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Neurodegeneration with brain iron accumulation (NBIA) encompasses a number of heritable disorders affecting children and adults characterized by diverse clinical manifestations and brain iron deposition detected on magnetic resonance imaging (MRI). The most frequent NBIA subtypes are pantothenate kinase-associated neurodegeneration, phospholipase A2-associated neurodegeneration, fatty acid-2 hydroxylase- associated neurodegeneration and mitochondrial- membrane proteinassociated neurodegeneration (MPAN). Here, we report a male patient presenting with optic atrophy, progressive cognitive and movement impairment, bilateral hypointensity of the basal ganglia on T2-weighted MRI and proven mutation for MPAN. The NBIA disorders can remain undiagnosed for 3 to 30 years. In children developing optic atrophy, NBIA should be taken into consideration.

Introduction: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are characterized by different phases of cognitive decline. In AD, there is a progressive impairment of acquired cognitive abilities while subjects with MCI show less severe cognitive disturbances. Cognitive dysfunction develops as a result of the complex interactions between multiple genetic, epigenetic, developmental, and environmental factors. Among many genes involved in cognition is the gene coding for catechol- O-methyltransferase (COMT), the enzyme responsible for the degradation of dopamine, resulting in the modulation of dopaminergic function. Therefore, COMT genetic variants were studied in various dementias characterized by cognitive loss. The aim of the study was to evaluate the possible association between COMT rs6269 and COMT rs4680 polymorphisms and cognitive decline in subjects with AD and MCI. Methods: Cognitive deterioration was assessed with the Mini-Mental State Examination (MMSE) and the Clock Drawing test (CDT) scores in 193 patients with AD and 269 subjects with MCI. COMT rs6269 and COMT rs4680 (Val158Met) were genotyped using the real-time PCR. Multiple linear regressions and Kruskal Wallis ANOVA were used to detect the association of the COMT rs6269 or COMT rs4680 genotypes with cognitive decline. Results: Multiple linear regression showed that COMT rs6269 was significantly associated with MMSE and CDT scores and these effects were affected by diagnosis and COMT rs6269 genotypes and age. In contrast, multiple linear regression revealed that COMT rs4680 was not significantly associated with MMSE or CDT scores, and the only significant effects were found for age and diagnosis. To further evaluate the effect of COMT polymorphisms on cognition, all subjects were subdivided into AA, GA, or GG genotype carriers of the COMT rs6269 or COMT rs4680, respectively, and according to MMSE or CDT scores. Carriers of the GG genotype of the COMT rs6269 had significantly (p=0.007) lower CDT scores than AA carriers, while other genotype groups did not differ significantly according to the CDT or MMSE scores. Conclusion: Although COMT rs4680 (Val158Met) was reported to be related to cognitive loss in various neuropsychiatric disorders, present results revealed a significant association between the other COMT polymorphism, rs6269, with cognitive deterioration in dementia.

The homeostasis of metals is altered in the brain of Alzheimer’s disease (AD) patients. It was proposed that changes in metal homeostasis are related to AD pathology. Additionally, metals that are not present in the brain under normal circumstances (such as mercury, lead and cadmium) were associated with AD pathogenesis. The aim of this study was to test if macro and microelements (Li, B, Na, Mg, Al, S, K, Ca, Cr, Fe, Co, Mn, Ni, Cu, Zn, As, Se, Sr, Mo, Cd, Ba, Tl, Pb, and Hg) measured in cerebrospinal fluid (CSF) and plasma of patients with dementia are associated with CSF biomarkers of AD. CSF AD biomarkers reflect pathological changes in AD brain, while the involvement of different metals in AD pathogenesis is still the matter of debate. Macro and microelements were determined by inductively coupled plasma mass spectroscopy (ICP-MS), while CSF biomarkers were measured by enzyme-linked immunosorbent assays (ELISA). Macro and microelements were measured in CSF of 194 subjects and in plasma of 144 subjects (study included overall 125 AD patients, 50 patients with mild cognitive disorder and 19 healthy controls). We used three different statistical methods to test the association of macro and microelements with CSF biomarkers of AD. All three methods (simple correlation and two machine learning algorithms ; redescription mining and principal component analysis [PCA]) demonstrated the association of macro and microelements with CSF biomarkers of AD. Possible explanations for association of macro and microelements with CSF biomarkers of AD await elucidation of their environmental sources or detection of their release from brain tissue due to cell death. Also, these results should be further validated on larger cohorts.

Parkinson's disease (PD) is a neurodegenerative disorder clinically characterized by motor dysfunctions due to progressive loss of dopaminergic neurons and a broad spectrum of non- motor symptoms. Interestingly, non-motor symptoms like depression, anxiety and psychosis are often present several years before the occurrence of classic motor features seriously affecting patient quality of life. Their presence is often misleading, delaying the correct diagnosis of PD. Despite its high incidence, the pathophysiology and aetiology of neuropsychiatric symptoms associated with PD remains unclear. Currently, a lot of interest lays in research looking for genetic predictors of motor and non-motor symptoms in PD. The availability of next-generation sequencing technology for genome, epigenetic and transcriptional analysis opens the door to a new way of studying multifactorial diseases like PD and their comorbidities. In this review we will present new insights in the genomic and epigenetic background of psychiatric comorbidity in Parkinson's disease.

Sporadični oblik Alzheimerove bolesti (AD) s kasnim početkom je najčešći uzrok demencije. Mnogobrojni rizični čimbenici za AD su starija dob, različiti čimbenici iz okoline i genetski čimbenici. Ti su rizični čimbenici iz okoline odgovorni za raniji početak bolesti, bržu progresiju, jaču težinu simptoma. Uz mnoštvo rizičnih gena, gen za moždanih neurotrofni čimbenik BDNF kodira protein BDNF koji je uključen u modulaciju plastičnosti mozga, rast neurona, preživljavanje, funkciju, neurogenezu, regeneraciju, ali i apoptozu. BDNF ima ulogu i u promjenama moždanih puteva jer njegove promjene utječu na fiziologiju i neuroplastičnost. Snižene koncentracije središnjeg i perifernog BDNF-a povezane su s različitim neurodegenerativnim i psihijatrijskim poremećajima, uključujući i AD. Genske varijante BDNF-a mogu objasniti interindividualne razlike koje se javljaju u AD-u. Budući da nema izlječenja AD-a, validirani, specifični i selektivni biomarkeri povezani s endofenotipovima koji se javljaju unutar kliničke slike AD-a potrebni su, ali još uvijek nedostupni. Studija je ciljala istražiti povezanost različitih BDNF polimorfizama (rs6265, rs11030104, rs7934165, rs1519480, rs56164415) s koncentracijom biomarkera iz cerebrospinalne tekućine (CSF): amiloida beta (1-42), ukupnih tau proteina, fosforiliranih tau proteina (p-tau181, p-tau199, p- tau231) i proteina nalik vizininu (VILIP-1) u bolesnika s AD s kasnim početkom. Mogući AD (N=114) je dijagnosticiran temeljem DSM-IV i NINDS-ADRDA kriterija. Pronađena je značajna povezanost između BDNF rs11030104, rs11030104 i rs7934165 i CSF biomarkera, dok drugi polimorfizmi nisu bili povezani s CSF biomarkerima. Naime, BDNF rs6265 bio je značajno povezan s koncentracijom p-tau181, jer su nositelji A alela prema nositeljima GG imali značajno sniženu koncentraciju p-tau181. Značajna je povezanost utvrđena između BDNF rs11030104 i koncentracije p-tau181 i p-tau199, jer su nositelji GG genotipa imali značajno nižu koncentraciju p- tau181 i p-tau199 naspram nositelja AA ili AG genotipova. Uz to je pronađen tren prema odnosu između BDNF rs7934165 i koncentracije VILIP-1, budući da su nositelji AA imali nižu VILIP-1 koncentraciju prema nositeljima G alela. Naši podatci trebaju potvrdu na većim skupinama ispitanika, no ti preliminarni podatci upućuju na povezanost između BDNF genskih varijanti (rs11030104, rs11030104 i rs7934165) i CSF biomarkera koji su inače povišeni u AD, fosforiliranih tau (p-tau181 i p-tau199), te VILIP-1 proteina u bolesnika s kasnim početkom AD.

Tijekom godina su nastale brojne hipoteze koje nastoje objasniti nastanak Alzheimerove bolesti (AB). Jedna od njih je hipoteza narušene homeostaze metala u mozgu oboljelih od AB. Ta hipoteza se uglavnom odnosi na metale koji su u normalnim okolnostima prisutni u organizmu i nužni su za funkcioniranje brojnih proteina i enzima. Gen za apolipoprotein E (ApoE), protein koji je uključen u transport kolesterola do neurona, glavni je genetički čimbenik rizika za nastanak sporadične AB. Cilj ovog istraživanja bio je istražiti potencijalnu povezanost ApoE i esencijalnih metala. Mjerili smo razine željeza, bakra, cinka, magnezija, natrija, kobalta, kalcija, mangana, molibdena, bora i kroma u likvoru i plazmi 126 osoba oboljelih od AB, 52 osobe s blagim spoznajnim poremećajem (BSP) i 19 zdravih kontrola s različitim APOE genetipovima. Rezultati su pokazali da su razine bakra, natrija i magnezija bile značajno povišene kod ispitanika s epsilon4 alelom. Razine natrija, kobalta i kalcija su bile značajno povišene u plazmi osoba s epsilon4 epsilonX genotipom. Razine bora mjerenog u plazmi su bile značajno snižene kod nositelja epsilon4 alela i epsilon4 epsilon4 genotipa. Dodatno su vrijednosti cinka i natrija mjerene u likvoru bile značajno povišene kod pacijenata s AB u odnosu na kontrole. Zaključno, rezultati ovog istraživanja upućuju na snažnu povezanost između APOE genotipa i koncentracija natrija, bakra, cinka, kalcija, magnezija, kobalta i metaloida bora mjerenih u plazmi osoba s AB i BSP.

Intracranial aneurysms have a prevalence of about 2% of the population. They are a common incidental finding of noninvasive neuroimaging methods, raising the question of the necessity of treatment of patients with an asymptomatic intracranial aneurysm. For long, the only treatment option was surgical clipping of aneurysm neck. In the last 25 years, endovascular techniques have been developed as an alternative solution for patients who are not eligible for neurosurgical procedures. Research has shown better results of embolization procedures with lower rates of complications, but a higher rate of recanalization is still a major drawback of endovascular coiling. There are no strict protocols and the treatment of choice for intracranial aneurysms should be agreed upon by both the physician and the patient. This review aims to provide an insight into the management of intracerebral aneurysms with emphasis on the decision making problems faced by clinicians., Intrakranijske aneurizme prisutne su u oko 2% populacije. Uobičajen su slučajni nalaz neinvazivnih neuroslikovnih metoda otvarajući pitanje nužnosti liječenja bolesnika s asimptomatskom intrakranijskom aneurizmom. Dugo je jedina mogućnost liječenja bila kirurško podvezivanje vrata aneurizme, no u posljednjih 25 godina usavršen je endovaskularni pristup pružajući alternativu bolesnicima koji ne ispunjavaju uvjete za neurokirurške zahvate. Istraživanja su pokazala bolje rezultate embolizacijskih postupaka s nižim stopama komplikacija, ipak, veća stopa rekanalizacija i dalje je glavni nedostatak endovaskularnog pristupa. Ne postoje strogi protokoli tretiranja intrakranijskih aneurizma te konačna odluka leži u dijalogu između liječnika i bolesnika. Cilj ovoga preglednog rada jest pružiti uvid u pristup intracerebralnim aneurizmama s naglaskom na probleme donošenja odluka s kojima se suočavaju kliničari.

The aim of this review is to emphasize the importance of mental activity and aerobic physical exercise as one of the most important health- related activities which may delay the onset or slow down the progression of Alzheimer's dementia. Studies have shown that the elderly who regularly engage in mental and physical activities have a lower risk of dementia development. Performing mental and physical activities regularly has a synergistic effect on the improvement of cognitive functions. Complex mental activity during life is associated with a reduction in the hippocampal atrophy rate, which is a sensitive early-stage biomarker of dementia while regular physical exercise can slow down the progressive reduction of the cortical brain volume which occurs during aging. Mental activity increases a person's "cognitive reserve" and promotes the formation of new communications between brain cells. Since it is not possible to influence genetic components of Alzheimer's dementia, preventative interventions such as encouraging regular engagement in mental and physical activities are extremely important. Activities need to be safe, moderate, comfortable, and adapted as to type, duration, and especially the health and functional status of the patient. In the near future, it is expected that genome analysis in personalized medicine will guide us in the right direction on certain types of physical and mental exercise.

U tijeku Alzheimerove bolesti (AB) poremećeno je normalno funkcioniranje dopaminskog sustava, što se odnosi i na aktivnost monoaminooksidaze B (MAOB), enzima uključenog u razgradnju dopamina. Točnije, aktivnost MAOB je u AB-u povišena. Povećana ekspresija MAOB je uočena u hipokampusu i moždanoj kori osoba s AB-om. Primijećeno je da MAOB rs1799836 polimorfizam može utjecati na transkripciju MAOB te posljedično i na translaciju proteina te aktivnost MAOB. Naše je nedavno istraživanje pokazalo da je razina amiloida beta 1-42 mjerenog u likvoru bila značajno snižena kod nositelja A alela u MAOB rs1799836 polimorfizmu. Cilj ovog istraživanja je bila usporedba MAOB rs1799836 polimorfizma s APOE genotipom, jedinim potvrđenim genetičkim rizičnim čimbenikom za razvoj sporadične AB. Istraživanje je obuhvatilo 253 ispitanika, od koji je 127 bolovalo od AB, 57 su bili pacijenti s blagim spoznajnim poremećajem, 11 su bili zdrave kontrole, a 58 ih je bolovalo od drugih primarnih uzroka demencije. Rezultati su pokazali povišen broj pacijenata s APOE epsilon4/epsilon4 genotipom i nositelja APOE epsilon4 alela među nositeljima AA MAOB rs1799836 genotipa. Ti rezultati upućuju da bi MAOB rs1799836 polimorfizam mogao biti važan genetički biljen AB-a.

Additional file 1. List of genes.

Introduction and objectives: The current population share of people in the age group of 75+ in EU28 in 2019 is 9.5% and has grown since 6.8% in 2001. Share increase in this age group is even bigger in less per forming countries such as Croatia (9.45% in 2019 and 5.3% in 2001), intensified additionally by emigration. Ageing population represents an evolving concern in many aspects of life. It influences economy, demography, intergenerational relationships, living arrangements, health care approaches and unsustainable health-care costs. All of these challenges triggered an increased interest in research of ageing in many disciplines. Advancement in medicine generated a plethora of new diseases among the ageing population that were not known before, comorbities being among the most challenging ones. Here we present the growing interest in the health research on this subject funded in EU programmes. We aim to determine the proportion of research on ageing within Horizon 2020 programme / Societal Challenges/Health (SC1). Methods. We searched the Calls for Proposals, projects and their results in the European Commission databases “Funding and Tenders” (https://ec.europa.eu/info/funding-tenders), “Cordis” (https://cordis.europa.eu/search/en), H2020 Dashboard (https://webgate.ec.europa.eu/dashboard/sense/app /93297a69-09fd-4ef5-889fb83c4e21d33e) and others. Results. In Horizon 2020 Work Programme 2018-2020 – Health, demographic change and wellbeing (SC1) word “Ageing” is mentioned ninety-six times. Twenty-nine calls were dedicated to ageing (out of 295) and approximately one third of the funded projects are related to ageing (341/1039). We will present the number of projects, EC contribution and results coming out from these projects ; publications together with their content analysis and intellectual property rights. We will show main areas of research, top funded projects, and geographical distribution of the participants. Conclusions. Ageing is a growing issue in various aspects and research fields. While research on ageing is present in the Horizon Framework Programme, the projects are scattered through various calls. The system for the monitoring of allocated funds, research topics, project results are overwhelming, but not harmonized nor easy to find. Based on the importance of ageing, but also other interand multi-disciplinary research fields, the systematic approach to tackle these issues are needed.

Metastatic breast cancer is an incurable disease with highly variable clinical course and outcome. Intrinsic genetic heterogeneity of the primary breast tumor may play a role in this variability and may explain it in part. The aim of the study was to determine pathogenic and likely pathogenic variants in a set of highly penetrance genes which can provide new information in the process of treatment decisionmaking. There is still an insufficient number of metastatic patients in our genetic assessment group because of limited resources. Nevertheless, multi-gene testing provided a substantial benefit in clinical management of breast cancer because the small subset of patients were found suitable for the PARP-inhibitor therapy.

Genetic testing is a powerful tool that allows detection of BRCA and non-BRCA germline pathogenic variants in breast cancer (BC) patients or in individuals at high risk of BC. Inherited pathogenic variants (PV) in genes related with moderate to high risk of BC may explain up to 50% of familial BC. Although established for BRCA pathogenic variants, indications and interpretations of genetic testing in non-BRCA pathogenic variants are not well defined. The aim of the study was identification of inherited PV of non-BRCA pathogenic variants in BC patients tested at the University Hospital Center (UHC) Zagreb. Identifying germline pathogenic variants in women with BC is important because it can influence their immediate and long-term management and has important implications on other family members. Multigene panel findings are likely to change clinical practice for substantially more patients than BRCA1/2 testing alone. For a large proportion of the genes included in hereditary cancer gene panels, clinical guidelines are to be established.

Astrocytic tumors show great heterogeneity in terms of genetic alterations, morphology and behavior. The objective of our study was to discover genomic copy number aberrations (CNA) that are constant across astrocytoma grades, but also those that are specific for progression. In order to identify regions that are driving cancer pathogenesis and novel candidate genes, a cohort of 14 astrocytomas was analyzed by Array Comparative Genomic Hybridization (aCGH) using SurePrintG3 Human microarrays 4×180K (Agilent Technologies). Bioinformatics was performed utilizing Genomic Identification of Significant Targets in Cancer (GISTIC) 2.0.23 and DAVID softwares. Subsequently, the expression data of mRNA, protein and mutations for each annotated gene were explored through cBioPortal web resource providing in silico validation. Altogether, 1438 CNA were found of which losses prevailed. GISTIC identified regions of aberration focusing on 0.25 q-value. Significant deletions affected 14 chromosomal regions, out of which deletions at 17p13.2, 9p21.3, 13q12.11 and 22q12.3 remained significant even at 0.05 q- value. The significantly deleted regions in high grades were: 9p21.3 ; 17p13.2 ; 10q24.2 ; 14q21.3 ; 1p36.11 and 13q12.11, while amplifications were: 3q28 ; 12q13.3 and 21q22.3. Low grades comprised significant deletions at 3p14.3 ; 11p15.4 ; 15q15.1 ; 16q22.1 ; 20q11.22 and 22q12.3 indicating early events. According to DAVID gene annotation software the above regions harbored 65 significantly over-represented genes that were assigned to a pathway or a functional category. Significantly enriched pathways were: PI3K-Akt, Cytokine-cytokine receptor, NOD-like receptor, Jak-STAT, RIG-I-like receptor and Toll-like receptor pathways. Pathways involved in HPV and herpex simplex infections, and pathways involved in inflammation, were also represented. Candidate genes out of 65 over-represented based on Biocportal data were: C1QBP, CCNA1 CHUK, CLDN7, CLEC10A, FGF8, FGF9, FGR, HPS6, NFKB2, PIK3AP1, TRIM8 and YWHAE. Present study brings biologically and functionally significant genetic regions involved in etiology of human astrocytoma which may provide better understanding of the disease for future diagnostics and therapeutics.

Introduction: In order to identify regions that drive cancer pathogenesis and novel candidate genes for glioma, a cohort of 10 high-grade astrocytomas was analyzed for copy number aberrations and bioinformatics and validated in silico. Methods: Astrocytomas were analyzed by Array Comparative Genomic Hybridization (aCGH) using SurePrintG3 Human microarrays 4×180K (Agilent Technologies). Bioinformatics was performed utilizing Genomic Identification of Significant Targets in Cancer (GISTIC) 2.0.23 and DAVID softwares. Subsequently, the expression data of mRNA, protein and mutations for each annotated gene were explored through the cBioPortal web resource providing in silico validation. Results: GISTIC identified regions of aberration in grade III and IV tumors focusing on 0.25 q-value. The regions identified as significantly deleted were: 9p21.3 ; 17p13.2 ; 10q24.2 ; 14q21.3 ; 1p36.11 and 13q12.11, while amplified regions were: 3q28 ; 12q13.3 and 21q22.3. According to DAVID software those regions harbored 65 significantly over- represented genes that were assigned to a pathway or a functional category via gene annotation. Significantly enriched pathways were: PI3K-Akt, Cytokinecytokine receptor, NOD- like receptor, Jak-STAT, RIG-II-like receptor and Toll-like receptor pathways. Pathways involved in HPV and herpex simplex infection, as well as several pathways involved in inflammation, were also significantly represented in terms of the number of genes identified. Relevant candidate genes based on cBioPortal data were: C1QBP, CCNA1 CHUK, CLDN7, FGF8, FGF9, FGR, NFKB2, TRIM8 and YWHAE. Discussion: Genes mapped in narrow regions with altered DNA copy number may represent potential candidate tumor suppressor genes and oncogenes. cBioPortal compiles 7, 893 cancer cases from the 33 most recent The Cancer Genome Atlas (TCGA) studies. Our results identified alterations, pathways and genes that are biologically and functionally significant. Conclusion: The present study identifies candidate genes involved in the etiology of human astrocytoma providing a better understanding of the disease for future diagnostics and therapeutics.

Razvili smo novi uređaj koji pomaže u ranoj dijagnozi blagog kognitivnog oštećenja (mild cognitive impairment - MCI, odnosno blagog neurokognitivnog poremećaja prema DSM-5) i demencije (velikog neurokognitivnog poremećaja prema DSM-5, najčešće uzrokovanog Alzheimerovom bolešću). Sustav se temelji na određivanju pozicije cilja koji nakon kratkotrajnog prikazivanja više nije vidljiv, pa ispitanik mora svoju navigaciju do cilja temeljiti na prethodno upamćenom položaju cilja u odnosu na svoj početni položaj (četiri egocentričke podvarijante) ili zadane orijentire (četiri alocentričke podvarijante testa). U tom smislu ovaj test podsjeća na Morrisov vodeni labirint za glodavce. Testiranje prosječno traje oko 20 minuta te omogućuje brz, jeftin i neinvazivan dijagnostički postupak. Sustav je namijenjen klinikama i znanstvenoj zajednici, farmaceutskoj industriji te zdravstvenim i drugim ustanovama koje se brinu za starije osobe za koje je važno rano otkrivanje spoznajnog urušavanja, kao i kontinuirano praćenje njihovog statusa i uspješnosti terapijskih postupaka. Tijekom predavanja bit će prikazani naši preliminarni rezultati, koji su pokazali izvrstan potencijal testa za probir osoba s početnim spoznajnim urušavanjem.

Background: Juvenile spondyloarthritis (jSpA) is a diverse group of related syndromes with shared symptoms and pathogenic mechanisms in which both extrinsic environmental factors and intrinsic genetic background perpetuate inflammatory response through immune system alterations. Recently obtained gene signatures in jSpA patients revealed TLR4 and CXCR4 gene had increased, while NLRP3 and PTPN12 had decreased expression.1 Although gene expression is regulated by various mechanisms, the increasing numbers of studies is showing the importance of epigenetic mechanisms in this fundamental biological process. Objectives: To investigate the possible mechanistic role of DNA promoter region methylation and several non-coding micro RNA (miR-150, miR-146a, miR-181a, miR-223) in jSpA patients regarding the expression of genes with previously observed alterations. Methods: The expression of specific microRNAs was analysed in 8 jSpA patients and 5 matched controls using RT-PCR with predeveloped microRNA assays. Methylated DNA Immunoprecipitation (MeDIP) was performed in 19 patients and 7 controls. Enrichment in MeDIP fraction was determined by qRT-PCR using the AriaMx. Results: The difference in fold enrichment of immunoprecipitated DNA was significant only for NLRP3 promotor site (p=0.0220). Expression analysis of selected miRs showed no significant difference in fold change between jSpA patients and healthy controls. Conclusions: Our study indicated epigenetic modifications are probably responsible for some of the expression alterations in jSpA patients in the initial phase of the disease. Since NLRP3 has a crucial role in inflammasome assembly and inflammasomes have been shown to shape microbiota, it is reasonable to assume dysbiosis in jSpA patients can at least partially be explained by reduced NLRP3 expression due to hypermethylation, stressing for the first time the epigenetic contribution to jSpA pathophysiology. While it is still not clear if these epigenetic alterations are caused by genetic mutations in epigenetic factors or exposure to certain environmental factors that mediate the occurrence of aberrant epigenetic profiles, the disocvery of DNA methylation-based signature of the NLRP3 gene could have important implications in addressing extrinsic and intrinsic contribution to jSpA pathophysiology, whereas the possibility of reverting epigenetic modifications opens whole new prospects for therapeutic treatment of this complex disease.

ntroduction and Aims: Upper urinary tract urothelial cancers(UUC) are rare in general population but occur in almost 50% of patients with endemic nephropathy(EN)/aristolochic acid nephropathy (AAN). Aristolochic acid(AA) was proven as the etiological factor both for EN/AAN and UUC. The goal of this study was to identify tumor suppressor genes(TSG) and oncogenes(OG) involved in AA induced carcinogenesis and their posttranscriptional regulation mehanisms by microRNAs. Methods: Paired samples of tumors and adjacent normal urothelial tissues of 13 patients from Croatian and Bosnian endemic regions were analyzed. MiRNA profiling was performed by high- capacity quantitative PCR, while mRNA expression profiling of the same RNAs was done using microarray technology. Immunohistochemistry was performed on tissue microarrays. Results: The broad involvement of known cancer genes in the process of UUC tumorigenesis was revealed by expression profiling analysis of the tumors, implicating on many OG(35 up-regulated ; 54 down- modulated), and TSG(17 up-regulated ; 3 down- modulated). We studied whether the upregulation of specific OG (MYC, FGFR3, HRAS and KRAS) and down regulation of TSG (PTEN and PTCH1) might be augmented in UUC by coordinated action of miRNAs. Figure 1. shows a correlative network implicating numerous down-modulated miRNAregulators of these OG, including tumor suppressor miRNAs miR-23b, miR-143 and miR-145, and also a broad inhibition of PTCH1 by increased oncogenic miRNAs including miR-21, miR-18a and miR-9, and of PTEN by oncogenic miRNAs of the miR- 17-92 family. Both PTEN and PTCH1 appear commonly inhibited by essentially all the members of the miR-200 family. The elevated MYC then represents a central node in these processes, functioning as the activator of miR-17, miR-20 and miR-9 and inhibitor of miR-23b, the repressor of FGFR3 and KRAS, and the tumor- suppressor miRNA let-7c. By means of immunohistochemistry a trend of lower expression of PTEN protein was observed in tumor versus the normal tissue. Conclusions: AAN-associated UTUC carcinogenesis is characterized by a major deregulation of oncogenes and tumor suppressor genes, whose activity may be broadly and modulated by coordinate action of miRNAs.

U vremenu i ekonomskim okolnostima u kojima živimo, prijedlog nacrta Hrvatske strategije za borbu protiv Alzheimerove bolesti podastrt je stručnim društvima, udrugama građana i svim zainteresiranima, pozvanima na javnu raspravu koju smo otvorili na Okruglom stolu u Brelima tijekom CROCAD-14, a nastavili u Zagrebu na 6. psihijatrijskom kongresu. Smioni je to početak otvaranja dijaloga s dionicima Hrvatske Alzheimer alijanse i svim zainteresiranim grupacijama i pojedincima našega društva, kako bi se usvojila strategija temeljem koje će se moći otvoriti dijalog i s predlagateljima zakona i predstavnicima vlasti s ciljem implementacije strategije te ostvarivanja znatne koristi za osobe koje su oboljele od Alzheimerove demencije, odnosno za članove njihovih obitelji.

Background: Clavicular cortical hyperostosis (CCH) is a sterile inflammatory bone disorder of unknown etiology clinically characterized by pain and/or swelling of the clavicle. It has been regarded as a variant of chronic nonbacterial/recurrent multifocal osteomyelitis (CNO/CRMO) but due to lack of other inflammatory sites and recurrence it could also be regarded as a separate disease in the spectrum [1]. Objectives: Identification of specific gene expression patterns in CCH patients. Methods: Total RNA was isolated from whole blood of 18 new-onset, untreated CCH patients and 8 healthy controls. DNA microarray gene expression was preformed in 5 CCH and 4 control patients along with bioinformatical analysis of retrieved data. Carefully selected differentially expressed genes (TRPM2, TRPM3, TRPM7, CASP2, MEFV, STAT3, EIF5A, ERBB2, TLR4, NLRP3, CD24, MYST3) where analyzed by qRT-PCR in all participants of the study. Results: Microarray results and bioinformatical analysis revealed 974 differentially expressed genes, while qRT-PCR analysis showed significantly higher expression of TRPM3 and TRPM7, and lower expression of ERBB2. Conclusions: Microarray data analysis reveled that majority of differentially expressed genes in CCH patients are involved in various inflammatory processes, while qRT-PCR analysis confirmed statistically significant expression change of 3 genes. Among them, TRPM3 and TRPM7 are members of transient receptor potential (TRP) gene superfamily, which encodes proteins that act as multimodal sensor cation channels for a wide variety of stimuli, one of which is environmental temperature that in the case of CCH could be elicited by overuse of sterno- clavicular joint (SCJ) [2]. Upon stimulation, TRP channels transduce electrical and/or Ca2+ signals. Dysfunctions in Ca2+ signaling due to altered TRP channel function can have strong effects on a variety of cellular and systemic processes, including the activation and the regulation of the inflammasomes, which are reported to be involved in CRMO pathogenesis [3, 4]. ERBB2, third gene with significant expression change, belongs to a family of genes that encodes for widely expressed cell surface growth factor receptors. Recently it has been shown that ErbB activation promotes protective cellular outcomes during inflammation, hence lower expression of this gene could cause damage due to inflammation [5]. Based on the results of these and previous studies, we hypothesize that CCH could be an autoinflammatory disease induced by SCJ overuse, TRP channel overexpression, inflammasome activation and reduced protection during inflammation. References: Borzutzky A, Stern S, Reiff A, et al. Pediatric chronic nonbacterial osteomyelitis. Pediatrics. 2012 Nov ; 130(5):e1190-1197. Shimizu S, Takahashi N, Mori Y. TRPs as chemosensors (ROS, RNS, RCS, gasotransmitters). Handbook of experimental pharmacology. 2014 ; 223:767-794. Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nature reviews Immunology. 2013 Jun ; 13(6):397-411. Scianaro R, Insalaco A, Bracci Laudiero L, et al. Deregulation of the IL- 1beta axis in chronic recurrent multifocal osteomyelitis. Pediatric rheumatology online journal. 2014 ; 12:30. Frey MR, Brent Polk D. ErbB receptors and their growth factor ligands in pediatric intestinal inflammation. Pediatric research. 2014 Jan ; 75(1-2):127-132.

Dementia is a syndrome of global and progressive impairment of cognitive abilities which is related to difficulties in performing normal daily activities. Brain-derived neurotrophic factor (BDNF) is a member of neurotrophin family which has been associated with dementia and cognitive decline. The aim of this study was to define the role of BDNF in the development of cognitive symptoms of dementia by analysing BDNF plasma concentration in patients with different types of dementia or diagnosed with mild cognitive impairment (MCI). The study included 207 patients with Alzheimer’s disease (AD), 59 patients with MCI and the total of 52 patients with other non-AD types of dementia (dementia with Lewy bodies, frontotemporal and vascular dementia), diagnosed according to NINCDS-ADRDA and DSM-IV criteria. Cognitive impairment was evaluated using Mini-Mental Status Examination (MMSE) and Clock Drawing Test (CDT). Plasma BDNF levels were measured with enzyme-linked immunosorbent assay, according to the procedures supplied by the manufacturer (R&D Systems GmbH). The association of plasma BDNF levels with cognitive decline was evaluated using Kruskal– Wallis one-way analysis of variance and Spearman correlation coefficient. The results revealed increased BDNF concentration in plasma from patients with AD compared to subjects with MCI or other types of dementia (H=14.22 ; df=4 ; p=0.007). After dividing the patients with AD according to MMSE scores into patients with mild (mild AD), moderate (moderate AD), and severe cognitive impairment (severe AD), a significant (H=9.45 ; df=4 ; p=0.050) association between plasma BDNF levels and cognitive decline was detected, due to a significantly higher BDNF plasma levels in patients with moderate AD compared to patients with mild and severe AD, and compared to patients with MCI or non-AD dementia. The study also points to the positive correlation between plasma BDNF concentration and the total CDT scores in a group of patients diagnosed with non-AD dementia (rs=0.34 ; p=0.028). This research further contributes to the current knowledge on the role of BDNF in the development of cognitive symptoms of dementia, with the purpose to offer new and easily accessible biochemical indicator of cognitive impairment and to provide new insights that will help us to better understand and treat these symptoms.

Introduction: Brain derived neurotrophic factor (BDNF) is an important member of neurotrophin family. Reduced BDNF concentration in different brain areas has been associated with dementia and cognitive decline. Since there is no cure for Alzheimer disease (AD), the studies of the early phases of AD have pointed out the importance of early detection of mild cognitive impairment (MCI). The aim of this study was to define the role of BDNF in the development of cognitive symptoms of dementia by analysing BDNF plasma concentration in patients with AD and MCI. Methods: The study included 119 patients with AD and 50 patients with MCI, diagnosed according to NINCDS-ADRDA and DSM-IV criteria. Cognitive impairment was evaluated using Mini-Mental Status Examination (MMSE). Plasma BDNF levels were measured with enzyme-linked immunosorbent assay, according to the procedures supplied by the manufacturer (R&D Systems GmbH Wiesbaden-Nordenstadt, Germany). The association of plasma BDNF levels with cognitive decline was evaluated using Kruskal–Wallis one-way analysis of variance and Mann–Whitney U test. Results: Our results showed no significant difference in plasma BDNF levels between patients with AD and MCI (U=3453.5 ; P=0.100). After dividing the patients with AD according to MMSE scores into patients with mild cognitive impairment (mild AD), moderate cognitive impairment (moderate AD), and severe cognitive impairment (severe AD), a significant (H=6.59 ; df=2 ; P=0.037) association between plasma BDNF levels and cognitive decline was detected, due to a significantly lower BDNF plasma levels in AD patients with severe cognitive impairment compared to patients with moderate and mild AD. After comparing the patients with MCI to AD patients, subdivided according to MMSE scores, a significant difference in plasma BDNF levels between these groups was confirmed (H = 9.62 ; df=3 ; P = 0.022). Conclusion: In all analyses, patients with severe AD had significantly lower levels of plasma BDNF compared to other groups of patients. Results showed significant trend toward lower plasma BDNF concentration in patients with lower cognitive abilities and these results indicated a possible upregulation of BDNF in patients with mild AD, which may reflect a compensatory mechanism for beta-amyloid accumulation in this early stage of neurodegeneration.

Endemic nephropathy is a syndrome that comprises two entities: chronic interstitial nephropathy and urothelial cell cancers predominantly of the upper urinary tract. The etiological agent for the disease is aristolochic acid, a compound found in the plants of Aristolochia spp. The development of urothelial cancers is characterized by the formation of aristolactam DNA adducts leading to mutations, predominantly A: T->T: A transversions. In order to comprehensively understand the gene regulation programs in upper urothelial cancers we performed integrated miRNA and mRNA expression profiling of paired tumours and unaffected urothelium samples. The obtained data will help us to understand the carcinogenesis caused by aristolochic acid and might be the source for the design of a diagnostic biomarker.