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Aim: Recurrent pregnancy loss (RPL) is a reproductive disorder defined as the loss of two or more pregnancies from the time of conception until 24 weeks of gestation. Despite the fact that several mechanisms have been previously described for the pathogenesis of RPL, the causes of approximately 50% remain unknown. However, recent studies indicate association of vitamin D with adverse pregnancy outcome, including RPL. The vitamin D receptor (VDR) is a crucial mediator of the pleiotropic cellular effects of vitamin D. It's function is influenced by several single nucleotide polymorphisms (SNPs). The main objective of the present study was to assess whether three different maternal VDR SNPs are associated with the risk of RPL in Slovenian and Croatian women. Methods: A case – control study including 320 women was designed to examine the potential association of VDR polymorphisms (FokI rs222857, Cdx2 rs115688 and Taq1 rs731236) with RPL. Genotyping was performed using PCR-RFLP methods. Results: We found a statistically significant higher frequency of the FokI rs222857 CC genotype (X2=6.61, P=0.036) and C allele (X2=5.93, P=0.015) in women with RPL compared to controls. Additionally, the odds for RPL were increased under the recessive (CCvsCT+TT: OR=1.78 ; 95% CI=1.12-2.82 ; P=0.015) and codominant genetic models (CCvsTT: OR=2.21 ; 95% CI=1.08-4.53 ; P=0.029 ; CCvsCT: OR=1.68 ; 95% CI=1.04-2.72 ; P=0.036). Furthermore, Taq1 rs731236 C allele showed a statistically significant higher frequency in women with RPL compared to controls (X2=4.13, P=0.042). Conclusion: Our results suggest that the CC genotype of the FokI rs222857 polymorphism in women might be a genetic marker for RPL.

Aim: Preterm birth (PTB) is defined as birth of a new-born prior to the completed 37th week of gestation. Prior studies confirmed the association between low levels of vitamin D and increased risk of PTB. Considering that polymorphisms of vitamin D receptor (VDR) gene may modify the effects of vitamin D, several studies investigated the potential association between FokI and ApaI single nucleotide polymorphisms of the VDR gene and PTB in different races. The aim of our study was to evaluate the association between FokI and ApaI polymorphisms of the VDR gene and PTB in European Caucasian women, as well as their effect on clinical characteristics of women with PTB and their new-borns (smoking, family history of PTB, maternal and gestational age at delivery, new-born birth weight). Patients and methods: A case-control study was conducted in 113 women with spontaneous PTB (SPTB ; PTB with intact membranes) and 119 women with term delivery. Genotyping of FokI and ApaI polymorphisms of the VDR gene were performed using polymerase chain reaction and restriction fragment length polymorphism methods. Results: No statistically significant differences were found in the distribution of genotype or allele frequencies of tested polymorphisms between patients and controls. We found a statistically significant effect of FokI polymorphism on new-born birth weight in women with SPTB using two-way ANOVA: Factorial design with Scheffe test (F=4.53, P=0.013), with the lowest birth weight identified in mothers carrying the FokI TT genotype (P=0.021). There was no statistically significant interaction between the FokI and ApaI polymorphisms on birth weight. Neither polymorphism was associated with any other clinical characteristic of women with SPTB and their new-borns. Conclusion: We determined that the TT genotype of the VDR FokI polymorphism is associated with new-born birth weight in European Caucasian women with SPTB.

Aim: Recurrent spontaneous abortion (RSA) is defined as three or more consecutive pregnancy losses before the 22nd week of gestation. It affects approximately 1% of couples and can be caused by several factors. However, the cause remains unidentified in about 50% of the cases, which are classified as idiopathic (IRSA). Among various possible etiological factors, aberrant DNA methylation has been suggested to be one of the possible causes of IRSA. Considering the growing evidence of the important roles of DNA methylation in gametogenesis and early pregnancy, as well as the results of multiple studies that indicate abnormal methylation patterns in the endometrium, spermatozoa and placenta of patients with IRSA, our aim was to investigate the potential association of DNA methyltransferase gene polymorphisms (DNMT1 rs2228611, DNMT3A rs1550117 and DNMT3B rs1569686) with IRSA in Slovenian reproductive couples. Patients and methods: 146 couples with ≥3 idiopathic spontaneous abortions and 149 control women and men were included in this case-control study. Genotyping was performed using polymerase chain reaction and restriction fragment length polymorphism methods. Results: We found a statistically significant higher frequency of the DNMT3B rs1569686 GG genotype (X2=7.37, P=0.025) and G allele (X2=6.33, P=0.012) in women with IRSA compared to controls. Additionally, the odds for IRSA in women were increased under the recessive genetic model (GGvsTG+TT: OR=1.92 ; 95% CI=1.18-3.09 ; P=0.008). There were no statistically significant differences in genotype and allele frequencies of any other tested polymorphism between IRSA patients and controls. Moreover, no significant associations occurred between the DNMT1 rs2228611 and DNMT3A rs1550117 polymorphisms and the risk of IRSA. Conclusion: Our results suggest that the GG genotype of the rs1569686 polymorphism in the DNMT3B gene in women might be a genetic marker for IRSA.

Aim: Preterm birth (PTB) is a birth that occurs before the 37th week of gestation and is the leading cause of neonatal mortality and morbidity. DNA methyltransferases (DNMTs) establish DNA methylation patterns at specific genome regions and contribute to gene regulation. Previous studies have reported on an association between spontaneous PTB (SPTB ; birth with intact membranes) and epigenetic changes (i.e. methylation levels) in maternal blood, placenta and cord blood. Additionally, certain DNMT3B gene polymorphisms in women were found to be associated with an increased risk for SPTB. The aim of this study was to evaluate the potential association between SPTB and DNMT1, 3A, 3B and 3L gene polymorphisms in European Caucasian women, and their contribution to clinical characteristics of women with SPTB and their new-borns. Patients and methods: A total of 113 women with SPTB and 119 women with term delivery were included in a case-control study. Genotyping of DNMT1 rs2228611 A/G, DNMT3A rs1550117 A/G, DNMT3B rs1569686 G/T and DNMT3L rs2070565 A/G single nucleotide polymorphisms was performed using polymerase chain reaction and restriction fragment length polymorphism methods. Results: No statistically significant differences were found in the distribution of genotype or allele frequencies of tested polymorphisms between patients and controls. However, the DNMT3B rs1569686 minor allele (T) was more frequent in women with familial SPTB than women with non-familial SPTB (Χ2=7.65, P=0.006), contributing to a 4.02 increased odds for familial SPTB under the dominant genetic model (TG+TTvsGG) (95% CI=1.56-10.40, P=0.004). None of the other polymorphisms contributed to the clinical characteristics of women with SPTB and their new-borns (family history of SPTB, maternal and gestational age at delivery, fetal birth weight). Conclusion: The DNMT3B rs1569686 T allele in European Caucasian women might be associated with a positive family history of SPTB.

U ovom kratkom preglednom članku prikazani su trenutni prijepori i napredci vezani uz definiciju i uzroke ponavljajućih spontanih pobačaja, s posebnim osvrtom na genetičke čimbenike. Prikazane spoznaje temeljene su na najnovijim rezultatima opažajnih i pokusnih istraživanja te sustavnih pregleda i metaanaliza., The aim of this mini-review is to give an overview of the current controversies and advances regarding the definition and causes of recurrent spontaneous abortion, with particular emphasis on genetic factors. The presented knowledge is based on the most recent findings of observational and experimental studies, as well as systematic reviews and meta-analyses.

Prvi pregledi koljena magnetskom rezonancijom u ovome dijelu Europe obavljeni su u Zagrebu, u Općoj bolnici „Sveti Duh” na Zavodu za radiologiju 1989. godine, već dvije godine nakon Minkova izdanja knjige „MRI koljenskoga zgloba”. U osamnaest godina kontinuiranoga rada na permanentnome rezonatoru Hitachi MRP 20, 0.2 T, u potpunosti je odgovoreno mnogobrojnim specifičnim zahtjevima i pitanjima kliničara iz svih područja radiologije, sukladno tome i pitanjima iz domene mišićnokoštane radiologije. Iako je samo nekoliko autora u počecima sugeriralo da se dijagnostički vrijedne snimke mogu napraviti i na rezonatorima niskoga polja, naši su pregledi kliničarima pokazali iznimno vrijedne dijagnostičke informacije. U ovome stručnom članku prikazuje se anatomiju koljenskoga zgloba na način na koji ga analiziramo na rezonatoru Philips Achieva 1.5T, instaliranome u veljači 2008. godine u Zavodu za radiologiju Kliničke bolnice „Sveti Duh”. Prilikom procjene patologije koljenskoga zgloba, kolegijalna suradnja uspostavljena je sa Zavodom za radiologiju Kliničkoga bolničkog centra Osijek, u svrhu najboljeg odabira relevantnih sekvenci za optimalni odgovor kliničaru. Mjesečno se napravi od 80 do 100 pregleda mišićnokoštanoga sustava, od čega i dalje prevladavaju pregledi koljenskoga zgloba. Prikazujemo najčešću patologiju u dnevnoj kliničkoj praksi pacijenata koji pristupaju pregledima po preporuci specijalista ortopedije ili fizikalne medicine. Treba istaknuti da su danas i liječnici opće medicine dobro obaviješteni i svjesni vrijednosti pregleda koljenskoga zgloba magnetskom rezonancijom, kao i sigurnosti kliničara u prijeoperativnoj pripremi. Stoga više nije rijedak slučaj da kliničari sami naručuju svoje bolesnike elektronski ili u konzultaciji s radiologom.

U ovom istraživanju nije utvrđena povezanost idiopatskih ponavljajućih spontanih pobačaja i insercijsko-delecijskih polimorfizama u ACE, NOS3 i VEGFA genima u žena.

Što viši stupanj opremljenosti broda prije porinuća jedan je od važnijih ciljeva svakog suvremenog brodogradilišta za novogradnje, a opremanje nakon porinuća broda teži se svesti na najmanju moguću mjeru. Stoga, u ovom će se radu analizirati sadašnje stanje u promatranom brodogradilištu te će se u procesu opremanja identificirati i analizirati čimbenici i njihov utjecaja na razinu opremljenosti broda prije porinuća. Nadalje, u radu će se identificirati oni čimbenici s najvišim utjecajem na razinu opremljenosti broda prije porinuća, te će se predložiti i poboljšanja od kojih se očekuje povećanje razine opremljenosti broda prije porinuća, skraćenje trajanja gradnje broda, povećanjem kvalitete broda i smanjenjem troškova gradnje broda.

Ove godine Medicina Fluminensis, stručno-znanstveni časopis Hrvatskoga liječničkog zbora – Podružnice Rijeka i Medicinskog fakulteta Sveučilišta u Rijeci, slavi respektabilnu obljetnicu polustoljetnog izlaženja. Pedeset je to kontinuiranih godina širenja biomedicinske misli, znanja i iskustva koji su pomogli da naše poslanje liječenja ljudi bude kvalitetnije, uvijek i iznova prilagođeno novom vremenu u koje neprestano kročimo. Dosadašnji razvoj, temeljen na viziji i predanom radu priznatih stručnjaka i znanstvenika, svih onih koji su svoje znanje i spoznaje podijelili sa zajednicom, bio je motiv – pokretač za novi iskorak u doprinosu modernoj riječkoj i hrvatskoj biomedicini. Stoga smo, po drugi put u mandatu ove redakcije, u obljetničkoj godini odlučili dodatno podignuti standarde kvalitete objavljivanja sa željom za uspješnim daljnjim razvojem znanstvenog i stručnog potencijala časopisa Medicina Fluminensis, odnosno kvalitete i specifičnosti znanja kojeg naše glasilo javno izlaže i promovira.

Spontaneous abortion is the loss of pregnancy before the fetus has reached viability. The prevalence of spontaneous abortion is extraordinarily high in humans, reaching up to 70% of all pregnancies. Additionally, approximately 1% of fertile couples comprise the group of recurrent spontaneous abortion (RSA), a distinct complication defined as three or more consecutive spontaneous abortions. Direct causes of RSA, including non-genetic and genetic factors, can be identified in merely 50% of couples. Although various hypotheses were tested, causative factors for the remaining couples have not been identified. Furthermore, despite the evidence for (epi)genetic contribution to this group of idiopathic RSA, as well as a growing number of studies, the relevance of different (epi)genetic factors remains unclear. Therefore, the aim of this talk is to give an overview of direct and potential (epi)genetic causes of RSA, as well as to outline recent advances in the research of the etiology of RSA. A special emphasis will be given to numerous controversies and setbacks that exist in the field of reproductive genetics, which complicate our understanding of the causative mechanisms of RSA.

Background: Recurrent spontaneous abortion (RSA) is the spontaneous loss of three or more consecutive pregnancies prior to the 22nd week of gestation. The etiology remains unknown in almost 50% of couples, who comprise the group of idiopathic RSA (IRSA). Previous studies have associated IRSA with abnormalities in the remodelling of endometrial extracellular matrix, as well as aberrant gene expression of matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) in mid-secretory endometrium and chorionic villi. Furthermore, we demonstrated that certain MMP-2 and -9 single nucleotide polymorphisms (SNP) in women might be risk factors for IRSA. Currently, we aimed to investigate the potential association of IRSA with TIMP-1, -2, -3 and -4 SNPs in reproductive couples. Method: 149 IRSA couples, as well as 149 fertile men and 149 fertile women with at least two live births and no pregnancy complications were included in a case-control study. Genotyping of TIMP-1 -372 C/T, TIMP-2 -303 C/T, TIMP-3 -915 A/G, TIMP-3 -1296 C/T and TIMP-4 -3'-UTR C/T SNPs was performed using polymerase chain reaction and restriction fragment length polymorphism methods. Results: There were no statistically significant differences in the distribution of neither individual nor combined genotype nor allele frequencies or any genetic model between IRSA couples and controls. Conclusion: We found no evidence for the association of IRSA with TIMP-1, -2, -3 and -4 SNPs in reproductive couples.

The island of Cres belongs to the group of Kvarner islands which is the most northern inhabited island group in the Croatian section of the Adriatic Sea. The population history of Cres provides relevant information for the interpretation of present day genetic relationships. There are many reasons why the island has been inhabited for thousands of years. First of all, the influence of world civilizations, important sea routes, the relatively high quality of natural resources and of the climate. The purpose of this anthropological and genetic study was to analyze genetic structure of the island of Cres by examining: 1) its sub-population level (eight settlements populations) 2) its relationship to five other Eastern Adriatic island populations, and 3) its relationship to the mainland Croatian population, which has substantially contributed to the current gene pool of the islands. We have analysed a sample of 122 unrelated autochthonous adult individuals from the island of Cres. Analysis of STR polymorphisms revealed genetic homogeneity among sub-populations of the island of Cres and small but significant levels of genetic heterogeneity among geographically distant Eastern Adriatic islands. Despite a considerable degree of genetic homogeneity among the studied Eastern Adriatic islands, small but significant differentiation between distant islands indicates geographic sub-structuring which follows the isolation by distance model. This study confirms that STR markers are useful tools for assessing levels of genetic differentiation between larger and geographically more distant populations.

Cilj: Izodicentrični X kromosom je strukturna kromosomska aberacija koja u svim slučajevima dovodi do disfunkcije jajnika koja se očituje kao primarna ili sekundarna amenoreja. Ostala klinička obilježja ovise o lokusu točke loma, staničnom mozaicizmu te obrascu inaktivacije X kromosoma. U ovom radu prikazujemo slučaj bolesnice s mozaičnim kariotipom i izodicentričnim X kromosomom s točkom loma u području terminalne pruge q28. Prikaz slučaja: Bolesnica je 47-godišnjakinja sa sekundarnom amenorejom, prekomjernom tjelesnom težinom, visokim rastom i kraniofacijalnom dismorfijom. Menarhu je dobila sa 16 godina, a nakon završenog četvrtog ciklusa nije imala spontane menstruacijske cikluse. Kliničkom obradom utvrđen je hipergonadotropni hipogonadizam, te je uvedena hormonska terapija koja je prekinuta u 45. godini. Posljednjim ultrazvučnim pregledom utvrđena je maternica primjerene veličine i strukture, te maleni jajnici jednolike strukture. Bolesnica ima prekomjernu tjelesnu težinu od djetinjstva, a u trenutku pregleda težina je iznosila 144 kg, visina 180 cm (ITM 44 kg/m²). Kliničkim pregledom utvrđena je kraniofacijalna dismorfija, uključujući usko i izduženo lice, ušiljenu bradu i velik nos. Klinička obilježja tipična za Turnerov sindrom nisu prisutna. Klasičnom i molekularnom citogenetičkom analizom utvrđen je mozaični kariotip. Na temelju fluorescentne in situ hibridizacije kariotip bolesnice je: mos 45,X[8]/46,X,idic(X)(pter→q28:q28→pter)[14]/46,XX[1].nuc ish(CEPXx1)[30/100]/ (CEPXx2)[18/100]/(CEPXx3)[52/100]. Rasprava: Klinička obilježja bolesnice prikazana su i uspoređena s kliničkim obilježjima prethodno opisanih slučajeva izodicentričnog X kromosoma s točkom loma u kromosomskoj regiji Xq28. Iako je izodicentrični X kromosom rijedak genetički poremećaj, nužno je prepoznati žene s primarnom ili sekundarnom amenorejom, poremećajem rasta te eventualnim drugim prirođenim anomalijama koje upućuju na genetički uzrok već na razini primarne zdravstvene zaštite te ih što prije uputiti na specijalističku obradu kao i citogenetičku analizu zbog pravilnog genetičkog informiranja., Aim: Isodicentric X chromosome is a structural chromosome aberration which leads to ovarian dysfunction associated with primary or secondary amenorrhea. The variability of clinical features depends on the position of the breakpoint, mosaicism and pattern of X inactivation. We present a case of a patient with mosaic karyotype and isodicentric X chromosome with breakpoint in the region q28. Case report: The patient is a 47-year-old woman with secondary amenorrhea, obesity, tall stature and craniofacial dysmorphy. She had menarche at the age of 16 and no spontaneous menstrual cycles after the fourth cycle. The patient was diagnosed with hypergonadotropic hypogonadism and hormone therapy was introduced. The latest pelvic sonography detected a normally shaped and sized uterus and small ovaries of homogenous structure. The patient has been obese since childhood and her current weight is 144kg, height 180cm (BMI 44kg/m2). She has craniofacial dysmorphy including thin and elongated face, pointed chin and large nose. Clinical features typical of Turner syndrome are not present. A mosaic karyotype was determined by classical and molecular cytogenetic analyses. The karyotype of the patient based on fluorescent in-situ hybridization is: mos45,X[8]/46,X,idic(X)(pter→q28:q28→pter)[14]/46,XX[1].nuc ish(CEPXx1) [30/100]/ (CEPXx2)[18/100]/(CEPXx3)[52/100]. Discussion: Clinical features of the patient are presented and compared with the clinical features of the previously published cases with isodicentric X chromosome with breakpoint located at the chromosomal region Xq28. Although isodicentric X chromosome is a rare genetic disorder, it is necessary to recognize women with primary or secondary amenorrhea, growth disorder and other congenital anomalies which point to a genetic cause, by primary healtcare physicians and other specialists and refer the women to the proper medical institution for genetic testing and genetic counseling.

The population of the island of Cres presents one of the few persisting Eastern Adriatic isolates and is thereby suitable for human population differentiation analyses. The aim of this study was to analyze genetic structure of the island of Cres with respect to its eight subpopulations, and to compare genetic variation of the island of Cres with other Eastern Adriatic islands and Croatian mainland. The 15 AmpFlSTR Identifiler loci were analyzed in the sample of 122 unrelated autochthonous individuals from the island of Cres, Croatia. The analysis of STR polymorphisms revealed genetic homogeneity among subpopulations of the island of Cres and small but significant levels of genetic heterogeneity among geographically distant Eastern Adriatic islands. Despite considerable degree of genetic homogeneity among studied Eastern Adriatic islands, small but significant differentiation between distant islands indicates geographic substructuring which follows the isolation by distance model. This study is supportive of the notion that STR markers might be more useful for genetic differentiation between larger and geographically more distant regions.

Kromosomi X i Y nastali su pred 300 milijuna godina, iz para tjelesnih kromosoma koji su postali spolni kromosomi. Tijekom iznimno brze evolucije, kromosom Y izgubio je većinu svojih gena te ih danas broji samo oko 90. Od tih 90 gena, 54 gena nalazi se i na kromosomu X. Kromosom Y tri je puta manji od kromosoma X, a žene, zbog prisutnosti dva kromosoma X u tjelesnim stanicama, imaju oko 3% više genetičkog materijala od muškaraca. To znači da žene imaju potencijalnu sposobnost stvarati i više proteinskih produkata nego muškarci, što se u životu i ne događa budući da žene i muškarci imaju identičan aktivni dio genoma.

Current view on genetics and epigenetics of RSA.

Aim: Langer-Giedion syndrome (LGS) is a contiguous gene syndrome caused by a hemizygous deletion on chromosome 8q23.3-q24.11 involving TRPS1 and EXT1 genes. We report on a girl with a microdeletion at 8q23.3-q24.13 and clinical features of LGS. In addition to the classical LGS phenotype, the patient also has premature adrenarche. Case report: The patient is a 4-year-old girl with delayed psychomotor development and craniofacial dysmorphic features consisting of large, laterally protruding ears, bulbous nose, broad nasal bridge, elongated upper lip, thin vermilion border, and sparse scalp hair. Radiographic examination of both hands revealed delayed bone age, brachyphalangia, brachymetacarpia and cone-shaped epiphyses. Multiple cartilaginous exostoses were detected on long and short tubular bones. Her pubertal development is classified as Tanner stage 3 premature pubarche. Hormonal analysis revealed elevated DHEAS and androstendion indicating premature adrenarche. Molecular genetic analysis was performed to confirm the diagnosis of LGS. Array-comparative genomic hybridization revealed a 7.5Mb interstitial deletion at 8q23.3-q24.13 (Chr8:116.921.245bp-124.442.990bp) leaving the TRPS1 gene intact. Conclusion: Although the deletion of TRPS1 and EXT1 genes is responsible for craniofacial and skeletal features of LGS, there have been previous reports of patients with features of LGS and 8q24 deletions leaving the TRPS1 gene intact. To our knowledge, this is the third such case. These three patients have similar proximal breakpoints suggesting a functional disturbance of TRPS1 gene and deletion of potential TRPS1 regulatory sequences. Also, the combination of LGS with premature adrenarche has not yet been described, however this combination in our patient is likely by chance.

Izodicentrični X kromosom je strukturna kromosomska aberacija koja u svim slučajevima dovodi do disfunkcije jajnika koja se očituje kao primarna ili sekundarna amenoreja. Ostala klinička obilježja ovise o lokusu točke loma, staničnom mozaicizmu te obrascu inaktivacije X kromosoma. U ovom radu prikazujemo slučaj bolesnice s mozaičnim kariotipom i izodicentričnim X kromosomom s točkom loma u području terminalne pruge q28. Bolesnica je 47-godišnjakinja sa sekundarnom amenorejom, prekomjernom tjelesnom težinom, visokim rastom i kraniofacijalnom dismorfijom. Menarhu je dobila sa 16 godina, a nakon završenog četvrtog ciklusa nije imala spontane menstruacijske cikluse. Kliničkom obradom utvrđen je hipergonadotropni hipogonadizam, te je uvedena hormonska terapija koja je prekinuta u 45. godini. Posljednjim ultrazvučnim pregledom utvrđena je maternica primjerene veličine i strukture, te maleni jajnici jednolike strukture. Bolesnica ima prekomjernu tjelesnu težinu od djetinjstva, a u trenutku pregleda težina je iznosila 144 kg, visina 180 cm (ITM 44 kg/m²). Kliničkim pregledom utvrđena je kraniofacijalna dismorfija, uključujući usko i izduženo lice, ušiljenu bradu i velik nos. Klinička obilježja tipična za Turnerov sindrom nisu prisutna. Klasičnom i molekularnom citogenetičkom analizom utvrđen je mozaični kariotip. Na temelju fluorescentne in situ hibridizacije kariotip bolesnice je: mos 45, X[8]/46, X, idic(X)(pter→q28::q28→pter)[14]/46, XX[1].nuc ish(CEPXx1) [30/100]/ (CEPXx2)[18/100]/(CEPXx3)[52/100]. Klinička obilježja bolesnice prikazana su i uspoređena s kliničkim obilježjima prethodno opisanih slučajeva izodicentričnog X kromosoma s točkom loma u kromosomskoj regiji Xq28. Iako je izodicentrični X kromosom rijedak genetički poremećaj, nužno je prepoznati žene s primarnom ili sekundarnom amenorejom, poremećajem rasta te eventualnim drugim prirođenim anomalijama koje upućuju na genetički uzrok već na razini primarne zdravstvene zaštite te ih što prije uputiti na specijalističku obradu kao i citogenetičku analizu zbog pravilnog genetičkog informiranja.

Matrix metalloproteinases (MMP) regulate various processes during human pregnancy, including decidualization, maintenance of corpus lutem, blastocyst implantation and placentation. The aim of this study was to investigate the association of functional promoter polymorphisms in MMP genes with idiopathic recurrent spontaneous abortion (iRSA). 149 couples with iRSA and 149 control couples with at least one live birth and no history of pregnancy loss were included. Polymerase chain reaction and restriction fragment lenght polymorphism analyses were performed to identify the MMP1 -1607 1G/2G, MMP2 -735C/T, MMP2 -1306C/T, MMP3 -1612 5A/6A, and MMP-9 -1562C/T genotypes. Our results show that the functional promoter polymorphisms, haplotype and genotype combinations of MMP-1, -2, -3- and -9 could be a genetic determinant for the risk of RSA.

Cilj: Prstenasti ili ring kromosom rijetka je strukturna promjena kromosoma koja najčešće nastaje zbog terminalne delecije na oba kraka kromosoma te ponovnog spajanja preostalih dijelova kratkog i dugog kraka kromosoma u prstenastu strukturu. Sindromi prstenastih kromosoma iznimno su rijetki s incidencijom od 1 : 50.000 živorođene djece. U ovom radu prikazujemo prvi slučaj djevojčice sa sindromom prstenastog kromosoma 18 zabilježenog na Zavodu za biologiju i medicinsku genetiku (Medicinski fakultet, Sveučilište u Rijeci). Prikaz slučaja: Bolesnica je dvanaestogodišnja djevojčica sa psihomotornom retardacijom, mikrocefalijom, niskim rastom, dismorfijom lica (hipertelorizam, hipoplazija srednjeg lica, usni kutovi okrenuti prema dolje, rascjep nepca, prognatija, nisko postavljene uške), obostranom stenozom vanjskog slušnog hodnika uz provodnu gluhoću i brahidaktilijom. Citogenetičkom analizom utvrđen je mozaični kariotip: 46,XX,r(18)(p11.3;q23)[97]/45,XX,-18[3] de novo. Daljnjom kliničkom obradom utvrđeno je kako bolesnica ima obilježja klasična za deleciju oba kraka 18. kromosoma. Klinička obilježja djeteta prikazana su i uspoređena s klasičnim kliničkim obilježjima sindroma. Rasprava i zaključak: Iako je sindrom prstenastog kromosoma 18 rijedak genetički poremećaj, nužno je prepoznati dijete s multiplim prirođenim anomalijama već na razini primarne zdravstvene zaštite te ga zbog pravilnog genetičkog informiranja i odabira odgovarajuće terapije što prije uputiti na specijalističku obradu, kao i na citogenetičku analizu., Aim: Ring chromosomes are rare structural chromosomal aberrations which form after the breakage in both terminal regions of the affected chromosome with fusion of the short and long arm into a ring formation. The incidence of ring chromosome syndromes is estimated to be about 1:50.000 live born children. Here we present the first case of a girl with ring chromosome 18 syndrome identifed at the Department of biology and medical genetics (School of medicine, University of Rijeka). Case report: The patient is a twelve-year old girl with psychomotor retardation, microcephaly, short stature, dysmorphic facies (hypertelorism, midface hypoplasia, downturned corners of mouth, cleft palate, prognathia, low-set ears), bilateral stenosis of the external auditory canal with conductive deafness and brachydactyly. Cytogenetic analysis determined a mosaic karyotype: 46,XX,r(18)(p11.3;q23)[97]/45,XX,-18[3] de novo. Our patient has the characteristic features of 18p and 18q deletion syndromes. We present the clinical features of the patient and compare them to the classical features of 18p and 18q deletion syndromes. Discussion and conclusion: Although ring chromosome 18 syndrome is a rare genetic disorder it is necessary to identify the child with multiple congenital anomalies by primary care physicians and refer the child to the proper medical instituti on for genetic testing and genetic counseling.

The aim of this talk was to present the scientific knowledge on genetics of recurrent miscarriage.

Postavljanje pravilne dijagnoze u djece i odraslih s dismorfnim kliničkim obilježjima, multiplim prirođenim anomalijama i/ili mentalnom retardacijom te poznavanje njihove etiologije i patogeneze nužno je radi predviđanja tijeka poremećaja, usmjeravanja kliničke obrade, budućeg genetičkog savjetovanja obitelji i srodnika te odabira pravilne terapije. Dismorfologija je grana kliničke genetike koja proučava obrasce ljudskog rasta, razvoja i prirođenih strukturnih poremećaja i podrazumijeva poznavanje kliničkih obilježja pojedinih genetičkih poremećaja te otkrivanje njihove molekularne etiologije i patogeneze. Pojam dismorfno označava fizička obilježja koja nisu tipična za osobe određene dobne skupine niti etničko podrijetlo, a posljedica su abnormalnog morfološkog razvoja. Proučavanje razvojnih dismorfija pridonijelo je trenutnom poimanju genetičke podloge izrazito složenih procesa normalnog rasta i razvoja čovjeka te otkrića uzročnih gena i mehanizama kojima ti geni utječu na normalnu embriogenezu. U ovom preglednom radu dajemo prikaz razvojnih anomalija te klinički pristup osobama sa strukturnim anomalijama., Determination of diagnosis in children and adults with dysmorphic clinical features, multiple congenital anomalies and/or mental retardation, as well as understanding their etiology and pathogenesis enables the prediction of the course of congenital disorders, direction of clinical analysis, genetic counselling and selection of proper therapy. Dysmorphology is the study of patterns of human growth, development and congenital structural anomalies and is one of the core areas of clinical genetics. It implies the understanding of clinical features of genetic disorders, their molecular etiology and pathogenesis. A dysmorphic feature is a medical term referring to any physical feature which is not typical for people of certain age and ethnical group and is the consequence of abnormal morphogenesis. Studies of these developmental anomalies have contributed to the current understandings of genetic etiology of normal human growth and development as well as discovery of causative genes and mechanisms through which they affect normal embryogenesis. We present a concise review of developmental anomalies and clinical approach to people with structural developmental anomalies.

Rijetke bolesti su one bolesti koje zahvaćaju vrlo mali broj ljudi u općoj populaciji, pa se u Europi smatraju rijetkima kada pogađaju manje od 1 na 2000 ljudi. Broj oboljelih značajno se razlikuje ovisno o vrsti rijetke bolesti, pa je tako učestalost pojedinih rijetkih bolesti manja od 1 na 100.000.

The unprecedented rate of discovery and application of medical genetics requires us to pause and ask if humanity as a species is well served or compromised by this development. Newborn screening tests practiced in developed countries, though beneficial, raise questions of ownership, identity, confidentiality and disclosure or results. Prenatal genetic testing, widely available, but not mandatory, creates pressure on physicians to offer and for patients to undergo them. A new, bizarre notion of ‘ responsible parenthood’ means to give birth only to children who are without genetic abnormalities and to abort all others. Most disturbingly, medical genetics’ goal of eliminating severe disorders has silently morphed into a collective evolutionary “ imperative” driven by an ideology of creating the perfect human specimen, and by default appropriating exclusive rights to the production and control of human life. Yet, history provides us with numerous examples to remind us that a prerequisite “ to being human, and to be worthy of life” is not synonymous with a state of biological perfection. In addition, human diversity may be the secret of humankind’ s success. Without diversity, there would be no effective selection. We must have a balanced ethical debate. This can happen only after scientists, physicians and all people become educated about the realities of genetics and willfully work at setting limits on these pursuits. Unfortunately, current normative bioethics does not provide a satisfactory solution for a unique, global approach. For the new ‘ genethics’ , we need to be mindful of bioethical, legal, psychological and social implications of genetic research and its applications. This must inform genetic counselling, which is critical for beneficial interventions, and it requires informed geneticists with imagination and intuition. The power of human genetics over the future of humankind is unprecedented. Imperceptibly, the range of genetic interventions is increasing without full consideration to benefits, harms, future consequences or responsibility. It is imperative to embrace genetic responsibility for maintenance of diversity and richness of human life.

Currently, there are over 4000 known genetic disorders and diagnostic tests are available for over 1400 of them. The rapid and constant advances in human genetics, as well as the possibility of prenatal and postnatal genetic analysis for predisposition to diseases, and genetic modification of humans, opens numerous bioethical questions because medical genetics is developing faster than law regulations and public opinion. The specificity of genetic disorders comes from the fact that they, for now, cannot be cured but with the proper medical and psychological support the quality of life can be improved. Genetic predisposition to diseases represents a life-long risk factor which often affects familiy relations and quality of life, including development of depression, tension and anxiety. The availability of more information and more possibilites, including the selection of embryos with favourable „ gene maps“ and with decreased risk of hereditary diseases, should facilitate important decisions, from personal to social level. This also leads to the problem of basic human rights of the „ less perfect“ concepts in relation to the collective „ evolutionary imperative“ for constant improvement of human species. Around us there is an unavoidable pressure on both doctors and parents to make sure that children are born healthy. The development of prenatal tests has promoted the idea that it is a part of responsible parenthood to avoid the birth of a disabled child. It is obvious that through the sofisticated alleviation of human „ imperfection“ – that is, through selection of values of human life according to hereditary features – we are returning to the old eugenics through a new approach, through individual eugenics. The increasing number of hereditary disorders, as well as the increasing interest of medical profession on the role of new genetics in health and disease, emphasizes the importance of genetic counselling, a lifelong process of providing professional and scientific genetic informations, with significant legal and social implications. Due to its distinctive social and psychological importance for an individual or a family, and with it for the society, it is appropriate to say that genetic counselling is also bioethical. This is why bioethics, in its interdisciplinarity, represents a „ bridge“ between ethical principles and genetic practice in extremely technologized clinical circumstances. At the same time, the initiation of premature ethical discussions raises the question on the ethics of the discussions themselves due to the fact that they are not based on the competent and detailed knowledge of the problems in medical genetics. This is why the critical area for the 21st century is to increase health professional and public education about genetics/genomics. Therefore genetic counseling might be considered more as patient-education than as actual advice and should include ethical information in addition to medical and social facts. Although in the managment of genetic disorders the prevention is dominant (meaning the prevention of giving birth to a „ different“ child), the main goal of genetic counselling is to help individuals and families understand or cope with genetic diseases as well as to provide lifelong medical and psychological support, and not only to decrease the incidence of genetic disease.

Most common approach to analyzing and solving ethical dilemmas in contemporary medicine is the four-principles-approach. However, as the critique of principalism has showed us back in the 1970’ s, this framework has its limitations. These limitations especially emerge when facing the challenges of new technologies and the consequences of their usage, such as the case of clinical genetics. Our time is one of genomics, HUGO, and similar accomplishments which bring us to the gene-sequence-approach vs. the good old fashioned “ holistic” approach of treating illness. We are not helping a person overcoming pain and suffering any more, we are now helping a genome to be as healthy as possible in order to allow our (good, healthy, adequate) genes to be transferred in the next generation. This is, of course, a very simplified deliberation on what has become of modern medicine in the context of clinical genetics, more precisely in the context of genetic counseling. Going back to basics, we are definitely facing the limitations of the principalistic approach. Principles do allow us to act with clarity, simplicity and universality (Campbell AV, 2003), on the other hand, they do not take account of the importance of the emotional element of human experience (Gardiner P, 2003), thus they suffer the neglect of emotional and personal factors, oversimplification of the issues, and excessive claims to universality (Campbell AV, 2003). Exactly this “ virtues and vices” of the four principles (Campbell AV, 2003) come in the focus of moral deliberation when we as health care providers have to offer advice which will create consequences not only for the patient coming for the advice and having to make a decision upon it, but the extend of these consequences goes beyond our patient (a person, a couple, the family) and intervenes with the future of the offspring. The patient of a genetic council is, thus, not only the person seeking it, but the entire family and future generations. In this context it is very difficult to determine the rightness of the decision-making-action, neither from the deontological point of view (underlying the duties and rules all moral agents involved in the case have to obey in order to make the best possible decision), nor from the one of consequentialism, that is the “ destiny” of (the consequences for) the offspring - the most often object of moral deliberation in genetic counseling. Virtue ethics could help facing moral challenges geneticists and their patients encounter in the everyday enterprise of practicing a “ harm reduction interventions” (Christie T, Groarke L, Sweet W, 2008), in the context where moral agents act as “ time/space travelers” and council/decide for both themselves and others, both now and for the future. Virtue ethics provides insights into moral characters, offering a blend of reason and emotion, and paying attention to the context of decisions (Campbell AV, 2003). In considering the relationships, emotional sensitivities, and motivations that are unique to human society, it is also relevant for understanding our (multi)cultural concerns (Gardiner P, 2003 ; Islam G, 2007). Generally, it provides a fuller ethical analysis and encourages more flexible and creative solutions than principlism or deontology/consequentialism alone (Gardiner P, 2003). The key concept for virtue-ethics-approach in genetic counseling is a strong sense for professionalism of the genetic counselor, which (summed up to the four fundamental virtues originating from John Gregory’ s concept of professionalism) consists of integrity, compassion, self-effacement and self-sacrifice (Coverdale JH, 2007). If we try to broaden up the virtue-ethics-approach to all moral agents (patients also) engaged in the process of genetic counseling, we could follow the “ seven basic virtues in medicine” approach, that is: prudence (practical wisdom), justice, temperance, courage, faith, hope, and love (Bryan CS, 2005 ; Bryan CS, 2006 ; Bryan CS, 2007). In conclusion, it should be stated that neither virtue-ethics-approach, nor the four-principles-approach should claim to be superior to the other. Only together they provide a morally adequate context for helping patients, families, surrogates, healthcare providers, or other involved parties address uncertainty or conflict regarding value-laden issues emerging in genetic counseling.

Ovaj rad opisuje rješavanje problema usmjeravanja vozila s prikupljanjem i dostavom, pri čemu se podrazumjeva samo jedno vozilo i jedna vrsta proizvoda. Problem je rješavan metodom iterativnog modificiranog simuliranog kaljenja. Simulacijskim programom eksperimentalno su određivani parametri koji daju najmanji srednji put. Povećavanjem područja pretraživanja promjenom parametara srednji put se smanjuje, a srednje vrijeme raste.

Kongenitalne anomalije zahvaćaju 3 – 5 % sve novorođene djece, te čine značajan postotak morbiditeta i mortaliteta u prenatalnom razdoblju i dojenačkoj dobi. Iako bolesnik s multiplim kongenitalnim anomalijama predstavlja dijagnostički izazov za pedijatre i kliničke genetičare, nužno je prepoznati specifične kombinacije kliničkih znakova, simptoma ili obrazaca ponašanja, koji bi upućivali na dijagnozu genetičkog poremećaja. Sve veći broj genetičkih poremećaja (više od 6.000 opisanih) s još većim brojem opisanih specifičnih kombinacija kliničkih obilježja doveo je do pokušaja njihovog sistematiziranja u baze podataka koje na jednom mjestu okupljaju relevantne informacije o svim poznatim genetičkim poremećajima. Elektroničke genetičke baze podataka zbog svoje su sveobuhvatnosti i jednostavnosti korištenja izvrstan medij za edukaciju iz kliničke genetike, ali i neizostavan dio svakodnevnog rada u kojem služe kao pomoć pri evaluaciji bolesnika i postavljanju ispravne diferencijalne dijagnoze malformacijskih sindroma i genetičkih poremećaja općenito. Klinička genetika je umjetnost i vještina vizualnog prepoznavanja i uspoređivanja obilježja; dijagnoza genetičkog poremećaja uvijek je zahtjevan, a ponekad i dugotrajan proces u kojem genetičke baze podataka mogu znatno pomoći. Iako sve baze podataka omogućuju pretraživanje po kliničkim obilježjima (simptomima i znakovima), odnosno njihovim kombinacijama, čime se dobiva ispis najizglednijih genetičkih poremećaja, dobiveni popis samo je prvi korak u dijagnostičkom procesu, te zahtijeva daljnje proučavanje medicinski relevantne literature, kao i ponovne preglede djeteta kada se ciljano traže specifična obilježja i dodatna klinička obrada., Congenital anomalies occur in 3-5 % of all newborn children and represent a significant part of prenatal and infant mortality and morbidity. Although patients with multiple congenital anomalies represent a diagnostic challenge for pediatricians and clinical geneticists, it is necessary to recognize specific combinations of clinical signs, simptoms and behaviour patterns which leads to the diagnosis of a genetic disorder. The constantly increasing number of genetic disorders (over 6.000 described) with an even larger number of specific combinations of clinical features has led to an attempt of systematization of all known genetic disorders into several genetic databases. The comprehensiveness and simple organization of electronic genetic databases makes them an exceptional educational media for the training of clinical genetics and an inevitable part of everyday work in clinical genetics where they are used in the evaluation of patients and establishment of proper differential diagnosis of malformation syndromes and genetic diseases in general. Clinical genetics is a combination of art and skills in visual recognition and comparison of features, and the diagnosis of a genetic disorder is always a demanding and sometimes a time-consuming process where genetic databases can be of significant help. However, although all genetic databases can be searched according to clinical features and their specific combinations which will provide a list of the most likely syndromes, the obtained list of disorders is only a first step in the diagnostic process and demands further investigation of medically relevant literature, as well as repeated examinations of the patient when specific features and additional analyses are sought.

Medical genetics, the science of human biological variations related to health and disease, is an inevitable part of modern medical practice. The specificity of hereditary diseases comes from the fact that they, for now, cannot be cured, but can be prevented, and with the proper medical and psychological support the quality of life can be improved. The rapid and constant advances in human genetics, as well as the possibility of prenatal and postnatal genetic analysis of various physical and psychological features, predisposition to diseases, and genetic modification of humans, opens numerous bioethical questions considering that medical genetics is developing faster than law regulations and public opinion. The human species hasn't precisely determined whether its priority is to „ shape“ new generations according to the will of their parents, or to create a society which is prepared for „ less perfect“ individuals. It is obvious that through the sofisticated alleviation of human „ imperfection“ – that is, through selection of values of human life according to hereditary features – we are returning to the old eugenics through a new approach. In this way we are alienating our progress from the basic bioethical concept of rescpecting the dignity of every human being regardless of its genetical qualities. As the progress of medicine has enabled the follow-up of health status since conception, the parents face an increasead pressure of a having a child with genetic burdeon. The important question is how will these progresses in biomedical sciences affect the will of maintaing one's pregnancy and future conceptions. Genetic predisposition to diseases represents a life-long risk factor which often affects familiy relations and quality of life, including development of depression, tension and anxiety, or the loss of spouse. Although the availability of more information and more possibilites, including the selection of embryos with favourable „ gene maps“ and with decreased risk of hereditary diseases, should facilitate important decisions (from personal to social level), the rapid development of genetics makes the unsolved questions become even more complex. This also leads to the problem of basic human rights of the „ less perfect“ concepts in relation to the collective „ evolutionary imperative“ of constant improvement of human species. The increasing number of hereditary diseases, as well as the increasing interest of medical profession on the role of new genetics in health and disease, emphasises the importance of genetic counselling, which is a lifelong process of providing professional and scientific genetic informations, with significant bioethical, leagal and social implications. Due to its distinctive social and psychological importance for an individual or a family, and with it for the society, it is appropriate to say that genetic counselling is also bioethical. This is why bioethics, in its interdisciplinarity, represents a „ bridge“ between medical/ethical principles and genetic practice in extremely technologized clinical circumstances. At the same time, the initiation of premature ethical discussions raises the question on the ethics of the discussions themselves due to the fact that they are not based on the competent and detailed knowledge of the problems in medical genetics.

Premda će "nova Medicina" kontinuirano progovarati “ jezikom molekula” , ona će i dalje biti dominantno stručni časopis, namijenjen liječnicima svih profila, kao i ostalim pripadnicima biomedicinske profesije, diplomantima i poslijediplomantima medicinskih fakulteta, znanstvenim novacima i svima onima koji se na bilo koji način dotiču biomedicine. Objavljivat ćemo stručne i znanstvene članke iz svih područja bazičnih i primijenjenih humanih biomedicinskih znanosti, ne zaboravljujući osobitosti podneblja kojem pripadamo, uključujući i povjesnicu struke. Promjene u Medicini obavljene su prema međunarodnim kriterijima, što je i bio najvažniji kratkoročni cilj. Uvjeti pisanja u Medicini, odnosno upute autorima časopisa, postavljeni su prema ICMJE standardima. Etičke norme postavljene su prema standardima koje normira COPE.

SAŽETAK. Gestacijska trofoblastična bolest (GTB) heterogena je skupina novotvorina koje nastaju iz trofoblastnih stanica placente. Pravilna diferencijacija i funkcija trofoblasta tijekom implantacije i placentacije od iznimne su važnosti za uspješnu trudnoću u sisavaca. Epigenetički mehanizmi koji omogućuju transkripcijsku kontrolu genske ekspresije bez promjene nukleotidnog slijeda samog gena, ključni su čimbenici koji određuju normalan rast i razvoj placente i embrija. Genomski upis je posljedica epigenetičkih modifikacija koje dovode do ekspresije samo jednog alela istog gena, ovisno o roditeljskom podrijetlu. Iako su po genskoj strukturi genomi oca i majke identični, oni nisu jednaki i funkcionalno, te je za uspješnu trudnoću nužna prisutnost oba roditeljska genoma u zigoti. Genomski upisani geni imaju ključnu ulogu u kontroli rasta i razvoja embrija, te reguliraju glavne funkcije na fetoplacentarnoj jedinici, kao što su prijenos hranjivih tvari, proliferacija i invazivnost trofoblasta, te angiogeneza. Nepravilnosti genomskog upisa, uključujući nepravilan omjer majčinih i očevih genoma, dovode do brojnih poremećaja u rastu i razvoju fetusa i placente, te imaju ključnu ulogu u patogenezi GTB. Stalni napredak u području (epi)genetike reprodukcije pruža mogućnost da će u skoroj budućnosti modifikacije epigenetičkih mehanizama koji kontroliraju gensku ekspresiju biti temeljem moderne dijagnostike, praćenja i liječenja patoloških trudnoća. U ovom preglednom radu dajemo prikaz sadašnjih spoznaja uloge (epi)genetičkih čimbenika u etiologiji GTB., Gestational trophoblastic disease (GTD) is a heterogeneous group of neoplastic conditions which arise from abnormal proliferation of trophoblastic tissues during pregnancy. The proper differentiation and function of trophoblast during embryo implantation and placentation is essential for successful pregnancy. Epigenetic mechanisms, which provide transcriptional control of gene expression without alterations in gene sequence, are critical components of normal development of placenta and embryo. Genomic imprinting is an epigenetic form of gene regulation which results in the parent-of-origin specific gene expression and leads to functional non-equivalency of parental genomes. This indicates that the presence of both the maternal and paternal genomes is required in the zygote for normal development. Genomically imprinted genes regulate embryonic and placental development and have major functions at the feto-maternal interface, including nutrient transport, trophoblast proliferation, invasion and angiogenesis. Abnormalities in genomic imprinting, including altered ratio between maternal and paternal genomes, lead to numerous disorders of fetal and placental growth, and have a key role in the pathogenesis of GTD. The constant progress in the field of reproductive (epi)genetics indicates that modification of epigenetic mechanisms which control gene expression will have an important role in the diagnosis, prognostic assessment and treatment of pathological pregnancies. In this review we present the current understanding of the (epi)genetic mechanisms involved in the etiology of GTD.

Problem The genetic background of recurrent spontaneous abortion (RSA) has been widely investigated and confirmed through its familial occurrence, linkage analysis and epidemiologic studies. A polygenic inheritance has been suggested and a number of association studies have been performed with the aim of identifying candidate genes, including genes coding coagulation factors, oxidative stress, vasoactive substances, endocrine and metabolic factors and genes involved in immunological processes. Method of study In order to avoid contradictions between reports, uncertainties regarding false positive or false negative associations, and to ensure certainty in statistical analyses due to sample sizes, a systematic review of the studies on candidate genes related to immunology involved in RSA was performed. The PUBMED and EMBASE databases were searched up for studies on candidate genes in RSA. All case-control studies were registered and those satisfying principles of evidence based medicine were included in further analysis. Results Up to December 2006, 172 citations were registered ; while 65 among them were studies of genetic polymorphisms in immunity– related genes. The most frequently investigated genes included HLA system (25), TNF (8), IL-10 (7) and IL-6 (6). Large variation among reported results in studies was found. Conclusions The magnitude of the association between polymorphism in the immunity-related genes and RSA varies, according to the type of RSA and the type of gene/ polymorphism investigated. Further studies are needed to assess polymorphisms in immunity-related genes as the RSA risk factors.

Genetic markers could be factors of predisposition to idiopathic recurrent spontaneous abortion (RSA). Igf2 and H19 genes undergo the phenomenon of genomic imprinting, Igf2 being expressed from paternal, and H19 only from maternal allele. Igf2 is a major fetal growth factor that stimulates angiogenesis, proliferation and transport of nutrients in placenta. H19 is a non coding gene whose untranslated RNA supresses growth by controlling the level of Igf2 gene expression and Igf2 mRNA cytoplasmic localization. The aim of this study is to evaluate the association between Igf2 and H19 gene polymorphisms and the susceptibility to RSA. A case-control study was conducted to determine the association between Igf2 and H19 gene polymorphisms and the risk of RSA in 113 couples with RSA, and 113 fertile couples as control. PCR was performed to analyse DNA for Igf2 ApaI polymorphism in exon 9 and H19 HhaI polymorphism in the 6th CTCF binding site. Statistically significant difference was found for Igf2 ApaI polymorphism in male partners of RSA women. Their genotype frequencies compared with controls were: 13%/56%(AA) ; 39%/20%(GG) ; 48%/25%(AG) ; when following dominant model for risk genotypes (AA+AG), OR=0.38, p=0.001. Conclusion: Considering that Igf2 gene is expressed only from paternal allele, the ApaI polymorphism in partners of RSA women could affect Igf2 level of expression in placenta and lead to RSA. The research of polymorphisms in genes undergoing the phenomenon of genomic imprinting and including male partners, represents a new approach in the research of genetic etiology of idiopathic RSA.

IL-12/IL-18 are involved in uNK control of uterine vascular development. Lower doses of IL-12/IL-18 are required for successful embryo development, while lack or high values of IL-12/IL-18 induce defects in uterine vascular remodeling during implantation and lead to pregnancy failure. Polymorphisms in the IL-12/IL-18 genes could modify the cytokine balance which might result in an increased susceptibility to recurrent spontaneous abortion (RSA). A case-control study was conducted to determine the association between the IL12 and IL18 (-607C>A, -137G>C) gene polymorphisms and the risk of RSA in 125 women with RSA and 136 controls. Polymerase chain reaction was performed to analyze genomic DNA for IL12B promoter insertion/deletion polymorphisms and IL18 (positions -607C>A, -137G>A) gene polymorphisms. The frequencies of CC, CA, AA genotypes for IL-18(-607) were: 34.4%, 54.4% and 11.2% in patients versus 30.1%, 58.1% and 11.8% in controls ; the frequencies of GG, GC, CC genotypes for IL-18(-137) were: 47.2%, 43.2% and 9.6% respectively in patients and 45.6%, 46.3% and 8.1% in controls ; the frequencies of DD, ID, II for IL-12 were, 25.6%, 52.8% and 21.6% in patients versus 21.3%, 51.5% and 27.2% in controls. When following recessive model for risk genotypes the resuls were as follows: for IL-18(-607 AA) OR=1.05, p=0.89 ; for IL-18 (-137 CC) OR=1.21, p=0.46 ; and for IL-12 (DD) OR=1.26, p=0.41). We found no significant association between IL-12 (ins/del) and IL-18 (-607 and -137) gene promoter polymorphisms and susceptibility to RSA in studied women.

Gene variability can affect expression, structure and function of key molecules in pregnancy and subsequently, gene polymorphisms in men and women can represent the possible factors of predisposition to recurrent spontaneous abortion (RSA). The aim of this study was to evaluate the possible role of polymorphisms in genes undergoing the phenomenon of genomic imprinting, a functional difference in the allelic expression that depends upon the parental origin of inheritance. We investigated important genes that regulate the process of implantation and placentation, paternally expressed Igf2 and maternally expressed H19. A case-control study was conducted to determine the association between Igf2 and H19 gene polymorphisms and the susceptibility to RSA in 113 couples with RSA and 226 fertile controls. PCR was performed to analyse DNA for Igf2 ApaI polymorphism and H19 HhaI polymorphism. Statistically significant difference was found for Igf2 ApaI polymorphism in male partners of RSA women. Their genotype frequencies compared with controls' were: 13%/56% (AA) ; 39%/20% (GG) ; 48%/25% (AG) ; when following dominant model (AA+AG vs GG), OR=0.38 [0.20-0.69] ; p=0.001 ; when following recessive model (AA vs GG+AG), OR=0.12 [0.06-0.23] ; p=0.000. Considering that Igf2 gene is expressed only from paternal allele, the presence of ApaI polymorphism in partners of RSA women could affect Igf2 level of expression in placenta and lead to RSA. The research on genes undergoing the phenomenon of genomic imprinting and including male partners in the study, represents a new approach in the research of genetic etiology of idiopathic RSA.

Starenje je univerzalan biološki proces obilježen nepovratnim promjenama fizioloških funkcija cijeloga organizma. Posljedica je međudjelovanja gena i okolišnih čimbenika, odnosno životnoga stila. Više je od 300 teorija zasnovanih na istraživanjima složenih mehanizama kontrole i regulacije starenja u mnogobrojnih vrsta. S obzirom na to da nema jedinstvene sistematizacije, u ovome smo ih radu uvjetno podijelili na programirane i neprogramirane teorije starenja koje se međusobno neizbježno isprepliću. Neprogramirane teorije ili “ teorije nakupljanja pogrešaka” , koje uključuju teorije nakupljanja somatskih mutacija, djelovanje slobodnih radikala kisika i ograničena unosa kalorija, određuju starenje kao kumulativno nakupljanje oštećenja. Protijekom vremena dolazi do gubitka ravnoteže između oštećenja i sustava popravka na molekularnoj i staničnoj razini, što postupno uzrokuje patološke promjene i smrt. Programirane teorije koje uključuju gensku teoriju, hormonalnu teoriju i teoriju replikativna starenja, pretpostavljaju da starenje - kao prirodni nastavak rasta i razvoja - reguliraju geni odgovorni za održavanje homeostaze i aktiviranje obrambenih mehanizama, uključeni u živ~ani, endokrini i imunosni sustav. Iako “ geni starenja” za sada nisu pronađeni, većina je teorija izravno ili posredno povezana s promjenama gena, ili posljedicama koje na njih ostavljaju okoliš i/ili životni stil. Cilj je ovoga preglednoga rada prikazati najzastupljenije teorije o starenju, uz genetički pogled zasnovan na istraživanjima gena koji utječu na metabolizam, stanično disanje, proizvodnju energije, stabilnost genoma, duljinu telomera, te kontrolu staničnoga ciklusa. U pojedinih vrsta modifikacija tih gena može produljiti životni vijek, što uz učinak kumulativnih oštećenja ukazuje na mogućnost postojanja programirana “ biološkoga sata” .

U radu su uspoređene tri metode analize mioelektričkih signala tijekom dinamičkog umaranja. Korištene su metode analize temeljene na skalogramu, spektrogramu i Choi-Williams distribuciji. Za potrebe usporedbe razvijen je model površinskog mioelektričkog signala dinamičkih kontrakcija temeljen na superpoziciji jednotonskih kutno moduliranih signala. Analiza i usporedba provedena je i na izmjerenim površinskim mioelektričkim signalima snimljenim u uvjetima voljnih kontrakcija. Frekvencija medijana spektra snage odabrana je za praćenje umora mišića i definiciju modela. Usporedba metoda analize na sintetiziranom signalu pokazala je značajnu zavisnost rezultata analize o izboru metode analize i parametara analize. Obrada izmjerenih signala potvrdila je zaključak donesen na temelju analize sintetiziranih signala, te ukazala na potreban oprez prilikom interpretacije rezultata. Rezultati rada mogu poslužiti za daljnja istraživanja utjecaja parametara analize, kao i razvoj općeg modela površinskog mioelektričkog signala tijekom umarajućih dinamičkih kontrakcija. In this work, three methods have been applied for analysis of myoelectrical signals during fatiguing dynamic contractions. Methods of analyisis applied: scalogram based, spectrogram based and Choi-Williams distribution based method. Model of surface myoelectrical signals during fatiguing contractions was developed for the purpose of comparison. The model is based on superposition of single tone angular modulated signals. Analysis and comparison was performed on both, sinthesized and measured surface myoelectrical signals of voluntary dynamic contractions. Median frequency of the power spectrum was choosen for tracking muscle fatigue and for model definition. When analyis is applied on sinthesized signal, choice of the method and parameters of the applied method showed significant influence on the final results. Analysis of measured myoelectric signals confirmed this conclusion and pointed out the problem of result interpretation. Presented results can be used for further investigation of analysis parameter influence on results, as well as for development of common surface electromyographic model during fatiguing dynamic contracions.

Microdeletions of the long arm of the chromosome Y and major chromosomal aberrations are common cause of male infertility. One hundred and twenty four infertile and fourty control fertile men from North-Adriatic part of Croatia were screened according to the Laboratory guidelines for molecular diagnosis of Y chromosome microdeletions. Microdeletions were determined in two patients in the nonobstructive azoospermia group (27 patients) making the frequency of 7, 4%. In the other investigated groups of patients: severe oligoasthenozoospermia (19), oligoasthenozoospermia (44) and normoasthenozoospermia (34) or in the control group, no microdeletions of the long arm of chromosome Y were found. Microdeletion found in one patient was spanning AZFb and AZFc regions, while in the other one was restricted to AZFc region. Cytogenetic analysis was made in 85 patients included in the microdeletion testing. The overall frequency of chromosomal aberrations was 4, 7%. Reciprocal translocation t(12, 22) was found in normoasthenozoospermic man (1, 2%), and Klinefelter syndrome was determined in three patients (3, 5%) with azoospermia. The frequency of Y chromosome microdeletions is within values reported by other authors.

Surface myoelectric signals recorded during fatiguing cyclic dynamic contractions are non- stationary signals with variable spectral parameters. In attempt to extract the essentials of their change and assess different time-frequency analysis methods many models have been developed. White noise based modeling is frequently used method. Accordingly, we developed model that allows control over power spectrum and signal amplitude. Synthesized signals were analyzed by continuous wavelet transform. The analysis show, that in general, white noise based models of cyclic dynamic contractions result in signals with high variability of modeled spectral parameters and therefore, are not suitable for assessment of different time-frequency analysis methods.

Brojna istraživanja mehanizama trudnoće nisu pružila jasne smjernice koje bi pomogle praktičarima kao dijagnostičko ili terapijsko sredstvo u rješavanju problema učestalih spontanih pobačaja nepoznate etiologije. Učestali spontani pobačaji su tri ili više uzastopna spontana prekida trudnoće prije 23. tjedna, s istim partnerom. Predstavljaju značajan klinički problem s obzirom da se javljaju u 0, 5-3% žena i da je njihov uzrok nepoznat u oko 40-50% slučajeva. Poznati uzroci učestalih spontanih pobačaja raznorodni su i uključuju negenetske i genetske čimbenike. Iako je njihov veći dio uzrokovan genetski, genskim ili kromosomskim abnormalnostima, pokušaj liječenja je zasad moguć samo u skupine negenetskih uzroka. Cilj je ovog rada prikaz sadašnjih spoznaja o genetskim razlozima učestalih spontanih pobačaja, o čemu se vrlo malo zna. Ukazat ćemo na HLA-podudarnost u roditelja, monogenske nasljedne bolesti, kao i gensku varijabilnost u obliku genskih polimorfizama, kao moguće čimbenike predispozicije za učestale spontane pobačaje. Opisat ćemo čimbenike koji su ušli u kliničku praksu, kao i nove, dobijene asocijacijskim studijama, poput gena povezanih s imunosnim sustavom, koagulacijom i vaskularizacijom. Naposlijetku, naš doprinos sustavnom istraživanju uloge genskih čimbenika u etiologiji učestalih spontanih pobačaja razvijat ćemo kroz projekt "HuMGeN" (Human Miscarriage Genetic Network), koji smo pokrenuli na međunarodnoj razini.