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Svrha ovog rada jest prikazati najčešće aneuploidije spolnih kromosoma i ukazati na njihovu dijagnostiku, etiologiju, epidemiologiju i patofiziologiju, najčešću kliničku prezentaciju i organizaciju cjeloživotne skrbi. Aneuploidije spolnih kromosoma su numerička kromosomska aberacija koja rezultira gubitkom jednog ili dobitkom jednog ili više spolnih kromosoma. Najčešće aneuploidije spolnih kromosoma su Klinefelter sindrom (47,XXY), Turner sindrom (45,X), Triplo X sindrom (47,XXX) i XYY sindrom (47,XYY). Inaktivacija X kromosoma dešava se kako bi se izjednačila doza gena između gena spolnih kromosoma i ostatka genoma. Međutim, određeni geni izbjegavaju inaktivaciju te njihovo prekomjerno izražavanje rezultira fenotipskim abnormalnostima Klinefelter i Triplo X sindroma, dok je izražavanje tih gena slabije u Turner sindromu zbog haploinsuficijencije. Klinefelter sindrom ima veliku varijabilnost kliničke prezentacije, ali iznadprosječna visina je najčešća fenotipska prezentacija. Često imaju male testise i ginekomastiju. Postoji sklonost poteškoćama pri učenju a mnogi pokazuju nižu verbalnu inteligenciju. Djevojčice s Turner su nižeg rasta. Česte srčane anomalije su koarktacija aorte i bikuspidalni aortalni zalistak. Disgeneza gonada je česta pojava, onemogućujući početak puberteta. Kvocijent inteligencije je u rasponu normale, a postoje deficiti u vizualno-prostornim sposobnostima. Triplo X sindrom rijetko uzrokuje očite fizičke abnormalnosti. Djevojke s trostrukim X sindromom mogu imati nešto nižu inteligenciju i poteškoće u verbalnim vještinama. Dječaci sa sindromom XYY obično su viši od prosjeka te pokazuju IQ za 10 bodova niže od prosjeka. Liječenje je uglavnom simptomatsko, s posebnom pažnjom posvećenom komorbiditetima pacijenta i ranom otkrivanju bolesti. Supstitucijska terapija testosteronom koristi se kod Klinefelter sindroma, a estrogenom i hormonom rasta kod Turner sindroma., The purpose of this work is to present the most common sex chromosome aneuploidies and to discuss their diagnosis, etiology, epidemiology, and pathophysiology, as well as the most frequent clinical presentation and lifelong care organization. Aneuploidies of sex chromosomes are numerical chromosomal aberrations that result in the loss or gain of one or more sex chromosomes. The most common aneuploidies of sex chromosomes are Klinefelter syndrome (47,XXY), Turner syndrome (45,X), Triple X syndrome (47,XXX), and XYY syndrome (47,XYY). X chromosome inactivation occurs to equalize gene dosage between sex chromosome genes and the rest of the genome. However, certain genes escape inactivation, and their overexpression results in phenotypic abnormalities in Klinefelter and Triple X syndromes, while expression of these genes is lower in Turner syndrome due to haploinsufficiency. Klinefelter syndrome exhibits a wide range of clinical presentations, but above-average height is the most common phenotype. They often have small testes and gynecomastia. There is a tendency for learning difficulties, and many show lower verbal intelligence. Turner girls have short stature. Common cardiac abnormalities include coarctation of the aorta and bicuspid aortic valve. Gonadal dysgenesis is common, preventing the onset of puberty. IQ ranges within the normal range, with deficits in visual-spatial abilities. Triple X syndrome rarely causes obvious physical abnormalities. Girls with Triple X syndrome may have slightly lower intelligence and difficulties in verbal skills. Boys with XYY syndrome are usually taller than average and exhibit an IQ 10 points lower than the average. Treatment is mainly symptomatic, with special attention given to the patient's comorbidities and early disease detection. Testosterone replacement therapy is used in Klinefelter syndrome, while estrogen and growth hormone therapy are used in Turner syndrome.

Cilj rada je opisati mehanizam djelovanja i kliničku primjenu genske terapije. Genska terapija je biološki medicinski proizvod s aktivnom supstancom koja se sastoji od rekombinantne nukleinske kiseline i primjenjuje se u ljudima s ciljem regulacije, popravka, nadomještanja, dodavanja ili brisanja genske sekvence. Prijenos egzogenog genetičkog materijala u stanice ili transfekcija se može odvijati in ex vivo ili in vivo. Ex vivo pristup uključuje izdvajanje stanica ili tkiva iz pacijenta, genetičku modifikaciju i kultivaciju izdvojenih stanica ili tkiva izvan tijela i zatim vraćanje istih u tijelo pacijenta. In vivo pristup podrazumijeva primjenu genskog terapeutika direkno u tijelo pacijenta, njegovu distribuciju u tkiva, transfekciju ciljnih stanica i genetičku modifikaciju tih stanica. Metode transfekcije mogu biti fizikalne, kemijske i biološke. Većina genske terapije koja se danas primjenjuje u kliničkoj praksi za transfekciju stanica koristi kemijske (nebiološke) i biološke vektore u obliku lipidnih nanočestica i virusa. Vektori su prijenosnici genetičkog materijala koji štite i dopremaju nukleinske kiseline do ciljnih stanica. Cilj genske terapije može biti dodavanje gena, utišavanje gena, uređivanje gena ili eliminacija tumorskih stanica. Dodavanje gena je metoda genske terapije namijenjena liječenju bolesti kod kojih nedostaje izražavanje produkta gena ili se stvara nefunkcionalni produkt. Utišavanjem gena nastoji se ukloniti ili smanjiti ekspresija nekog gena jer njegov produkt prekomjerno izražen i/ili toksičan. Uređivanje gena omogućuje izmjenu DNK sekvence gena, čime se utjecati na ekspresiju proteina, ali i strukturu proteinskog produkta na genomskoj razini. Metoda eliminacije tumorskih stanica temelji se na primjeni onkotropnih virusa koji induciraju staničnu smrt ili pojačavaju imunosnu reakciju domaćina na tumor., The goal of this review is to describe the mechanism of action and clinical applications of gene therapy. Gene therapy is a biological medical product which contains an active substance consisting of recombinant nucleic acid that is used in humans with the goal of regulating, repairing, replacing, adding or deleting the gene sequence. The transfer of exogenous genetic material into cells or transfection can take place ex vivo or in vivo. The ex vivo approach involves extracting cells or tissue from the patient, genetically modifying and cultivating the extracted cells or tissue outside the body and then returning them to the patient's body. The in vivo approach involves the application of gene therapeutics directly into the patient's body, distribution to tissues, transfection of target cells and genetic modification of these cells. Transfection methods can be physical, chemical and biological. Most gene therapy products used in clinical practice today use chemical (non-biological) and biological vectors in the form of lipid nanoparticles and viruses for transfection. Vectors are carriers of genetic material that protect and deliver nucleic acids to target cells. The aim of gene therapy can be to add genes, silence genes, edit genes or eliminate tumor cells. Gene addition is a method of gene therapy intended for the treatment of diseases in which the expression of the gene product is lacking or a non-functional product is created. The goal of gene silencing is to remove or reduce the expression of a gene because its product is overexpressed and/or toxic. Gene editing makes it possible to change the DNA sequence of a gene, thereby influencing protein expression, as well as the structure of the protein product at the genomic level. The method of eliminating tumor cells is based on the application of oncotropic viruses that induce cell death or enhance the host's immune response to the tumor.

Epigenetic changes include all modifications affecting expression of genes without changing the nucleotide sequence of the genome. Most studied epigenetic changes include DNA methylation, histone alterations and non-coding RNAs (ncRNA). DNA methylation is an important epigenetic mark, protecting the genome during gametogenesis and early embryo development. Demethylation process is a genome-wide event, taking place in two distinct waves during gametogenesis. The first event helps restore naïve pluripotency of the zygote, while the second event aids the loss of parental epigenetic memory and facilitates specification of gametes. Histone modifications were recognized in murine and human primordial germ cells where their subsets condense chromatin protecting it from dynamic changes taking place during gamete maturation. Deacetylation of histones was recognized as an important prerequisite of chromosomal segregation during metaphase II. Germline-specific ncRNAs, piRNA is important in inhibiting transposon activity during gametogenesis, protecting overall genome stability. All epigenetic changes are prone to disruption, especially by exogenous factors. In recent years, connection between ARTs and its effects on epigenome remodeling of gametes gained importance. The idea was that medical procedures done to oocytes with the aim of achieved pregnancy could harm these delicate processes and lead to disease. Even though this hypothesis requires more research, a subtle link between the two was discovered. The aim of this thesis is to mention the major epigenetic modifications crucial for normal oocyte and embryo development, all while highlighting their role in reproductive disorders and ART.

Genetics is rapidly advancing, with new technologies revolutionizing research. However, opportunities provided by NGS seemingly cannot be replicated in clinics, due to lack of genetic expertise among specialists. NGS is a DNA sequencing method, allowing rapid detection of genetic variants in probands by comparison to a reference genome. NGS is an important diagnostic tool in the field of Neurology, as the prevalence of genetic factors in etiology is high, such as in a multitude of causes for movement disorders, developmental delay and morphological brain anomalies, epilepsy, and other neurological diseases. The aim of this study was to assess the usefulness of NGS. A retrospective study was per-formed, evaluating the indications for NGS in Neurology and pediatric Neurology from 2018-2022, at the University of Rijeka. Of 116 NGS tests performed across 5 years, 31 pathological variants could be detected across 27 genes, providing a diagnosis for 27 patients (23%). The highest outcome of posi-tive genetic results occurred in developmental anomalies, while the lowest, compared to negative findings, was in dystonia. Genetic movement disorders were found to be more frequent in the younger population, which is in concordance with previous research. Diagnosed developmental delay is a strong indicator for NGS, especially with concomitant structural brain malformations, sei-zures, or movement disorders. NGS is the gold standard for the diagnosis of primary epi-lepsy, indicating that in Rijeka epilepsy is an underrepresented indication for NGS. In conclusion, the guidelines for applications of NGS in Neurology could be optimized, with emphasis on genetic education of neurologists.

Modern teaching and learning in biomedical education require introducing new learning methods with students in focus. Student-oriented pedagogies represent new approaches in the European higher education area, in particular for biomedical studies. Their introduction strives to modernize biomedical education and increase its quality. Personalized, predictive, participatory, and preventive (P4) medicine is revolutionizing medical care in all its aspects. However, the appropriate training that develops the P4 medicine understanding and the skills to implement this new approach needs to be improved in biomedical studies. Various initiatives are promoting new innovative pedagogies in biomedical education, striving to develop research, knowledge, and transversal skills, crucial for the students of the 21st century. Erasmus+ project “Personalized Medicine Inquiry-Based Education - PROMISE” in partnership with five European countries Mediterranean Institute for Life Sciences (Croatia), University of Split (Croatia), University of Zagreb (Croatia), University Pompeu Fabra (Spain), European Alliance for Personalized Medicine (Belgium) and Tamara Milosevic (France) tried to achieve “P4 Education” in biomedical studies. The target group of the project was students from Croatia and Spain. The main objective of the PROMISE project was to prepare students in different biomedical fields, such as biology, biotechnology, pharmacy, and medicine, for the rapidly changing landscape of medical practice and research by creating innovative inquiry-based teaching tools in an online format on the principles of P4 Medicine and Responsible Research and Innovation (RRI). During the project, the partnership developed and implemented the PROMISE program with four online modules, each dealing with one element of P4 Medicine, supplemented with in-person learning expeditions held in Paris, Split, and Zagreb where students deepened their knowledge and skills crucial for their future careers in the biomedical field. Students, after finishing the course, identified several key elements as high-quality content: 1) relevant topics for their future career, 2) raised awareness about the importance of P4 Medicine, 3) relevance of integration with different disciplines, and 4) opportunity to develop transversal skills. Students evaluated the PROMISE program as excellent regarding the methodology used, acquired knowledge, and skills. As a result of their satisfaction with the project activities, students created their youth association through which they are now raising awareness and educating others about P4 Medicine and RRI principles. The project results were evaluated by external evaluators and achieved a high score of 94/100 for project implementation.

Napretkom genetičke tehnologije, genomike i bioinformatike znanje medicinske genetike postaje sve nužnije i korisnije u svakodnevnoj praksi studenata, liječnika, drugih stručnjaka i zdravstvenih djelatnika. Za dobro funkcioniranje multidisciplinarnog tima koji uključuje medicinske genetičare i druge stručnjake važno je poznavanje vokabulara medicinske genetike te alata za dijagnostiku. Upravo su glavni alati za dijagnostiku genetičkih poremećaja dijagnostičke i edukativne baze podataka genetičkih bolesti. Većina takvih baza slobodno je dostupna na internetu, a pružaju relevante informacije temeljene na dokazima. Genetičke baze podataka imaju dvije osnovne funkcije, edukativnu i dijagnostičku. Svrha ovog rada je dati pregled edukativnih i dijagnostičkih elektroničkih baza podataka s ciljem omogućavanja njihovog lakšeg korištenja te uputiti čitatelja gdje i na koji način potražiti informacije o genetičkim poremećajima. Poznavanje genetičkih baza podataka, njihovo razumijevanje i korištenje ima nevjerojatnu vrijednost za današnju i buduću medicinsku praksu. U prvom dijelu rada prikazan je pregled i upute za korištenje najznačajnijih edukativnih elektroničkih genetičkih baza podataka, uključujući OMIM, GeneReviews, Orphanet te PharmGKB. U drugom dijelu rada slijedi kratkih pregled najčešće korištenih dijagnostičkih elektroničkih genetičkih baza podataka, uključujući Human Phenotype Ontology, Face2Gene, ClinVar, gnomAD te Decipher., With the advancement of genetic technology, genomics and bioinformatics, knowledge of medical genetics is becoming more and more necessary and useful in the daily practice of students, doctors, health professionals and others. Knowledge of medical genetics vocabulary and diagnostic tools is important for the proper functioning of a multidisciplinary team that includes medical geneticists and other experts. Diagnostic and educational databases of genetic diseases are the main tools for diagnosing genetic disorders. Most such databases are freely available online and provide relevant evidence-based information. Genetic databases have two basic functions, educational and diagnostic. The purpose of this paper is to provide an overview of educational and diagnostic electronic databases to facilitate their use and instruct the reader where and how to look for information about genetic disorders. Knowledge of genetic databases, their understanding and use is of incredible value for current and future medical practice. The first part of this paper presents an overview and instructions for using the most important educational electronic genetic databases, including OMIM, GeneReviews, Orphanet and PharmGKB. The second part of the paper follows a brief overview of the most used diagnostic electronic genetic databases, including Human Phenotype Ontology, Face2Gene, ClinVar, gnomAD, and DECIPHER.

Maligna hipertermija (MH) farmakogenetička je bolest koja se nasljeđuje autosomno dominantno i ima nepotpunu penetrabilnost. Njezina je procijenjena učestalost 1:100 000 – 1:250 000 u općoj populaciji. Varijante sekvence gena koji su uključeni u regulaciju otpuštanja kalcija iz sarkoplazmatskog retikuluma uzrokuju nastanak ove bolesti. Trenutno je priznato 48 varijanti sekvence gena za rijanodinski RyR1 receptor koji se nalazi na 19. kromosomu i 2 za dihidropiridinski receptor (CACNA1S - engl. Calcium Voltage-Gated Channel Subunit Alpha1 S), a od spominju se još i varijante sekvence STAC3 (engl. SH3 And Cysteine Rich Domain) gena. Zbog tih varijanti sekvence dolazi do promijenjenog odgovora na hlapljive anestetike i sukcinilkolin, koji izazivaju pojačano otpuštanje kalcijevih iona iz sarkoplazmatskog retikuluma i posljedično mišićne kontrakcije koje pak dovode do hipermetaboličkog stanja. U praksi se to očituje povišenjem tjelesne temperature, spazmom mišića, razvojem acidoze, hipoksijom, hiperkapnijom, acidozom i tahikardijom. Komplikacije koje se mogu javiti jesu diseminirana intravaskularna koagulopatija, akutno bubrežno zatajenje i multiorgansko zatajenje. Klinička se dijagnoza postavlja na temelju Kriterija za kliničko stupnjevanje maligne hipertermije koji su bazirani na kliničkoj slici, dok se sama dijagnoza postojanja MH zasniva na testu kontrakture i farmakogenetičkom testiranju. Kliničko se zbrinjavanje sastoji od 4 glavne komponente – uklanjanja okidajućeg agensa, primjene dantrolena, snižavanja tjelesne temperature i zbrinjavanja komplikacija. Cilj ovog diplomskog rada je prikazati farmakogenetičku bolest – malignu hipertermiju, ukazati na njezinu genetičku pozadinu, opisati kliničku sliku i dijagnostički postupak., Malignant hyperthermia is an autosomal dominant pharmacogenetic disease with incomplete penetrance. Its prevalence is estimated to be 1:100 000 – 1:250 000 in the general population. Variants of genes involved in sarcoplasmic calcium release cause this disorder. Currently, there are 48 variants of the RyR1 gene located on the 19th chromosome, and 2 variants of CACNA1S (Calcium Voltage-Gated Channel Subunit Alpha1 S) gene that are accepted as disease-causative genes but variants of the STAC3 (SH3 And Cysteine Rich Domain) gene are also mentioned in literature. Because of these variants, there is an altered response to volatile anaesthetics and succinylcholine leading to an increased release of calcium ions from the sarcoplasmic reticulum thus causing a hypermetabolic state. Clinically, this state manifests as increase in core body temperature, muscle spasm, hypoxia, hypercapnia, acidosis, and tachycardia. The complications that can occur include disseminated intravascular coagulopathy, acute kidney failure and multiorgan failure. The clinical diagnosis is established following the Criteria for clinical grading of malignant hyperthermia proposed by Larach et al. (1994) and Rosenberg et al. (2015). These criteria are based upon the clinical presentation. For the final diagnosis, contracture test and/or pharmacogenetic testing are needed. Treatment follows four base principles – discontinuation of triggering agent, admission of dantrolene, lowering of core body temperature and treating complications. The aim of this graduate thesis is to present a pharmacogenetic disease – malignant hyperthermia, to indicate its genetic background, describe the clinical presentation and diagnostic procedure.

Delecije i duplikacije najčešće su strukturne varijacije genoma čovjeka te se zajedno nazivaju varijacije broja kopija (engl. copy number variation, CNV). CNV se definira kao dodatak ili gubitak dijela DNK u usporedbi s referentnim humanim genomom. Veličina im varira od 1.000 parova baza do nekoliko milijuna parova baza. Rekurentni mikrodelecijski sindromi nastaju promjenama u količini ukupne DNK-a uvijek na istom mjestu u genomu te dovode do prepoznatljivih fenotipova s dobro definiranom korelacijom genotip-fenotip. Nastaju malim delecijama koje iznose manje od 5 Mb dijelova kromosoma te se ne mogu detektirati kariotipizacijom. Ovisno o vrsti rekurentnog mikrodelecijskog sindroma, pacijenti najčešće imaju intelektualno zaostajanje i moguća obilježja poremećaja autističnog spektra, izrazite značajke ponašanja, poremećaje spavanja te kraniofacijalne i skeletne dismorfije. Genomski poremećaji se istražuju i otkrivaju metodom komparativne genomske hibridizacije na mikročipu te se dodatno mogu potvrditi neovisnom metodom kao što je FISH, MLPA ili kvantitativni PCR., Deletions and duplications are the most common structural variations of the human genome and referred to as copy number variations (CNV). CNV is defined as the addition or loss of DNA amount compared to the reference human genome. Their size varies from 1.000 base pairs to several million base pairs. Recurrent microdeletion syndromes are caused by changes in the amount of total DNA always at the same place in the genome and lead to recognizable phenotypes with a well-defined genotype-phenotype correlation. They are formed by small deletions that are less than 5 Mb of chromosome parts and can not be detected by karyotyping. Depending on the type of recurrent microdeletion syndrome, patients most often have intellectual retardation and possible features of autism spectrum disorders, mood or sleep disorders and craniofacial or skeletal dysmorphia. Genomic disorders are investigated and detected by the method of comparative genomic hybridization on a microchip and can be further confirmed by an independent method such as FISH, MLPA or quantitative PCR.

Znanstveni napredak u području genetike otvorio je nove mogućnosti u dijagnostici nasljednih kardiovaskularnih bolesti, kao što je genetičko testiranje. Prema indikaciji, kod kardiovaskularnih bolesti sa genetičkim uzrokom, najčešće se primjenjuju dijagnostičko i prediktivno testiranje. Najčešće kardiovaskularne bolesti, kod kojih se primjenjuje genetičko testiranje uključuju: kardiomiopatije, kanalopatije, aortopatije i obiteljsku hiperkolesterolemiju. Genetičko testiranje kod navedenih bolesti najčešće se provodi kod osoba sa sumnjom na dijagnozu ili kod već postavljene kliničke dijagnoze kako bi se potvrdila. Također se preporuča i testiranje u članova obitelji i rođaka, najprije onih koji pokazuju simptome ili znakove bolesti, ali i u asimptomatskih osoba. Osobe sa pozitivnim rezultatom na genetski poremećaj, treba redovito klinički pratiti. Prije genetičkog testiranja, kao i nakon njega, važno je provesti genetičko savjetovanje u osoba koje se testiraju. Genetičko testiranje na kardiovaskularne bolesti dostupno je u brojnim zdravstvenim ustanovama diljem svijeta, najviše u SAD-u i Zapadnoj Europi. U Hrvatskoj je ono dostupno u nekoliko privatnih zdravstvenih ustanova isključivo u obliku genetičkog testiranja neposredno ponuđenog potrošaču (DTC)., Scientific advances in genetics have opened up new possibilities in the diagnosis of hereditary cardiovascular diseases, such as genetic testing. According to the indication, in cardiovascular diseases with a genetic cause, diagnostic and predictive testing is most often used. The most common cardiovascular diseases in which genetic testing is used include; cardiomyopathies, channelopathies, arthropathies, and familial hypercholesterolemia. Genetic testing for these diseases is most often performed on people with a suspected diagnosis or an already established clinical diagnosis in order to confirm it. It is also recommended to test family members and relatives, first of all, those who show symptoms or signs of the disease, but also in asymptomatic people. People with a positive result for a genetic disorder should be monitored regularly in the clinic. Before and after genetic testing, it is important to conduct genetic counseling for the people being tested. Genetic testing for cardiovascular disease is available in a number of healthcare facilities around the world, most notably in the United States and Western Europe. In Croatia, it is available in several private health care institutions in the form of direct-to-consumer tests.

Cilj ovog istraživanja bio je provesti sveobuhvatnu analizu broja NGS testova te utvrditi indikacije i rezultate testiranja provedenih na Medicinskom fakultetu u Rijeci od uvođenja te dijagnostičke metode. Materijali i metode: Ovom retrospektivnom studijom obuhvaćeno je vremensko razdoblje od 2017. do 2021. godine, a uključuje analizu uputnih dijagnoza i rezultata NGS testova pacijenata, upućenih iz Kliničkog bolničkog centra Rijeka na genetičko testiranje na Medicinski fakultet u Rijeci. NGS je izveden u suradnji s Kliničkim institutom za medicinsku genetiku u Ljubljani (Slovenija), koristeći Illumina NovaSeq 6000 (Illumina Inc.). Rezultati: Tijekom 2017. godine radilo se na uspostavi sustava te su se, u tu svrhu, organizirale brojne edukacije i razgovori s kliničarima. Od travnja 2018. do prosinca 2021. godine je provedeno ukupno 118 dijagnostičkih NGS-a, od čega 8 u 2018. (7 %), 29 u 2019. (25 %), 42 u 2020. (35 %) i 39 u 2021. godini (33 %). Od 2018. godine broj pretraga raste za 425 % u 2019. godini, od 2019. do 2020. za 141 %, te od 2020. do 2021. pada za 8 %. Najčešće indikacije za testiranje bile su neuromišićne bolesti (41 %), kardiomiopatije (19 %) i multiple prirođene anomalije (15 %). Pozitivni rezultati dobiveni su u 53/118 (45 %) slučajeva,od kojih je utvrđeno 14 (26 %) vjerojatno patogenih i 26 (49 %) patogenih varijanti sekvence te 13 (25 %) varijanti nejasnog značaja. U 65/118 (55 %) slučajeva nije pronađena genetička aberacija. Od ukupnog broja pozitivnih nalaza, potvrđeno je 75 % uputnih dijagnoza te samo 34 % od ukupnog broja nalaza. Zaključak: Dobiveni rezultati ukazuju na porast broja provedenih dijagnostičkih NGS testiranja u razdoblju od 2017. do 2021. godine, što odražava povećanu svijest kliničara o potrebi genetičkog testiranja u kliničkoj praksi. Nažalost, veliki broj pogrešnih indikacija za genetičko testiranje upućuje na nužnost genetičke edukacije kliničara, u svrhu boljeg dijagnostičkog učinka., Aim: The aim of this study was to determine the number, indications and results of diagnostic NGS tests performed at the Faculty of medicine in Rijeka, Croatia since its implementation. Materials and Methods: A retrospective study was performed from 2017 to 2021 and included the analysis of referral diagnoses and NGS test reports of patients who were referred to the Faculty of Medicine in Rijeka for diagnostic NGS testing from Clinical Hospital Center Rijeka. NGS was performed in collaboration with the Clinical Institute of Genomic Medicine in Ljubljana (Slovenia), using Illumina NovaSeq 6000 (Illumina Inc). Results: During 2017 was worked on the establishment of the system, and for this purpose, numerous educations and interviews with clinicians were organized. From April 2018 to December 2021, a total od 118 diagnostic NGS were performed, including 8 in 2018 (7 %), 29 in 2019 (25 %), 42 in 2020 (35 %) and 39 in 2021 (33 %). From 2018, the number of NGS testing increase by 425% in 2019, from 2019 to 2020 by 141%, from 2020 to 2021 it decrease by 8%. The most common indications for testing were neuromuscular diseases (41 %), cardiomyopathies (19 %) and multiple congenital anomalies (15 %). Positive test results were obtained in 53/118 (45 %) cases in whom likely pathogenic (26 %) or pathogenic sequence variants (49 %) were determined. Class 3 sequence variants were identified in 13 (11 %) cases. In 65/118 (55 %) cases no genetic aberration could be found. Out of the total number of positive findings, 75 % of referral diagnoses were confirmed and only 34% of the total number of findings. Conclusion: Our results show an increase in the number of diagnostic NGS tests from 2017 to 2021, which reflects the increased awarness of clinicians for the need of genomic testing in clinical practise. Unfortunately, the large number of incorrect indications for genetic testing, indicates that genetic education of clinicians is needed for an improved diagnostic yield.

Cilj: Cilj istraživanja je bio utvrditi internetsku ponudu DTC genetičkih testova u Republici Hrvatskoj s osvrtom na indikacije, prisutnost genetičkog savjetovanja i oglašavanje. Materijali i metode: Za pretraživanje internetske ponude korištena je Google tražilica u razdoblju od 3.2.2022. do 5.2.2022. godine. Ključne riječi korištene u pretraživanju bile su zasebno u svakom pretraživanju: genetičko testiranje, genetsko testiranje, gensko testiranje, genetički testovi, genetski testovi, genski testovi, genetička analiza, genetska analiza, genska analiza, prenatalna dijagnostika, prenatalni testovi, farmakogenetika, farmakogenomika, DNA testiranje, DNA testovi. Rezultati za svaku ključnu riječ pretraživani su do 15. Google stranice. Uključni kriteriji za analizu internetske stranice s DTC ponudom bili su: poliklinike, tvrtke, obrti, specijalne bolnice, laboratoriji, osiguravajuće kuće, istraživački instituti i ustanove za zdravstvenu njegu koje nude genetičke testove. Podaci koji su preuzeti i analizirani za svaku stranicu bili su: vrsta, ime i adresa internetske stranice ponuđača DTC genetičkih testova, vrste genetičkih testova prema indikaciji, uključenost genetičkog savjetovanja u DTC ponudu te način oglašavanja. Rezultati: U Republici Hrvatskoj 68 ponuđača nudi DTC testiranje. Od toga: dijagnostičko (7 ponuđača), prediktivno (1 ponuđač), određivanje statusa nositelja (0 ponuđača), farmakogenomsko testiranje (4 ponuđača), testovi probira (41 ponuđač) i testovi bez indikacije (38 ponuđača). Od toga njih 10 % nudi uslugu genetičkog savjetovanja. Oglašavanje testova je usmjereno na pozitivne učinke genetičkog testiranja. Zaključak: S obzirom na veliki broj ponuđača testova, a mnogi od njih nude testove bez nužnosti postojanja indikacije, potrebna je bolja kontrola DTC tržišta u Republici Hrvatskoj., Objective: The aim of the study was to determine the online offer of DTC genetic tests in the Republic of Croatia with reference to indications, the presence of genetic counseling and advertising. Materials and methods: Google search engine was used to search the Internet offer in the period from 3.2.2022. to 5.2.2022. years. The keywords used in the search were separate in each search: genetic testing, genetic testing, genetic testing, genetic testing, genetic testing, genetic testing, genetic analysis, genetic analysis, genetic analysis, prenatal diagnosis, prenatal testing, pharmacogenetics, pharmacogenomics, DNA testing, DNA tests. The results for each keyword were searched up to the 15th Google page. Including criteria for analyzing the DTC website were: clinics, companies, crafts, special hospitals, laboratories, insurance companies, research institutes, and health care facilities that offer genetic testing. The data downloaded and analyzed for each page were: type, name and address of the DTC genetic testing provider's website, types of genetic testing as indicated, inclusion of genetic counseling in the DTC offer, and method of advertising. Results: In the Republic of Croatia, 68 bidders offer DTC testing. Of which: diagnostic (7 bidders), predictive (1 bidder), carrier status determination (0 bidders), pharmacogenomic testing (4 bidders), screening tests (41 bidders) and non-indication tests (38 bidders). Of these, 10% offer a genetic counseling service. Advertising is focused on the positive effects of genetic testing. Conclusion: Given the large number of test providers, and many of them offer tests without the need for an indication, better control of the DTC market in the Republic of Croatia is needed.

Pojam editiranje gena odnosi se na izmjenu željenog nukleotidnog slijeda DNA molekule. Otkriće novih, revolucionarnih metoda genetičkog editiranja, od kojih su trenutno najpopularnije i najkorištenije nukleaze cinkovih prstiju (engl. zinc finger nucleases, ZFN), efektorske nukleaze nalik aktivatoru transkripcije (engl. transcription activator-like effector nucleases, TALEN) te niz međusobno razdvojenih kratkih, klasteriranih, palindromskih ponavljanja povezanih s proteinom 9 (engl. clustered regularly interspaced short palindromic repeat – CRISPR– associated protein 9, CRISPR-Cas9), uspostavilo je naprednu generaciju alata koji imaju ključnu ulogu u molekularnoj biologiji, ali i nizu drugih biotehnoloških disciplina. Međutim, vjerojatno najveći potencijal za primjenu metoda editiranja genoma čovjeka je u medicini zbog pretpostavke da se promjenama u specifičnim genima mogu suzbiti brojne bolesti i poremećaji koji se još uvijek smatraju neizlječivima na razini uzroka. U tijeku je razvoj novih terapijskih mogućnosti, a jedna od trenutno klinički primjenjivih terapija je stanična imunoterapija T limfocitima koji su genetički modificirani kimernim antigenskim receptorom (engl. chimeric antigen receptor, CAR), za liječenje novotvorina. U ovom završnom radu, osim opisane metodologije alata za editiranje genoma te perspektivnih pretkliničkih i kliničkih ispitivanja za otkriće novih strategija liječenja bolesti, razmatraju se i etički aspekti editiranja genoma, kao i opisane smjernice za njegovu primjenu, koja je za sada moguća isključivo na somatskim stanicama. Kako bi se dostigla pouzdana razina učinkovitosti i sigurnosti metoda editiranja gena, potrebno je daljnje usavršavanje u odabiru adekvatnih metoda dostave programabilnih nukleaza u stanice te ustrajanje u razvoju pouzdanijeg in vivo editiranja, a ponajviše u donošenju etičkih i pravnih okvira za razumno, svrsishodno i nemanipulativno korištenje editiranja genoma., The term gene editing refers to the modification of the desired nucleotide sequence of a DNA molecule. Discovery of new, revolutionary methods of genetic editing, of which the most popular and most used are zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) and clustered regularly interspaced short palindromic repeat – CRISPR–associated protein 9, (CRISPR-Cas9), has established an advanced generation of tools that play a key role in molecular biology, as well as a number of other biotechnological disciplines. However, probably the greatest potential for the application of human genome editing methods is medicine due to the assumption that changes in specific genes can suppress a number of diseases and disorders that are still considered incurable at the cause level. New therapeutic options are being developed, and one of the currently clinically applicable therapies is cellular immunotherapy that uses T lymphocytes that are genetically modified by the chimeric antigen receptor (CAR), for the treatment of neoplasms. In this undergraduate thesis, in addition to the described methodology of genome editing tools and perspective preclinical and clinical trials for the discovery of new treatment strategies, the ethical aspects of genome editing are discussed, as well as the described guidelines for its application, which is currently possible only on somatic cells. In order to achieve a reliable level of efficiency and safety of the gene editing methods, further improvement in the selection of adequate methods for delivering programmable endonucleases to cells is needed, but also persistence in the development of more reliable in vivo editing and in adopting ethical and legal frameworks for the reasonable, purposeful and non-manipulative use of genome editing.

Cilj: Cilj ovog istraživanja bio je ispitati znanje, stavove i ponašanje prema medicinskoj genetici u specijalista i specijalizanata neurologije u Republici Hrvatskoj. Materijali i metode: U istraživanju je sudjelovalo 66 specijalista i specijalizanata neurologije u Republici Hrvatskoj. Ispitanici su anonimno i dobrovoljno ispunjavali online upitnik između siječnja i travnja 2021. Validirani upitnik se sastojao od 84 pitanja koja su podijeljena u pet skupina: Osnovna demografija, znanja, ponašanje u vlastitoj praksi, stavovi o genetičkom testiranju i dodatna edukacija iz medicinske genetike. Rezultati: Medijan znanja neurologa bio je: 10 (raspon 6-10) od 10 mogućih bodova za ulogu genetičkih čimbenika u medicini, 5 (raspon 2-8) od 8 mogućih bodova za podlogu nastanka određenih bolesti, 6 (raspon 3-8) od 9 mogućih bodova za genetičko testiranje, 4 (raspon 3-6) od 6 mogućih bodova za ulogu liječnika specijalista neurologije u skrbi pacijenta s genetičkom bolešću, te 7 (raspon 4-11) od 13 mogućih bodova za ulogu genetičkih čimbenika u neurologiji. Također, 93,9 % neurologa navodi da postoji mogućnost da ne prepoznaju dovoljno pacijente s genetičkim poremećajima, a 63,3 % njih ne upućuje redovito pacijente na genetičko testiranje. Stavovi ispitanika o genetičkom testiranju su bili pozitivni, a 91,3 % ispitanika misli da treba dodatnu edukaciju iz medicinske genetike. Zaključak: Provedeno istraživanje upućuje na činjenicu da specijalisti i specijalizanti neurologije posjeduju vrlo dobra znanja iz područja opće genetike, a lošije iz područja primjenjene genetike u neurologiji. Dobiveni rezultati upućuju na činjenicu da su potrebne dodatne edukacije u skupine neurologa s ciljem podizanja razine znanja iz neurogenetike, što bi omogućilo uspješniju skrb za pacijente s genetičkim poremećajima u neurologiji., Aim: Aim: The aim of this study was to examine knowledge, attitudes and behavior towards medical genetics in specialists and neurology residents in the Republic of Croatia. Materials and Methods: 66 specialists and neurology residents in the Republic of Croatia participated in the study. Respondents filled out an online questionnaire anonymously and voluntarily between January and April 2021. The validated questionnaire consisted of 84 questions that were divided into five groups: Basic demographics, knowledge, behavior in their own practice, attitudes towards genetic testing and additional education in medical genetics. Results: The median knowledge was: 10 (range 6-10) of 10 possible points for the role of genetic factors in medicine, 5 (range 2-8) of 8 possible points for the basis of the occurrence of certain diseases, 6 (range 3-8) of 9 possible points for genetic testing, 4 (range 3-6) of 6 possible points for the role of a neurology specialist doctor in the care of patients with genetic diseases, and 7 (range 4-11) of 13 possible points for the role of genetic factors in neurology. Also, 93.9% of neurologists report that there is a chance that they may not sufficiently identify patients with genetic disorders, and 63.3% do not regularly refer patients for genetic testing. Participants' attitudes towards genetic testing were positive, and 91.3% of respondents thinking they needed additional education in medical genetics. Conclusion: Our research points to the fact that neurology specialists and residents possess very good knowledge in the field of general genetics, and worse in the field of applied genetics in neurology. The obtained results point to the fact that additional educations are needed with the aim of raising the level of knowledge in neurogenetics, which would allow more successful care for patients with genetic disorders in neurology.

Cilj: Cilj ovog istraživanja bio je ispitati znanja i stavove o medicinskoj genetici u specijalista i specijalizanata pedijatrije u Republici Hrvatskoj, kao i ponašanje u vlastitoj praksi te u kojim bi segmentima medicinske genetike liječnici htjeli usavršiti svoje znanje. Materijali i metode: Ispitanici ( 82 ispitanika, medijan dobi 42,5 (min. 26- max. 70), ženskih ispitanica 68 (83 %), muških ispitanika 14 (17 %) ) su ispunjavali online upitnik koji im je bio proslijeđen na adrese elektroničke pošte u siječnju i veljači 2021. godine. Upitnik se sastojao od 86 pitanja podijeljenih u 5 skupina: opće informacije, znanje, ponašanje u vlastitoj praksi, stavovi o genetičkom testiranju i dodatna edukacija iz medicinske genetike. Rezultati: Medijan bodova ukupnog znanja ispitanika je 29 (21,2-34) od mogućih 41, a ispitanici svoje znanje ocjenjuju ocjenom 3 (1-5). Uočava se pozitivan stav prema genetičkom testiranju i dijagnostici te nema protivljenja genetičkom testiranju. Čak 84 % ispitanika je voljno sudjelovati na dodatnom usavršavanju iz medicinske genetike. Zaključak: Naši rezultati pokazuju da trenutne razine znanja o medicinskoj genetici u specijalizanata i specijalista pedijatrije upućuju na potrebu za dodatnim edukacijama iz medicinske genetike., Aim: The aim of this research was to examine the knowledge and attitudes towards medical genetics in specialists and residents of pediatrics in Republic of Croatia as well as behaviour in their job and which segments of medical genetics they want to improve they knowledge about. Materials and methods: The study was conducted by filling online questionaire that was forwarded to e-mail adresses during January and February of the year 2021 to respondents ( 82 respondents, age median 42,5 (min. 26- max. 70), 68 (83 %) respondents were female and 14 (17 %) respondents were male) . Respondents filled valid online questionnaire consisting of 86 questions divided into five groups: general information, knowledge, behaviour in their own practice, attitudes toward genetic testing and additional medical genetic education Results: Median of points of total knowledge of respondents is 29 (21,2-34) out of 41, they rate their knowledge with grade 3 (1-5) , and 84 % of respondents would like to participate in additional education. Conclusion: It is neccesarry to improve the knowledge of doctors about medical genetics. Our respondents have positive attitude about genetic testing and are aware of fact that there is great chance of not recognising patients with genetical disorder.

Cilj: Cilj istraživanja je bio ispitati genetičku pismenost u specijalizanata i specijalista ginekologije i porodništva u Hrvatskoj. Ispitanici i postupci: U istraživanje su bili uključeni liječnici specijalisti ginekologije i porodništva Republike Hrvatske koji su dobrovoljno ispunjavali anonimni online upitnik u periodu od siječnja do travnja 2021. godine. Upitnik se sastojao od 88 pitanja podijeljenih u pet skupina (opće informacije, znanja o medicinskoj genetici, ponašanja u vlastitoj praksi, stavovi o genetičkom testiranju, potrebe za dodatnom edukacijom iz medicinske genetike). U istraživanju je sudjelovalo 42 ispitanika. Rezultati: Ispitujući znanja o medicinskoj genetici, medijan je točnih odgovora ukupno bio 29,5 (21-34) , a specijalisti i specijalizanti u Hrvatskoj imaju izrazito pozitivne i ispravne stavove prema genetičkom testiranju. Također, naše je ispitivanje pokazalo kako ispitanici prepoznaju potrebu za dodatnom edukacijom iz medicinske genetike i spremni su sudjelovati u provođenju iste. Zaključak: Ukupno je znanje specijalista i specijalizanata ginekologije i porodništva u Republici Hrvatskoj prosječno, što naglašava potrebu za dodatnom edukacijom kako bi se u svakodnevnoj praksi pacijentima pružala što bolja skrb iz brzorastućeg područja medicinske genetike., Aim: Aim of this research was to look into genetic literacy among residents and specialists of gynecology and obstetrics in Croatia. Participants and methods: Participants included in this research were residents and specialists of gynecology and obstetrics in Croatia. They volunteered to participate in anonymous online survey in period from January to April of 2021. Survey consisted of 88 questions divided into 5 categories (general information, knowledges on medical genetics, behaviors in clinical practice, attitude on genetic testing, need for further education in medical genetics). Survey was carried out by 42 participants. Results: Questioning knowledges about medical genetics median of correct answers was 29,5. Residents and specialists of gynecology and obstetrics have pronouncedly positive and correct attitudes towards genetic testing. Also, our research showed that participants recognized the need for further education in medical genetics and are willing to participate if such education would be organized. Conclusion: All together, knowledge of residents and specialists of gynecology and obstetrics in Republic of Croatia is average which emphasizes the need for further education so patients in everyday medical care would be given better care in field of medical genetics.

Deficijencija PAH-a je metabolička autosomno recesivna bolest uzorokovana varijantama sekvence gena za PAH ili deficijencijom kofaktora BH4 potrebnog za pretvorbu fenilalanina u tirozin. Karakterizirana je povećanim koncentracijama aminokiseline fenilalanina u krvi te fenilpiruvične kiseline u mokraći. U kliničkoj slici javlja se specifičan tjelesni miris, intelektualno zaostajanje, epileptični napadi, mikrocefalija. Simptomi variraju od blagih do teških. U ranom prepoznavanju deficijencije PAH-a, veliku važnost ima novorođenački probir. Ukoliko novorođenački probir ukaže na postojanje deficijencije PAH-a, provodi se dijagnostičko genetičko testiranje. Određivanje statusa nositelja kod srodnika provodi se nakon dijagnosticiranja bolesti u probanda. Ako su oba partnera nositelji, rizik za autosomno recesivnu bolest iznosi 25 %. Osnovni korak liječenja deficijencije PAH-a je kontrolirana prehrana, a mogu se primjeniti sapropterin i transporteri za velike neutralne aminokiseline. Također, istražuje se učinak fenilalanin-amonij-lijaze i transplantacije hepatocita. Kod žena koje imaju povišene koncentracije fenilalanina u plazmi tijekom trudnoće, postoji visoki rizik nastanka disrupcija i intelektualnog zaostajanja kod djeteta. Iz tog razloga se preporučuje prekoncepcijsko genetičko savjetovanje te postizanje i održavanje koncentracije fenilalanina u majčinom serumu manjom od 360 μmol / L tri mjeseca prije začeća. U posljednje vrijeme, provodi se prošireni genomski probir statusa nositelja čime se, uz informiranje javnosti i genetičko savjetovanje, može spriječiti pojava autosomno recesivnih bolesti. Cilj rada je opisati mogućnosti novorođenačkog probira i genetičkog testiranja u svrhu što ranije dijagnostike deficijencije PAH-a, ali i istaknuti važnost prepoznavanja kliničkih obilježja te modernog pristupa genetičkom testiranju kojim se otkrivaju nositelji autosomno recesivnih bolesti, Deficiency of PAH is a metabolic autosomal recessive disease caused by a PAH gene sequence variants or a BH4 cofactor deficiency required to convert phenylalanine to tyrosine. It is characterized by increased levels of the amino acid phenylalanine in the blood and phenylpyruvic acid in the urine. In the clinical presentation there is a specific body odor, intellectual retardation, seizures, microcephaly. Symptoms range from mild to severe. In the early recognition of PAH deficiency, neonatal screening is of great importance. If newborn screening indicates PAH deficiency, diagnostic genetic testing is performed. Determination of the status of the carrier in a relative is made after the diagnosis of the disease in the proband. If both partners are carriers, the risk of autosomal recessive disease is 25%. A basic step in the treatment of PAH deficiency is a controlled diet, and sapropterin and transporters for large neutral amino acids can be used. The effect of phenylalanine-ammonium lyase and hepatocyte transplantation is also being investigated. In women with elevated plasma phenylalanine concentrations during pregnancy, there is a high risk of dysfunction and intellectual disability in the newborn. For this reason, pre-conceptual genetic counseling and the attainment and maintenance of maternal serum phenylalanine concentrations less than 360 μmol / L for three months prior to conception are recommended. Recently, an extended genomic screening of carrier status has been carried out, which, in addition to general public education and genetic counseling, can prevent the occurrence of autosomal recessive diseases. The aim of this study is to describe the possibilities of newborn screening and genetic testing for early diagnosis of PAH deficiency, but also to emphasize the importance of recognizing clinical features and a modern approach to genetic testing revealing carriers of autosomal recessive diseases. is a metabolic autosomal recessive disease caused by a PAH gene sequence variants or a BH4 cofactor deficiency required to convert phenylalanine to tyrosine. It is characterized by increased levels of the amino acid phenylalanine in the blood and phenylpyruvic acid in the urine. In the clinical presentation there is a specific body odor, intellectual retardation, seizures, microcephaly. Symptoms range from mild to severe. In the early recognition of PAH deficiency, neonatal screening is of great importance. If newborn screening indicates PAH deficiency, diagnostic genetic testing is performed. Determination of the status of the carrier in a relative is made after the diagnosis of the disease in the proband. If both partners are carriers, the risk of autosomal recessive disease is 25%. A basic step in the treatment of PAH deficiency is a controlled diet, and sapropterin and transporters for large neutral amino acids can be used. The effect of phenylalanine-ammonium lyase and hepatocyte transplantation is also being investigated. In women with elevated plasma phenylalanine concentrations during pregnancy, there is a high risk of dysfunction and intellectual disability in the newborn. For this reason, pre-conceptual genetic counseling and the attainment and maintenance of maternal serum phenylalanine concentrations less than 360 μmol / L for three months prior to conception are recommended. Recently, an extended genomic screening of carrier status has been carried out, which, in addition to general public education and genetic counseling, can prevent the occurrence of autosomal recessive diseases. The aim of this study is to describe the possibilities of newborn screening and genetic testing for early diagnosis of PAH deficiency, but also to emphasize the importance of recognizing clinical features and a modern approach to genetic testing revealing carriers of autosomal recessive diseases.

Cilj ovog istraživanja bio je ispitati znanja i stavove o medicinskoj genetici u studenata Medicinskog fakulteta u Rijeci, kao i utjecaj edukacije iz istoimenog obaveznog kolegija na njihovu promjenu. Materijali i metode: Istraživanje je provedeno na 191 studenata pete i šeste godine Integriranog preddiplomskog i diplomskog Sveučilišnog studija Medicina u akademskoj godini 2019/2020 na Medicinskom fakultetu u Rijeci. Studenti su anonimno i dobrovoljno ispunjavali validirani „online“ upitnik koji se sastojao od 60 pitanja podijeljenih u četiri skupine (demografija, znanja, stavovi, osobna uvjerenja). Studenti pete godine dva su puta ispunjavali upitnik (na početku i završetku kolegija) dok su studenti šeste godine upitnik ispunjavali samo jednom, tri mjeseca nakon završenog kolegija. Edukacija je pomno osmišljena za studente medicine i temeljena je na dokumentu o stjecanju osnovnih kompetencija iz medicinske genetike kojeg propisuje Europsko udruženje za humanu genetiku. Rezultati: Stupanj odaziva bio je 84,7 % za ispitanike pete, a 85,8 % za ispitanike šeste godine. Korištenjem Kruskal-Wallis testa pronađena je statistički značajna razlika prije i poslije obrazovanja između pete godine prije i nakon edukacije, te između pete godine prije edukacije i šeste godine za: (a) ukupno znanje (P, Aim: The aim of this research was to examine the knowledge and attitudes towards medical genetics in students of the Medical Faculty in Rijeka, as well as the impact of education from the compulsory course of the same name on their change. Materials and methods: The study was conducted on 191 fifth and sixth year students of the Integrated Undergraduate and Graduate University Study of Medicine in the academic year 2019/2020 at the Faculty of Medicine in Rijeka. Students completed anonymously and voluntarily a validated "online" questionnaire consisting of 60 questions divided into four groups (demography, knowledge, attitudes, personal beliefs). Fifth-year students completed the questionnaire twice (at the beginning and end of the course) while sixth-year students completed the questionnaire only once, three months after completing the course. The education is carefully designed for medical students and is based on a document on the acquisition of basic competencies in medical genetics prescribed by the European Association for Human Genetics. Results: The response rate was 84.7% for fifth-year respondents and 85.8% for sixth-year respondents. Using the Kruskal-Wallis test, a statistically significant difference was found between fifth year before and after education and between the fifth year before education and sixth year for: (a) total knowledge (P

Cilj istraživanja: Istražili smo kliničke i metaboličke značajke pretilosti i indeksa tjelesne mase (ITM) u dvije grupe nemediciranih bolesnika sa shizofrenijom iz hrvatske populacije: bolesnika s prvom epizodom shizofrenije (nikada nisu uzimali antipsihotike) i neadherentnih kroničnih bolesnika. Ispitanici i metode: Anamnestički podaci korišteni su u procjeni nemediciranosti. Pretilim su bolesnicima smatrani oni s vrijednostima ITM-a > 30, dok su bolesnici s normalnom tjelesnom masom (ITM: 20 – 25) i prekomjernom tjelesnom masom (ITM: 25 – 30) smatrani nepretilima. Rezultati: U odnosu na nepretile bolesnike s prvom epizodom shizofrenije, pretili su imali višu dob nastupa bolesti, niže vrijednosti depresivnog faktora, više omjere LDL kolesterol (engl. low density lipoprotein cholesterol)/HDL kolesterol (engl. high density lipoprotein cholesterol) i trigliceridi/HDL kolesterol te više koncentracije glukoze (P < 0,05). U usporedbi s nepretilim neadherentnim kroničnim bolesnicima, kod pretilih su opaženi veći broj psihotičnih epizoda, niže vrijednosti pozitivnog faktora i više koncentracije HDL kolesterola (P < 0,05). U bolesnika s prvom epizodom shizofrenije ITM pozitivno korelira s koncentracijama triglicerida i glukoze te omjerima LDL kolesterol/HDL kolesterol i trigliceridi/HDL kolesterol (P < 0,05). Kod neadherentnih kroničnih bolesnika, vrijednosti ITM-a pozitivno koreliraju s brojem psihotičnih epizoda, a negativno, sa zbrojem općih i ukupnih simptoma PANSS-a (Positive and Negative Syndrome Scale) te kognitivnim faktorom (P < 0,05). Multipla regresijska analiza pokazala je da pretilost doprinosi s ~3,1 % do 9 % istraženim varijablama, dok se doprinos ITM-a kreće od ~4,5 % do 29,4 %. Zaključak: Pretilost i više vrijednosti ITM-a djeluju protektivno na kliničku psihopatologiju kod kroničnih bolesnika. Pretilost odgađa nastup bolesti u bolesnika s prvom epizodom shizofrenije. Više vrijednosti ITM-a rizičan su čimbenik za broj psihotičnih epizoda i snizuju vrijednosti HDL kolesterola u kroničnih bolesnika, a u bolesnika s prvom epizodom shizofrenije prvenstveno povisuju rizik za poremećaj metabolizma lipida i glukoze., Aim: We investigated clinical and metabolic variables of obesity and body mass index (BMI) among two groups of unmedicated schizophrenia patients from the Croatian population: antipsychotic-naïve first-episode patients and nonadherent chronic patients. Patients and methods: Information about medication nonadherence was obtained via self-report. Patients were classified as obese with BMI > 30, and non-obese, those who were overweight (BMI: 25 – 30), or those having a normal weight (BMI: < 25). Results: Compared with non-obese patients with first-episode schizophrenia, obese with first-episode schizophrenia were older at disease onset; scored lower for depression factor; had higher ratios for LDL cholesterol (low density lipoprotein cholesterol, LDL-c)/HDL cholesterol (high density lipoprotein cholesterol, HDL-c) and triglycerides/HDL-c, and higher glucose levels (P < 0,05). Compared with non-obese nonadherent chronic individuals, obese nonadherent chronic individuals manifested higher number of psychotic episodes; scored lower for positive factor and experienced lower HDL-c levels (P < 0,05). Among first-episode schizophrenia individuals, BMI positively correlates with triglyceride and glucose levels, ratios for LDL-c/HDL-c and triglycerides/HDL-c, and negatively with HDL-c levels (P < 0,05). Among nonadherent chronic individuals, BMI positively correlates with number of psychotic episodes and negatively with Positive and Negative Syndrome Scale (PANSS) general psychopathology scores, PANSS total symptom scores, cognitive factor and HDL-c levels (P < 0,05). Multiple regression analysis indicated that the contribution of obesity to investigated variables ranged from ~3.1% to 9%, while the contribution of BMI ranged from ~4.5% to 29.4%. Conclusion: Obesity and higher BMI protect against clinical psychopathology among chronic patients. Obesity delays disease onset among first-episode schizophrenia patients. Higher BMI is a risk factor for number of psychotic episodes and lower HDL-c levels among chronic patients, while among first-episode schizophrenia patients predominantly increases the risk for lipid and glucose metabolism abnormalities.

Cilj: Metilentetrahidrofolat reduktaza (MTHFR) je enzim koji remetilira i odstranjuje homocistein iz organizma, aminokiselinu koja u visokim razinama može dovesti do oštećenja krvnih žila. DNA metilacija je epigenetički mehanizam čija razina ima bitnu ulogu u raznim bolestima. Radi se o promjenama u (epi)genetičkom materijalu koje su međusobno povezane i mogle bi imati utjecaj na tijek trudnoće. Cilj ovog završnog rada bio je istražiti povezanost između MTHFR C677T SNP-a jednog nukleotida i prijevremenog poroda (PP) u žena hrvatske i slovenske populacije te provesti sustavni pregled literature o povezanosti između razine DNA metilacije i PP-a. Ispitanici i metode: U naše istraživanje bilo je uključeno 50 žena s PP-om i 50 žena kontrola. Genotipizacija MTHFR C677T provedena je kombinacijom polimerazne lančane reakcije (engl. polymerase chain reaction, PCR) i polimorfizma dužine restrikcijskih fragmenata (engl. restriction fragment-lenght polymorphism, RFLP). Sustavni pregled literature izvršen je pomoću baza podataka PubMed i Scopus, a odabrani su izvorni znanstveni članci na engleskom jeziku. Rezultati: Nisu utvrđene statistički značajne razlike u frekvenciji genotipa i alela MTHFR C677T između žena s PP-om i žena kontrolne skupine, po nijednom genetičkom modelu. Pretraživanjem literature pronađeno je četiri članka koja su istraživala povezanost DNA metilacije s PP-om, ali s oprečnim rezultatima. Zaključak: MTHFR C677T ne povećava predispoziciju za PP u žena europske populacije. Na temelju provedenog sustavnog pregleda literature i oprečnih rezultata ne mogu se donijeti konačni zaključci o ulozi MTHFR C677T polimorfizma jednog nukleotida i DNA metilacije kao čimbenika podložnosti za PP. Potrebna su dodatna istraživanja, Aim: Methylenetetrahydrofolate reductase (MTHFR) is an enzyme important for remethylation of homocysteine, a toxic amino acid that can lead to the damage of blood wessels. DNA methylation is an epigenetic mechanism with a significant role in many diseases. Both are associated with various pathological conditions and could also have an essential role during pregnancy. We tried to determine the connection between MTHFR C677T polymorphism and preterm birth (PTB) in Croatian and Slovenian women and conducted a systematic review on the role of DNA methylation as a predisposing factor for PTB. Patients and methods: In our case-control study we included 50 women with PB and 50 control women. The MTHFR C677T polymorphism was identified using the combination of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). We used PubMed and Scopus to search for original scientific articles in English. Results: We found no statistically significant difference in the frequency of MTHFR C677T polymorphism between the women with PTB and the control women. Also, no association was detected under all genetic models. We identified four articles that studied the association between DNA methylation and PTB in the literature search, with different results. Conclusion: The MTHFR C677T polymorphism is not a predisposing factor for PTB in Croatian and Slovenian women. Based on our systematic review, there is no conclusive connection between DNA methylation and PTB. Additional studies are needed.