GH secretion. Having in mind that the girl was born small for the gestational age, due to her short stature, she started using HR, before the diagnosis of sdEDS was made. Based on the lack of improvement in growth velocity as well as the girl's phenotype, genetic analyses were performed and the diagnosis of sdEDS due to biallelic mutations of the B4GALT7 gene was established. After the diagnosis of sdEDS was made and due to suboptimal response in growth velocity to the GH treatment, the GH therapy was stopped at the age of 11 years. Conclusion: This is a first case report regarding GH treatment in a child with sdEDS and normal GH secretion, demonstrating a very limited therapeutic effect of GH on linear growth in the presented patient.

We aimed to collect data on all paediatric patients who were diagnosed with type 1 diabetes mellitus (T1DM) between the years 2000 and 2019 in Serbia and estimate for the first time its prevalence. Also, the trends of diabetes ketoacidosis (DKA) occurrence at the time of diagnosis are monitored. We collected and retrospectively analysed the data of patients

BackgroundOxidative stress is implicated in both, the onset and the progression of type 1 diabetes mellitus (T1DM). There is accumulated evidence of increased biomarkers of oxidative stress in newly diagnosed, T1DM patients without complications, and in those with advanced disease. In this cross-sectional study, we investigated factors affecting oxidative stress status in pediatric patients with T1DM.MethodsAdvanced oxidation protein products (AOPP), prooxidant-antioxidant balance (PAB), total sulfhydryl (SH) groups, and superoxide dismutase (SOD) activity were determined in 170 children and adolescents with T1DM. Principal component analysis was used to investigate clustering of clinical and laboratory variables associated with elevated oxidative stress and reduced antioxidative defense biomarkers.ResultsFactor analysis extracted five factors, interpreted as (1) “weight status factor” including age, BMI, waist and hip circumferences; (2) “proatherogenic factor” that included LDL-cholesterol, non-HDL-cholesterol, and triglycerides; (3) “metabolic control factor” including glucose and HbA1c; (4) “renal marker factor” with positive loading of urinary albumin excretion rate and negative loading of GFR; and (5) “antiatherogenic factor” that included HDL-cholesterol. High AOPP levels were independently predicted by “proatherogenic” (OR: 2.32; 95% CI: 1.44–3.71; p ConclusionsCardiometabolic risk factors and renal function are associated with oxidative stress in pediatric T1DM patients.

Persistent hypoglycaemia in newborns and infants is most commonly caused by congenital hyperinsulinism (CHI). Most CHI studies report outcomes in children from both consanguineous and non-consanguineous families which can affect the phenotype-genotype analysis. The aim of this study was to analyze characteristics of patients with CHI in 21 non-consanguineous families from Serbia. This retrospective cohort study included a total of 21 patients with CHI treated in the Mother and Child Healthcare Institute of Serbia during the past 20 years. The prevalence of macrosomia at birth was very low in our cohort (4.8%). Median age at presentation was 6 days, with seizures as the presenting symptom in 76% of patients. Only four patients (19%) were diazoxide unresponsive, and eventually underwent pancreatectomy. Genetic testing was performed in 15 patients and genetic diagnosis was confirmed in 60%, with all patients being heterozygous for detected mutations. The ABCC8 gene mutations were detected in 55.6%, GLUD1 in three patients (33.3%) with HIHA syndrome and one patient had HNF4A gene mutation and unusual prolonged hyperglycaemia lasting 6 days after diazoxide cessation. Neurodevelopmental deficits persisted in 33% of patients.Conclusion: This is the first study regarding CHI patients in Serbia. It suggests that in countries with low consanguinity rate, majority of CHI patients are diazoxide responsive. The most common mutations were heterozygous ABCC8, followed by GLUD1 and HNF4A mutations, suggesting the potential benefit of population-tailored genetic analysis approach, targeting the mutations causing CHI via dominant inheritance model in regions with low consanguinity rates. What is Known: • Persistent hypoglycaemia during infancy and early childhood is most commonly caused by congenital hyperinsulinism (CHI). • Consanguinity is a very important factor regarding the genetics and phenotype of CHI, increasing the risk of autosomal recessive genetic disorders, including the severe, diazoxide-unresponsive forms caused by recessive inactivating mutations in ABCC8 and KCNJ11. What is New: • Results of the present study which included CHI patients from 21 non-consanguineous families suggest that in countries with low consanguinity rates, majority of CHI patients can be diazoxide responsive, with most common mutations being heterozygous ABCC8, followed by GLUD1 and HNF4A mutations. • Unusually prolonged hyperglycaemic reaction to diazoxide treatment in a patient with HNF4A mutation was also described in the present study.

Introduction/Aim: Diabetic ketoacidosis (DKA) is one of the most important causes of acute mortality in youth with type 1 diabetes mellitus (T1DM). Recently published data suggested worryingly high frequency of DKA at the onset of T1DM in Belgrade youth. The goal of this study was to assess the frequency of DKA at the onset of T1DM and the associated risk factors in Belgrade youth during the previous 10 years at a tertiary centre. Methods: Data were collected retrospectively from the medical records of all children with new-onset T1DM admitted to our centre during the study period between 1st January 2007 and 1st January 2017. Results: During the study period, a total of 501 subjects (233 girls and 268 boys) were diagnosed with new-onset T1DM, with a mean age of 9.55 ± 4.26 years, and mean pH at the time of diagnosis of 7.28 ± 0.14 (6.78-7.51). Girls with T1DM were younger compared to boys (9.05 ± 4.04 years vs. 9.98 ± 4.41 years, respectively, p 11 years (35%), although this difference was not statistically significant. Conclusion: There is an alarmingly high rate of DKA at the onset of T1DM in Belgrade youth with no significant differences between different age groups. These findings emphasize the need for intensive public health preventive actions aimed at early diagnosis of T1DM in all age groups.

Background and aims: Dyslipidemia in type 1 diabetes mellitus (T1DM) is characterised by altered distributions of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclasses. Recent studies suggested that proprotein convertase subtilisin/kexin 9 (PCSK9) may contribute to the development of dyslipidemia in T1DM. In this cross-sectional study, we investigated the association between PCSK9 and lipoprotein subclasses in young T1DM patients, with respect to glycemic control. Methods: Plasma PCSK9 and lipoprotein subclasses were determined in 207 patients with T1DM (106 boys and 101 girls), aged 13.9 +/- 3.0 years and treated by intensive insulin therapy. Results: Plasma PCSK9 levels significantly increased with worsening of glycemic control (p lt 0.001). T1DM patients with poor glucoregulation had the highest proportion of small, dense LDL (sdLDL) and smaller HDL particles, as well. PCSK9 was positively associated with markers of glucose homeostasis and serum lipid parameters only in patients with suboptimal/poor glucoregulation. In well-controlled T1DM, plasma PCSK9 level was inversely associated with a relative proportion of sdLDL particles (p lt 0.01) and this association remained significant in multivariate analysis. In T1DM patients with suboptimal/poor glycemic control, PCSK9 was positively associated with the proportion of the smallest HDL3c particles (p lt 0.001), but negatively with HDL size (p lt 0.05). Conclusions: The extent of achieved metabolic control modifies the association between PCSK9 and lipoprotein subclasses in T1DM. Further investigations are needed to reveal whether the observed effects of glycemic control on PCSK9 and sdLDL levels have causal consequences on CVD risk in young patients with T1DM.

This paper reviews the life and work of Srebrica Knežević (1930-2012) in order to present her career, achievements and fields of study that she contributed to. Special attention will be paid to the importance of her role in pioneer research of folk medicine, nutrition and world ethnology, as well as comprehension of the significance of interdisciplinary approach in Serbian ethnology. Also, this paper will depict Srebrica Knežević as a researcher loyal to her ethnographic field, therefore indicating the compromises she had to make for her very frequent trips and researches. Finally, I will speak of Srebrica Knežević as a lecturer and a professor who adjusted her impressions for the classroom setting and her students, during four decades of work at the Department of Ethnology and Anthropology of the Faculty of Philosophy in Belgrade. As a gifted lecturer who implemented innovations in the classroom, she is remembered as a creative, passionate and dedicated professor, who brought distant topics and ethnographic fields to life. The life and work of Srebrica Knežević are presented and analyzed based on the relevant literature and conversations with her colleagues, students, friends and family.

Establishing characteristics of the shelter animal which determine its outcome is an important task for solving the problem of homeless and abused animals. The main goal of this research was to identify which machine learning algorithm can provide the most accurate prediction of the outcome for an animal, based on its main features. The first step in this research was the transformation of data into a proper form for the implementation of the algorithms. Furthermore, several machine learning algorithms were trained in order to achieve the best possible classification results. The results of the algorithms were compared and the most suitable algorithms were selected based on their performance metrics. This research proposes using a combination of multiple data preprocessing techniques, imbalanced data and machine learning algorithms for predicting the outcome for shelter animal based on its characteristics. K-Nearest Neighbors and C4.5 algorithms provided the best classification results in this research.

Hyperinsulinism/hyperammonemia (HI/HA) syndrome is considered as the second most common type of hereditary HI. Correlation of genotype and phenotype in HI/HA syndrome has been described in several studies. We present three Serbian patients with HI/HA syndrome with emphasis on a possible correlation between genotype and clinical manifestations. Patient 1 was heterozygous for a de novo mutation p.S445L in the GLUD1 gene, while patients 2 and 3 (son and mother) both carry the p.R221C mutation. Early onset of hypoglycaemia with generalized seizures was recorded in infancy in all three patients. The two male patients had mild developmental delay, while the female patient presented with epilepsy. Analysis of Serbian patients with HI/HA syndrome confirms the association of p.S445L and p.R221C mutations with hypoglycaemic seizures noted within the first three months of life and with subsequent risk for cognitive impairment and/or epilepsy.

After two centuries of Bulgarian domination, Belgrade came under Byzantum empire rule in 1018. Together with other fifteen cities, Belgrade was mentioned as a bishop centre in a thorough act of the Ohrid Archbishopric, the first sigilion of Tzar Vasilije II Macedonian, from 1019. Belgrade episcopate also comprised Church centres in Gradac, Uzice, Bela Crkva and Glavetin with 40 clergymen and 40 village mayors, which means that it was one of the richest diocese of the Ohrid Archbisopric. Since Belgrade came under Byzantium rule, there have not been any big changes in the character of Church authorities as the Ohrid Archdiocese was established on the spiritual and cultural traditions of The first Bulgaran empire and Samuil`s state, its head was called an archbishop of Bulgaria and in terms of jurisdiction, it was completely independent of Contantinople patriarch. Short reign of Hungarian king Salomon in Belgrade (1071/72) did not lead to any changes in Church organistaion, although certain bishop Franco was mentioned by the King`s counselors. The consolidation of the Catholic Church organisation was enabled only from the fourth decade of the XIII century when Belgrade belonged to the Hungarian king. No later than the beginning of March 1232, according to the decision of the Pope Gregory IX of the Orthodox Eparchy, Belgrade and Branicevo were united with the newly established Episcopate of Syrmia which was founded as a missionary one with the clearly defined aim of the spread of Catholicism among the population of the other part of Syrmia (the regions on the south of the Sava, between the rivers of Drina and Kolubara) which, not long time ago, had been a part of the Diocese of Syrmia under the jurisdiction of the Ohrid Archbishopric. In the period of 1284-1389, Belgrade was under Serbian rule. King Dragutin built the Temple, the headquarters of the bishop of Macva of Serbian Church with the famous Icon of the Most Holy Mother of God, a well-known relic from the period of Byzantium rule, and some other churches, so there were many Orthodox priests in Belgrade and its surroundings. Episcopate of Macva Serbian Church was established in the period of 1284-1290, and it was situated on the country of Macva, i.e. Syrmia. The river Sava was on its northern border, the river of Drina was on the western one, while the Kolubara and the slopes of Avala and Kosmaj were on the eastern border, and the territory reached Crna Gora and Rudnik on the south. Its territory covered the regional unit of Macva only partially. On the basis of the data written down by the Archbishop Danilo II, an expert in Church issues of the time, it is quite uncertain whether there was a metropolitan`s residence in Belgrade. In order to solve the puzzle, some hypotheses were outlined in the reference to the political circumstances and Church practices. The firmly established organisation of the Serbian Church endangered the rights of Belgrade Diocese of the Roman Church; that is why the pope Nicholas IV (1288-1292) and John XXII (1316-1334) reacted in order to establish the Catholic jurisdiction. Although Belgrade bishops Martin and Benedict were mentioned in Latin sources from the nineties of the XIV century, Albensis capitulum, Magister Theodor Albensis Ecclesie Prepositus, Magister Demetrius Canonicus Albensis, those were only titlings. The moment of the formal establishment of the already founded clerical organisation was patiently awaited for. It happened after Belgrade had fallen under Hungarian rule again. Hungarian king Charles Robert was active in the strengthening of the position of the Roman Church. After 1319, the headquarters of the Macva bishop was relocated from Belgrade, but the Episcopate of Macva of the Serbian Church seemed to have continued its activities. The counties of Ub, Nepricava, Rabas, Pepeljevac, Ljig, Toplica, Upper and Lower Obna and the region of Crna Gora and Rudnik were under its jurisdiction, undoubtedly under the authority of the Serbian King. Most likely the Serbian bishop of Macva also had jurisdiction over the Orthodox clergy and the religious people in the regional units of Macva which were returned to Hungary in 1319.

Congenital hypothyroidism (CH) is the most frequent congenital endocrine disorder. The purpose of the present study was to determine the incidence of CH in Central Serbia from 1983 to 2013. Newborn screening for CH was based on measuring neonatal thyroid-stimulating hormone (TSH) using a 30 mU/l cutoff (CO) until 12/1987 (P1), 15 mU/l until 12/1997 (P2), 10 mU/l until 12/2006 (P3), and 9 mU/l thereafter (P4). During the study period, there were 1,547,122 live births screened for CH. Primary CH was detected in 434 newborns, with incidence of 1:3728. With gradual lowering of the CO, the incidences of CH increased from 1:5943 in P1 to 1:1872 in P4 (p 0.001). Incidence of CH with ectopic and enlarged gland doubled (p 0.001), while prevalence of athyreosis remained relatively constant. The most prominent finding was the increase in the transient CH from none in P1 to 35 % of all CH patients in P4.The overall incidence of CH in Central Serbia during study period nearly tripled, with a significant increase in almost all etiological categories, and was associated with lowering TSH cutoffs as well as other yet unidentified factors. Further studies are needed to identify other factors associated with increasing incidence of CH.Congenital hypothyroidism (CH) is the main cause of preventable mental retardation. Recent reports have indicated a progressive increase in the incidence of primary CH throughout the world, partially explained by lowering of the TSH cutoff values.During the study period associated with lowering of the TSH cutoffs, the overall incidence of CH in Serbia tripled, including transient CH, ectopy, and dyshormonogenesis, while prevalence of athyreosis remained stable during 30 years. Significant increase in the incidence of both permanent and transient CH was observed, associated with lowering of TSH cutoffs as well as other yet unidentified factors.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease characterized by impaired adrenal steroidogenesis and most often caused by CYP21A2 gene mutations. For the first time, we reported complete spectrum and frequency of CYP21A2 gene mutations in 61 unrelated patients with classical and non-classical CAH from Serbia. Direct DNA sequencing of whole CYP21A2 gene and polymerase chain reaction with sequence-specific primers for detection of CYP21A1P/CYP21A2 chimeras were combined. We identified 18 different pathogenic alleles—two of them novel. Mutation detection rate was highest in patients with salt-wasting form of CAH (94.7 %). The most prevalent mutation was intron 2 splice site mutation, c.290-13A/C>G (18.5 %). Other mutation frequencies were: CYP21A1P/CYP21A2 chimeras (13 %), p.P30L (13 %), p.R356W (11.1 %), p.G110fs (7.4 %), p.Q318X (4.6 %), p.V281L (4.6 %), p.I172N (2.8 %), p.L307fs (2.8 %), p.P453S (1.9 %), etc. Mainly, frequencies were similar to those in Slavic populations and bordering countries. However, we found 6.5 % of alleles with multiple mutations, frequently including p.P453S. Effects of novel mutations, c.386T>C (p.Leu129Pro) and c.493T>C (p.Ser165Pro), were characterized in silico as deleterious. The effect of well-known mutations on Serbian patients’ phenotype was as expected. The first comprehensive molecular genetic study of Serbian CAH patients revealed two novel CYP21A2 mutations. This study will enable genetic counseling in our population and contribute to better understanding of molecular landscape of CAH in Europe.

Available data on metabolically healthy obese (MHO) phenotype in children suggest that gender, puberty, waist circumference, insulin sensitivity, and other laboratory predictors have a role in distinguishing these children from metabolically unhealthy obese (MUO) youth. The goal of this study was to identify predictors of MHO phenotype and to analyze glucose and insulin metabolism during oral glucose tolerance test (OGTT) in MHO children. OGTT was performed in 244 obese children and adolescents aged 4.6-18.9 years. Subjects were classified as MHO in case of no fulfilled criterion of metabolic syndrome except anthropometry or as MUO (≥2 fulfilled criteria). Among the subjects, 21.7 % had MHO phenotype, and they were more likely to be female, younger, and in earlier stages of pubertal development, with lower degree of abdominal obesity. Insulin resistance was the only independent laboratory predictor of MUO phenotype (OR 1.59, CI 1.13-2.25), with 82 % sensitivity and 60 % specificity for diagnosing MUO using HOMA-IR cutoff point of ≥2.85. Although no significant differences were observed in glucose regulation, MUO children had higher insulin demand throughout OGTT, with 1.53 times higher total insulin secretion.Further research is needed to investigate the possibility of targeted treatment of insulin resistance to minimize pubertal cross-over to MUO in obese children.• Substantial proportion of the obese youth (21-68 %) displays a metabolically healthy (MHO) phenotype. • Gender, puberty, waist circumference, insulin sensitivity, and lower levels of uric acid and transaminases have a possible role in distinguishing MHO from metabolically unhealthy obese (MUO) children.• Insulin resistance was found to be the only significant laboratory predictor of MUO when adjusted for gender, puberty, and the degree of abdominal obesity. • Besides basal insulin resistance, MUO children were found to have a significantly higher insulin secretion throughout OGTT in order to maintain glucose homeostasis.

The St George Abbey was founded on an island near Perast by the Benedictine Monastic Order by the beginning of the 11th century. From the mid-13th century, the community of Kotor had the right of patronage over the abbey, which allowed the patriciate of Kotor to elect abbots as well as have a say in numerous monastery affairs, including propriety rights. Therefore, on November the 2nd 1530, Minor Council of Kotor named Pompejus de Pasqualibus, a nobleman from Kotor, the abbot of the St George Abbey. After the official consent from Rome and Venice, father Pompejus took over the abbey. Soon after, a gruesome crime took place on the island, a crime unseen in the history of the Kotor church. On the Feast of the Invention of the Holy Cross, May 3rd 1535, a group of Perast locals, armed with sticks and daggers, broke into the abbey and killed abbot Pasqualibus at the altar as he was saying Pater Noster. Nikola Krosic, the chaplain of the St George Abbey, and a few others tried to stop the murderers, but to no avail. The killers went on to humiliate the body of the deceased by throwing it out of the church and dumping it into a nearby pit, which added to the resentment, especially among the patriciates of Kotor. Three days later, on the Feast of the Ascension, the bishop of Kotor, Luka Bizanti, publicly excommunicated the killers and their men in the cathedral, while Pope Paul III forbade all service at the church where the crime had been committed. The interdict wasn?t recalled until 1546. In the decree of excommunication, Bishop Luka Bizanti emphasized the fact that father Pompejus hadn?t said or done anything to provoke the killers. What are the reasons of such an outpour of mass anger among dozens of Perast locals? Around that time, for several decades, Perast, a village founded on St George?s fief, started to improve its economy as a result of the expansion of ship-building and trading. More and more inhabitants of Perast started to sail and take part in the trade, especially on the rye and salt market. They had the support of the Venetian authorities, which caused envy among the inhabitants of Kotor, who considered Perast a part of their district. The tendency to achieve a full emancipation from the community of Kotor included church interests as well. After a gradual weakening of church life on the island, the St George church took on the role of a parish church under the patronage of Kotor. Perast locals were evidently dissatisfied with the idea of their parish priest being a noble Pasqualibus of Kotor, whose descent and position were representative of everything they despised and fought against. The motive of the murder was a trivial one - father Pompejus refused to hold service at the St Church on the Feast of the Holy Cross, which deeply insulted the people of Perast. The exceedingly long process of turning the Benedictine abbey into a parish church and a sepulchral chapel of Perast reached its peak on November the 17th1634 with the edict of the Venetian Senate taking the right of patronage away from the community of Kotor. From then on, ius patronatus belonged to the Venetian Senate, while the choice of the abbot, the parish priest of Perast in fact, was left to the locals.

Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive, fatal childhood disorder associated with skeletal dysplasia, renal dysfunction, and T-cell immunodeficiency. This disease is linked to biallelic loss-of-function mutations of the SMARCAL1 gene. Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T-cell immunodeficiency is unclear. Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7R alpha) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor. No pathogenic mutations were detected in the exons of IL7R in these patients; however, CpG sites in the IL7R promoter were hypermethylated in SIOD T cells. We propose therefore that the lack of IL7R alpha expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients. (C) 2015 Elsevier Inc. All rights reserved.

Background/Aim. Although total body irradiation (TBI) was considered to be the primary cause of thyroid dysfunction following hematopoietic stem cells transplantation (HSCT), a significant prevalence of subclinical hypothyroidism after HSCT with chemotherapy-only conditioning regimens has been observed in several studies. The aim of this study was to assess changes in thyroid stimulating hormone (TSH) levels in children after HSCT, without the use of irradiation at any time in the course of the treatment. Methods. Our cohort consisted of 41 children and adolescents who underwent autologous or allogeneic HSCT and were available for follow-up for at least one year after transplantation. Irradiation was not performed in any of the subjects, neither during pretransplatation therapy, nor during conditioning. The median duration of follow-up was 2.9 years. The indications for HSCT were hematologic malignancy (41.5%), solid malignant tumor (34.1%), and other disorders (24.4%). The thyroid status of all the subjects was assessed prior to HSCT and after follow-up period. Results. Thyroid dysfunction after HSCT was present in 27 (65.8%) subjects. Subclinical hypothyroidism was the most common abnormality, presenting in 23 (56.1%) patients, primary hypothyroidism was present in one (2.4%) patient, while 3 (7.3%) subjects had low free T4 with normal TSH values. Significantly (p < 0.01) higher elevations in TSH levels were present in the patients who received chemotherapy for the underlying disease prior to HSCT. Conclusion. Our findings emphasize the need for long-term monitoring of thyroid function following HSCT, regardless of whether or not irradiation was used.

Background/Aim. An ideal insulin regimen for children and adolescents with type 1 diabetes mellitus (T1DM) should be physiological, flexibile and predictable, protecting against hypoglycaemia. The aim of this study was to evaluate the influence of insulin analogues on glycaemic control and the occurrence of hypoglycaemic episodes in children and adolescents with T1DM. Methods. The study group consisted of 151 children and adolescents (90 boys, 61 girls) treated with human insulins for at least 12 months before introducing insulin analogues. All the patients were divided into two groups: the group I consisted of 72 (47.7%) patients treated with three injections of regular human insulin before meals and long-acting analogue (RHI/LA), and the group II of 79 (52.3%) patients treated with a combination of rapid-acting and long-acting analogue (RA/LA). The levels of glycated hemoglobin (HbA1c) and the number of hypoglycaemic episodes were assessed at the beginning of therapy with insulin analogues, and after 6 and 12 months. Results. The mean HbA1c was significantly lower in the group I (RHI/LA) after 6 months (9.15% vs 8.20%, p < 0.001) and after 12 months (9.15% vs 8.13%, p < 0.001) as well as in the group II (RA/LA) after 6 months (9.40% vs 8.24%, p < 0.001) and after 12 months of insulin analogues treatment (9.40% vs 8.38%, p < 0.001). The frequency of severe hypoglycaemia was significantly lower in both groups after 6 months (in the group I from 61.1% to 4.2% and in the group II from 54.4% to 1.3%, p < 0.001), and after 12 months (in the group I from 61.1% to 1.4% and in the group II from 54.4% to 1.3%, p < 0.001). Conclusion. Significantly better HbA1c values and lower risk of severe hypoglycaemia were established in children and adolescents with T1DM treated with insulin analogues.

Background The dichotomous nature of the current definition of metabolic syndrome (MS) in youth results in loss of information. On the other hand, the calculation of continuous MS scores using standardized residuals in linear regression (Z scores) or factor scores of principal component analysis (PCA) is highly impractical for clinical use. Recently, a novel, easily calculated continuous MS score called siMS score was developed based on the IDF MS criteria for the adult population. Objective To develop a Pediatric siMS score (PsiMS), a modified continuous MS score for use in the obese youth, based on the original siMS score, while keeping the score as simple as possible and retaining high correlation with more complex scores. Subjects and methods The database consisted of clinical data on 153 obese (BMI ≥95th percentile) children and adolescents. Continuous MS scores were calculated using Z scores and PCA, as well as the original siMS score. Four variants of PsiMS score were developed in accordance with IDF criteria for MS in youth and correlation of these scores with PCA and Z score derived MS continuous scores was assessed. Results PsiMS score calculated using formula: (2xWaist/Height) + (Glucose(mmol/l)/5.6) + (triglycerides(mmol/l)/1.7) + (Systolic BP/130)—(HDL(mmol/l)/1.02) showed the highest correlation with most of the complex continuous scores (0.792–0.901). The original siMS score also showed high correlation with continuous MS scores. Conclusion PsiMS score represents a practical and accurate score for the evaluation of MS in the obese youth. The original siMS score should be used when evaluating large cohorts consisting of both adults and children.

Background:Postprandial hyperinsulinemic hypoglycemia (PHH) is an increasingly recognized complication of gastric bypass surgery in obese adults, distinct from the “dumping syndrome”.Case presentation:Upon birth, primary repair of esophageal atresia was performed, and at the age of 14 months definite esophageal reconstruction was performed. At the age of 3 years, recurrent brief episodes of symptomatic hypoglycemia started. At the age of 5.7 years the girl was admitted to our clinic and investigations indicated hyperinsulinemic hypoglycemia. Oral glucose tolerance test (OGTT) and continuous glucose monitoring results revealed frequent postprandial hypoglycemic events, which were always preceded by early postprandial hyperglycemia. It was concluded that the patient had PHH caused by a delayed and hyperinsulinemic response to carbohydrate intake as a result of esophagogastric surgery. Treatment with acarbose was titrated using flash glucose monitoring, which resulted in satisfactory glucose regulation.Conclusions:This is the first described case of a child with PHH following esophageal reconstruction.

Introduction. Growth hormone deficiency (GHD) can be isolated or associated with deficiency of other pituitary gland hormones. According to age at diagnosis, causes of GHD are divided into congenital or acquired, and according to etiology into recognized and unknown. Objective. We analyzed etiology and prevalence of GHD, demographic data at birth, age, body height (BH) and bone age at diagnosis as well as the frequency of other pituitary hormone deficiencies. Methods. The study involved 164 patients (109 male). The main criterion for the diagnosis of GHD was inadequate response of GH after two stimulation tests. The patients were classified into three groups: idiopathic, congenital and acquired GHD. Results. Idiopathic GHD was confirmed in 57.9% of patients, congenital in 11.6% and acquired in 30.5%. The mean age at diagnosis of GHD was 10.1±4.5 years. The patients with congenital GHD had most severe growth retardation (-3.4±1.4 SDS), while the patients with idiopathic GHD showed most prominent bone delay (-3.6±2.3 SDS). The prevalence of multiple pituitary hormone deficiency was 56.1%, in the group with congenital GHD 73.7%, acquired GHD 54.0% and idiopathic GHD 53.7%. The frequency of thyrotropin deficiency ranged from 88.2-100%, of adrenocorticotrophin 57.1-68.8% and of gonadotrophins deficiency 57.1- 63.0%, while deficiency of antidiuretic hormone was 2.0-25.0%. Conclusion. Although regular BH measurements enable early recognition of growth retardation, patients’ mean age and degree of growth retardation indicate that GHD is still diagnosed relatively late. A high incidence of other pituitary hormone deficiencies requires a detailed investigation of the etiology of disorders and evaluation of all pituitary functions in each child with confirmed GHD.

Background/Aim. Children with type 1 diabetes typically spend one-third of the day in school and they should achieve the same level of diabetes management there as they do outside the school environment. The aim of this study was to identify problems in diabetes management in children with type 1 diabetes at school according to the perceptions reported by children and parents. Methods. This crosssectional survey was carried out at nine public hospitals in Serbia with a cohort of 6-18-year old children/adolescents. The parents were personally informed about the objectives of the survey and the necessity to involve their children. The self-reporting questionnaire included demographic information as well as some questions that helped to evaluate the general situation of children with type 1 diabetes at school. Results. The obtained results show that not all children test blood glucose levels at school (50% of children in the 6-10- year-old age group and 67.3% in the age group over 11 years) and that not all children receive insulin at school (81.1% vs 18.9%, and 57.7% vs 42.3%, respectively). The frequency of severe hypoglycemia was 2.7% in children and 3.3% in adolescents. A high proportion of teachers did not have diabetes training. Conclusion. This brief report about problems in children and adolescents with type 1 diabetes at school in Serbia indicates what happens in the school setting and suggests how to improve control of this disease and facilitate the complete integration of children with diabetes at school.

Most of what is known about the metabolically healthy obese phenomenon is derived from studies in the adult population and no standardized criteria to identify these individuals exist to date. The aim of this study was to determine if the preserved insulin sensitivity evaluated by homeostatic model assessment of insulin resistance (HOMA-IR) index is associated with favorable metabolic profile in the obese children. We studied a group of 248 children and adolescents (150 female, 98 male), aged 5.9–18.9 years with diet-induced obesity (BMI >95th percentile). The entire cohort was divided into quartiles based on levels of insulin resistance determined by HOMA-IR index. Subjects in the lower quartile of HOMA-IR were classified as insulin-sensitive group (ISG), whereas children in the upper quartile were categorized as insulin-resistant group (IRG). The ISG subjects had values of HOMA-IR ≤2.75 while the children from the IRG group had HOMA-IR ≥6.16. Subjects from ISG group had lower basal β-cell activity and were less likely to have impaired fasting glucose or impaired glucose tolerance. Concentrations of LDL and total cholesterol, triglycerides, and transaminases were lower and HDL cholesterol levels were higher in ISG subjects. Findings obtained by the use of Matsuda index correlated well with the findings obtained by the use of HOMA-IR. Conclusion: Lower HOMA-IR values were significantly associated with favorable metabolic profile in studied children, which correlates with findings in the adult population and emphasizes the need for further, longitudinal studies of insulin resistance development in childhood obesity.

Rising prevalence of childhood obesity is accompanied by the increased risk of associated metabolic complications and other comorbidities. Nevertheless, a distinct subgroup of the obese appear to have a normal metabolic phenotype, and these individuals are referred to as the metabolically healthy obese. Prevalence of metabolically healthy individuals within the population of the obese is estimated up to 44%. Metabolically healthy obese are at lesser risk for impaired glucose regulation, dyslipidemia, non-alcoholic fatty liver disease and hypertension, and the preserved insulin sensitivity is the most frequently used criterion in identification of these individuals. Results of the research conducted in Institute for Mother and Child Health Care of Serbia 'Dr Vukan Cupic' indicate that a subgroup with low prevalence of metabolic complications of obesity is also present within population of obese children and adolescents in Serbia. A significant association of preserved insulin sensitivity with favorable metabolic phenotype is also supported by the results. Known data suggest the need for a different approach in the treatment of obesity in the subpopulation of the metabolically healthy obese. Due to differences in terms of complications and treatment, these individuals should also be regarded as a separate entity in further research.

Milenkovic T, Vukovic R, Radojicic B, Mitrovic K, Todorovic S, Zatezalo L. Thirty years of the newborn screening program in Central Serbia: the missed cases of congenital hypothyroidism. Turk J Pediatr 2019; 61: 319- 324. Newborn Screening (NS) program for congenital hypothyroidism (CH) has completely changed the natural history of this devastating disorder for the vast majority of children with CH. However, cases of missed CH do happen, and it is important to keep this possibility in mind during every day clinical practice. The objective of this study was to analyze the recognized cases of undiagnosed CH by the NS program in Central Serbia in order to evaluate the reasons for such omissions. Data regarding the recognized missed cases of CH between the years of 1983 and 2013 were collected and analyzed. During 30 years of the NS program for CH on the territory of Central Serbia, 1,547,122 newborns were screened, and during this period, 14 children with CH were missed by the NS. Five missed cases were children with athyreosis (35.8%), 8 had ectopic thyroid gland (57.1%) and one child had dyshormonogenesis (7.1%). The median age at diagnosis of CH in these missed cases was 1.12 years (range 0.08-13.5 years). In the group of children with missed diagnosis of CH, 71.4% were missed due to errors during sample collection, and 28.6% of patients were missed due to false negative screening results. Continuous education of neonatologists as well as nurses in neonatal units of maternity hospital are necessary to avoid errors in sample collection. It is of high importance to notice in a discharge list if a child is referred to the hospital before the sample is taken in a maternity hospital. On the other hand, the maternity hospital has to inform the screening laboratory about any child who was referred to another hospital if the blood samples for screening are not taken. Parents should be better informed that each child has to be included in the NS which is obligatory in Serbia. In addition, awareness amongst pediatricians in primary care should be raised regarding the possibility of missed cases of CH.

The increasing incidence of obesity among children and adolescents has become a problem in Serbia as in the rest of the world. Obesity is defined as a BMI of 97 or more percentile specific for sex and age, calculated as an individual's weight divided by the square of their height. Overweight is defined as a BMI greater than 90. percentile. The differentiation between simple exogenous obesity and morbid obesity is based mostly on clinical findings. The investigation of obese adolescent includes the recognition of related comorbidities and complications. Given its detrimental affects on public health and the costs of its management, prevention of obesity and its treatment in childhood and adolescence has gained significance. Dietary and exercise advice remains the mainstay of the medical management of obesity. In these respects, the prescription of minimally one hour of daily physical activity for obese children and adolescents and the maintenance of this regimen has become one of the two most important measures. Physical exercise facilitates weight loss by increasing energy expenditure and increasing basal metabolic rate through an increase in muscle mass. The second most important measure is dietary control. Unfortunately, lifestyle interventions alone rarely result in long-term weight loss and the majority of obese patients return to baseline weight within 3-5 years. In the midst of obesity-related health crisis, the case for safe and efficacious pharmacotherapies is clear. Unfortunately, drugs currently available for long-term weight management are limited in number and efficacy. At present, the most effective means of significant and sustained weight loss for obese patients is bariatric surgery. An effective treatment of obesity at early ages has a greater success rate as compared to interventions in adulthood.

Triple A syndrome is an autosomal recessive disorder characterized by alacrima, achalasia, ACTH-resistant adrenal insufficiency, autonomic dysfunction, and neurodegeneration. Mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN have been reported in these patients. Over the period 1977-2008 we evaluated ten subjects with the clinical diagnosis of triple A syndrome. Molecular analysis was performed in seven patients and revealed that all except one are compound heterozygotes for two mutations in the AAAS gene. Two novel mutations were detected: c.123+2T>C resulted in splice defect while c.1261_1262insG mutation resulted in a truncated protein (p.V421fs), which most probably is not functional. Genotype-phenotype correlation could not be established. In all our patients, except one sibling of previously diagnosed brother and sister, genetic analysis was performed when at least two symptoms were present, usually alacrima and achalasia. Based on our experience, we recommend that in case of the presence of alacrima and at least one more symptom of triple A syndrome, adrenal function testing and molecular analysis should be performed. In all children with mutation in AAAS gene, regular follow up of adrenal function is necessary to avoid adrenal crisis and start substitution therapy as soon as adrenal insufficiency is noted.

Introduction. Precocious puberty in girls is generally defined as appearance of secondary sexual characteristics before eight years of age. Menarche before the ninth birthday may serve as an additional criterion. Precocious puberty is divided in central precocious puberty and pseudoprecocious puberty. Central precocious puberty (GnRH dependent) occurs because of premature activation of hypothalamic-pituitarygonadal axis and activity of gonadotrophins. Pseudoprecocious puberty (GnRH independent) is caused by activity of sexual steroids that are not the result of gonadotrophin activity. Objective. Objective of our study was to examine the etiology, clinical and laboratory manifestations of isosexual pseudoprecocious puberty in girls. Method. In the period between 1995 and 2004, clinical and laboratory sings of 34 girls with precocious puberty were studied at the Endocrine Department of the Institute of Mother and Child Health Care of Serbia. Initial evaluations included height measurement, staging of puberty, bone age assessment and pelvic ultrasound. Important diagnostic sonographic parameters of precocious puberty were the volumes of ovaries and uterus as well as ovarian structure. The initial hormonal evaluation included measuring of plasma oestradiol, luteinizing hormone (LH) and follicle stimulating hormone (FSH). The luteinizing hormone releasing hormone (LHRH) stimulation test was used to evaluate LH and FSH responsiveness (60 ?g/m2 LHRH- Relefact LHRH?, Ferring). Blood samples were collected at 0, 20 and 60 minutes. Basal and GnRH stimulated LH and FSH were determined by immunoradiometric assay. Estradiol concentration was measured using the fluoroimmunometric assay. Results. Thirty-four girls aged 6 months to 9 years (mean age 4.5 years) with precocious puberty were studied during the period of 9 years. Eleven girls presented with breast development, six with vaginal bleeding and seventeen with signs of puberty. On the basis of clinical signs, bone age, estradiol levels and LHRH test, premature the larche was diagnosed in eleven patients (32.4%), premature menarche in six (17.6%) and central precocious puberty in ten girls (29.4%). Seven girls (20.6%) presented with pseudoprecocious puberty. Pelvic ultrasound examination revealed unilateral ovarian cysts in six patients and granulosa cell tumor in one. Elevated estrogen serum levels and failure of gonadotropin responses after gonadotropin releasing hormone were the classical findings in patients with isosexual pseudoprecocious puberty during the acute period of disease. In four patients, the cyst decreased spontaneously after several months, while in two patients, the cyst was removed by laparotomy. Surgical treatment was performed in a patient with granulosa cell tumor. Conclusion. Our work demonstrates that autonomous functional ovarian follicle cyst is the most often cause of isosexual pseudoprecocious puberty. Short period of observation is suggested because the cyst can resolve spontaneously. On the other hand, juvenile granulosa cell tumor, as highly malignant tumor, should be removed as soon as diagnosis is established.

To assess the prevalence of metabolic syndrome (MS) in obese children and adolescents in Serbia.The study group consisted of 254 subjects (148 female and 106 male), aged 4.6–18.9 years with diet-induced obesity (body mass index ≥95th percentile). Presence of MS using the International Diabetes Federation definition was assessed in all subjects, as well as oral glucose tolerance test and insulin resistance indices.Overall prevalence of MS in all subjects aged ≥10 years was 31.2%, namely, 28.7% in children aged 10 to High prevalence of MS emphasizes the need for prevention and treatment of childhood obesity.

Introduction. Differentiated thyroid carcinoma (DTC) is a rare childhood malignancy, as it represents 0.3-0.4% of pediatric malignancies. Papillary carcinoma is the most common type of pediatric DTC and it represents about 90% of all DTC patients. Although rare, DTC arising from dyshormonogenetic goiter is the most serious complication of congenital hypothyroidism. Case report. We presented the development of thyroid papillary carcinoma in a 15-year-old girl diagnosed with congenital dyshormonogenetic hypothyroidism at neonatal age. Considering the early initiation and proper dosage of hormonal substitution, normal levels of thyreotropin and thyroid hormones were achieved quickly and maintained through a follow-up period. The girl remained euthyroid and asymptomatic until 13.8 years of age, when she presented with a large multinodular goiter. The patient underwent total thyroidectomy. Pathological examination revealed intrathyroid microcarcinoma in the right lobe. Conclusion. Although differentiated thyroid carcinoma is a rare pediatric malignancy, it is of great importance to have a certain degree of clinical caution and provide a multidisciplinary approach during the follow-up of patients with dyshormonogenetic hypothyroidism.

Ostojic S, Vukovic R, Milenkovic T, Mitrovic K, Djuric M, Nikolic L. Alpha coma in an adolescent with diabetic ketoacidosis. Turk J Pediatr 2017; 59: 318-321. This is the first report of alpha coma (AC) caused by brain edema in a patient with diabetic ketoacidosis (DKA). A previously healthy 15-year-old girl was admitted to the intensive care unit due to altered state of consciousness during the course of treatment for DKA. Patient was in a coma, intubated and had tachycardia with poor peripheral perfusion. Results of laboratory analyses indicated severe DKA and computed tomography scan indicated diffuse brain edema. The EEG pattern showed uniform alpha activity. Treatment with intravenous fluids, insulin and mannitol was started. Patient`s state of consciousness gradually improved and on the third day she was extubated. On the fifth day, her neurologic status and EEG findings were completely normal with no residual neurological deficits. In conclusion, although AC is associated with a high fatality rate, favorable outcome can be achieved with prompt recognition and treatment of cerebral edema in pediatric patients with DKA.

An increase in the prevalence of pediatric type 2 diabetes mellitus (T2DM) has been reported by numerous studies in the United States during the past two decades. Available data from Europe are scarce, but also suggest the rising prevalence of this disease in overweight children. The aim of this study was to determine the prevalence of previously undiagnosed T2DM, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in a clinic cohort of otherwise healthy overweight and obese Caucasian children and adolescents living in Serbia. The study group consisted of 301 subjects (176 girls, 125 boys) aged 5.2-18.9 years, with body mass index >90th percentile. Oral glucose tolerance test was performed in all subjects. Previously undiagnosed T2DM was discovered in 0.3% (n=1) and impaired glucose regulation in 15.9% (n=48) of the subjects. Isolated IFG was detected in 4.3% (n=13), isolated IGT in 8.3% (n=25) and combined IFG and IGT in 3.3% (n=10) of the subjects. Disturbances of glucose metabolism were present in a substantial number of the subjects, which emphasizes the need for prevention and treatment of childhood obesity.