Browsing by Author "Jankovic, Milena"

Pediatric stroke (PS) is an injury caused by the occlusion or rupture of a blood vessel in the central nervous system (CNS) of children, before or after birth. Hemiparesis is the most common motoric deficit associated with PS in children. Therefore, it is important to emphasize that PS is a significant challenge for rehabilitation, especially since the consequences may also appear during the child's growth and development, reducing functional capacity. The plasticity of the child's CNS is an important predecessor of recovery, but disruption of the neural network, specific to an immature brain, can have harmful and potentially devastating consequences. In this review, we summarize the complexity of the consequences associated with PS and the possibilities and role of modern rehabilitation. An analysis of the current literature reveals that Constraint-Induced Movement Therapy, forced-use therapy, repetitive transcranial magnetic stimulation, functional electrical stimulation and robot-assisted therapy have demonstrated at least partial improvements in motor domains related to hemiparesis or hemiplegia caused by PS, but they are supported with different levels of evidence. Due to the lack of randomized controlled studies, the optimal rehabilitation treatment is still debatable, and therefore, most recommendations are primarily based on expert consensuses, opinions and an insufficient level of evidence.

Background: Recognized as one of the most serious musculoskeletal deformities, occurring in 1-2 per 1000 newborns, 80% of clubfeet are idiopathic while 20% present with associated malformations. The etiopathogenesis of clubfoot is described as multifactorial, including both genetic and environmental risk factors. The aim of this study was to analyze possible genetic causes of isolated and syndromic clubfoot in Serbian children, as well as to correlate clinical and genetic characteristics that would provide insight into clubfoot etiopathogenesis and possibly contribute to global knowledge about clinical features of different genetically defined disorders. Methods: We evaluated 50 randomly selected, eligible children with clubfoot aged 3 to 16 years that were initially hospitalized and treated at University Children's Hospital between November 2006 and November 2022. The tested parameters were gender, age, dominant foot, affected foot, degree of deformity, treatment, neuromuscular disorders, positive family history, and maternal smoking. According to the presence of defined genetic mutation/s by whole exome sequencing (WES), patients were separated into two groups: positive (with genetic mutation/s) and negative (without genetic mutation/s). Results: Seven patients were found to be positive, i.e., with genetic mutation/s. A statistically significant difference between categorical variables was found for families with a history of clubfoot, where more than half (57.14%) of patients with confirmed genetic mutation/s also had a family history of genetic mutation/s (p = 0.023). Conclusions: The results from this study further expand the genetic epidemiology of clubfoot. This study contributes to the establishment of genetic diagnostic strategies in pediatric patients with this condition, which can lead to more efficient genetic diagnosis.

Amyotrophic Lateral Sclerosis (ALS), neurodegenerative motor neuron disorder is characterized as multisystem disease with important contribution of genetic factors. The etiopahogenesis of ALS is not fully elucidate, but the dominant theory at present relates to RNA processing, as well as protein aggregation and miss-folding, oxidative stress, glutamate excitotoxicity, inflammation and epigenetic dysregulation. Additionally, as mitochondria plays a leading role in cellular homeostasis maintenance, a rising amount of evidence indicates mitochondrial dysfunction as a substantial contributor to disease onset and progression. The aim of this review is to summarize most relevant findings that link genetic factors in ALS pathogenesis with different mechanisms with mitochondrial involvement (respiratory chain, OXPHOS control, calcium buffering, axonal transport, inflammation, mitophagy, etc.). We highlight the importance of a widening perspective for better understanding overlapping pathophysiological pathways in ALS and neurodegeneration in general. Finally, current and potentially novel therapies, especially gene specific therapies, targeting mitochondrial dysfunction are discussed briefly.

Migraine is a prevalent neurological disorder that significantly impacts the quality of life for affected individuals. The pathogenesis behind migraines is not yet fully understood, but hormonal changes, especially fluctuations in, estrogen and progesterone levels, have a significant role in the susceptibility of women to migraines. Pregnancy introduces a unique set of challenges for women who experience migraines, as they must navigate the complexities of managing their condition while safeguarding the health of both them and their unborn child. Pharmacological options for treating migraines during pregnancy are limited, and, therefore, there is a growing interest in exploring alternative approaches to migraine symptom relief and management. Physical activity during pregnancy provides a range of benefits, and it has gained attention as a potentially valuable tool for alleviating migraine symptoms in pregnant patients. This review explores the intricate relationship between migraines and pregnancy, emphasizing how physical activity and other alternative approaches may influence the frequency, severity, and overall experience of migraines during pregnancy. Through collaboration with healthcare providers and the adoption of personalized management strategies, women can strike a balance that supports both their own well-being and the healthy development of their unborn child. By examining existing research and emerging insights, we aim to provide a comprehensive understanding of the potential benefits and considerations of incorporating physical activity and other treatment options into migraine management strategies for pregnant women. Further research is needed to elucidate the specific mechanisms linking migraines, pregnancy, and physical activity, enabling the development of more targeted interventions and guidelines.

Diabetic neuropathy (DN), the most common chronic and progressive complication of diabetes mellitus (DM), strongly affects patients' quality of life. DN could be present as peripheral, autonomous or, clinically also relevant, uremic neuropathy. The etiopathogenesis of DN is multifactorial, and genetic components play a role both in its occurrence and clinical course. A number of gene polymorphisms in candidate genes have been assessed as susceptibility factors for DN, and most of them are linked to mechanisms such as reactive oxygen species production, neurovascular impairments and modified protein glycosylation, as well as immunomodulation and inflammation. Different epigenomic mechanisms such as DNA methylation, histone modifications and non-coding RNA action have been studied in DN, which also underline the importance of "metabolic memory" in DN appearance and progression. In this review, we summarize most of the relevant data in the field of genetics and epigenomics of DN, hoping they will become significant for diagnosis, therapy and prevention of DN.

Genetic determinants play important role in the complex processes of inflammation and immune response in stroke and could be studied in different ways. Inflammation and immunomodulation are associated with repair processes in ischemic stroke, and together with the concept of preconditioning are promising modes of stroke treatment. One of the important aspects to be considered in the recovery of patients after the stroke is a genetic predisposition, which has been studied extensively. Polymorphisms in a number of , such as , , , , and could be associated with stroke outcome and recovery. Recent GWAS studies pointed to the variant in and as new genetic markers of long term outcome. Epigenetic regulation of immune response in stroke is also important, with mechanisms of histone modifications, DNA methylation, and activity of non-coding RNAs. These complex processes are changing from acute phase over the repair to establishing homeostasis or to provoke exaggerated reaction and death. Pharmacogenetics and pharmacogenomics of stroke cures might also be evaluated in the context of immuno-inflammation and brain plasticity. Potential novel genetic treatment modalities are challenged but still in the early phase of the investigation.

Background and objectives: Maternal obesity influences pregnancy course in several different manners, and imbalanced nutrition during pregnancy may lead to various adverse pregnancy outcomes. Additionally, nutritional status during pregnancy may have implications for the health of the offspring and may possibly influence early motor development in children. The aim of this study was to assess the impact of excessive gestational weight gain (EGWG) on pregnancy outcomes and infant's motor development within the first twelve months of life. Materials and methods: The study included 200 participants divided in two groups based on their gestational weight gain. Maternal, perinatal, and neonatal factors were analyzed, and early motor development was assessed using the Alberta infant motor scale (AIMS). Results: EGWG was significantly associated with: pre-pregnancy BMI (p < 0.001), family history for cardiovascular diseases (p = 0.013) and diabetes mellitus (p = 0.045), hypertensive disorder of pregnancy (p = 0.003), gestational diabetes mellitus (p < 0.001), gestational anemia (p = 0.001), vitamin D deficiency (p = 0.001), metformin use (p = 0.045), pre-labor premature rupture of membranes (p = 0.031), amniotic fluid index (p = 0.047), and APGAR score in the first five min of life (p = 0.007). Scored by AIMS, EGWG was significantly associated with parameters of early motor development at the age of three AIMS total (p < 0.001), six AIMS total (p < 0.001), nine AIMS total (p < 0.001), and twelve AIMS total (p < 0.001) months of infant's life. Conclusions: The link between EGWG and adverse neurodevelopmental outcomes in offspring is a complex and multifaceted issue. Our results imply significant alterations in early motor development in the group of infants born from mothers who gained weight excessively during pregnancy. Further studies are needed to unravel the intricacies of this relationship and inform strategies for preventive interventions and supportive care during pregnancy and infancy.

During the last three years, since the emergence of the COVID-19 pandemic, a significant number of scientific publications have focused on resolving susceptibility to the infection, as well as the course of the disease and potential long-term complications. COVID-19 is widely considered as a multisystem disease and a variety of socioeconomic, medical, and genetic/epigenetic factors may contribute to the disease severity and outcome. Furthermore, the SARS-COV-2 infection may trigger pathological processes and accelerate underlying conditions to clinical entities. The development of specific and sensitive biomarkers that are easy to obtain will allow for patient stratification, prevention, prognosis, and more individualized treatments for COVID-19. miRNAs are proposed as promising biomarkers for different aspects of COVID-19 disease (susceptibility, severity, complication course, outcome, and therapeutic possibilities). This review summarizes the most relevant findings concerning miRNA involvement in COVID-19 pathology. Additionally, the role of miRNAs in wide range of complications due to accompanied and/or underlying health conditions is discussed. The importance of understanding the functional relationships between different conditions, such as pregnancy, obesity, or neurological diseases, with COVID-19 is also highlighted.

Mitochondrial encephalomyopathies (MEMP) are heterogeneous multisystem disorders frequently associated with mitochondrial DNA (mtDNA) mutations. Clinical presentation varies considerably in age of onset, course, and severity up to death in early childhood. In this study, we performed molecular genetic analysis for mtDNA pathogenic mutation detection in Serbian children, preliminary diagnosed clinically, biochemically and by brain imaging for mitochondrial encephalomyopathies disorders. Sanger sequencing analysis in three Serbian probands revealed two known pathogenic mutations. Two probands had a heteroplasmic point mutation m.3243A>G in the gene, which confirmed mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode syndrome (MELAS), while a single case clinically manifested for Leigh syndrome had an almost homoplasmic (close to 100%) m.8993T>G mutation in the gene. After full mtDNA MITOMASTER analysis and PhyloTree build 17, we report MELAS' association with haplogroups U and H (U2e and H15 subclades); likewise, the mtDNA-associated Leigh syndrome proband shows a preference for haplogroup H (H34 subclade). Based on clinical-genetic correlation, we suggest that haplogroup H may contribute to the mitochondrial encephalomyopathies' phenotypic variability of the patients in our study. We conclude that genetic studies for the distinctive mitochondrial encephalomyopathies should be well-considered for realizing clinical severity and possible outcomes.

Stroke during pregnancy and preeclampsia are two distinct but interrelated medical conditions, sharing a common denominator-blood control failure. Along with cardiovascular diseases, diabetes, dyslipidemia, and hypercoagulability, hypertension is undoubtedly a major risk factor associated with stroke. Even though men have higher age-specific stroke rates, women are facing higher life-long stroke risk, primarily due to longer life expectancy. Sex hormones, especially estrogen and testosterone, seem to play a key link in the chain of blood pressure control differences between the genders. Women affected with stroke are more susceptible to experience some atypical stroke manifestations, which might eventually lead to delayed diagnosis establishment, and result in higher morbidity and mortality rates in the population of women. Preeclampsia is a part of hypertensive disorder of pregnancy spectrum, and it is common knowledge that women with a positive history of preeclampsia are at increased stroke risk during their lifetime. Preeclampsia and stroke display similar pathophysiological patterns, including hypertension, endothelial dysfunction, dyslipidemia, hypercoagulability, and cerebral vasomotor reactivity abnormalities. High-risk pregnancies carrying the burden of hypertensive disorder of pregnancy have up to a six-fold higher chance of suffering from stroke. Resemblance shared between placental and cerebral vascular changes, adaptations, and sophisticated auto-regulatory mechanisms are not merely coincidental, but they reflect distinctive and complex cardiovascular performances occurring in the maternal circulatory system during pregnancy. Placental and cerebral malperfusion appears to be in the midline of both of these conditions; placental malperfusion eventually leads to preeclampsia, and cerebral to stoke. Suboptimal performances of the cardiovascular system are proposed as a primary cause of uteroplacental malperfusion. Placental dysfunction is therefore designated as a secondary condition, initiated by the primary disturbances of the cardiovascular system, rather than an immunological disorder associated with abnormal trophoblast invasion. In most cases, with properly and timely applied measures of prevention, stroke is predictable, and preeclampsia is a controllable condition. Understanding the differences between preeclampsia and stroke in pregnancy is vital for healthcare providers to enhance their clinical decision-making strategies, improve patient care, and promote positive maternal and pregnancy outcomes. Management approaches for preeclampsia and stroke require a multidisciplinary approach involving obstetricians, neurologists, and other healthcare professionals.

Strokes within pediatric populations are considered to be the 10th leading cause of death in the United States of America, with over half of such events occurring in children younger than one year of life. The multifactorial etiopathology that has an influence on stroke development and occurrence signify the importance of the timely recognition of both modifiable and non-modifiable factors for adequate diagnostic and treatment approaches. The early recognition of a stroke and stroke risk in children has the potential to advance the application of neuroprotective, thrombolytic, and antithrombotic interventions and rehabilitation strategies to the earliest possible timepoints after the onset of a stroke, improving the outcomes and quality of life for affected children and their families. The recent development of molecular genetic methods has greatly facilitated the analysis and diagnosis of single-gene disorders. In this review, the most significant single gene disorders associated with pediatric stroke are presented, along with specific therapeutic options whenever they exist. Besides monogenic disorders that may present with stroke as a first symptom, genetic polymorphisms may contribute to the risk of pediatric and perinatal stroke. The most frequently studied genetic risk factors are several common polymorphisms in genes associated with thrombophilia; these genes code for proteins that are part of the coagulation cascade, fibrolysis, homocystein metabolism, lipid metabolism, or platelets. Single polymorphism frequencies may not be sufficient to completely explain the stroke causality and an analysis of several genotype combinations is a more promising approach. The recent steps forward in our understanding of the disorders underlying strokes has given us a next generation of therapeutics and therapeutic targets by which to improve stroke survival, protect or rebuild neuronal connections in the brain, and enhance neural function. Advances in DNA sequencing and the development of new tools to correct human gene mutations have brought genetic analysis and gene therapy into the focus of investigations for new therapeutic options for stroke patients.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder that affects central vision in young adults and is typically associated with mitochondrial DNA (mtDNA) mutations. This study is based on a mutational screening of entire mtDNA in eight Serbian probands clinically and genetically diagnosed with LHON and four of their family members, who are asymptomatic mutation carriers. All obtained sequence variants were compared to human mtDNA databases, and their potential pathogenic characteristics were assessed by bioinformatics tools. Mitochondrial haplogroup analysis was performed by MITOMASTER. Our study revealed two well-known primary LHON mutations, m.11778G>A and m.3460G>A, and one rare LHON mutation, m.8836A>G. Various secondary mutations were detected in association with the primary mutations. MITOMASTER analysis showed that the two well-known primary mutations belong to the R haplogroup, while the rare LHON m.8836A>G was detected within the N1b haplogroup. Our results support the need for further studies of genetic background and its role in the penetrance and severity of LHON.