Publications (13)41.09 Total impact
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Article: Hashimoto Thyroiditis in Childhood – Review of the Epidemiology, Genetic Susceptibility and Clinical Aspects of the Disease
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ABSTRACT: Chronic autoimmune thyroiditis or Hashimoto’s thyroiditis (HT) is the most common cause of thyroid diseases in children and adolescents. It is also the most common cause of acquired hypothyroidism with or without goiter. The incidence of autoimmune thyroiditis has increased dramatically over the past few decades, affecting up to 5% of the general population in iodine sufficient areas. HT is caused by the complex interplay of genetic, environmental, and endogenous factors. Significant progress has been made in identifying and characterizing the genes involved in pathogenesis of the disease. The aim of this review is to analyze current opinions and options regarding the etiology, genetic contribution to the pathogenesis, evaluation, diagnosis, treatment, and prognosis of the HT in children.Macedonian Journal of Medical Sciences 10/2012; 2012:5(3):336-345. -
Article: Metabolic outcomes in young children with type 1 diabetes differ between treatment centers: the Hvidoere Study in Young Children 2009.
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ABSTRACT: OBJECTIVE: To investigate whether center differences in glycemic control are present in prepubertal children <11 yr with type 1 diabetes mellitus. RESEARCH DESIGN AND METHODS: This cross-sectional study involved 18 pediatric centers worldwide. All children, <11 y with a diabetes duration ≥12 months were invited to participate. Case Record Forms included information on clinical characteristics, insulin regimens, diabetic ketoacidosis (DKA), severe hypoglycemia, language difficulties, and comorbidities. Hemoglobin A1c (HbA1c) was measured centrally by liquid chromatography (DCCT aligned, range: 4.4-6.3%; IFFC: 25-45 mmol/mol). RESULTS: A total of 1133 children participated (mean age: 8.0 ± 2.1 y; females: 47.5%, mean diabetes duration: 3.8 ± 2.1 y). HbA1c (overall mean: 8.0 ± 1.0%; range: 7.3-8.9%) and severe hypoglycemia frequency (mean 21.7 events per 100 patient-years), but not DKA, differed significantly between centers (p < 0.001 resp. p = 0.179). Language difficulties showed a negative relationship with HbA1c (8.3 ± 1.2% vs. 8.0 ± 1.0%; p = 0.036). Frequency of blood glucose monitoring demonstrated a significant but weak association with HbA1c (r = -0.17; p < 0.0001). Although significant different HbA1c levels were obtained with diverse insulin regimens (range: 7.3-8.5%; p < 0.001), center differences remained after adjusting for insulin regimen (p < 0.001). Differences between insulin regimens were no longer significant after adjusting for center effect (p = 0.199). CONCLUSIONS: Center differences in metabolic outcomes are present in children <11 yr, irrespective of diabetes duration, age, or gender. The incidence of severe hypoglycemia is lower than in adolescents despite achieving better glycemic control. Insulin regimens show a significant relationship with HbA1c but do not explain center differences. Each center's effectiveness in using specific treatment strategies remains the key factor for outcome.Pediatric Diabetes 09/2012; · 2.16 Impact Factor -
Article: Unique concurrent appearance of two rare conditions in a young girl: central precocious puberty due to hypothalamic hamartoma and uncommon type of diabetes.
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ABSTRACT: Hypothalamic hamartomas (HH) are rare congenital nonneoplastic lesions of the tuber cinereum, which usually present as precocious puberty of central origin in young girls and respond well to treatment with long acting gonadotropin releasing hormone (GnRH) analogs. No association of this condition with diabetes mellitus of any form has been reported so far. On the other hand, diabetes mellitus in children and adolescents, when it is not autoimmune type 1 diabetes, is difficult to classify. We present a girl with early onset of central precocious puberty at the age of 8 months, due to hypothalamic hamartoma. Treatment with depot of a GnRH analog for a period of 9 years and 8 months was successful, and her puberty continued 6 months after the discontinuation of triptorelin. At the age of 9 years 6 months, the girl presented with diabetes. She was negative for islet, GAD and IA2 antibodies and her insulinemia and C-peptide remained within normal limits during the 2 years of follow-up. Her metabolic control is excellent with a combination of metformin and a low-dose of mixed insulin. To our knowledge, this is the first description of the simultaneous appearance of these two endocrinological conditions.Journal of pediatric endocrinology & metabolism: JPEM 01/2011; 24(9-10):815-8. · 0.88 Impact Factor -
Article: Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies.
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ABSTRACT: To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA), glutamic acid decarboxylase antibodies (GADA) and insulinoma-associated antigen-2 antibodies (IA-2A)]. Furthermore the study aimed at determining whether mutations in KCNJ11, ABCC8, HNF1A, HNF4A or INS are common in AAB negative diabetes. In 261 newly diagnosed children with type 1 diabetes, we measured residual β-cell function, ICA, GADA, and IA-2A at 1, 6 and 12 months after diagnosis. The genes KCNJ11, ABCC8, HNF1A, HNF4A and INS were sequenced in subjects AAB negative at diagnosis. We expressed recombinant K-ATP channels in Xenopus oocytes to analyse the functional effects of an ABCC8 mutation. Twenty-four patients (9.1%) tested AAB negative after one month. Patients, who were AAB-negative throughout the 12-month period, had higher residual β-cell function (P = 0.002), lower blood glucose (P = 0.004), received less insulin (P = 0.05) and had lower HbA1c (P = 0.02) 12 months after diagnosis. One patient had a heterozygous mutation leading to the substitution of arginine at residue 1530 of SUR1 (ABCC8) by cysteine. Functional analyses of recombinant K-ATP channels showed that R1530C markedly reduced the sensitivity of the K-ATP channel to inhibition by MgATP. Morover, the channel was highly sensitive to sulphonylureas. However, there was no effect of sulfonylurea treatment after four weeks on 1.0-1.2 mg/kg/24 h glibenclamide. GAD, IA-2A, and ICA negative children with new onset type 1 diabetes have slower disease progression as assessed by residual beta-cell function and improved glycemic control 12 months after diagnosis. One out of 24 had a mutation in ABCC8, suggesting that screening of ABCC8 should be considered in patients with AAB negative type 1 diabetes.BMC Endocrine Disorders 01/2010; 10:16. · 2.16 Impact Factor -
Article: HLA-DR-DQ haplotypes and type 1 diabetes in Macedonia.
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ABSTRACT: The lowest incidence of childhood type 1 diabetes in Europe has been reported from the Republic of Macedonia. To assess the possible genetic contribution we analyzed the distribution of HLA-DR-DQ haplotypes among 163 diabetic children and 239 healthy controls. Similar disease associations were found as in other Caucasian populations. HLA-(DR3)-DQA1*05-DQB1*02 was the most common disease associated haplotype, but several DRB1*04-DQB1*0302 haplotypes were also found increased among patients. DRB1*0402 was the most common DR4 allele among them. The high frequency of protective (DR11/12)-DQA1*05-DQB1*0301 and (DR14)-DQB1*0503 haplotypes as well as of neutral (DR1/10)-DQB1*0501 and (DR16)-DQB1*0502 haplotypes were characteristic for the background population. Although a relatively low frequency of predisposing and a high frequency of protective haplotypes was detected, the haplotype frequency distribution did not markedly differ from that reported from other Eastern Mediterranean populations and these differences cannot be the sole explanation for the low disease incidence in Macedonia.Human immunology 04/2009; 70(6):461-3. · 2.55 Impact Factor -
Article: Evaluation of a type 1 diabetes serum cohort by SELDI-TOF MS protein profiling.
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ABSTRACT: Proteomics analysis of serum from patients with type 1 diabetes (T1D) may lead to novel biomarkers for prediction of disease and for patient monitoring. However, the serum proteome is highly sensitive to sample processing and before proteomics biomarker research serum cohorts should preferably be examined for potential bias between sample groups. SELDI-TOF MS protein profiling was used for preliminary evaluation of a biological-bank with 766 serum samples from 270 patients with T1D, collected at 18 different paediatric centers representing 15 countries in Europe and Japan over 2 years (2000-2002). Samples collected 1 (n = 270), 6 (n = 248), and 12 (n = 248) months after T1D diagnosis were grouped across centers and compared. The serum protein profiles varied with collection site and day of analysis; however, markers of sample processing were not systematically different between samples collected at different times after diagnosis. Three members of the apolipoprotein family increased with time in patient serum collected 1, 6, and 12 months after diagnosis (ANOVA, p<0.001). These results support the use of this serum cohort for further proteomic studies and illustrate the potential of high-throughput MALDI/SELDI-TOF MS protein profiling for evaluation of serum cohorts before proteomics biomarker research.Proteomics. Clinical applications 03/2009; 3(3):383-93. · 1.97 Impact Factor -
Article: Variation within the PPARG gene is associated with residual beta-cell function and glycemic control in children and adolescents during the first year of clinical type 1 diabetes.
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ABSTRACT: Conflicting evidence exists as to whether the Pro12Ala single nucleotide polymorphism of the type 2 diabetes susceptibility gene peroxisome proliferator-activated receptor gamma (PPARG) also confers risk for type 1 diabetes (T1D). The objective of this study was to investigate the PPARG gene in relation to residual beta-cell function and glycemic control in newly diagnosed T1D. Prospective, non-interventional, 12-month follow-up study, conducted in 18 centers in 15 countries. Two hundred and fifty-seven children and adolescents (aged <16 yr) with newly diagnosed T1D. Beta-cell function was determined as 90-min meal-stimulated C-peptide (Boost test) 1, 6, and 12 months after diagnosis. Hemoglobin A1c (HbA1c) and daily insulin dose (IU/kg/d) were recorded at 1, 3, 6, 9, and 12 months after diagnosis. Haplotypes within PPARG were estimated by SNPHap program. Statistical analyses were performed in a repeated measurements model. Five haplotypes within PPARG were generated (h1, 68.4%; h2, 16.3%; h3, 8.3%; h4, 3.5%; and hx, 3.5%). Compared with the most frequent h1 haplotype, the haplotypes h3 and h4 of the PPARG associated with residual beta-cell function during the first year of clinical disease: h3 with a 27% lower C-peptide (p = 0.02) and h4 with a 39% lower C-peptide (p = 0.01). Haplotype h4 also associated with a 0.86% (absolute) higher HbA1c, after adjustment for the insulin dose (p = 0.02). Variation in the PPARG locus may influence disease progression during the first year after the presentation of T1D.Pediatric Diabetes 05/2008; 9(4 Pt 1):297-302. · 2.16 Impact Factor -
Article: Association of IL-1ra and adiponectin with C-peptide and remission in patients with type 1 diabetes.
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ABSTRACT: We investigated the association of anti-inflammatory cytokine interleukin (IL)-1 receptor antagonist (IL-1ra), adiponectin, proinflammatory cytokines IL-1 beta, IL-6, and CCL2, and tumor necrosis factor-alpha with beta-cell function, metabolic status, and clinical remission in patients with recent-onset type 1 diabetes. Serum was obtained from 256 newly diagnosed patients (122 males and 134 females, median age 9.6 years). Stimulated C-peptide, blood glucose, and A1C were determined in addition to circulating concentration of cytokines at 1, 6, and 12 months after diagnosis. Analyses were adjusted for sex, age, and BMI percentile. Anti-inflammatory IL-1ra was positively associated with C-peptide after 6 (P = 0.0009) and 12 (P = 0.009) months. The beneficial association of IL-1ra on beta-cell function was complemented by the negative association of IL-1 beta with C-peptide after 1 month (P = 0.009). In contrast, anti-inflammatory adiponectin was elevated in patients with poor metabolic control after 6 and 12 months (P < 0.05) and positively correlated with A1C after 1 month (P = 0.0004). Proinflammatory IL-6 was elevated in patients with good metabolic control after 1 month (P = 0.009) and showed a positive association with blood glucose disposal after 12 months (P = 0.047). IL-1ra is associated with preserved beta-cell capacity in type 1 diabetes. This novel finding indicates that administration of IL-1ra, successfully improving beta-cell function in type 2 diabetes, may also be a new therapeutic approach in type 1 diabetes. The relation of adiponectin and IL-6 with remission and metabolic status transfers observations from in vitro and animal models into the human situation in vivo.Diabetes 04/2008; 57(4):929-37. · 8.29 Impact Factor -
Article: Continuing stability of center differences in pediatric diabetes care: do advances in diabetes treatment improve outcome? The Hvidoere Study Group on Childhood Diabetes.
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ABSTRACT: To reevaluate the persistence and stability of previously observed differences between pediatric diabetes centers and to investigate the influence of demography, language communication problems, and changes in insulin regimens on metabolic outcome, hypoglycemia, and ketoacidosis. This was an observational cross-sectional international study in 21 centers, with clinical data obtained from all participants and A1C levels assayed in one central laboratory. All individuals with diabetes aged 11-18 years (49.4% female), with duration of diabetes of at least 1 year, were invited to participate. Fourteen of the centers participated in previous Hvidoere Studies, allowing direct comparison of glycemic control across centers between 1998 and 2005. Mean A1C was 8.2 +/- 1.4%, with substantial variation between centers (mean A1C range 7.4-9.2%; P < 0.001). There were no significant differences between centers in rates of severe hypoglycemia or diabetic ketoacidosis. Language difficulties had a significant negative impact on metabolic outcome (A1C 8.5 +/- 2.0% vs. 8.2 +/- 1.4% for those with language difficulties vs. those without, respectively; P < 0.05). After adjustement for significant confounders of age, sex, duration of diabetes, insulin regimen, insulin dose, BMI, and language difficulties, the center differences persisted, and the effect size for center was not reduced. Relative center ranking since 1998 has remained stable, with no significant change in A1C. Despite many changes in diabetes management, major differences in metabolic outcome between 21 international pediatric diabetes centers persist. Different application between centers in the implementation of insulin treatment appears to be of more importance and needs further exploration.Diabetes care 10/2007; 30(9):2245-50. · 8.09 Impact Factor -
Article: Meal-stimulated glucagon release is associated with postprandial blood glucose level and does not interfere with glycemic control in children and adolescents with new-onset type 1 diabetes.
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ABSTRACT: The role of glucagon in hyperglycemia in type 1 diabetes is unresolved, and in vitro studies suggest that increasing blood glucose might stimulate glucagon secretion. Our objective was to investigate the relationship between postprandial glucose and glucagon level during the first 12 months after diagnosis of childhood type 1 diabetes. We conducted a prospective, noninterventional, 12-month follow-up study conducted in 22 centers in 18 countries. Patients included 257 children and adolescents less than 16 yr old with newly diagnosed type 1 diabetes; 204 completed the 12-month follow-up. The study was conducted at pediatric outpatient clinics. We assessed residual beta-cell function (C-peptide), glycosylated hemoglobin (HbA(1c)), blood glucose, glucagon, and glucagon-like peptide-1 (GLP-1) release in response to a 90-min meal stimulation (Boost) at 1, 6, and 12 months after diagnosis. Compound symmetric repeated-measurements models including all three visits showed that postprandial glucagon increased by 17% during follow-up (P = 0.001). Glucagon levels were highly associated with postprandial blood glucose levels because a 10 mmol/liter increase in blood glucose corresponded to a 20% increase in glucagon release (P = 0.0003). Glucagon levels were also associated with GLP-1 release because a 10% increase in GLP-1 corresponded to a 2% increase in glucagon release (P = 0.0003). Glucagon levels were not associated (coefficient -0.21, P = 0.07) with HbA(1c), adjusted for insulin dose. Immunohistochemical staining confirmed the presence of Kir6.2/SUR1 in human alpha-cells. Our study supports the recent in vitro data showing a stimulation of glucagon secretion by high glucose levels. Postprandial glucagon levels were not associated with HbA(1c), adjusted for insulin dose, during the first year after onset of childhood type 1 diabetes.Journal of Clinical Endocrinology & Metabolism 09/2007; 92(8):2910-6. · 6.50 Impact Factor -
Article: Parent and health professional perspectives in the management of adolescents with diabetes: development of assessment instruments for international studies.
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ABSTRACT: Assessment of quality of life (QOL) in adolescents with diabetes requires patient, parent and health professional input. Psychometrically robust instruments to assess parent and professional perspectives are required. Questionnaires concerning adolescent QOL were developed for completion by parents and health professionals. In an international study assessing QOL in 2,101 adolescents with diabetes (median age 14 years, range 10-18; from 17 countries including Europe, Japan and North America), parents and health professionals completed their respective questionnaires between March and August 1998. Feasibility and acceptability of the new questionnaires were indicated by high questionnaire completion rates (adolescents 92%; parents 89%; health professionals 94%). Internal consistency was confirmed (Cronbach's alpha coefficients 0.80 parent; 0.86 health professional). Correlations of Diabetes Quality of Life Questionnaire for Youths (DQOLY) scores with parent and health professional global QOL ratings were generally low (r ranging from 0.12 to 0.36). Parent-rated burden decreased incrementally across adolescence, particularly for girls. Professional-rated burden followed a similar profile but only after age 15 years. Until then, burden was rated as uniformly high. Clinically relevant discrepancies in parent and professional burden scores were noted for one-parent families and families where adolescents had been referred for psychological help. In both cases, health professionals but not one-parent families perceived these as high burden situations. The clinical significance of this relates to the significantly poorer metabolic control recorded for adolescents in both situations. Parent and health professional questionnaires were found to have adequate internal consistency, and convergent and discriminant validity in relation to key clinical and QOL outcomes. The questionnaires are brief, easy to administer and score. They may also enable comparisons across countries and languages to facilitate development of international health outcome parameters. The inclusion of the parent and health professional perspectives completes a comprehensive assessment of adolescent QOL relevant to diabetes.Quality of Life Research 09/2006; 15(6):1033-42. · 2.30 Impact Factor -
Article: Biphasic insulin aspart vs. human insulin in adolescents with type 1 diabetes on multiple daily insulin injections.
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ABSTRACT: The aim was to compare clinical efficacy and safety of two treatment regimens: biphasic insulin aspart (BIAsp) injected at all three meals plus neutral protamine Hagedorn (NPH) insulin at bedtime vs. a human insulin regimen, premixed human insulin at breakfast and soluble insulin at lunch and dinner and NPH at bedtime. A total of 167 adolescents (80 males and 87 females) with type 1 diabetes was included in the trial (multinational, randomized, open-label, and parallel group). Each subject received either of two treatment regimens for a 4-month period. BIAsp was injected immediately before main meals, human insulin products 30 min before meals, and NPH at night. Glycemic control was monitored by eight-point evaluations (after 6 and 16 wks) and hemoglobin A1c (HbA1c) (after 2, 6, and 16 wks). Safety evaluations included adverse events and incidence of hypoglycemic episodes. HbA1c (mean+/- SD) after 4 months on BIAsp (9.39+/- 0.14) was not significantly different from that with human insulin (9.30+/- 0.15). The average postprandial glucose increment in the BIAsp group was about half the increment in the human insulin group; the difference not statistically significant. The body mass index (BMI) increased in both groups, but significantly (p=0.005) less in the BIAsp group. However, in males on BIAsp, the BMI decreased compared with those on human insulin (p=0.007). No significant group differences were found for the rate of hypoglycemic episodes. We concluded that the BIAsp regimen was associated with similar glycemic control and similar incidence of hypoglycemic episodes as human insulin. However, the BIAsp regimen caused a significantly smaller increase in BMI, particularly in males, compared with the human insulin regimen.Pediatric Diabetes 03/2006; 7(1):4-10. · 2.16 Impact Factor -
Article: Insulin injection regimens and metabolic control in an international survey of adolescents with type 1 diabetes over 3 years: results from the Hvidore study group.
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ABSTRACT: The optimal insulin regimen for paediatric patients with type 1 diabetes remains controversial. Therefore this multicentre study was performed in adolescents over a 3-year period to assess metabolic control, severe hypoglycaemia, and weight gain in relation to insulin injection regimens. Out of 2873 children and adolescents in an international survey in 1995, 872 adolescents (433 boys, 439 girls, mean age in 1995 11.3+/-2.2 years) were restudied in 1998, relating insulin regimens to HbA(1c) measured in a central laboratory. In addition, the daily dose of insulin, changes in body mass index (BMI), and events of severe hypoglycaemia were evaluated. Over 3 years, the use of multiple injection regimens increased from 42% to 71%: 251 patients remained on twice daily insulin, 365 remained on multiple injections and 256 shifted from twice daily insulin to multiple injections. In all three subgroups an increase in insulin dose, a deterioration of metabolic control, and an increase in BMI were observed. Metabolic control deteriorated less than expected over 3 years during adolescence (HbA(1c) 1995: 8.7+/-1.6%; 1998 observed: 8.9+/-1.6%, HbA(1c) expected for 1998: 9.0%). BMI increased more than expected, the increase was greatest in patients switching from twice daily to multiple injections, and higher in females compared to males. CONCLUSION: in this international study, metabolic control was unsatisfactory in many adolescents with type 1 diabetes irrespective of the insulin regimen. No improvement in metabolic control was observed in this cross-sectional survey, over 3 years in any of the subgroups. Even the group switching from twice to multiple injections did not improve blood glucose control and the increase in body mass index was most pronounced in this group. Conclusive evidence, however, should be based on prospectively planned, randomised therapeutic trials in paediatric patients.European Journal of Pediatrics 02/2003; 162(1):22-9. · 1.88 Impact Factor
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Institutions
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2012
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Ss. Cyril and Methodius University
- Faculty of Medicine
Skopje, Opstina Karpos, Macedonia
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2008
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University American College Skopje
Skopje, Opstina Karpos, Macedonia
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