Identification of potentally causal variants for myasthenia gravis: a bioinformatics-driven fine-mapping approach combined with genetic association study

Introduction: Genome-wide association studies (GWAS) identify genomic loci that contain genetic determinants of complex diseases. Subsequent functional genomic approaches, such as bioinformatic finemapping and transcriptome-wide association studies (TWAS), can reveal potentially causal single nucleotide variants (SNVs) that can be tested on patient samples. We applied this approach to study causal SNVs for acetylcholine receptor (AChR) seropositive myasthenia gravis (MG). We focused on CHRNA1 and CHRNB1 loci, coding AChR subunits, and CTLA-4 locus, coding protein transmitting an inhibitory signal to T cells. Methods: CHRNA1 was fine-mapped by PAINTOR using data from GWAS summary statistics, 1000 genome and RegulomeDB. Alongside, rs4151121 identified by TWAS in CHRNB1, and rs231735 and rs231770 identified by fine-mapping in CTLA-4 were studied. SNVs were genotyped using allele discrimination assays in 447 Serbian AChR-MG patients (183 early-onset and 264 late-onset) and 447 sex- and age-matched controls. Results: CHRNA1 rs35274388 was fine-mapped as a potentially causal variant (PIP2=92%) exhibiting transcription factor binding and chromatin accessibility peaks. CHRNA1 rs35274388 minor allele A and CHRNAB1 rs4151121 minor allele G increased the risk for late-onset MG (OR=1.669, 95% CI=1.05-2.638, p=0.027, p10e6 permutation=0.031 and OR=1.322, 95% CI=1.063-1.644, p10e6 permutation=0.014, respectively). On the other hand, CTLA-4 rs231735 recessive genotype TT decreased, while rs231735- rs231770 haplotype GC increased the susceptibility to early-onset MG (OR=0.548, 95% CI=0.339-0.888, p=0.014, p10e6 permutation=0.014 and OR=1.360, p=0.027, p10e6 permutation=0.027, respectively). Conclusion: CHRNA1 rs35274388 and CHRNAB1 rs4151121 loci could be causal genetic factors for lateonset MG while CTLA-4 rs231735 and rs231770 could be causal genetic factors for early-onset MG in Serbian population

Genetic risk factors in patients with Myasthenia gravis

Myasthenia gravis (MG) is a rare autoimmune disease mediated by antibodies against components of the neuromuscular junction, particularly the acetylcholine receptor (AChR). The prevalence of MG in Belgrade has been estimated at 189 cases per 1,000,000 inhabitants, which is among the highest prevalence reported to date. Genetic studies have mainly pointed to specific HLA alleles associated with MG. However, CTLA-4 and TNFRSF11A, playing a role in the immune response, have recently been associated with MG in genome-wide association studies. Since CTLA-4 and TNFRSF11A promote other autoimmune diseases, the main objective of this casecontrol study was to determine the association between these candidate genes and the risk for developing MG in Serbian population. Genotyping of rs231735 and rs231770 within the CTLA-4 gene and rs4263037 within TNFRSF11A in 447 AChR-MG patients and 447 individually sex- and age-matched controls revealed no association with MG (p=0.344, p=0.923 and p=0.557, respectively). However, when stratifying patients into those with early-onset (n=183) and late-onset MG (n=264), we found an association of minor rs231735 allele T with early-onset MG under the recessive genetic model (OR=0.548, 95% CI=0.339-0.888, p=0.014, p10e6 permutation=0.014). Haplotype analysis revealed that individuals with the GC haplotype rs231735-rs231770 had a higher risk for developing earlyonset MG (OR =1.360, p=0.027, p10e6 permutation =0.027). Considering the sufficient statistical power of the study (>90%) and the selection criteria for controls, our results suggest that the CTLA-4 may be associated with early-onset MG in Serbian population. Analysis of additional variants is needed to understand the association of CTLA-4 with MGBOOK OF ABSTRACTS: 8th CONGRESS OF SERBIAN NEUROSCIENCE SOCIETY with international participation 31 May – 2 June 2023. Belgrade, Serbi

Between art and engineering: Studies on postwar architecture in Belgrade and Serbia

Publikacija nastaje kao prod višegodišnje saradnje sa gostujućim profesorom Lukom Skansijem u sklopu predmeta "Posebni problemi istraživanja arhitekture i urbanizma" na prvoj godini doktorskih studija. Tema trogodišnjeg ciklusa predavanja i diskusija, koje je vodio prof. Skansi između 2015 i 2017. godine, bio je pojam tektonike u arhitekturi, odnosno razvoj tog teoretskog i analitičnog pojma od sredine devetnaestog veka do danas. Studenti su bili pozvani da za svoj seminarski rad izvedu složenu i iscrpnu tektonsku analizu na jednoj relevantnoij arhitekturi izgrađenoj u Srbiji u konktekstu socijalističke Jugoslavije, u periodu između pedesetih i osamdesetih godina prošlog veka.urednik: Biljana JotićKategorija: M105 Učešće na 45. Salonu arhitekture, 28. mart - 29. april 2023. godine. u Muzeju primenjene umetnosti, Beograd, u kategoriji: Arhitektonska kritika i publikacij

Na međi umetnosti i inženjerstva : studije o posleratnoj arhitekturi u Beogradu i Srbiji [45. Salon arhitekture]

Publikacija je rezultat višegodišnje saradnje sa gostujućim prof. Lukom Skansijem u sklopu predmeta »Posebni problemi istraživanja arhitekture i urbanizma« na prvoj godini doktorskih studija. Tema trogodišnjeg ciklusa predavanja i diskusija, koje je vodio prof. Luka Skansi između 2015. i 2017. godine, bio je pojam tektonike u arhitekturi, odnosno razvoj tog teoretskog i analitičkog pojma od sredine devetnaestog veka do danas. Studenti su bili pozvani da za svoj seminarski rad izvedu složenu i iscrpnu tektonsku analizu na jednoj relevantnoj arhitekturi izgrađenoj u Srbiji u kontekstu socijalističke Jugoslavije, u periodu između pedesetih i osamdesetih godina prošlog veka

The effect of benfothiamine in the therapy of diabetic polyneuropathy

Introduction. Diabetic polyneuropathy (DPN) is one of the most common diabetic complications, which can result in a significant functional impairment and reduction of the quality of life in affected individuals. It occurs due to alterations in different biochemical mechanisms which require the presence of thiamine, which is why this vitamin is used in the therapy of DPN. Due to the low bioavailability of the hydrosolubile forms of thiamine, its liposolubile preparations (benfotiamine) are preferentially used. Objective. The aim of this study was to determine the efficacy of benfotiamine in combination with vitamin B6 in the therapy of DPN. Methods. The study group comprised of 22 patients with DPN who were treated with the combination of benfotiamine and vitamin B6 during 45 days. The effect of the therapy was evaluated by the analysis of different clinical, laboratory and electrophysiological parameters before and after conducted treatment. Results. After the treatment period, a statistically highly significant reduction of pain (p<0.01) was noted with the reduction of pain score on visual analogue scale in 86.4% of patients. A significant reduction of subjective complaints was also noted, with decreased modified total symptom score in 95.5% of patients (p<0.01). The presence of alodynia was reported at the beginning of the study in 77.3%, and after the benfotiamine therapy only in 22.7% of patients, while hyperpathy was initially present in 90.9%, and after treatment in 31.8% of patients (p<0,01). Neurophysiological parameters of polyneuropathy also significantly improved, with the improvement of the compound muscle action potential amplitude in 68.2% (p<0.01) and motor conduction velocity of the peroneal nerve in 45.5% of patients (p<0.01). The improvement of the sensory nerve action potential amplitude (p<0.01) and sensory conduction velocity (p=0.05) of the sural nerve was found in 45.5% of patients. After the treatment period, there was a highly statistically significant lowering of the glycosylated haemoglobin (p<0.01), with improved findings in 63.6% of patients. After completed study treatment protocol 86.4% of patients rated their overall condition as improved. Conclusion. Our results showed that the conducted treatment resulted in significant subjective and objective improvement of the disease signs symptoms, which confirmed that benfotiamine was good starting choice for the treatment of diabetic polyneuropathy

Bulbar-onset amyotrophic lateral sclerosis in a patient with genetically confirmed Huntington’s disease: a case study

Abstract Background The rationale for this paper is a description of a patient from Southeast Europe with genetically confirmed Huntington’s disease (HD), coexisting with sporadic, bulbar-onset amyotrophic lateral sclerosis (ALS). To the best of our knowledge, the total number of reported cases with confirmed coexistence of HD and ALS is less than 20. Thus, it is an extremely rare condition speculated to be in a range from 2 to 6 per billion, and data from this part of the World are completely missing. Case presentation Here we report a 72-year-old female with a family history of HD who had generalized chorea and hyperreflexia. Using the PCR-based test for the detection of the CAG triplet repeat expansion, the presence of HD was confirmed. After several months, our patient had progressively developed dysarthria and dysphagia, followed by spastic quadriparesis, generalized muscle wasting, spontaneous fasciculations and sialorrhea. The diagnosis of definite ALS was established based on the patient’s neurological status, electromyography findings and current El Escorial criteria. Conclusions Our study emphasizes the need for the recognition of the co-occurrence of clinically distinct and rare genetic disorders, such as HD and ALS. New insights from the studies dealing with these rare topics could significantly contribute to the contest of new gene therapy trials

Significance of magnetic resonance imaging in differential diagnosis of nontraumatic brachial plexopathy

Background/Aim. Nontraumatic brachial plexopathies may be caused by primary or secondary tumors, radiation or inflammation. The aim of this study was to present the significance of MRI in revealing the cause of nontraumatic brachial plexopathy. Methods. A two-year retrospective study included 22 patients with nontraumatic brachial plexopathy. In all the patients typical clinical findings were confirmed by upper limb neurophysiological studies. In all of them MRI of brachial plexus was performed by 1.5 T scanner in T1 and T1 FS sequence with and without contrast, as well as in T2 and T2 FS sequences. Results. Seven (32%) patients had brachial plexopathy with signs of inflammatory process, 5 (23%) patients had secondary tumors, in 4 (18%) patients multifocal motor neuropathy was established and in the same number (18%) of the patients postradiation fibrosis was found. Two patients (9%) had primary neurogenic tumors. Conclusion. According to the results of this study MRI is a method which may determine localization and cause of brachial plexopathy. MRI can detect focal nerve lesions when other methods fail to find them. Thus, MRI has a direct impact on further diagnostic and therapeutical procedures