Browsing by Author "Novakovic, I. (6603235567)"

Unbiased genome-wide screens combined with imaging data on brain function may identify novel molecular pathways related to human cognition. Here we performed a dense genome-wide screen to identify episodic memory-related gene variants. A genomic locus encoding the brain-expressed beta-catenin-like protein 1 (CTNNBL1) was significantly (P=7 × 10 -8) associated with verbal memory performance in a cognitively healthy cohort from Switzerland (n=1073) and was replicated in a second cohort from Serbia (n=524; P=0.003). Gene expression studies showed CTNNBL1 genotype-dependent differences in beta-catenin-like protein 1 mRNA levels in the human cortex. Functional magnetic resonance imaging in 322 subjects detected CTNNBL1 genotype-dependent differences in memory-related brain activations. Converging evidence from independent experiments and different methodological approaches suggests a role for CTNNBL1 in human memory. © 2013 Macmillan Publishers Limited.

Unbiased genome-wide screens combined with imaging data on brain function may identify novel molecular pathways related to human cognition. Here we performed a dense genome-wide screen to identify episodic memory-related gene variants. A genomic locus encoding the brain-expressed beta-catenin-like protein 1 (CTNNBL1) was significantly (P=7 × 10 -8) associated with verbal memory performance in a cognitively healthy cohort from Switzerland (n=1073) and was replicated in a second cohort from Serbia (n=524; P=0.003). Gene expression studies showed CTNNBL1 genotype-dependent differences in beta-catenin-like protein 1 mRNA levels in the human cortex. Functional magnetic resonance imaging in 322 subjects detected CTNNBL1 genotype-dependent differences in memory-related brain activations. Converging evidence from independent experiments and different methodological approaches suggests a role for CTNNBL1 in human memory. © 2013 Macmillan Publishers Limited.

Recent advances in the development of high-throughput genotyping platforms allow for the unbiased identification of genes and genomic sequences related to heritable traits. In this study, we analyzed human short-term memory, which refers to the ability to remember information over a brief period of time and which has been found disturbed in many neuropsychiatric conditions, including schizophrenia and depression. We performed a genome-wide survey at 909 622 polymorphic loci and report six genetic variations significantly associated with human short-term memory performance after genome-wide correction for multiple comparisons. A polymorphism within SCN1A (encoding the α subunit of the type I voltage-gated sodium channel) was replicated in three independent populations of 1699 individuals. Functional magnetic resonance imaging during an n-back working memory task detected SCN1A allele-dependent activation differences in brain regions typically involved in working memory processes. These results suggest an important role for SCN1A in human short-term memory. © 2011 Macmillan Publishers Limited All rights reserved.

Recent advances in the development of high-throughput genotyping platforms allow for the unbiased identification of genes and genomic sequences related to heritable traits. In this study, we analyzed human short-term memory, which refers to the ability to remember information over a brief period of time and which has been found disturbed in many neuropsychiatric conditions, including schizophrenia and depression. We performed a genome-wide survey at 909 622 polymorphic loci and report six genetic variations significantly associated with human short-term memory performance after genome-wide correction for multiple comparisons. A polymorphism within SCN1A (encoding the α subunit of the type I voltage-gated sodium channel) was replicated in three independent populations of 1699 individuals. Functional magnetic resonance imaging during an n-back working memory task detected SCN1A allele-dependent activation differences in brain regions typically involved in working memory processes. These results suggest an important role for SCN1A in human short-term memory. © 2011 Macmillan Publishers Limited All rights reserved.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common heritable cause of stroke and vascular dementia in adults. We present a family from Serbia presenting with stroke and depression in the lack of vascular risk factors, with brain MRI indicating CADASIL. A novel NOTCH3 Gly89Cys mutation was located in exon 3. This report illustrates that in the setting of a positive family history with typical clinical and MRI features, even with an atypical form of pedigree, a high suspicion of CADASIL should lead to genetic testing. © 2013 Belgian Neurological Society.

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[No abstract available]

Aim. The aim of this study was to evaluate correlation and influence of recreational physical activity during 10 years of follow-up on four types of lipid fractions in school children of the YUSAD study. Methods. School children from Serbia were evaluated on three different occasions when they were 10, 15 and 19/20 years of age, respectively. Four types of lipid fractions, total cholesterol, triglycerides, HDL and LDL, were separately evaluated in physically active boys and girls. Results. We evaluated 1172 children when they were 10 years of age, 870 children when they were 15 and 1230 children when they were 19/20. All children were from the same population. Our results pointed out that there is no linear correlation between the two evaluated variables: physical activity and lipid fractions. However there is a very weak positive or negative correlation of coherence regarding recreational physical activity and the four types of evaluated lipid fractions. Conclusion. Since this period of growth is very specific for metabolic processes that can influence variations of evaluated parameters, such investigation can give us additional knowledge and further directions that could lead to better understanding the correlation of different risk factors on the atherosclerosis development.

Aim. The aim of this study was to evaluate correlation and influence of recreational physical activity during 10 years of follow-up on four types of lipid fractions in school children of the YUSAD study. Methods. School children from Serbia were evaluated on three different occasions when they were 10, 15 and 19/20 years of age, respectively. Four types of lipid fractions, total cholesterol, triglycerides, HDL and LDL, were separately evaluated in physically active boys and girls. Results. We evaluated 1172 children when they were 10 years of age, 870 children when they were 15 and 1230 children when they were 19/20. All children were from the same population. Our results pointed out that there is no linear correlation between the two evaluated variables: physical activity and lipid fractions. However there is a very weak positive or negative correlation of coherence regarding recreational physical activity and the four types of evaluated lipid fractions. Conclusion. Since this period of growth is very specific for metabolic processes that can influence variations of evaluated parameters, such investigation can give us additional knowledge and further directions that could lead to better understanding the correlation of different risk factors on the atherosclerosis development.

Background – Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults. There is a complete lack of studies that assessed quality of life (QoL) trajectory during time in DM1 cohorts. Aim – To analyze changes of QoL in patients with DM1 during a 5-year follow-up period and to assess responsiveness of the SF-36 questionnaire. Patients and Method – At the baseline, this study comprised 84 DM1 patients, of whom 62 were retested after the mean period of 64.2 ± 3.9 months. Severity of muscular weakness was assessed using the Muscular Impairment Rating Scale (MIRS). Patients completed Serbian version of the SF-36 questionnaire as a measure of health-related QoL. Results – After 5 years, MIRS score of our DM1 patients showed significant progression of 0.5 grade (P < 0.01). All mental subdomains, role physical, and total SF-36 scores significantly improved after 5 years (P < 0.01). Unexpectedly, worsening of muscular weakness from mild to severe was in association with improvement of QoL. Conclusion – QoL improved in our cohort of DM1 patients during a 5-year period despite the progression of the disease. SF-36 should be used with caution as a patient-reported outcome measure in DM1 clinical trials. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Background – Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults. There is a complete lack of studies that assessed quality of life (QoL) trajectory during time in DM1 cohorts. Aim – To analyze changes of QoL in patients with DM1 during a 5-year follow-up period and to assess responsiveness of the SF-36 questionnaire. Patients and Method – At the baseline, this study comprised 84 DM1 patients, of whom 62 were retested after the mean period of 64.2 ± 3.9 months. Severity of muscular weakness was assessed using the Muscular Impairment Rating Scale (MIRS). Patients completed Serbian version of the SF-36 questionnaire as a measure of health-related QoL. Results – After 5 years, MIRS score of our DM1 patients showed significant progression of 0.5 grade (P < 0.01). All mental subdomains, role physical, and total SF-36 scores significantly improved after 5 years (P < 0.01). Unexpectedly, worsening of muscular weakness from mild to severe was in association with improvement of QoL. Conclusion – QoL improved in our cohort of DM1 patients during a 5-year period despite the progression of the disease. SF-36 should be used with caution as a patient-reported outcome measure in DM1 clinical trials. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Mutations in the PARK2 (PRKN) gene are the most common cause of autosomal-recessive (AR) juvenile parkinsonism and young-onset Parkinson's disease (YOPD). >100 different variants have been reported, including point mutations, small indels and single or multiple exon copy number variations. Mutation screening of PARK2 was performed in 225 Serbian PD patients (143 males and 82 females) with disease onset before 50 years and/or positive family history with apparent AR inheritance. All coding regions and their flanking intronic sequences were amplified and directly sequenced. Whole exon multiplications or deletions were detected using Multiple Ligation Probe Amplification (MLPA) method. We identified 12 PD patients with PARK2 mutations (5.3%). Five patients (2.2%) had biallelic mutations and seven (3.1%) were single mutation carriers. Patients with compound heterozygous mutations had earlier onset of the disease compared to non-carriers (p = 0.005) or heterozygotes (p = 0.001). Other clinical features in mutation carriers were not different compared to non-carriers. In our cohort, sequence and dosage variants were equally represented in patients, inducing their first symptoms mainly before the age of 30. For efficient genetic testing strategy, patients with early, especially juvenile onset of PD were strong candidates for both dosage and sequence variants screening of PARK2 gene. © 2018 Elsevier B.V.

Mutations in the PARK2 (PRKN) gene are the most common cause of autosomal-recessive (AR) juvenile parkinsonism and young-onset Parkinson's disease (YOPD). >100 different variants have been reported, including point mutations, small indels and single or multiple exon copy number variations. Mutation screening of PARK2 was performed in 225 Serbian PD patients (143 males and 82 females) with disease onset before 50 years and/or positive family history with apparent AR inheritance. All coding regions and their flanking intronic sequences were amplified and directly sequenced. Whole exon multiplications or deletions were detected using Multiple Ligation Probe Amplification (MLPA) method. We identified 12 PD patients with PARK2 mutations (5.3%). Five patients (2.2%) had biallelic mutations and seven (3.1%) were single mutation carriers. Patients with compound heterozygous mutations had earlier onset of the disease compared to non-carriers (p = 0.005) or heterozygotes (p = 0.001). Other clinical features in mutation carriers were not different compared to non-carriers. In our cohort, sequence and dosage variants were equally represented in patients, inducing their first symptoms mainly before the age of 30. For efficient genetic testing strategy, patients with early, especially juvenile onset of PD were strong candidates for both dosage and sequence variants screening of PARK2 gene. © 2018 Elsevier B.V.

Objective: Elevated plasma total homocysteine (tHcy) is an independent risk factor for ischemic stroke and has been linked to cerebral small vessel disease (SVD), in particular. Controversy persists as to whether increased tHcy is associated with functional status and cognitive decline in these patients. Methods: Plasma tHcy, MTHFR polymorphism, vascular risk factors, functional and cognitive status and severity of lesions on MRI, assessed with the Age-Related White Matter Changes (ARWMC) visual grading scale, were analyzed in 95 patients with SVD and 41 healthy control subjects. Results: Plasma tHcy levels were higher in patients with SVD (14.4 ± 5.0 μmol/L) compared to healthy SVD-free controls (8.9 ± 3.9 μmol/L). In SVD patients, tHcy levels strongly correlated with cognitive status (age-adjusted risk 5.8, 95% CI 1.3-25.3, p = 0.015), functional status (age-adjusted risk 3.2, 95% CI 1.2-8.8, p = 0.022) and severity of MRI lesions (age-adjusted risk 1.2, 95% CI 1.1-1.4; p = 0.004). Only total ARWMC score was independently associated with increased tHcy levels (OR 1.2, 95%CI 1.1-1.4, p = 0.004). Independent predictors of WMC occurrence were tHcy levels (OR 1.2, 95%CI 1.1-1.3, p = 0.003) and mRS score (OR 2.2, 95%CI 1.2-4.1, p = 0.017). Conclusions: In patients with cerebral SVD there is a positive association of increased plasma tHcy levels with clinical status and severity of WMC. © 2011 Elsevier B.V. All rights reserved.

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy during childhood. Mutations in dystrophin (DMD) gene are also recognized as a cause of cognitive impairment. We aimed to determine the association between intelligence level and mutation location in DMD genes in Serbian patients with DMD. Forty-one male patients with DMD, aged 3 to 16 years, were recruited at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia. All patients had defined DMD gene deletions or duplications [multiplex ligation-dependent probe amplification (MLPA), polymerase chain reaction (PCR)] and cognitive status assessment (Wechsler Intelligence Scale for Children, Brunet-Lezine scale, Vineland-Doll scale). In 37 patients with an estimated full scale intelligence quotient (FSIQ), six (16.22%) had borderline intelligence (70

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy during childhood. Mutations in dystrophin (DMD) gene are also recognized as a cause of cognitive impairment. We aimed to determine the association between intelligence level and mutation location in DMD genes in Serbian patients with DMD. Forty-one male patients with DMD, aged 3 to 16 years, were recruited at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia. All patients had defined DMD gene deletions or duplications [multiplex ligation-dependent probe amplification (MLPA), polymerase chain reaction (PCR)] and cognitive status assessment (Wechsler Intelligence Scale for Children, Brunet-Lezine scale, Vineland-Doll scale). In 37 patients with an estimated full scale intelligence quotient (FSIQ), six (16.22%) had borderline intelligence (70

The aim of this study was to detect the loss of putative tumor suppressor genes (TSG) mapping on chromosome 11 in a series of 15 cervical carcinomas. Highly polymorphic microsatellite markers mapping on the selected regions on 11p (11p12 and 11p15.2), and 11q (11q13 and 11q23) were amplified by PCR and used to detect the loss of heterozygosity in our sample. All the tumors were squamous cell carcinomas with various degrees of differentiation. We found that 3 out of 15 cases showed LOH of at least one microsatellite locus on chromosome 11p. LOH on chromosome 11q occurred in 4 samples. All the tumors except one were histologic grade 2, but had heterogeneous clinical stages. The overall incidence of LOH on 11p and 11q in our sample was 18,5% and 29%, respectively. These results might suggest the presence of new tumor suppressor genes (except the well-known WT1) within these chromosomal regions as well as their involvement in cervical carcinogenesis.

The aim of this study was to detect the loss of putative tumor suppressor genes (TSG) mapping on chromosome 11 in a series of 15 cervical carcinomas. Highly polymorphic microsatellite markers mapping on the selected regions on 11p (11p12 and 11p15.2), and 11q (11q13 and 11q23) were amplified by PCR and used to detect the loss of heterozygosity in our sample. All the tumors were squamous cell carcinomas with various degrees of differentiation. We found that 3 out of 15 cases showed LOH of at least one microsatellite locus on chromosome 11p. LOH on chromosome 11q occurred in 4 samples. All the tumors except one were histologic grade 2, but had heterogeneous clinical stages. The overall incidence of LOH on 11p and 11q in our sample was 18,5% and 29%, respectively. These results might suggest the presence of new tumor suppressor genes (except the well-known WT1) within these chromosomal regions as well as their involvement in cervical carcinogenesis.

The aim of this study was to detect frequency of microdeletions of Y chromosome in idiopathic cases of male infertility in Serbian population. Patients were subjected to detailed clinical, endocrinological and cytogenetic examinations. Ninety patients with normal cytogenetic findings with azoospermia and severe oligozoospermia were included in the study. In these patients microdeletion analysis was performed by multiplex polymerase chain reaction (PCR) method on DNA extracted from peripheral blood. In each case 6 markers in azoospermia factor (AZF) regions were tested: sY84, sY86 (AZFa); sY127, sY134 (AZFb); sY254, sY255 (AZFc). Deletions on Y chromosome were detected in 14 of 90 cases (15.6%), 9 with azoospermia and 5 with severe oligozoospermia. Of total number of 17 deletions, 11 (64.7%) were detected in AZFc region, 3 (17.6%) in AZFa region and 3 (17.6%) in AZFb region. Microdeletions in AZF region of Y chromosome, especially AZFc microdeletions, represent common genetic cause of idiopathic azoospermia and severe oligozoospremia in Serbian infertile men. Therefore, testing for Y chromosome microdeletions should be considered as an important element in diagnosis and genetic counseling of infertile men in Serbia and decisions regarding the assisted reproduction should be made based on the presence and type of AZF microdeletions.

The primary myelodysplastic syndrome (MDS) is a heterogeneous group of disorders characterized by a failure of the hematopoietic progenitors to differentiate normally, resulting in ineffective and dysplastic hematopoiesis of one or more cell lines. MDS is considered to be preleukemic state and in this context, it provides an opportunity to study molecular mechanisms that precede the development of leukemia. Molecular lesions underlying the evolution of MDS are largely unknown. Mutations of RAS genes have been found in variety of human hematologic malignancies including 5% to 30% of patients with MDS. The ras family of genes encodes 21-Kd guanosine triphosphate (GTP) - binding proteins that play an important role in growth and differentiation signal transduction. Usually, the mutations occur in codon 12, 13 and 61 of the exon I. These three positions are related to the domain of GTP-ase activity and if one of these suffer from mutation, activity of GTP-ase will be affected. The frequency of K-RAS point mutation was studied in 20 pediatric patients with MDs. Archival bone-marrow samples were screened by DNA amplification followed by single-strand conformation polymorphism (SSCP) at codon 12/13 and 61 of K-RAS exon I. No mutations of K-RAS gene were observed in our study suggesting that frequency of K-RAS mutation in childhood primary MDS may be lower than that for adults and that its role in leukemogenesis in primary and secondary MDS is different.