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.
Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait (idiopathic basal ganglia calcification (IBGC)). Recently, mutations in ...the PDGFRB gene coding for the platelet-derived growth factor receptor β (PDGF-Rβ) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-Rβ. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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.
Background
Niemann Pick type C is an autosomal recessive lysosomal storage disorder caused by mutations in
NPC1
and
NPC2
genes. It is a neuro-visceral disease with a heterogeneous phenotype. Clinical ...features depend on the age at onset. Visceral manifestations are more prominent in the early onset (infantile) form, while neuro-psychiatric symptoms are more prominent in the late disease onset (juvenile and adult forms).
Methods
A total number of 150 patients have been screened for changes in
NPC1
and
NPC2
gene at the Neurology Clinic, University Clinical Centre of Serbia in the period 2012–2020. Clinical data were extracted for patients with biallelic mutations.
Results
Fifteen patients carried biallelic mutations in the
NPC1.
Out of eight different reported
NPC1
variants, four are novel (c.1204_1205TT>GC, p.F402A; c.2486T>G, p.L829R; c.2795+5 G>C; c.3722T>A, p.L1241*). The mean age at the disease onset was 20.3 ± 11.9 years with the average diagnostic delay of 7.7 ± 4.3 years. Movement disorders and psychiatric or cognitive disturbances were the most common initial symptoms (in 33% and 28% patients, respectively). The average age at the first neurological manifestation was 21 ± 12.0 years. At the last examination, eye movement abnormalities (vertical slow saccades or vertical supranuclear gaze palsy), and ataxia were present in all patients, while dystonia was common (in 78.6% of patients). Presence of c.2861C>T, p.S954L mutation in homozygous state was associated with older age at the neurological symptom onset.
Conclusions
Clinical findings were in line with the expected, but the diagnostic delay was common. We hypothesize that the presence of c.2861C>T, p.S954L mutation may contribute to the phenotype attenuation.
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.
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.
Objective
Interleukin-1-B (IL1B) is a proinflammatory cytokine that plays an important role in sepsis. The aim of this study was to evaluate the relationships between
IL1B
-
511G/A
polymorphism and ...susceptibility and outcome of early-onset sepsis (EOS) in preterm infants.
Methods
DNA was extracted from the buccal swabs of 471 (285 with EOS and 186 control) preterm infants. Genotypes of rs16944 polymorphism were determined with real-time PCR method.
Results
We found statistically significant higher frequency of
IL1B
-
511AA
genotype in EOS group than in control group (
p
= 0.012). Also,
IL1B
-
511AA
genotype is statistically significantly more frequent in patients with lethal EOS outcome (
p
= 0.011).
Conclusion
Genotype
IL1B
-
511AA
was associated with susceptibility to EOS and it is a significant predictor of lethal outcome in preterm infants with EOS.
Medical students usually do not meet the recommendations on the minimum level of physical activity, despite knowing the impact that physical activity has on the prevention and treatment of various ...diseases. Medical students are considered to be insufficiently physically active. The aim of this study is to determine the prevalence of physically active fifth-year medical students at five universities in Serbia, as well as to identify factors associated with insufficient physical activity of students.
A cross-sectional study was performed in the population of fifth-year medical students from five different universities in Serbia. The research instrument was a questionnaire specially designed based on similar research. Descriptive and analytical statistics methods were used in statistical analysis.
The study included a total of 573 fifth-year medical students from five universities in Serbia: 311 (54.3%) Belgrade; 86 (15.0%) Kragujevac; 58 (10.1%) Nis; 66 (11.5%) Kosovska Mitrovica; 52 (9.1%) Novi Sad. Insufficient physical activity was statistically significantly associated with studying at the University of Kosovska Mitrovica (OR = 3.98, 95% CI: 1.83-8.57). There was a statistically significant difference in the frequency of anti-anxiety medications use in the last 12 months between students with sufficient and insufficient physical activity (p = 0.040) as well as in the average number of cigarettes smoked per day between students with sufficient and those with insufficient physical activity (2.82 ± 6.35 vs. 4.50 ± 8.29, p = 0.043). There was also a statistically significant difference in the average score on the Beck's depression scale between students with sufficient and students with insufficient physical activity (6.51 ± 6.59 vs. 10.03 ± 9.37, p < 0.001) and in the average score on Zung's anxiety scale (34.86 ± 8.18 vs. 38.07 ± 8.71, p = 0.003).
A high percentage of medical faculty students (86.6%) are physically active. Differences in the level of physical activity were observed between students of these five universities as well as between students with different levels of physical activity.
The genetic etiology and the contribution of rare genetic variation in multiple sclerosis (MS) has not yet been elucidated. Although familial forms of MS have been described, no convincing rare and ...penetrant variants have been reported to date. We aimed to characterize the contribution of rare genetic variation in familial and sporadic MS and have identified a family with two sibs affected by concomitant MS and malignant melanoma (MM). We performed whole exome sequencing in this primary family and 38 multiplex MS families and 44 sporadic MS cases and performed transcriptional and immunologic assessment of the identified variants. We identified a potentially causative homozygous missense variant in NLRP1 gene (Gly587Ser) in the primary family. Further possibly pathogenic NLRP1 variants were identified in the expanded cohort of patients. Stimulation of peripheral blood mononuclear cells from MS patients with putatively pathogenic NLRP1 variants showed an increase in IL-1B gene expression and active cytokine IL-1β production, as well as global activation of NLRP1-driven immunologic pathways. We report a novel familial association of MS and MM, and propose a possible underlying genetic basis in NLRP1 gene. Furthermore, we provide initial evidence of the broader implications of NLRP1-related pathway dysfunction in MS.
Introduction: Febrile seizures (FS) are the most common neurological disease in childhood. The etiology of FS is the subject of numerous studies including studies regarding genetic predisposition. ...Aim: The aim of the study was to analyze the association of TRPV1 rs222747 and KCC2 rs2297201 gene polymorphisms with the occurrence of FS. Materials and Methods: The study included 112 patients diagnosed with FS classified as simple febrile seizures (SFS) or complex febrile seizures (CFS). We analyzed selected polymorphisms of KCC2 and TRPV1 genes using the Real-time PCR method. Results: The CT and TT genotypes of the rs2297201 polymorphism of the KCC2 gene are significantly more common in the group of children with FS than the control group (p = .002) as well as the allele T of this polymorphism (p = .045). Additionally, genotypes CT and TT of the rs2297201 polymorphism of the KCC2 gene were more frequent in the group of children with CFS compared to the control group (p < .001). Different genotypes and alleles of the rs222747 TRPV1 gene polymorphism were not associated with the occurrence of febrile seizures or epilepsy, nor were associated with the occurrence of a particular type of febrile seizure (p = .252). Conclusion: These results indicate that the CT and TT genotypes, as well as the T allele of rs2297201 polymorphism of the KCC2 gene, could be a predisposing factor for the FS, as well as the occurrence of CFS.
PDF
