Comparison of efficacy of biofeedback, electrical stimulation and therapeutic exercise in patients with knee osteoarthritis

Cilj ovog istraživanja bio je usporediti učinkovitost pojedinih fizikalnih postupaka u liječenju početnog OA koljena. Uspoređivali smo EMG BFB terapiju, ES terapiju i terapijsko vježbanje s pretpostavkom da će najbolji učinak imati EMG BFB terapija. Ispitivali smo bol, funkciju koljena, snagu mišića, m. vastus medialis obliquus. Pomoću upitnika SF 36 i kratkog sržnog seta MKF klasifikacije, ispitivali smo utjecaj liječenja na kvalitetu života i na biopsihosocijalno funkcioniranje ispitanika. U istraživanje smo uključili 94 ispitanika koji su proveli tri tjedna na fizikalnoj terapiji te smo ih pratili tijekom 6 mjeseci. Rezultati su pokazali dobar učinak fizikalne terapije na ispitivane parametre bez statistički značajne razlike između skupina. Ovo istraživanje pokazalo je da 6 mjeseci nakon fizikalne terapije dolazi do blagog pada snage mišića, ali bez pogoršanja u osjećaju boli i funkciji koljena. S obzirom na to da nije pronađena razlika između navedenih fizikalnih procedura, zaključili smo da je terapijsko vježbanje učinkovito u liječenju OA koljena i da nije potrebno uključivati EMG BFB terapiju, ni ES terapiju u rehabilitacijske protokole.The aim of this research was to compare the effectiveness of specific physical procedures in treating initial knee osteoarthritis (OA). We compared EMG BFB therapy, ES therapy and therapeutic exercise with the assumption that EMG BFB therapy would have the best effect. We examined pain, knee function, and the strength of the vastus medialis obliquus muscle. The SF 36 questionnaire and the brief ICF core set for osteoarthritis were used to assess the impact of treatment on the subjects' quality of life and biopsychosocial functioning. This research included 94 subjects who underwent three weeks of physical therapy and they were followed up for 6 months. The results showed a positive effect of physical therapy on the examined parameters with no statistically significant difference between the groups. The study revealed that 6 months after physical therapy there was a slight decrease in muscle strength, but no deterioration in pain sensation and knee function. Given these findings, no significant differences were observed between the mentioned physical procedures. In conclusion, we found that therapeutic exercise is effective in treating knee OA and there is no necessity to include EMG BFB therapy or ES therapy in rehabilitation protocols

Selective degradation of misfolded proteins in quiescent yeast Saccharomyces cerevisiae

Kako bi se zaštitile od nakupljanja pogrešno smotanih proteina, stanice su razvile mehanizme za kontrolu kvalitete proteina, uključujući put selektivne razgradnje sustavom ubikvitin-proteasoma. Prethodna istraživanja kontrole kvalitete proteina uglavnom su provedena u stanicama koje se aktivno dijele, međutim mnoge stanice, poput neurona i matičnih stanica u mirovanju, se ne dijele. U ovoj disertaciji istražili smo puteve selektivne razgradnje proteina u stanicama u mirovanju, koristeći modelni organizam, kvasac Saccharomyces cerevisiae. Po ulasku stanica kvasca u mirovanje aktivira se autofagija, a veliki dio proteasoma reorganizira se u granule u kojima proteasomi vjerojatno nisu aktivni, stoga nije bilo jasno oslanjaju li se stanice u mirovanju na sustav ubikvitin-proteasoma za eliminaciju pogrešno smotanih proteina. U ovom radu uspostavili smo ekspresiju modelnih pogrešno smotanih proteina tGnd1, stGnd1 i Ubc9ts u stanicama u mirovanju, koristeći PIR3- i Z-promotore. Pokazali smo da stanice u mirovanju prepoznaju pogrešno smotane proteine te ih usmjeravaju u selektivnu razgradnju, čak i u kasnijim fazama mirovanja. Nadalje, razgradnja je ovisila o aktivnosti E3 ligaza ubikvitina Ubr1 i San1, te proteasomu, što upućuje na sličan put razgradnje kao u proliferirajućim stanicama. Sveukupno rezultati pokazuju da stanice kvasca u mirovanju zadržavaju funkcionalnu kontrolu kvalitete proteina, te da se ona primarno temelji na selektivnoj razgradnji proteina.To prevent the negative impact of misfolded protein accumulation, cells have developed protein quality control pathways, including selective degradation by the ubiquitin-proteasome system. Previous research on protein quality control has mostly been conducted in actively dividing cells. However, many cells, such as neurons and quiescent stem cells, are non-dividing. In this thesis, we investigated selective protein degradation in quiescent cells, using yeast Saccharomyces cerevisiae as a model organism. Upon entry into quiescence, yeast cells induce autophagy, and a large portion of the proteasomes relocalizes into cytoplasmic granules, presumably in an inactive form. Therefore, it has been unclear whether quiescent cells rely on the ubiquitin-proteasome system for the elimination of misfolded proteins. In this study, we established an expression system of model misfolded proteins tGnd1, stGnd1, and Ubc9ts in quiescent cells using PIR3- and Z-promoters. We show that quiescent cells recognize misfolded proteins and direct them to selective degradation, even in the later stages of quiescence. Furthermore, degradation was dependent on the E3-ubiquitin ligases Ubr1 and San1 and the proteasome, suggesting a similar pathway as in proliferating cells. Overall, the results show that quiescent yeast cells maintain functional protein quality control, which is primarily based on selective protein degradation

Association of serum concentrations of interleukins IL-18, IL-19, IL-21 and IL-22 with the etiopathogenesis and assessment of clinical activity of nonsegmental form of vitiligo

Vitiligo je stečeni, kronični idiopatski poremećaj pigmentacije koji se očituje pojavom depigmentiranih makula na koži, a nastaje zbog selektivnog gubitka melanocita. Autoimunosna teorija se smatra vodećom etiopatogetskom teorijom nastanka vitiliga. Citokini su ključni medijatori stanične komunikacije i imaju značajnu ulogu u razvoju, diferencijaciji i regulaciji upalnog odgovora koji dovodi do pojave autoimunosti. Stoga je cilj ovog istraživanja bilo ispitati povezanost nesegmentalnog oblika vitiliga i serumske koncentracije interleukina (IL) IL-18, IL-19, IL-21 i IL- 22 te dobivene vrijednosti usporediti s težinom kliničke slike, aktivnošću te trajanjem bolesti. U istraživanje je bilo uključeno 78 ispitanika, od kojih 52 bolesnika sa nesegmentalnim vitiligom i 26 ispitanika u kontrolnoj skupini. U skupini bolesnika s nesegmentalnim oblikom vitiliga su izmjerene značajno više serumske koncentracije IL-19 i IL-21 te niže serumske koncentracije IL-18 i IL-22 u odnosu na kontrolnu skupinu ispitanika. Nije pronađena značajnija korelacija između težine kliničke slike, aktivnosti i trajanja bolesti. Ovim istraživanjem je prvi puta do sada učinjena analiza serumskih koncentracija kombinacije citokina IL-18, IL-19, IL-21 i IL-22 te su po prvi puta određene serumske koncentracije IL-18 i IL-19. Rezultati ovog istraživanja mogu doprinijeti boljem razumijevanju kompleksne etiopatogeneze vitiliga, ali mogu i poslužiti kao prilog spoznaji za mogući razvoj ciljane terapije, uključivši i proizvodnju monoklonskih protutijela. S obzirom da je u ovo istraživanje bio uključen relativno mali broj ispitanika, potrebne su dodatne studije na većem broju ispitanika u različitim fazama bolesti koje bi razjasnile značenje IL-18, IL-19, IL-21 i IL-22 u etiopatogenezi i kliničkim značajkama ove bolesti, kao i u mogućem razvoju ciljane terapije.Vitiligo is an acquired, chronic idiopathic pigmentation disorder that presenting with depigmented macules, caused by the selective loss of melanocytes. The autoimmune theory is considered to be the leading aetiopathogetic theory of vitiligo. Cytokines are key mediators of cellular communication and play a significant role in the development, differentiation, and regulation of the autoimmune inflammatory response. The aim of this study was to determine the association between the non-segmental form of vitiligo and the interleukins (IL) IL-18, IL-19, IL-21 and IL- 22 by measuring the serum concentration of these interleukins and to compare them with clinical severity, activity and disease duration. Seventy-eight patients were included into this study, out of whom 52 patients with nonsegmental vitiligo and 26 patients in the control group. Significantly higher serum concentrations of IL-19 and IL-21 and lower serum concentrations of IL-18 and IL- 22 were assessed in the group of patients with non-segmental vitiligo compared to the control group. No significant correlation was found between the severity, activity, and duration of the disease. This study was the first so far to analyze serum concentrations of the combination of cytokines IL-18, IL-19, IL-21 and IL-22 and to determine serum concentrations of IL-18 and IL- 19. The results of this research might contribute to the better understanding of the complex aetiopathogenesis of vitiligo, but might also contribute to the development of targeted biological therapy, i.e. the production of monoclonal antibodies. Given that a relatively small number of subjects were included in this study, additional studies are needed on a larger number of patients at different stages of the disease to clarify the role of IL-18, IL-19, IL-21 and IL-22 in the aetiopathogenesis of vitligo, its clinical characteristics and in the potential development of targeted therapy

Epigenetic status and expression of SALL4 in normal and impaired testicular development

Uloga gena SALL4, koji kontrolira razvoj spermatogonija, nije dovoljno istražena u razvoju sjemenika sisavaca, a u neplodnosti čovjeka je potpuno neistražena. Cilj disertacije bio je analizirati izražaj Sall4/SALL4 u razvoju sjemenika štakora in vivo i in vitro te u ljudskim sjemenicima s različitim dijagnozama neopstruktivne azoospermije (NOA) in vivo, kao i njegov metilacijski status u in vivo uzorcima. Pirosekvenciranjem je pokazano da je SALL4/Sall4 uvijek hipometiliran u sjemeniku. qRT-PCR-om je pokazan značajno veći izražaj Sall4 mRNA u fetalnom štakorskom sjemeniku nego u postnatalnom; a u ljudskim sjemenicima sa sindromom samo Sertolijevih stanica (SCOS) SALL4 mRNA je snižena u odnosu na hipospermatogenezu (HS) i zastoj u sazrijevanju (MA). Osim u spermatogonijama, poboljšanim IHC i IF protokolima je po prvi put pokazan SALL4 u XY tjelešcu primarnih spermatocita. Također, pokazan je pojačan izražaj SALL4 u pre-pahitenskim spermatocitama i citoplazmi intersticijskih stanica u neplodnom sjemeniku u odnosu na zdravi i HS sjemenik čovjeka. Nadalje, uspostavljen je novi 3D in vitro sustav za uzgoj tkiva sjemenika štakora, a primjena siRNA snizila je izražaj Sall4 na mRNA (za 42 %) i proteinskoj razini uzrokujući smanjeni rast i narušenu histologiju. Ovi rezultati ukazuju na SALL4 kao novi potencijalni biljeg u dijagnostici NOA te podrobnije rasvjetljavaju njegovu ulogu u procesu spermatogeneze.The role of the SALL4 gene which controls the development of spermatogonia, has been insufficiently investigated in the development of the mammalian testis, and is completely unexplored in human infertility. The doctoral thesis aimed to analyze the expression of Sall4/SALL4 in the rat testis development in vivo and in vitro as well as in the human testis with a different diagnosis of nonobstructive azoospermia (NOA) and its DNA methylation status. The pyrosequencing showed that SALL4/Sall4 is always hypomethylated in the testis. The qRT-PCR has shown significantly higher expression of the Sall4 mRNA in fetal rat testis than in postnatal; while SALL4 mRNA was lower in human testis with Sertoli cell only syndrome (SCOS) than in hypospermatogenesis (HS) and maturation arrest (MA). Except in spermatogonia, improved IHC and IF protocols showed the expression of the SALL4 protein in the XY body of primary spermatocytes of human testes. Also, increased expression of SALL4 in pre-pachytene spermatocytes and cytoplasm of interstitial cells in infertile compared to healthy human testis was demonstrated. Furthermore, an original 3D in vitro system for the cultivation of rat testis tissue was established, and the application of siRNA decreased Sall4 at the mRNA (by 42 %) and protein levels, causing reduced growth and impaired histology. These results indicate SALL4 as a new potential marker in the diagnosis of NOA and shed more light on its role in the process of spermatogenesis

Assessment of cognitive functions in psoriatic arthritis patients

Uvod: Cilj istraživanja bio je procijeniti kognitivne funkcije u bolesnika sa psorijatičnim artritisom (PsA). Ispitanici i metode: U istraživanje presječnog tipa konsekutivno su uključeni bolesnici sa PsA (N= 67) i zdravi ispitanici (N= 69). Kognitivne funkcije procijenjene su pomoću Montrealskog testa kognitivne procjene (MoCA) i testa utiranja puta (TMT) A i B. Simptomi depresije i anksioznosti testirani su pomoću Beckovog inventara depresije-II te Upitnika anksioznosti kao stanja i osobine ličnosti. Učinjena je standardna klinička procjena PsA i psorijaze. Rezultati: Bolesnici sa PsA imali su značajno lošije rezultate na TMT-A testu (p˂0,01). Nije bilo razlike između skupina u rezultatima MoCA i TMT-B testa. Svi testovi procjene kognitivnih funkcija korelirali su s dobi ispitanika, a TMT-B dodatno s obrazovnim statusom. Nije nađena korelacija između testova procjene kognitivnih funkcija i kliničkih parametara psorijatične bolesti, depresije i anksioznosti. U regresijskoj analizi, dob ispitanika pokazala se značajnom u predviđanju rezultata MoCA testa, objašnjavajući oko 18% varijance. U bolesnika sa PsA primijećene su značajno više razine depresivnosti, anksioznosti i umora (p=0,02; 0,015; odnosno 0,004). Zaključak: Bolesnici sa PsA potencijalno imaju povišen rizik kognitivnog oštećenja. Potrebna su daljnja istraživanja kako bi se preciznije odredio rizik kognitivnog propadanja u PsA.Objective: The objective of this study was to assess cognitive functions in patients with psoriatic arthritis (PsA). Methods: Patients with PsA (N= 67) and healthy subjects (N= 69) were consecutively enrolled in this cross-sectional study. Cognitive functions were assessed using the Montreal Cognitive Assessment (MoCA) and the Trail Making Test (TMT) A and B. Depression and anxiety were evaluated using the Beck Depression Inventory-II and the State-Trait Anxiety Inventory. A standard clinical assessment of PsA and psoriasis was performed. Results: Patients with PsA scored significantly worse on the TMT-A test (p˂0.01). No differences in the MoCA and TMT-B scores were found. All cognitive assessment tests correlated with age, and TMT-B also correlated with educational status. No correlation was found between cognitive assessment tests and PsA disease-related parameters, depression or anxiety. In the regression analysis, age was found to be a significant predictor of the MoCA score, explaining 18% of the variance. Patients with PsA exhibited significantly higher levels of depression, anxiety and fatigue (p=0.02, 0.015, and 0.004, respectively). Conclusion: Patients with PsA may be at an increased risk of cognitive impairment. Further research is needed to specify the risk of cognitive decline in PsA

Development of cerebral cortex and neurodegenerative changes in Down syndrome on human cerebral organoids model

Cerebralni organoidi uzgojeni od induciranih pluripotentnih matičnih stanica čovjeka su trodimenzionalne strukture koje rastu oko 100 dana u staničnoj kulturi te razvijaju morfološka obilježja specifična za ljudski mozak. Cilj istraživanja bio je iskoristiti model koji je dobiven od iste osobe, mozaika za trisomiju 21 kromosoma, što omogućava usporedbu diferencijacije kore ljudskog mozga u osoba s Downovim sindromom i njegovom izogeničnom kontrolom. Istraživanje je pokazalo kako cerebralni organoidi čovjeka ispoljavaju sve biljege karakteristične za koru velikog mozga, čime se potvrdila vrijednost ovog modela u istraživanju normalne i narušene strukture mozga. Također pokazano je kako izražaj biljega RELN, CTIP2 i TBR1 kasni u trisomičnim organoidima u odnosu na disomične, što upućuje da kod ljudi s ovom kromosopatijom dolazi do kašnjenja u najranijim fazama razvoja tkiva mozga. Također, zamijećen je manji izražaj svih biljega u trisomičnim organoidima u odnosu na disomične, čime se potvrđuje činjenica kako je cjelokupan broj živčanih stanica u mozgu ljudi s DS smanjen. Nadalje, trisomični organoidi imali su izražene biljege neurodegeneracije 6E10, 4G8 i Aßx-40 čime je potvrđena pretpostavka kako cerebralni organoidi s tri kopije 21 kromosoma predstavljaju koristan model u istraživanju neurodegenerativnih bolesti pridruženih Downovu sindromu, kao što je Alzheimerova demencija. Uspoređujući rezultate na organoidima s rezultatima analize mozgova fetusa s Downovim sindromom, starosti 18.-23. gestacijska tjedna, uočeno je kako organoidi mozga mogu vjerodostojno odražavati zbivanja tijekom embrionalnog razvoja čovjeka.Cerebral organoids grown from human induced pluripotent stem cells are three-dimensional structures that grow for approximately 100 days in cell culture and develop morphological features specific to the human brain. This study aimed to use a model derived from the same individual, a mosaic for trisomy 21, which allowed us to compare cortical differentiation in individuals with Down syndrome and their isogenic control. The study showed that human cerebral organoids express all markers characteristic of the cerebral cortex, confirming the value of this model in studying normal and disrupted brain structure. It was also found that the expression of the RELN, CTIP2, and TBR1 is delayed in trisomic organoids compared to disomic ones, indicating a delay in the earliest stages of brain tissue development in individuals with this chromosomal disorder. Additionally, a lower expression of all markers was observed in trisomic organoids compared to disomic ones, confirming that the total number of neurons in the brains of individuals with Down syndrome is reduced. Furthermore, trisomic organoids exhibited neurodegeneration markers 6E10, 4G8, and Aßx-40, confirming the hypothesis that cerebral organoids with three copies of chromosome 21 are a useful model for studying neurodegenerative diseases, such as Alzheimer's dementia. Comparing the results from the organoids with the results from the analysis of brains of fetuses with Down syndrome, aged 18-23 gestational weeks, it was observed that brain organoids can authentically replicate events that occur during human embryonic development

Diagnostic ultrasound in monitoring patients with rheumatoid arthritis compared to standard clinical disease activity indices

Unatoč ACR/EULAR preporukama o korištenju dijagnostičkog UZV u RA, UZV pregled za sada nije dio standardnih indeksa kojima se prati aktivnosti bolesti, niti je uključen u kriterije remisije. Cilj ovog istraživanja je bio procijeniti vrijednost dijagnostičkog UZV u praćenju bolesnika s RA u odnosu na standardne metode praćenja. Ispitati odnos UZV nalaza s kliničkim, laboratorijskim, radiološkim pokazateljima aktivnosti bolesti, kliničkim indeksima aktivnosti bolesti, funkcionalnim upitnicima te ACR/EULAR kriterijima kliničke remisije. Predložiti model hrvatskog zglobnog bodovnog sustava te novi kompozitni bodovni sustav. Od uključenih 117 RA bolesnika koji su praćeni tokom 3 mjeseca, ukupno ih je 88 završilo istraživanje. UZV pregled je učinjen na predefiniranom setu zglobova i tetiva, a UZV promjene su bodovane prema posljednjim publiciranim konsenzusima stručnih društava. Broj otečenih zglobova, procjena aktivnosti bolesti na VAS skali od strane liječnika, CRP, radiološki verificirane erozivne promjene, CDAI i SDAI indeks su bili najsnažnije značajno povezani s objektiviziranjem upale pomoću UZV. UZV aktivnost je utvrđena kod do 75% (Boolean) odn. 57,1% (SDAI) ispitanika koji su bili u remisiji prema ACR/EULAR kliničkim kriterijima. Kreiran je i validiran CroUS koji obuhvaća RC, MCP2, MCP3, PIP3, koljena, MTP5 zglobove i tetive ECRL/ECRB, EDC, ECU, tibialis posterior, PB/PL bilateralno. Rezultat kreiranog kompozitnog SonoFIA indeksa (CroUS, HAQ, DAS 28 SE) >8, uz osjetljivost od 83,33% i specifičnost od 61,54% upućuje na visoko aktivnu bolest. Potvrdili smo nužnost implementiranja UZV pregleda u redovni klinički pregled i njegovu dodatnu vrijednost i superiornost u objektiviziranju aktivnosti bolesti i remisije. Smatramo kako bi UZV praćenje aktivnosti RA, temeljem reduciranih bodovnih sustava i kompozitnih bodovnih sustava baziranih na UZV, svoju glavnu primjenu u praksi trebalo naći u dvojbenim kliničkim slučajevima, posebice kod bolesnika u stabilnoj remisiji kod kojih se razmatra redukcija terapije.Although ACR/EULAR recommends using diagnostic US in RA, it is still not incorporated into disease activity indices or remission criteria. The aim was to determine the value of diagnostic US in monitoring RA regarding standard methods of monitoring. To examine the relationship of US finding with clinical, laboratory, radiological disease activity indicators, clinical disease acitivity indices, functional questionnaires, ACR/EULAR remission criteria. To propose a model of a Croatian joint scoring system and a novel composite scoring system. 117 RA patients were included and 88 finished the study during the 3 month follow up. US examination was conducted on a predefined joint and tendon set and scored according to the latest published consensus. SJC, evaluator GDA, CRP, X-ray erosive changes, CDAI and SDAI had the strongest correlation with US findings. US activity was found in up to 75% (Boolean) and 57,1% (SDAI) patients in remission. CroUS (RC, MCP2, MCP3, PIP3, knee, MTP5, ECRL/ECRB, EDC, ECU, tibialis posterior, PB/PL bilateraly) was developed and validated. Composite SonoFIA index (CroUS, HAQ, DAS28 SE) > 8 indicates high disease activity with 83,33% sensitivity and 61,54% specificity. We confirmed the necessity of US implementation into RA monitoring and it's added value and superiority in objectifying disease activity and remission. US monitoring using reduced joint counts and US based composite scoring systems should take place in questionable clinical cases and patients in sustained remission with perspecitve of drug tapering

Regional differences in expression of molecular markers during formation of the expanded subplate zone in the human fetal cerebral cortex

U doktorskoj disertaciji prikazane su regionalne citoarhitektonske razlike između čeone, tjemene, zatiljne i cingularne moždane kore u fazi ekspanzije i stvaranja subplate zone (od 13. do 15. TNZ). Pomoću imunohistokemijskih metoda na prenatalnom postmortalnom tkivu mozga čovjeka praćena je dinamika ekspresije molekularnih biljega. Rezultati su pokazali kako regionalne razlike između pojedinih izokortikalnih regija fetalne moždane kore čovjeka postaju vidljive rano tijekom prenatalnog razvoja, a postaju najistaknutije upravo tijekom razdoblja formiranja SP-a. Proces stvaranja SP-a iz dubokog dijela KP prikazan je biljegom SP neurona TBR1. Pokazano je i kako je obrazac formiranja SP-a važan kriterij za diferenciranje dorzalne izokortikalne i ventralne mezokortikalne cingularne moždane kore u ranom fetalnom razdoblju. Nadalje, karakteristike rane diferencijacije mezokortikalne cingularne moždane kore su: proširenje MZ, suženje KP i SVZ. Jedna od glavnih karakteristika mezokortikalnog dijela cingularne moždane kore je nepotpuna ekspanzija SP-a, a navedeno je prikazano pomoću biljega projekcijskih neurona. Analiza ranog razvoja cingularne moždane kore važna je radi njezine uloge u stvaranju ranih neuralnih krugova uključenih u ponašanje i emocije. Nadalje, poznavanje regionalnog razvoja bitno je za razumijevanje arealne diferencijacije i kasnije funkcionalne specifikacije moždane kore što je preduvjet za razumijevanje neurorazvojnih poremećaja.In the doctoral thesis, regional cytoarchitectonic differences between the frontal, parietal, occipital, and cingulate cortex were analyzed in the the subplate formation phase (13 to 15 PCW). Immunohistochemical methods were used on prenatal postmortem human brain tissue to analyze the molecular markers` expression pattern dynamics. The results showed that regional differences between isocortical regions of the human fetal cortex become visible early during prenatal development, and are most prominent during the SP formation period. The SP formation process is shown with the SP neuron marker TBR1. Additionally, we showed that the SP formation pattern is an important criterion for differentiating the dorsal isocortical and ventral mesocortical cingulate cortex in the early fetal period. Furthermore, the early mesocortical cingulate cortex is characterized by the widening of the MZ and the narrowing of the CP and SVZ. One of the main characteristics of the mesocortical part of the cingulate cortex is an incomplete SP expansion, and this is shown in the results using projection neuron markers. The early cingulate cortex development analysis is important because of its involvement in the formation of early neural circuits involved in behavior and emotions. Furthermore, analysis of regional differences is essential for understanding areal differentiation and later functional specification of the cerebral cortex, which is a prerequisite for understanding diverse neurodevelopmental disorders

Recurrence of hepatocellular carcinoma after liver transplantation

Transplantacija jetre predstavlja kurativnu opciju za hepatocelularni karcinom (HCC), no recidiv bolesti i dalje se javlja u 8–20 % bolesnika, osobito u uvjetima trajne imunosupresije. Glavni rizični čimbenici uključuju mikrovaskularnu i makrovaskularnu invaziju, visoko tumorsko opterećenje, povišeni alfa-fetoprotein, transplantaciju izvan prihvaćenih kriterija i nedovoljan odgovor na prethodnu terapiju. Novija istraživanja ukazuju i na potencijalnu ulogu metaboličkih poremećaja u nastanku recidiva. U ovom diplomskom radu provedeno je retrospektivno istraživanje na 231 bolesniku transplantiranom zbog HCC-a u KB Merkur (2016.–2024.). Analizirani su klinički, laboratorijski i patohistološki podaci, uključujući primjenu TACE terapije i razine takrolimusa. Recidiv je zabilježen kod 10,39 % bolesnika. Statistički značajna povezanost s recidivom utvrđena je za veći broj tumorskih čvorova, prisutnost mikrovaskularne i limfovaskularne invazije te viši stadij bolesti. Također, zabilježena je veća učestalost hiperlipoproteinemije u skupini s recidivom, što može upućivati na metaboličku komponentu rizika. Zaključno, broj tumorskih čvorova i mikrovaskularna invazija potvrđeni su kao ključni čimbenici rizika za recidiv HCC-a, dok metabolički poremećaji mogu dodatno doprinijeti procjeni rizika. Potrebna su daljnja prospektivna istraživanja za precizniju stratifikaciju bolesnika nakon transplantacije.Liver transplantation represents a curative treatment option for hepatocellular carcinoma (HCC), but disease recurrence still occurs in 8–20% of patients, particularly in the context of lifelong immunosuppression. Major risk factors include microvascular and macrovascular invasion, high tumor burden, elevated alpha-fetoprotein levels, transplantation beyond accepted criteria, and inadequate response to downstaging therapies. Recent studies also suggest a potential role of metabolic disorders in increasing the risk of recurrence. This thesis presents a retrospective study of 231 patients who underwent liver transplantation for HCC at Merkur University Hospital between 2016 and 2024. Clinical, laboratory, and histopathological data were analyzed, including the use of TACE therapy and tacrolimus levels. Disease recurrence was observed in 10.39% of patients. Statistically significant associations with recurrence were found for a higher number of tumor nodules, the presence of microvascular and lymphovascular invasion, and more advanced tumor stage. Additionally, hyperlipoproteinemia was more frequent in the recurrence group, indicating a possible metabolic contribution to recurrence risk. In conclusion, the number of tumor nodules and microvascular invasion were confirmed as key risk factors for HCC recurrence, while metabolic factors such as hyperlipoproteinemia may have additional prognostic value. Further prospective studies are needed to improve risk stratification after liver transplantation

Comparable outcomes after busulfan- or treosulfan-based conditioning for allo-HSCT in children with ALL: results of FORUM

The superiority of total body irradiation (TBI)-based vs chemotherapy conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with acute lymphoblastic leukemia (ALL) has been established in the international, prospective phase-3 FORUM study, randomizing 417 patients aged 4-18 years in complete remission (CR), who received allo-HSCT from HLA-matched sibling or unrelated donors. Because of the unavailability of TBI in some regions and to accommodate individual contraindications, this study reports the prespecified comparison of outcomes of patients receiving busulfan (BU)- or treosulfan (TREO)-based regimens from 2013 to 2018. Overall, 180 and 128 patients received BU/thiotepa (THIO)/fludarabine (FLU) or TREO/THIO/FLU, respectively. Data were analyzed as of February 2023, with a median follow-up of 4.2 years (range, 0.3-9.1). 3-year overall survival was 0.71 (BU, 95% confidence interval [0.64-0.77]) and 0.72 (TREO, [0.63-0.79]) and 3-year event-free survival was 0.60 (BU, [0.53-0.67]) and 0.55 (TREO, [0.46-0.63]). The 3-year cumulative incidence of relapse (BU, 0.31 [0.25-0.38]; TREO, 0.36 [0.27-0.44]); and nonrelapse mortality (BU, 0.08 [0.05-0.13]; TREO, 0.09 [0.05-0.15]) were comparable. One case of fatal veno-occlusive disease occurred in each group. No significant differences in acute and chronic graft-versus-host disease (GVHD) or 3-year GVHD-free and relapse-free survival (BU, 0.48 [0.41-0.55]; TREO, 0.45 [0.37-0.54]) were recorded. Outcomes for patients in first and second CR were similar irrespective of the regimen. In conclusion, BU/THIO/FLU or TREO/THIO/FLU regimens can be an alternative to TBI for patients with ALL aged >4 years with contraindications or lack of access to TB