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THE EFFECT OF ASCORBATE ON SARCOMA-DERIVED CANCER STEM CELLS
No full textAgresivnost sarkoma koja se očituje u otpornosti na terapiju i jakoj sklonosti metastaziranju se
pripisuje tumorskim matičnim stanicama (CSC, engl. cancer stem cells). Kako bi se ispitala
osjetljivost CSC sarkoma na askorbat, CSC su izolirane iz šest uzoraka sarkoma te je potvrđen
njihov matični karakter. Ispitivanje citotoksičnosti askorbinske kiseline, dehidroaskorbinske
kiseline i askorbil palmitata ugrađenog u čvrste lipidne nanočestice na CSC je pokazalo kako je
optimalno primjenjivati askorbat u slobodnom obliku. Uz to, prisutnost bazičnog fibroblastnog
faktora rasta (bFGF) utječe na citotoksični učinak askorbata. Sedmodnevni tretman CSC
askorbatom u slobodnom obliku je ukazao kako dehidroaskorbinska kiselina u prisutnosti bFGF
postiže jači učinak na oksidacijski stres, ali i stanični metabolizam. Ustanovljeno je kako u
liposarkomu i rabdomiosarkomu proliferacijski signali od bFGF i mutiranih signalnih puteva u
prisutnosti dehidroaskorbinske kiseline ne dovode do proliferacije već do stanične smrti.The aggressiveness of sarcomas, characterized by therapy resistance and high metastatic potential,
is attributed to cancer stem cells (CSC). To investigate the sensitivity of sarcoma CSC to ascorbate,
CSC were isolated from six sarcoma samples, and their stemness was confirmed. Cytotoxicity
testing of ascorbic acid, dehydroascorbic acid, and ascorbyl palmitate incorporated into solid lipid
nanoparticles on CSC demonstrated that ascorbate in free form is optimal for application.
Additionally, the presence of basic fibroblast growth factor (bFGF) influenced cytotoxic effects. A
seven-day treatment of CSCs with free-form ascorbate revealed that dehydroascorbic acid in the
presence of bFGF had a stronger impact on oxidative stress and cellular metabolism. It was found
that, in liposarcoma and rhabdomyosarcoma, proliferative signals from bFGF and mutated
signaling pathways, in the presence of dehydroascorbic acid, do not lead to proliferation but
instead cause cell death
Predictors of patient satisfaction and nurse satisfaction as indicators of process in the nursing care quality management system
No full textCilj istraživanja: Glavni je cilj doktorskoga rada bio ispitati doprinos varijabli vezanih uz demografska obilježja, posao i crte ličnosti medicinskih sestara i medicinskih tehničara na razinu zadovoljstva bolesnika kao indikatora procesa u sustavu upravljanja kvalitetom zdravstvene njege te ispitati doprinos varijabli vezanih uz demografska obilježja, zdravstveno stanje i crte ličnosti bolesnika na razinu zadovoljstva bolesnika kao indikatora procesa u sustavu upravljanja kvalitetom zdravstvene njege.
Nacrt studije: Provedena je presječna studija.
Ispitanici i metode: U istraživanju je sudjelovalo 212 hospitaliziranih bolesnika u Općoj županijskoj bolnici Požega i 108 medicinskih sestara i medicinskih tehničara zaposlenih na odjelima gdje su bolesnici hospitalizirani. Istraživanje je provedeno od 2022. do 2024. godine.
Rezultati: Dobiveno je kako zadovoljstvo poslom pozitivno (p<0,001), dok neuroticizam (p<0,001) i bračno stanje (oni koji nisu u braku) (p=0,010) medicinskih sestara i medicinskih tehničara negativno doprinosi zadovoljstvu kvalitetom zdravstvenom njegom bolesnika. S druge strane, kod bolesnika muški spol (p=0,011), bolje zdravstveno stanje (p=0,006), boravak u sobi s dvije i više osoba u sobi (p=0,002) i crte ličnosti ugodnosti (p=0,012) i savjesnosti (p=0,004) bolesnika značajno pozitivno doprinose zadovoljstvu kvalitetom zdravstvene njege bolesnika, dok bračno stanje (oni koji nisu u braku) negativno doprinosi zadovoljstvu bolesnika kvalitetom zdravstvene njege.
Zaključak: Najznačajniji su prediktori zadovoljstva bolesnika kvalitetom zdravstvene njege neuroticizam medicinskih sestara i crte ličnosti ugodnosti i savjesnosti te boravak u sobi s dvije i više osoba kod bolesnika. Nešto manje važni, ali i dalje značajni prediktori su bračno stanje onih koji nisu u braku, zdravstveno stanje i spol bolesnika te bračno stanje onih koji nisu u braku i zadovoljstvo poslom medicinskih sestara i medicinskih tehničara.Objectives: The main objective of the doctoral thesis was to examine the contribution of variables related to demographic characteristics, job, and personality traits of nurses and technicians to the level of patient satisfaction as an indicator of processes in the nursing care quality management system, and to examine the contribution of variables related to demographic characteristics, health status, and personality traits of patients to the level of patient satisfaction as an indicator of processes in the nursing care quality management system.
Study Design: A cross-sectional study was conducted.
Participants and Methods: The study involved 212 hospitalized patients at the General County Hospital Požega and 108 nurses and technicians employed in the departments where the patients were hospitalized. The research was conducted from 2022 to 2024.
Results: Job satisfaction positively contributes to patient satisfaction with the quality of nursing care (p<0.001), while neuroticism (p<0.001) and marital status (those who are not married) (p=0.010) of nurses and technicians negatively contribute to patient satisfaction with the quality of nursing care. On the other hand, for patients, male gender (p=0.011), better health status (p=0.006), staying in a room with two or more people (p=0.002), and the personality traits of agreeableness (p=0.012) and conscientiousness (p=0.004) significantly positively contribute to patient satisfaction with the quality of nursing care. Conversely, marital status (those who are not married) negatively contributes to patient satisfaction with the quality of nursing care.
Conclusion: The most significant predictors of patient satisfaction with the quality of nursing care are the neuroticism of nurses and the personality traits of agreeableness and conscientiousness, as well as staying in a room with two or more people for patients. Less important but still significant predictors include marital status (those who are not married), the health status and gender of patients, as well as job satisfaction and marital status (those who are not married) of nurses and technicians
Predictors of receptive language skills in children with cochlear implants
No full textUvod: Jezično-govorni ishodi djece s kohlearnim implantatom uvelike su varijabilni nekada čak i usprkos odličnim predoperativnim predispozicijama. Obzirom da je prediktivni potencijal demografskih, audioloških i habilitacijskih čimbenika previše ograničen za objašnjenje navedene varijabilnosti recentna istraživanja su se usmjerila na kognitivne čimbenike, preciznije, karakteristike verbalnog i neverbalnog radnog pamćenja.
Cilj: istraživanja je utvrditi koji do sada predloženi pojedinačni kognitivni, demografski, audiološki i habilitacijski čimbenici nude optimalan multivarijatni model predikcije vještina receptivnog jezika prirođeno teško nagluhe ili gluhe djece s kohlearnim implantatima.
Ispunjenje definiranog cilja obuhvatilo je ispitivanje jezičnog razumijevanja, kao i mogućih osobitosti verbalnog i neverbalnog radnog pamćenja kod djece korisnika kohlearnih implantata te njihovog doprinosa varijabilnosti u jezičnim ishodima kod ove djece, u zajedništvu s demografskim, audiološkim i habilitacijskim čimbenicima.
Metodologija: U istraživanju je sudjelovalo 35 djece s kohlearnim implantatom i 23 čujuća djeteta, osnovnoškolske dobi (6 do 15,9 godina). Kriteriji odabira sudionika s kohlearnim implantatom su bili: prirođena gluhoća, rana implantacija (prije 4. godine života), oralna komunikacija, uključenosti u redovni obrazovni program, uredna neverbalna inteligencija te nepostojanja drugih teškoća.
Rezultati: Ovo istraživanje je pokazalo značajno slabije razumijevanje receptivnog jezika skupine djece s kohlearnim implantatom u odnosu na čujuće vršnjake. Djeca s kohlearnim implantatom pokazuju osobitosti radnog pamćenja u odnosu na čujuće vršnjake u njegovom verbalnom aspektu, ali ne i u neverbalnom aspektu, te imaju značajno bolje pohranu nego obradu i verbalnih i neverbalnih informacija u radnom pamćenju. Značajni prediktori receptivnih jezičnih vještina djece s kohlearnim implantatom prema rezultatima ovog istraživanja su audiološki prediktori koji se odnose na čujnost s kohlearnim implantatom i dob implantacije, te kognitivni prediktori koji se odnose na pohranu verbalnih i neverbalnih informacija u radnom pamćenju.Cochlear implants have become a standard option for children with severe hearing loss or deafness, enabling access to speech sounds sufficient for the development of receptive and expressive language (Crowson i sur., 2017). This access, in turn, supports emotional, social, and academic development in a hearing/verbal society (Wieringen & Wouters, 2014). However, language outcomes for children with cochlear implants are highly variable (Geers & Nicholas, 2013; Percy-Smith et al., 2013; Boons et al., 2012; Niparko et al., 2010; Dettman et al., 2016), sometimes despite excellent preoperative conditions (Pisoni et al., 2017). Available research clearly shows that numerous personal, technical, and habilitative factors can influence a child’s ability to function well in a hearing world, develop receptive language at a level comparable to hearing peers, and produce intelligible speech. One of the most critical factors for optimal cochlear implant outcomes is the age of implantation (Almomani, et al. 2021; Boons et al., 2012; Nott et al., 2009; Holt & Svirsky, 2008; Dettman et al., 2007; Tait et al 2007a; Tait et al 2007b; Connor at al. 2006). The best outcomes are achieved when implantation occurs by the age of 4 years, as the plasticity of the auditory pathway and auditory centers in the brain is maximal at this age (Kral & Sharma, 2012). Specific personal and environmental factors—such as gender, non-verbal IQ, affinity for developing listening and oral language, and family educational and socio-economic characteristics—also play significant roles in the ultimate outcomes of cochlear implantation (Geers & Sedey, 2011; Nicholas & Geers, 2007; Geers, 2003; Moog & Geers, 2010). Language outcomes in children with cochlear implants can be influenced by technical variables—speech processing strategies, the number of active electrodes, regular programming (Velandia et al., 2020; Wouters et al., 2015; Patrick at al., 2006)—as well as the duration of use (months/years) and daily usage (hours) of the cochlear implant (Geers et al., 2003). Habilitative factors are also crucial, as studies have shown better language outcomes in children who grow up in an oral environment, receive more hours of therapy, have continuous support from a specialized team, and are educated in regular programs (Geers et al., 2003).
Authors in the field agree that the predictive potential of all listed factors is too limited to fully explain the significant individual differences in language skills among this population (Harris et al., 2013). Therefore, recent research has focused on the neurobiological and neurocognitive aspects of spoken language learning (Pisoni et al., 2017), leading to the development of two opposing theories: cognitive and sensory. According to the cognitive theory, cochlear implants cannot compensate for early auditory deprivation, which is evident in the impaired and modest development of skills for coding stimuli from the cochlear implant and their linguistic processing. This theory focuses on the weak verbal working memory skills of children with cochlear implants, suggesting that the absence of early auditory pathway stimulation hinders the development of phonological awareness mechanisms in the neurocognitive development of some children with cochlear implants (Pisoni et al., 2017; Kronenberger et al., 2014; Conway et al., 2009). The sensory theory posits that the verbal working memory of children with cochlear implants does not develop typically due to the poor quality of stimuli from the implant (Nittrouer et al., 2014), which prevents the formation of standard acoustic images of phonemes (Nittrouer et al., 2017). The poor signal resolution from the cochlear implant prevents the development of good sequential memory skills (phonological awareness), thus hindering (meta)linguistic skills because information storage for processing is compromised (Nittrouer et al.. 2013).
Recent research in this area suggests that a large part of the variance in language outcomes after cochlear implantation in children can be explained by cognitive factors responsible for the efficiency of information storage and retrieval, specifically the characteristics of verbal and non-verbal working memory. Both cognitive and sensory theories are based on the information processing approach and related working memory. Verbal working memory, as part of working memory, is crucial for the development of speech perception and spoken language. Recent research on individual differences among deaf children with cochlear implants who experienced auditory deprivation during early, critical years for the development of skills dependent on verbal information processing has focused on this aspect (Davidson et al., 2019; Pisoni & Cleary, 2003; Pisoni & Geers, 2000). Previous research implies that prelingually deaf children with cochlear implants show deficiencies in verbal working memory compared to their hearing peers. The question of whether these children have problems storing verbal information in working memory or if the problem also exists in processing verbal information remains unanswered based on current research. Further studies are needed to better understand the neurocognitive factors influencing language outcomes after cochlear implantation. To gather evidence for stronger arguments in favor of cognitive or sensory theories, further research has focused on non-verbal (visual-spatial) working memory, which some authors suggest is inferior in children with cochlear implants compared to hearing peers (AuBuchon et al., 2015; Kronenberger et al., 2014; Harris et al., 2013; Pisoni et al., 2011). However, Davidson et al. (2019) and Conway et al. (2011) believe that weak working memory skills primarily pertain to its verbal aspect, even with good hearing, while in the visual-spatial aspect (storage and processing of non-verbal information), children with cochlear implants demonstrate skills comparable to hearing peers. Thus, it is possible that the different organization of working memory in children with cochlear implants is not solely a consequence of early auditory deprivation but results from difficulties in coding speech sounds in its verbal component and from verbal mediation of visual information in its non-verbal component. When verbal mediation of visual information is controlled, the performance of non-verbal tasks by children with cochlear implants improves (Davidson et al., 2019).
Research Objective
Given that personal, audiological, technical, and habilitative factors cannot fully explain the significant variability in language outcomes of children with cochlear implants, further research needs to include factors pointed out by recent studies on cognitive processes in children with cochlear implants. At the same time, it is necessary to observe their synergistic effect through testing a predictive model of specific cognitive factors (specifically verbal and non-verbal working memory), auditory and related language experiences enabled by the cochlear implant, and personal, environmental, technical, and habilitative variables. Continuing research on new predictive models of receptive language skills in children with cochlear implants offers several scientific and clinical benefits: it contributes to gathering new evidence for sensory or cognitive theories of variability in language outcomes after cochlear implantation by establishing the relationship between verbal and non-verbal working memory and receptive language skills of children with cochlear implants; it advances scientific knowledge related to evaluating existing explanations for weaker language skills of children with cochlear implants compared to hearing peers; it points out variables relevant to the development of receptive language skills after cochlear implantation, indicating the specifics on which the success of spoken language development in this population depends. Understanding the reasons for specificities in spoken language development due to the specific participation of all mentioned factors in children using cochlear implants can help refine these devices, accelerate decision-making on optimal ways of early stimulation of auditory centers in the brain, specify language interventions according to verbal working memory function characteristics, involve families in habilitation to maximize natural early language input, and identify individuals with early noticeable delays in language outcomes after implantation, necessitating changes in intervention.
Research Aim
The aim of this study is to determine which proposed individual cognitive, demographic, audiological, technical, and habilitative factors provide an optimal multivariate model for predicting receptive language skills in children with congenital severe hearing loss or deafness using cochlear implants.
The research examined how verbal and non-verbal working memory in children with cochlear implants affects their language outcomes, while also considering individual, technical, and rehabilitation factors. In accordance with the defined research objectives, the following research hypotheses were formulated:
H1: Children with cochlear implants will have significantly poorer results on standardized measures of receptive language than hearing peers.
H2: Children with cochlear implants will have significantly poorer verbal working memory skills than hearing peers.
H3: Children with cochlear implants will have significantly poorer non-verbal working memory skills than hearing peers.
H4: The development of verbal and non-verbal working memory skills in children with cochlear implants is significantly different.
H5: Children with cochlear implants will have significantly poorer working memory skills in the domain of processing compared to the domain of storing verbal and non-verbal information.
H6: Cognitive working memory skills contribute significantly more to predicting receptive language skills in children with cochlear implants than their demographic, audiological, technical, and habilitative characteristics.
Methodology
Participants. The study involved 58 children: 35 children with cochlear implants, of primary school age (6 to 15.9 years), and 23 hearing children matched by age and gender with the group of children using cochlear implants. All participants had a normal nonverbal intelligence quotient, confirmed by psychological testing using Raven's Progressive Matrices. Given the highly heterogeneous population of children with hearing loss, the participants were homogenized by selecting only those who were congenitally deaf. The criteria for early implantation (before the age of 4), oral communication, inclusion in the regular education program, normal nonverbal intelligence, and the absence of other difficulties aimed to encompass children with the best predispositions for good language outcomes after cochlear implantation. All participants with hearing loss were equipped with modern cochlear implant systems from Cochlear and Med-el, used advanced speech processing strategies, regularly programmed their cochlear implant speech processors, and actively used the device during all waking hours. Most participants had only one cochlear implant.
Materials. The Peabody Picture Vocabulary Test (PPVT-III-HR) and the Test for Reception of Grammar (TROG-2: HR) were used to assess language comprehension. PPVT-III-HR (Kovačević et al., 2009) is the Croatian version of the Peabody Picture Vocabulary Test – 3rd Edition (PPVT-III; Dunn & Dunn, 1997). It contains 204 words divided into 17 sets, each set consisting of 12 words arranged by difficulty. The words are depicted by pictures, with the target word shown alongside three other pictures (Kovačević et al., 2009). Testing begins with the set corresponding to the chronological age and ends when the participant makes 8 mistakes in one set. TROG-2: HR is a receptive language test that assesses the understanding of Croatian grammar, based on the TROG-2 test developed by Dorothy Bishop in 1989. It contains 80 test items divided into 20 blocks with specific grammatical structures progressing in complexity. Each block contains four grammatically and lexically different items accompanied by four pictures, from which the participant selects the one corresponding to the sentence read by the examiner. A block is completed when all items are answered correctly, and five consecutive block errors end the testing. For assessing verbal working memory, the Wechsler Intelligence Scale for Children (WISC) - Digit Span subtest (Wechsler, 1991) was used, which measures the capacity to process verbal information. The task requires participants to repeat a list of numbers in the correct order, starting with two-digit sequences and progressing to longer sequences. Testing continues with correct repetition of at least one sequence of the given length, and stops when the participant fails to repeat two sequences of the same length. Forward digit span tests the storage of verbal information, while backward digit span tests both storage and processing of verbal information. The longer the correctly remembered sequence, the better the result. Nonverbal working memory was assessed using the Corsi Block-Tapping Task (Corsi, 1972). The participant's task is to tap the blocks, fixed on a board, in the same order as the examiner. To assess nonverbal data storage, the participant must tap the blocks in the order presented by the examiner, while for processing assessment, the blocks must be tapped in reverse order (Kessels et al., 2008). The final test score is the longest sequence the participant successfully reproduced correctly, represented as the number of correctly recalled sequences.
Procedure and Data Processing. After administrative and preparatory tasks, individual data collection began. Testing was conducted individually with each research participant in a quiet, well-lit, and comfortable room, adhering to the original instructions for standardized test administration, scoring, and interpretation. Collected data were statistically processed after appropriate preparation (coding and scaling). Descriptive analysis was first performed for the sample data. Comparisons of receptive language, verbal and nonverbal working memory between the cochlear implant group and their hearing peers were conducted using descriptive analysis and the Mann-Whitney U test, with results considered significant at p<0.05. Comparisons of verbal and nonverbal information storage and processing among participants with cochlear implants were conducted using the non-parametric sign test (at a significance level of p<0.05). To determine which cognitive, demographic, audiological, technical, and habilitation factors observed in the study offer a good multivariate model for predicting receptive language skills in children with cochlear implants, multiple regression analysis was performed. The Shapiro-Wilk test was used to check the distribution of the dependent language variable and the cognitive, demographic, audiological, technical, and habilitation variables, and logarithmic transformation of the dependent variable Language Comprehension and continuous independent demographic and cognitive variables was also performed. Since the sample of independent variables included categorical variables, indicator variables were introduced for the analysis of the relationship with the dependent variable Language Comprehension after recoding to fewer categories. Further analysis was performed using a stepwise procedure to define the regression solution with the most important predictors for the dependent variable and reduce the initial set of predictors in the final regression model.
Results
The results showed statistically significant differences in vocabulary and grammatical knowledge and the overall receptive language comprehension between the group of children with cochlear implants and their hearing peers, confirming the first hypothesis. The study found poorer storage and processing of verbal information (confirming the second hypothesis), which can be linked to the cognitive theory suggesting that weaknesses in verbal working memory in children with cochlear implants are generally a result of early auditory deprivation, preventing the development of cognitive skills necessary for oral language development. However, equally nonverbal working memory between children with cochlear implants and their hearing peers (disproving the third hypothesis) can be partly explained by the spectrally degraded signal provided by the cochlear implant, suggesting that early auditory deprivation is not generally related to cognitive functions as the cognitive theory claims, but specifically and limitedly to its verbal aspect, supporting the sensory theory. Given the established peculiarities of working memory in children with cochlear implants compared to hearing peers, the nature of these peculiarities was examined within the group of children with cochlear implants, and it was found that there is no significant difference between the storage of verbal and nonverbal information in working memory. However, there are statistically significant differences between the processing of verbal and nonverbal information, making it possible to partially accept the fourth hypothesis. Furthermore, it was found that children with cochlear implants have significantly less developed working memory skills in processing than in storing information in working memory, confirming the fifth hypothesis.
Although the specific characteristics of working memory in children with cochlear implants are simultaneously a consequence of poorer storage and processing of verbal information, supporting the so-called cognitive theory, which posits that the weaknesses in working memory among pediatric cochlear implant users are a result of early auditory deprivation, this group of children does not differ from their hearing peers in nonverbal working memory skills. This challenges the cognitive theory’s claim about a different cognitive structure of working memory. The weak verbal working memory in children with cochlear implants could be explained not only by early auditory deprivation but also by linguistic deprivation, that is, an underdevelopment of specific strategies for complex processing of spoken language information. At the same time, their strong nonverbal working memory could be explained by the so-called sensory theory, specifically the incomplete auditory input provided by the cochlear implant, but also more broadly – by the general issue of access to language.
This research has identified a model of predictive factors whose synergistic effect determines the receptive language skills of congenitally deaf children with cochlear implants. The study demonstrated that average post-implant hearing threshold and age of implantation are significant audiological predictors of receptive language, while verbal and nonverbal working memory capacity are important cognitive predictors. Therefore, the sixth hypothesis, which stated, "Cognitive working memory skills contribute significantly more to the prediction of receptive language skills in children with cochlear implants than their demographic, audiological, and habilitation characteristics," can be partially accepted.
A lower hearing threshold in the implanted ear enables better speech perception, which contributes to more successful language development, while implantation within the sensitive period further optimizes outcomes. Good practice in Croatia regarding audiological intervention – systematic early detection of hearing loss on a n
Comparsion of effects of stress and noise on salivary cortisol values
No full textOva studija ispituje potencijalnu povezanost između koncentracije kortizola u slini i rezultata subjektivnih testova stresa kod zdravih osoba izloženih zvučnim, psihološkim i fizičkim stresovima. Studija je provedena kao jednocentrično opažajno presječno istraživanje s uzorkom od 36 ispitanika regrutiranih u tercijarnom audiološkom centru. U razdoblju od 2023. do 2024. godine regrutirani su ispitanici s normalnim sluhom, urednim razinama kortizola u slini te urednim subjektivnim razinama stresa. Sudionici su ispunili STAI-Y1 upitnik i dali uzorke sline za mjerenje kortizola prije i nakon izlaganja zvučnim, psihološkim i fizičkim testovima stresa. Izlaganje psihološkom i fizičkom stresu znatno je povećalo STAIY1 rezultate (Friedmanov test, χ 2 = 57.118, df = 2, p = 0.377). To je povećanje bilo veće nego u odgovoru na glasnu, omiljenu muziku (Friedmanov test, χ2 = 57.118, df = 2, p 0.05). Izlaganje omiljenoj glasnoj glazbi povećava koncentraciju kortizola u slini, kao i akutni fizički i psihološki stres. Zanimljivo je da glasna muzika, za razliku od psihološkog i fizičkog stresa, nije objektivno percipirana kao stres, što može prikriti fiziološke znakove stresa, čime se potencijalno povećava rizik od akutnih i kroničnih zdravstvenih problema povezanih sa stresom.Purpose: The purpose of this study was to investigate the effects of three different stressors—noise exposure, psychological stress, and physical stress—on salivary cortisol levels in healthy adult individuals. The aim was to determine whether exposure to loud music (as a form of noise) triggers a similar physiological stress response to psychological and physical stressors, and to assess subjective stress perceptions in relation to these stressors.
Methods: The study involved 36 healthy participants (18 males and 18 females, aged 20– 30), all of whom had normal hearing and baseline cortisol levels. The participants were exposed to three different stressors. For the noise exposure, participants listened to loud concert music for 60 minutes. To induce psychological stress, the Trier Social Stress Test (TSST) was used, which involves public speaking and mental arithmetic tasks. For physical stress, participants submerged their hand in ice-cold water for 2 minutes. Salivary cortisol levels were measured before and after each stressor using an electrochemiluminescent immunoassay. Additionally, subjective stress levels were evaluated using the State-Trait Anxiety Inventory (STAI-Y1). Data were analyzed using the Friedman test to compare cortisol levels across the different stress conditions, and the Mann-Whitney test to compare subjective stress responses between the groups.
Results : The results showed a significant increase in cortisol levels following all three stressors—noise exposure, sychological stress, and physical stress—indicating a physiological stress response. While subjective stress ratings were higher after the psychological and physical stressors, loud music (noise exposure) caused a cortisol increase similar to the other two stressors, even though it was rated as the least stressful by participants. Statistical analysis revealed significant differences in cortisol levels across conditions (Friedman test, χ² = 95.264, p < 0.0001). Subjective stress ratings were notably higher following the psychological and physical stress tests compared to the noise exposure.
Conclusions: Exposure to loud music significantly elevates salivary cortisol levels, suggesting that noise can act as a potent stressor, even if individuals do not perceive it as such. This finding highlights the potential impact of noise on physiological stress and calls for further research on the long-term effects of noise exposure on health. The study emphasizes the need to reconsider how noise is viewed in relation to stress and its contribution to chronic stress-related conditions
The Role of Abbreviated Breast Magnetic Resonance Imaging in Women with the Family History of Breast Cancer Involved in National Breast Cancer Early Detection Program
No full textCilj: Utvrditi korisnost prepoznavanja žena s obiteljskom anamnezom raka dojke, uključenih u Nacionalni program ranog otkrivanja raka dojke, i probira magnetskom rezonancijom dojki kao dodatnom dijagnostičkom metodom.
Metode: Uključeno je 178 ispitanica s obiteljskom anamnezom raka dojke u dobi od 50 do 69 godina koje su se odazvale na poziv za mamografiju u 7. ciklusu programa probira. Nakon mamografije napravljen je MR dojki prema skraćenom protokolu. Zlatni standard za ocjenu dijagnostičke točnosti mamografije i MR-a dojki, a s obzirom na sumnjive nalaze BI-RADS 4 i BI-RADS 5, bila je patohistološka dijagnoza nakon učinjene biopsije pod nadzorom UZV-a dojki.
Rezultati: Otkriveno je 12 novih slučajeva raka dojki, od čega je njih 7 (58,3%) bilo otkriveno samo MR-om dojki, njih 4 (33,3%) bilo je otkriveno i s mamografijom i s MR-om dojki, a 1 (8,3%) rak dojke bio je otkriven samo mamografijom. Osjetljivost magnetske rezonancije dojki prema skraćenom protokolu za otkrivanje raka dojke bila je 91,7%, specifičnost 94,6%, PPV 55,0% i NPV 99,4%, a kod mamografije te su vrijednosti bile 41,7%, 96,4%, 45,5% i 95,8%.
Zaključci: Ovi podatci potvrđuju da smo uvođenjem MR-a dojki otkrili 7 slučajeva raka dojke koji bi ostali neotkriveni da u program probira uz mamografiju nije dodan pregled MR-om dojki. S obzirom na rezultate provedenog istraživanja može se preporučiti da se ženama s obiteljskom anamnezom raka dojke najprije procijeni imaju li povećani rizik, a nakon toga uz mamografiju omogući i godišnji pregled MR-om dojki s ciljem što ranijeg otkrivanja i početka liječenja bolesti.Objective: To determine the utility of identifying women with a family history of breast cancer, enrolled in the National Breast Cancer Early Detection Program, through breast magnetic resonance imaging (MRI) screening as an additional diagnostic method.
Methods: A total of 178 participants with a family history of breast cancer aged 50 to 69 who responded to the invitation for mammography in the 7th screening cycle were included. Following mammography, a breast MRI was performed according to an abbreviated protocol. The gold standard for assessing the diagnostic accuracy of mammography and breast MRI, considering suspicious BI-RADS 4 and BI-RADS 5 findings, was the histopathological diagnosis after ultrasound-guided breast biopsy.
Results: Twelve new cases of breast cancer were detected, with 7 (58.3%) identified only by breast MRI, 4 (33.3%) detected by both mammography and breast MRI, and 1 (8.3%) diagnosed only by mammography. The sensitivity of breast MRI according to the abbreviated protocol for breast cancer detection was 91.7%, specificity 94.6%, positive predictive value (PPV) 55.0% and negative predictive value (NPV) 99.4%, while for mammography, these values were 41.7%, 96.4%, 45.5%, and 95.8%, respectively.
Conclusions: These data confirm that the introduction of breast MRI led to the discovery of 7 cases of breast cancer that would have remained undetected if breast MRI had not been added to the screening program alongside mammography. Considering the results of the conducted research, it is recommended to assess whether women with a family history of breast cancer have an increased risk, and subsequently, provide annual breast MRI screening in addition to mammography for the early detection and initiation of treatment
Prognostic Value of Apparent Diffusion Coefficient (ADC) in Patients with Diffuse Gliomas
No full textCiljevi: Cilj ovog istraživanja bio je procijeniti postoje li promjene pojavnog difuzijskog koeficijenta (engl. apparent diffusion coefficient, ADC) uz područje imbibicije gliomske lezije koje bi mogle odgovarati zonama infiltracije nevidljivima standardnim metodama MR snimanja. Također, istražene su promjene ADC vrijednosti u izgledom normalnoj bijeloj tvari mozga na standardnim MR sekvencama (engl. normal appearing white matter, NAWM) ipsilateralne i kontralateralne hemisfere u bolesnika s gliomskim novotvorinama. Dodatni cilj bio je istražiti postoji li korelacija ADC vrijednosti i vremena preživljenja. Materijali i metode: U istraživanje je uključeno ukupno 49 pacijenata liječenih u KBC-u Split u razdoblju od 2016. do 2021. godine zbog glioma visokog gradusa. Analizirane su MR pretrage prije početka liječenja te kontrolne MR pretrage nakon završetka terapije. ROI (engl. region of interest) su postavljani u peritumorsku regiju, uz leziju koja je pokazivala imbibiciju kontrastom (dvije zone) te u ipsilateralnu i simetrično u kontralateralnu NAWM. Rezultati: Analiza je pokazala povišene ADC vrijednosti u NAWM u bolesnika s kraćim vremenom preživljenja u odnosu na one s duljim preživljenjem u obje moždane hemisfere. Na početnom MR-u prije terapije ova razlika nije bila statistički značajna, no na kontrolnoj MR pretrazi nakon liječenja postala je značajna. Također je uočena negativna korelacija između ADC vrijednosti u NAWM i preživljenja, pri čemu su viši ADC bili povezani s lošijim ishodom. ADC vrijednosti u peritumorskoj regiji bile su niže u fpacijenata s kraćim vremenom preživljenja, no razlike nisu bile statistički značajne na oba mjerenja. Zaključak: Naše istraživanje sugerira da ADC vrijednosti u NAWM mogu imati prognostičku vrijednost kod pacijenata s gliomima. Također, iako nisu statistički značajne u svim mjerenjima, ADC vrijednosti u peritumorskoj regiji pokazuju trend prema nižim vrijednostima u pacijenata s lošijim ishodom, što može ukazivati na višu celularnost i agresivniji tumorski fenotip. Dodatna istraživanja s većim brojem ispitanika, standardiziranim metodologijama i multimodalnim pristupima, uključujući MR spektroskopiju i perfuziju, mogla bi pomoći u boljem razumijevanju prognostičkog potencijala ADC mapa u gliomima.Objectives: The aim of this study was to evaluate whether changes in the apparent diffusion coefficient (ADC) values in the region adjacent to contrast enhanced glioma lesions could correspond to infiltration zones that are not visible using standard MR imaging techniques. Additionally, we aimed to assess changes in ADC values in the normal-appearing white matter (NAWM) of the ipsilateral and contralateral hemispheres in glioma patients. Another objective was to explore the correlation between ADC values and overall survival. Materials and Methods: The study included 49 patients treated at the University Hospital Center Split between 2016 and 2021 for high-grade gliomas. MR imaging was analyzed before treatment initiation and after the completion of treatment. Regions of interest (ROI) were placed in the peritumoral region adjacent to the contrast-enhancing lesion (two zones) and in the ipsilateral and symmetrically contralateral NAWM. Results: The analysis revealed higher ADC values in the NAWM of patients with shorter survival compared to those with longer survival in both hemispheres. Although this difference was not statistically significant on pre-treatment MR imaging, it became significant on post-treatment control MR imaging. A negative correlation was observed between ADC values in the NAWM and survival, with higher ADC values associated with worse outcomes. ADC values in the peritumoral region were lower in patients with shorter survival compared to those with longer survival, but these differences were not statistically significant in one of the measurements. Conclusion: Our findings suggest that ADC values in the NAWM may have prognostic value for glioma patients. While not statistically significant in all measurements, ADC values in the peritumoral region showed a trend toward lower values in patients with worse outcomes, potentially indicating higher cellularity and a more aggressive tumor phenotype. Further research with larger sample sizes, standardized methodologies, and multimodal approaches, including MR spectroscopy and perfusion, could enhance our understanding of the prognostic potential of ADC analysis in gliomas
In vitro antimicrobial and anti-inflammatory activity of Erodium cicutarium (L.) L'Her. ex Aiton
No full textU okviru doktorskog rada provedena su ispitivanja antimikrobnog, protuupalnog te antioksidacijskog djelovanja ekstrakata
vrste Erodium cicutarium (L.) L’Hér. ex Aiton, Geraniaceae u uvjetima in vitro. Ispitivanja navedenih aktivnosti praćena su
opsežnom fitokemijskom analizom ektrakata i eteričnog ulja. Antimikrobna aktivnost iscrpina poglavito je izražena na
sojeve vrste Staphylococcus aureus, uključujući i kliničke MRSA sojeve. Uz pokazanu kinetiku bakteriostatskog i
baktericidnog učinka u vremenu te anti-biofilm aktivnost, bioautografijom je uz semipreparativnu izolaciju i UHPLC-LTQ
OrbiTrap MS4 analizu, kao vrhunac ovog doktorskog rada, provedena izolacija i karakterizacija antimikrobno aktivnih
frakcija. Dobiveni rezultati ukazuju na derivate galne kiseline kao spojeve poglavito odgovorne za opaženi antimikrobni
učinak. Među njima je najzastupljeniji spoj galoil šikiminska kiselina. Poseban je naglasak i na 7 spojeva iz antimikrobno
aktivnih frakcija, koji su po prvi puta unutar ovog doktorskog rada identificirani za vrstu E. cicutarium, rod Erodium, te
porodicu Geraniaceae. To su narcisin, galoil pentozid izomer 1 i izomer 2, metilgaloil-kafeoil heksozid, metilgaloil-kumaroil
heksozid, te izomer 1 i izomer 2 trimetilelagične kiseline. Protuupalni potencijal vrste E. cicutarium u uvjetima in vitro
ponajprije je pokazan kroz rezultate izravne inhibicije enzima COX1 i COX2 i inhibiciju citokina IL-6, te inhibiciju lučenja
dušik (II) oksida na modelu THP-1 stanica. Antioksidacijsku aktivnost u uvjetima in vitro, ispitanu metodama DPPH, ABTS,
FRAP, CUPRAC te metodom izbjeljivanja β-karotena, pokazali su svi ispitani uzorci u svim provedenim pokusnim
uvjetima. Detaljan polifenolni profil vrste E. cicutarium utvrđen je metodom UHPLC-LTQ OrbiTrap MS4. Analizirane su
metanolne i vodene iscrpine ove vrste s četiri lokaliteta na području Republike Hrvatske (Podvinje, Plitvice, Trešnjevka,
Buzin), a identificirano je ukupno 85 sastavnica. Najzastupljeniji su derivati galne kiseline (24 sastavnice), derivati elagične
kiseline – uključujući elagitanine (22 sastavnice), 19 flavonolnih glikozida, 8 derivata fenolnih kiselina, 7 derivata drugih
hidroksibenzojevih kiselina, 3 flavonolna aglikona te 2 procijanidina. Nagasak je na 25 identificiranih sastavnica, koje do
sada nisu pronađene unutar roda Erodium, te porodice Geraniaceae. Od ukupno 17 kvantificiranih sastavnica metodom
UHPLC-QqQ-MS/MS provedena je kvantifikacija sastavnica, među kojima je najzastupljenija galna kiselina. GC-MS
analizom eteričnog ulja ukupno je identificirano 50 spojeva, s ugljikovodicima kao glavnom skupinom spojeva
(najzastupljeniji spoj je heksadekanoična kiselina).Research in this doctoral thesis was focused on in vitro antimicrobial, ani-infammatory, and antioxidative activity of
Erodium cicutarium (L.) L’Hér. ex Aiton, Geraniaceae extracts, strongly underlined with phytochemical characterization of
extracts and the essential oil. Antimicrobial activity was evident, especially against Staphylococcus aureus strains, including
MRSA. Next to observed anti-biofilm activity, the time-kill assay was performed and bactericidal and bacteriostatic activity
were studied in time. As a highlight of this work, active antimicrobial fractions were identified, isolated and extensively
phytochemically characterized using UHPLC-LTQ OrbiTrap MS4. Obtained results indicate that gallic acid derivatives
could be the compounds most responsible for the observed in vitro antimicrobial activity. Galloyl-shikimic acid was
identified as the most abundant compound among them. To stress out, 7 of the identified compounds are compounds
detected for the first time not only for E. cicutarium, but in the Geraniaceae family as well. Among them narcissin, galloyl
pentoside isomer 1 and isomer 2, methylgalloyl-caffeoyl hexoside, methylgalloyl-coumaroyl hexoside, trimethylellagic acid
isomer 1 and isomer 2. In vitro anti-inflammatory activity testing of E. cicutarium extracts showed inhibitory activity on
COX-1 and COX-2, cytokine IL-6 production, as well as on production of NO, indicating their anti-inflammatory activity.
TNF-α production was induced, showing the potential of E. cicutarium extracts for immunomodulation. In vitro antioxidant
activity was shown for all samples in all performed assays – DPPH, ABTS, FRAP, CUPRAC and the β-carotene bleaching
assay. Detailed phenolic profiling of water and methanol extracts was undertaken with UHPLC-LTQ OrbiTrap MS4 for
identification, and UHPLC-QqQ-MS/MS for quantification. Samples were collected from 4 localities in Croatia (Podvinje,
Plitvice, Trešnjevka, Buzin). In total, 85 phenolic compounds were identified. Among them mainly gallic acid derivatives
(24 compounds), ellagic acid derivatives, including ellagitannins (22 compounds), 19 flavonol glycosides, 8
hydroxycinnamic acid derivatives, 7 other hydroxybenzoic acid derivatives, 3 flavonol aglycones, and 2 procyanidins. Very
important results from this study show the presence of newly identified compounds – 25 new compounds were found, that
have not been reported for the Erodium genera or the Geraniaceae family before. Among 17 quantified components, gallic
acid stands out as the phenolic constituent with highest quantified content among all samples. The GC-MS analysis of
essential oils showed a total of 50 identified compounds. Hydrocarbons are the main class of constituents, with hexadecanoic acid as the major component
Three Avar-age microcommunities in Srijem
No full textU ovom su radu obrađeni rezultati istraživanja tri avarodobna lokaliteta u zapadnom Srijemu; iskopavanja na lokalitetima Otok-Gradina/Mandekov vinograd, Privlaka-Gole njive i Stari Jankovci-Gatina vršena su u nekoliko kampanja tokom druge polovice 20. Stoljeća. Rezultati istraživanja dosada su bili samo sumarno naznačeni u kratkim izvještajima. Nakon lociranja, konsolidacije i digitalizacije sve danas dostupne i znane dokumentacije, pristupilo se obradi podataka i analizi rezultata istraživanja: 346 grobova je katalogizirano, utvrđene su prostorne odrednice lokaliteta i same mikroregije, izvršena je detaljna tipološkokronološka analiza svih nalaza, ustanovljena je detaljna kronologinja lokaliteta na temelju tipološko-kronološke analize materijala, računalne serijacije i horizontalne stratigrafije lokaliteta; provedena je i socijalna kategoirizacija mikrozajednica koje su se pokapale na svakom lokalitetu zasebno i socijalna kategorizacija zajednice na temelju statistike pogrebnih običaja, prosječne slike nalaza i analize stabilnih izotopa osteoloških uzoraka određenog dijela pokojnika na dva lokaliteta (Privlaka i Stari Jankovci) kako bi se definirale prehrambene navike mikrozajednica, a posebna je pozornost posvećena eventulanim tragovima kasnoantičkog ili bolje rečeno, utjecaja mediteranskog kutlurnog kruga na materijalnu kulturu zajednice koja se pokapala na ovim lokalitetima. Osnovni je cilj bio izvršiti analizu rezultata istraživanja u maniri današnjeg stanja istraživanja avarske arheologije, kako bi rezultati bili usporedivi s rezultatima istraživanja istovremenih lokaliteta diljem Karpatske kotline; također, po prvi puta je metoda računalne serijacije pri uspostavljanju tipološko-kronološke slike lokaliteta primijenjena na sva tri lokaliteta zajedno, kako bi se dobili što kvalitetniji rezultati te je po prvi puta računalna serijacija primijenjena na lokalitetima jugoistočne periferije Kaganata. S ciljem što kompletnije obrade lokaliteta, u radu su prikazani i rezultati istraživanja ostalih stratigrafskih jedinica otkrivenih na lokalitetima; stratigrafskih jedinica i nalaza koji upućuju na funkcioniranje lokaliteta i u kasnijem srednjem vijeku, ali i naseobinskog dijela lokaliteta Stari Jankovci koji je barem djelomično bio u funkciji u vrijeme funkcioniranja groblja na dotičnom lokalitetu.This paper deals with the results of research on three Avar sites in western Srijem; excavations at the sites of Otok-Gradina / Mandekov vinograd, Privlaka-Gole njive and Stari Jankovci-Gatina were carried out in several campaigns during the second half of the 20th century. The results of the research so far have only been summarized in brief reports. After locating, consolidating and digitalizing all currently available and known documentation, data processing and analysis of research results were started: 346 graves were cataloged, spatial determinants of localities and microregions were determined, detailed typological-chronological analysis of all findings was performed, detailed chronology of the sites was established based on typological-chronological analysis of materials, computer serialization and horizontal stratigraphy of sites; the social categorization of micro-communities buried in each locality was carried out and the social categorization of the community based on funeral customs statistics, image of average funerary equipment and stable isotope analysis of osteological samples of a certain number of the deceased at two sites (Privlaka and Stari Jankovci) to define dietary habits of micro-communities, and special attention is paid to possible traces of the Late Antique or better said, the influence of the Mediterranean cultural circle on the material culture of the community buried in these sites. The main goal was to analyze the research results in the manner of the current state of research in Avar archeology, so that the results were comparable with the results of research of simultaneous sites throughout the Carpathian Basin; also, for the first time the method of computer serialization was applied to all three localities together to establish a typological-chronological picture of the site, in order to obtain the best possible results; it is also the first time computer seriation was used in southeastern periphery of the Khaganate. With the aim of more complete processing of localities, the paper also presents the results of research of other stratigraphic units discovered at the sites in question; stratigraphic units and finds that indicate the functioning of the site in the later Middle Ages, but also the settlement part of the site Stari Jankovci which was at least partially in operation during the functioning of the cemetery at the site. At Gole Njive the earliest burial, double grave 53 can be dated to the very beginning of the Late Avar period, in the first decades of the 8th century, although it seems that the earliest horizon can be connected with the very end of the Middle Avar period (grave 66 and grave 104); cemetery can be traced throughout the 8th century, and probably in the first decades of the 9th (grave 220, GA) according to graves with belt sets; a group of graves with belt-sets was noticed at this site, which differs from the rest of the cemetery in terms of spatial distribution and richness of finds (group of graves 202+) ) and in them we recognize the latest surely dataable finds (stick beads) that allude to the possible (short) functioning of the cemetery even after the political fall of the Avar state organization. At Stari Jankovci, the earliest certainly dated burial is the equestrian grave 88, whose equipment and accessories fully reflect the later phase of the Middle Avar period; the functioning of the cemetery can be traced back to the second half of the 8th century, but most of the excavated part of the cemetery can be dated to the early phase of the Late Avar period, the first half of the 8th century; it is to be assumed that the later part of the cemetery is still unexcavated or destroyed by the action of (illegal) clay dig before the archeological excavations themselves. A small part of a larger Avar cemetery has been excavated at Gradina in Otok, a total of 22 graves: the earliest excavated burial is the equestrian grave 4, which dates to the very beginning of the Late Avar period and the first decades of the 8th century , just as grave 53 from Privlaka, while grave 13 is probably the latest dated grave, based on a belt set dated to the very end of late Avar production. It seems that in the earliest burial horizon one can recognize the greater influence of the Mediterranean-Byzantine cultural ecumenism, especially the Black Sea area through the similarity of the burial findings of the deceased in grave 104 and the large belt end from grave 66; the choice of decorative motifs on the belt set of horsemen from grave 88 in Stari Jankovci speaks in favor of the influence of the Mediterranean cultural circle, which supports the theory of greater intensity of communication between the Kaganates and Byzantium or the Byzantine cultural circle, the Black Sea area and (the southeastern periphery) of the Kaganate during the last third of the 7th century; in the same period, a part of women's graves with several pairs of earrings appear on Gole njive, a phenomenon that in the same period is also registered on Austrian Avar age cemeteries; at Gole njive this phenomenon will reappear in the later phase of the late Avar period, in the 202+ group of graves. It should be emphasized that a very similar type of luxury silver lunular earrings with star-shaped and teardrop pendants appears on Gradina and Gole njive, as well as their cast bronze imitations, raising the question of existence of local, highly specialized workshop in the area and survival of cultural traditions of Late Antiquity (modes of production). The presence of two separate groups of graves with belt sets on Gole njive raises the question of determining the status symbolized by the presence of belt set in a grave, and the composition of the belt sets, group as well as the presence of unique iron damascened phalerae in the separate group, distinctively different from the central group of graves with belt sets raises the question of different activities connected with the right to wear a belt set – perhaps the difference is due to the connection of the bearer of the set from the group 202+ with trade activity, in accordance with the theory of the Balkan area as a possible communication link between Byzantium and Khaganate through Bulgaria. Social categorization paints a picture of tipical rural community of the Kaganate peripheral area, a relatively similar way of life of microcommunities with certain differences in funeral customs (food items) and food distribution that could signal identity differences between the inhabitants of Privlaka and Stari Jankovci: these two sites show some differences in jewelry, mostly earrings where it is noticeable that in Stari Jankovci there is a classic range of earring types (earrings with glass beads), expected in late Avar cemeteries, while women's and children's graves in Privlaka reveal a much wider range of types whose appearance can not be limited to one generation. In conclusion, as in other parts of the Carpathian Basin that are part of the former Roman provinces, there is a tendency for Avar age sites to be located near (Late) Antique communications (the pattern is explicitly clear when it comes to graves with large phalerae), crossroads or important strategic positions, which was noticed in the wider area of Eastern Slavonia, but also in these sites, given the proximity of the former Roman Cibalae and the location of these sites in the hinterland of the former Roman Danube Limes
Design, synthesis and biological evaluation of biscarbamates as potential selective inhibitors of butyrylcholinesterase
No full textInhibicija butirilkolinesteraze (BChE) predstavlja novi, obećavajući pristup liječenju Alzheimerove bolesti (AB). U sklopu ove disertacije dizajnirani su i sintetizirani biskarbamati s različito supstituiranim atomima dušika karbamatnih skupina i 1-hidroksi-2-aminoetilnog lanca. Za 25 biskarbamata određena je sposobnost inhibicije ljudske BChE i acetilkolinesteraze (AChE), procijenjena je sposobnost prelaska krvno-moždane barijere pasivnim transportom, in vitro toksičnost prema jetrenim, bubrežnim i živčanim stanicama te sposobnost kelatiranja biometala Cu2+, Zn2+ i Fe2+. Svi ispitivani biskarbamati pokazali su vremenski ovisnu inhibiciju s konstantama brzine inhibicije od 103−106 mol-1 dm3 min-1i općenito većom selektivnošću prema BChE u odnosu na AChE. Za tri biskarbamata utvrđena je mogućnost prolaska krvnomoždane barijere pasivnim transportom, dok je za njih devet ta sposobnost ograničena. Većina biskarbamata nije pokazala citotoksični učinak prema odabranim staničnim linijama, dok su svi pokazali sposobnost kelatiranja najmanje jednog od ispitanih iona biometala. Radi visoke BChE selektivnosti, netoksičnosti, sposobnosti kelatiranja biometala i prolaska krvno-moždane barijere, za daljnji razvoj kao lijekova za liječenje kasnijih stadija AB istaknula su se tri spoja (3, 9 i 26).Inhibition of butyrylcholinesterase (BChE) represents a new, promising approach to the treatment of Alzheimer's disease (AD). As part of this dissertation, biscarbamates with different substituted nitrogens of carbamate groups and 1-hydroxy-2-aminoethyl chain were designed and synthesized. For 25 biscarbamates, the ability to inhibit human BChE and acetylcholinesterase (AChE) was determined, the ability to cross the blood-brain barrier (BBB) by passive transport, in vitro toxicity to liver, kidney and neural cells and the ability to chelate biometals Cu2+, Zn2+ and Fe2+ were evaluated. All of the tested biscarbamates showed a timedependent inhibition with inhibition rate constants in 103 − 106 mol-1 dm3 min-1 range with a generally higher preference for BChE compared to AChE. For three biscarbamates it was found that they should be able to cross the BBB by passive transport, while this ability was limited for nine biscarbamates. Most of the biscarbamates did not show a cytotoxic effect against the selected cell lines. All of the biscarbamates were shown to have the ability to chelate at least one of the biometals. Due to the high BChE selectivity, non-toxicity, ability to chelate biometals and pass the BBB, three compounds (3, 9 and 26) were pointed out for further development as drugs for the treatment of later stages of AD
The role of bradykinin receptor type 2 in the development of brain and retinal ischemic lesion
No full textUsprkos velikom broju kliničkih i pretkliničkih dokaza o korelaciji ishemije mozga i mrežnice, malo je pažnje posvećeno zajedničkim patološkim mehanizmima razvoja ishemijske ozljede istih. Cilj ovog istraživanja bio je longitudinalnim in vivo praćenjem razjasniti ulogu bradikininskog receptora tipa 2 u razvoju ishemijske ozljede mozga i mrežnice te odrediti primjenjivost in vivo snimanja mrežnične vaskulature za određivanje cerebrovaskularnih promjena u mišjem modelu moždanog udara. Usporedbom Koizumi i Longa zahvata okluzije srednje moždane arterije i dugotrajnim praćenjem statusa cerebralne vaskularne perfuzije magnetskom rezonancijom pokazano je da kod Koizumi zahvata ishemiju prati kronična hipoperfuzija i ishemija mozga i mrežnice, za razliku od Longa zahvata, u kojem nakon ishemije nastupa potpuna reperfuzija koja rezultira izraženijom cerebralnom atrofijom bez znakova oštećenja mrežnice. Usporedbom miševa s onemogućenim genom za bradikininski receptor tipa 2 te njihovih kontrola nakon Koizumi zahvata, dugotrajnim praćenjem razvoja ishemije magnetskom rezonancijom, fotografijom i fluoresceinskom angiografijom očne pozadine, testovima ponašanja i mjerenjem vaskularne propusnosti pokazano je da nedostatak bradikininskog receptora tipa 2 u akutnoj fazi ishemije smanjuje oštećenje i propusnost cerebralne vaskulature, a kronično povećava atrofiju moždanog tkiva i funkcionalni deficit. U mrežnici je pokazano slično djelovanje, odnosno povećanje vaskularne propusnosti u subakutnoj fazi, te povećanje ishemijskog oštećenja u kroničnoj fazi ishemije.Despite ample clinical and preclinical evidence correlating cerebral and retinal ischemia, not enough attention has been paid to common pathological mechanisms of ischemic lesion development in these tissues. This research aimed to clarify the role of bradykinin receptor type 2 in the development of brain and retinal ischemia and to examine the applicability of in vivo retinal vascular imaging to determine cerebrovascular changes in a murine model of stroke. Comparing the Koizumi and Longa middle cerebral artery occlusion procedures by long-term cerebrovascular perfusion monitoring with magnetic resonance imaging showed that ischemia was followed by chronic hypoperfusion in both brain and retina in the Koizumi model. In contrast, complete reperfusion occurred in the Longa model, resulting in greater cerebral atrophy without retinal damage. By comparing bradykinin receptor type 2 knock-out mice and their controls after the Koizumi procedure using long-term monitoring with magnetic resonance, fundus photography, fluorescein angiography, behavioral tests and vascular permeability measurements, bradykinin receptor type 2 deficiency has been shown to reduce acute cerebral vascular permeability, while increasing cerebral atrophy and functional deficit in the chronic phase. Retinal findings showed a similar effect, increased subacute vascular permeability and increased ischemic damage in the chronic phase of ischemia