Puzzling functions of HSV-1 miRNAs in productive and latent infection

Herpes simplex virus (HSV) is a widespread human pathogen able to cause a broad spectrum of diseases of varying severity. HSV-1, and closely related virus HSV-2, employ a number of functions to evade host defense mechanisms and tailor the cellular environment during their complex life cycle comprised of productive and life-long latent infection. Once the latency is established, the virus can periodically reactivate in response to different stimuli and cause recurrent disease. Despite being one of the most intensively studied viruses, many biological aspects involved in the control of the lytic-latent switch and regulation of viral and host gene expression remained unclear. Discovery of the HSV-encoded miRNAs, a class of small regulatory RNAs, led to the hypothesis that they could have a central role in the establishment and maintenance of latency. HSV-1 and HSV-2 encode many miRNAs, differentially expressed during both phases of infection. The functions of HSV-encoded miRNAs have been experimentally addressed by several laboratories; however, the exact roles remain inconclusive. In this review, we will discuss the function of HSV-encoded miRNAs described to date, in terms of their viral and host targets, and the potential significance of such regulation for viral infection.</p

Surgical Scientific Publication and the 1991–1995 War in Croatia

The aim of this study was to evaluate surgical scientific publication in relation to the 1991–1995 war in Croatia, based on the articles indexed in Medline database that were published in 1980–2005 period. The number of articles was extracted from PubMed and analysed with trend analysis, which is preferred analytic approach over calculation of crude publication rates. The results indicate sporadic pre-war output, which was almost completely reduced by the onset of war. During wartime, a significant increasing trend in the number of published surgical articles that were related to warfare was detected (p=0.003). During the post-war period a gradual shift towards surgical articles that were not related to warfare was detected, also marked by the significant increasing trend (p=0.027). Both trends were significantly steeper than the overall Croatian biomedical output, suggesting that surgical scientific articles were being published more dynamically than in other biomedical areas in Croatia. The results suggest that war in Croatia has had a strong modifying effect on the surgical scientific output

Hepatotoksični potencijal smeše toluena, stirena i etanola: in silico toksikogenomička analiza

Organic solvents are still widely used in various industries and considered the most common chemicals associated with liver injury in workers. For research into the relationships between these chemicals and genes, interactions among chemicals, molecular pathways and biological processes, a significant place in toxicity testing has been taken by in silico methodologies. This study aims to provide evidence for the involvement of a selected mixture of organic solvents (toluene, styrene, ethanol) in liver disease development and show the potential of in silico toxicogenomic data-mining in determining possible mechanisms of mixture toxicity. The Comparative Toxicogenomics Database (CTD), GeneMania and ToppGene Suite were used for data-mining. The results showed that there were 17 genes connected with liver injury common for all the tested solvents. Co-expression (61.73%) was the most prominent interaction between the genes, while physical interactions were present at 14.56%, co-localization at 12.54% and interactions predicted by the server at 6.62%. Gene ontology analysis revealed biological processes affected by the investigated mixture (reactive oxygen species metabolic and biosynthetic process, response to oxidative stress, and response to organic cyclic compound). Oxidative stress response, antioxidant and oxidoreductase activity, vitamin B12 metabolism were noted as the key molecular pathways contributing to liver disease development. Our results emphasize the role of oxidative stress as one of the mechanisms of organic solvents' mixture toxicity and provide new insights into molecular mechanisms involved in hepatotoxicity.Organski rastvarači se još uvek široko koriste u raznim industrijama i smatraju se najčešćim hemikalijama povezanim sa oštećenjem jetre kod radnika. Za istraživanje odnosa između ovih hemikalija i gena, interakcija među hemikalijama, molekularnih puteva i bioloških procesa, značajno mjesto pripada i in silico metodologijama. Cilj ove studije je da pruži dokaze za povezanost odabrane smeše organskih rastvarača (toluen, stiren, etanol) u razvoju bolesti jetre, i da pokaže potencijal in silico toksikogenomičke analize podataka u određivanju mogućih mehanizama toksičnosti smješe. Za prikupljanje podataka korišteni su Comparative Toxicogenomics Database (CTD), GeneMania i ToppGene Suite. Rezultati ove analize su pokazali da postoji 17 gena povezanih s oštećenjem jetre zajedničkih za sva tri navedena rastvarača. Koekspresija (61,73%) bila je najistaknutija interakcija između gena, dok su fizičke interakcije bile prisutne sa 14,56%, kolokalizacije sa 12,54%, a interakcije predviđene od strane servera sa 6,62%. Analiza ontologije gena izdvojila je biološke procese na koje utiče ispitivana smeša (metabolički i biosintetski proces reaktivnih kiseonikovih vrsta, odgovor na oksidativni stres i odgovor na organska ciklična jedinjenja). Odgovor na oksidativni stres, aktivnost antioksidanata i oksidoreduktaze, i metabolizam vitamina B12 su navedeni kao ključni molekularni putevi koji dobrinose razvoju bolesti jetre. Rezultati ovog rada naglašavaju ulogu oksidativnog stresa kao jednog od mehanizama toksičnosti smeše organskih rastvarača i daju novi uvid u molekularne mehanizme uključene u hepatotoksičnost.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Human Papillomaviruses-Associated Cancers: An Update of Current Knowledge

Human papillomaviruses (HPVs), which are small, double-stranded, circular DNA viruses infecting human epithelial cells, are associated with various benign and malignant lesions of mucosa and skin. Intensive research on the oncogenic potential of HPVs started in the 1970s and spread across Europe, including Croatia, and worldwide. Nowadays, the causative role of a subset of oncogenic or high-risk (HR) HPV types, led by HPV-16 and HPV-18, of different anogenital and head and neck cancers is well accepted. Two major viral oncoproteins, E6 and E7, are directly involved in the development of HPV-related malignancies by targeting synergistically various cellular pathways involved in the regulation of cell cycle control, apoptosis, and cell polarity control networks as well as host immune response. This review is aimed at describing the key elements in HPV-related carcinogenesis and the advances in cancer prevention with reference to past and ongoing research in Croati

PARP14 and PARP9/DTX3L regulate interferon-induced ADP-ribosylation

PARP-catalysed ADP-ribosylation (ADPr) is important in regulating various cellular pathways. Until recently, PARP-dependent mono-ADP-ribosylation has been poorly understood due to the lack of sensitive detection methods. Here, we utilised an improved antibody to detect mono-ADP-ribosylation. We visualised endogenous interferon (IFN)-induced ADP-ribosylation and show that PARP14 is a major enzyme responsible for this modification. Fittingly, this signalling is reversed by the macrodomain from SARS-CoV-2 (Mac1), providing a possible mechanism by which Mac1 counteracts the activity of antiviral PARPs. Our data also elucidate a major role of PARP9 and its binding partner, the E3 ubiquitin ligase DTX3L, in regulating PARP14 activity through protein-protein interactions and by the hydrolytic activity of PARP9 macrodomain 1. Finally, we also present the first visualisation of ADPr-dependent ubiquitylation in the IFN response. These approaches should further advance our understanding of IFN-induced ADPr and ubiquitin signalling processes and could shed light on how different pathogens avoid such defence pathways

Povećani oksidacijski stres u obućarskih radnika izloženih mješavini niskih razina hlapljivih organskih spojeva

This study aimed to assess the redox status and trace metal levels in 49 shoe industry workers (11 men and 38 women) occupationally exposed to a mixture of volatile organic compounds (VOCs), which includes aliphatic hydrocarbons, aromatic hydrocarbons, ketones, esters, ethers, and carboxylic acids. All measured VOCs were below the permitted occupational exposure limits. The control group included 50 unexposed participants (25 men and 25 women). The following plasma parameters were analysed: superoxide anion (O2•-), advanced oxidation protein products (AOPP), total oxidative status (TOS), prooxidant-antioxidant balance (PAB), oxidative stress index (OSI), superoxide dismutase (SOD) and paraoxonase-1 (PON1) enzyme activity, total SH group content (SHG), and total antioxidant status (TAS). Trace metal levels (copper, zinc, iron, magnesium, and manganese) were analysed in whole blood. All oxidative stress and antioxidative defence parameters were higher in the exposed workers than controls, except for PON1 activity. Higher Fe, Mg, and Zn, and lower Cu were observed in the exposed vs control men, while the exposed women had higher Fe and lower Mg, Zn, and Cu than their controls. Our findings confirm that combined exposure to a mixture of VOCs, even at permitted levels, may result in additive or synergistic adverse health effects and related disorders. This raises concern about current risk assessments, which mainly rely on the effects of individual chemicals, and calls for risk assessment approaches that can explain combined exposure to multiple chemicals.Cilj istraživanja bio je procijeniti redoks status i koncentracije metala u tragovima kod 49 radnika (11 muškaraca i 38 žena) zaposlenih u industriji obuće, izloženih mješavini hlapljivih organskih spojeva (engl. volatile organic compounds, krat. VOC) koju su činili alifatski i aromatični ugljikovodici, ketoni, esteri, eteri i karboksilne kiseline. Sve izmjerene razine VOC bile su ispod dozvoljenih granica profesionalne izloženosti. U kontrolnoj je skupini bilo 50 neizloženih ispitanika (25 muškaraca i 25 žena). U plazmi obućarskih radnika analizirani su sljedeći parametri: superoksid anion radikal (O2 •- ), uznapredovali produkti oksidacije proteina (AOPP), totalni oksidacijski status (TOS), prooksidacijsko- antioksidacijski balans (PAB), indeks oksidacijskoga stresa (OSI), aktivnost superoksid-dismutaze (SOD), aktivnost enzima paraoksonaze-1 (PON1), ukupni sadržaj sulfhidrilnih grupa (SHG) i totalni antioksidacijski status (TAS). Koncentracije metala u tragovima (bakar, cink, željezo, magnezij i mangan) analizirane su u punoj krvi. U usporedbi s kontrolnom skupinom, svi parametri oksidacijskoga stresa i antioksidacijske obrane u izloženih radnika bili su povišeni, osim aktivnosti PON1. Povećana koncentracija Fe, Mg i Zn te smanjena koncentracija Cu uočene su u izloženih muškaraca u usporedbi s kontrolnima, a u žena je primijećena povišena koncentracija Fe, a niža koncentracija Mg, Zn i Cu u odnosu na kontrolnu skupinu. Naši nalazi potvrđuju da kombinirano izlaganje mješavini VOC, čak i pri dozvoljenim koncentracijama, može dovesti do aditivnih ili sinergističkih štetnih učinaka na zdravlje i popratnih poremećaja. Trenutna procjena rizika, koja se uglavnom oslanja na učinke pojedinačnih kemikalija, izaziva zabrinutost i upućuje na potrebu za novim pristupima koji će objasniti kombiniranu izloženost većem broju kemikalija

Roles of ADAR1 protein in herpes simplex virus 1 replication

Infekcija virusom herpes simpleksa 1 (HSV-1) uzrokuje nekoliko bolesti, u rasponu od kožnih, oralnih i genitalnih infekcija do fatalnog encefalitisa (1). Unatoč napretku protuvirusnih terapija koje su značajno smanjile morbiditet i mortalitet HSV-a kod imunokompromitiranih osoba, i dalje je od velikog interesa pobliže razumijevanje elemenata koji pridonose virulenciji HSV-1. Iz tog razloga postoji velika potreba za detaljnom analizom, različitih faktora domaćina koje virus koristi za promicanje infekcije kao i faktora obrane koji djeluju protivno HSV-1 infekciji (2). Jedan od potencijalnih faktora koji utječe na HSV-1 virulenciju je adenozin deaminaza koja djeluje na RNA (ADAR1). Njegova funkcija A-u-I uređivanja dvolančanih RNA nedavno je prepoznata kao ključan proces u označavanju dsRNA kao vlastite, prevenirajući tako aktivaciju urođenog imunološkog odgovora te djelujući na razvoj i ishod imunološki posredovanih bolesti i infekcija. Prethodna istraživanja pokazala su da, ovisno o specifičnim interakcijama virusa i domaćina, ADAR1 može djelovati protuvirusno, ali i provirusno. Do danas, njegova uloga u HSV-1 infekciji nije istražena, stoga je cilj ovog rada bio odrediti utjecaj ADAR1 enzima na replikaciju HSV-1. U svrhu ostvarenja tog cilja korištene se stanice s utišanom ekspresijom ADAR1 te stanice negativne kontrole, kod kojih je praćena razina faktora urođenog imunološkog odgovora i virusnih proteina. Dobiveni rezultati ukazuju na protuvirusni učinak ADAR1 tijekom rane faze HSV-1 infekcije s obzirom da se njegovim utišavanjem značajno povećala razina neposredno ranih virusnih proteina te faktora uređenog imunološkog odgovora eIf-2α, čija aktivnost potiče ekspresiju virusnih gena. S druge strane, utišavanje ekspresije ADAR1 nije dovelo do značajne promjene u replikaciji virusa između ispitivanih stanica, stoga je pretpostavljeno da njegova protuvirusna aktivnost nema dovoljno snažan učinak koji bi uzrokovao veći poremećaj u replikaciji HSV-1. Zaključno, rezultati ovog rada potvrđuju ulogu ADAR1 tijekom HSV-1 infekcije te ukazuju na ADAR1 kao potencijalnu metu za pojačavanje protuvirusnog imunološkog odgovora.Herpes simplex virus type-1 (HSV-1) infection can cause several diseases, ranging from cutaneous, oral and genital infections to fatal encephalitis (1). Despite advances in antiviral therapies that have significantly reduced HSV morbidity and mortality, a closer understanding of the elements contributing to HSV-1 virulence remains of great interest. For this reason, there is a great need for a detailed analysis of the host factors that the virus uses to promote infection as well as defense factors that act against HSV-1 infection (2). One of the potential factors affecting HSV-1 virulence is ADAR1. A-to-I editing by ADAR1 has recently been recognized as a key process in marking dsRNA as self, thus preventing activation of the innate immune response and affecting the development and outcome of immune-mediated diseases and infections. Previous research has shown that depending on different virus-host combinations, ADAR1 can have both antiviral and proviral effects. To date, its role in HSV-1 infection has not been evaluated, therefore the aim of this study was to investigate the role of ADAR1 in HSV-1 infection. To achieve this goal, cells with downregulated ADAR1 expression and negative control cells were used to examine the level of innate immune factors and viral proteins. The obtained results indicate the antiviral effect of ADAR1 during the early phase of HSV-1 infection since its downregulation significantly increased the level of immediate-early viral proteins and translation initiation factor eIf-2α, which promotes the expression of viral genes. On the other hand, we did not observe a difference in virus replication when ADAR1 was downregulated, therefore this data suggests that its antiviral activity is not strong enough to cause HSV-1 replication defect. In summary, the results of this study confirm the role of ADAR1 during HSV-1 infection and pointing towards ADAR1 as a potential target to boost antiviral immune response

Roles of ADAR1 protein in herpes simplex virus 1 replication

Infekcija virusom herpes simpleksa 1 (HSV-1) uzrokuje nekoliko bolesti, u rasponu od kožnih, oralnih i genitalnih infekcija do fatalnog encefalitisa (1). Unatoč napretku protuvirusnih terapija koje su značajno smanjile morbiditet i mortalitet HSV-a kod imunokompromitiranih osoba, i dalje je od velikog interesa pobliže razumijevanje elemenata koji pridonose virulenciji HSV-1. Iz tog razloga postoji velika potreba za detaljnom analizom, različitih faktora domaćina koje virus koristi za promicanje infekcije kao i faktora obrane koji djeluju protivno HSV-1 infekciji (2). Jedan od potencijalnih faktora koji utječe na HSV-1 virulenciju je adenozin deaminaza koja djeluje na RNA (ADAR1). Njegova funkcija A-u-I uređivanja dvolančanih RNA nedavno je prepoznata kao ključan proces u označavanju dsRNA kao vlastite, prevenirajući tako aktivaciju urođenog imunološkog odgovora te djelujući na razvoj i ishod imunološki posredovanih bolesti i infekcija. Prethodna istraživanja pokazala su da, ovisno o specifičnim interakcijama virusa i domaćina, ADAR1 može djelovati protuvirusno, ali i provirusno. Do danas, njegova uloga u HSV-1 infekciji nije istražena, stoga je cilj ovog rada bio odrediti utjecaj ADAR1 enzima na replikaciju HSV-1. U svrhu ostvarenja tog cilja korištene se stanice s utišanom ekspresijom ADAR1 te stanice negativne kontrole, kod kojih je praćena razina faktora urođenog imunološkog odgovora i virusnih proteina. Dobiveni rezultati ukazuju na protuvirusni učinak ADAR1 tijekom rane faze HSV-1 infekcije s obzirom da se njegovim utišavanjem značajno povećala razina neposredno ranih virusnih proteina te faktora uređenog imunološkog odgovora eIf-2α, čija aktivnost potiče ekspresiju virusnih gena. S druge strane, utišavanje ekspresije ADAR1 nije dovelo do značajne promjene u replikaciji virusa između ispitivanih stanica, stoga je pretpostavljeno da njegova protuvirusna aktivnost nema dovoljno snažan učinak koji bi uzrokovao veći poremećaj u replikaciji HSV-1. Zaključno, rezultati ovog rada potvrđuju ulogu ADAR1 tijekom HSV-1 infekcije te ukazuju na ADAR1 kao potencijalnu metu za pojačavanje protuvirusnog imunološkog odgovora.Herpes simplex virus type-1 (HSV-1) infection can cause several diseases, ranging from cutaneous, oral and genital infections to fatal encephalitis (1). Despite advances in antiviral therapies that have significantly reduced HSV morbidity and mortality, a closer understanding of the elements contributing to HSV-1 virulence remains of great interest. For this reason, there is a great need for a detailed analysis of the host factors that the virus uses to promote infection as well as defense factors that act against HSV-1 infection (2). One of the potential factors affecting HSV-1 virulence is ADAR1. A-to-I editing by ADAR1 has recently been recognized as a key process in marking dsRNA as self, thus preventing activation of the innate immune response and affecting the development and outcome of immune-mediated diseases and infections. Previous research has shown that depending on different virus-host combinations, ADAR1 can have both antiviral and proviral effects. To date, its role in HSV-1 infection has not been evaluated, therefore the aim of this study was to investigate the role of ADAR1 in HSV-1 infection. To achieve this goal, cells with downregulated ADAR1 expression and negative control cells were used to examine the level of innate immune factors and viral proteins. The obtained results indicate the antiviral effect of ADAR1 during the early phase of HSV-1 infection since its downregulation significantly increased the level of immediate-early viral proteins and translation initiation factor eIf-2α, which promotes the expression of viral genes. On the other hand, we did not observe a difference in virus replication when ADAR1 was downregulated, therefore this data suggests that its antiviral activity is not strong enough to cause HSV-1 replication defect. In summary, the results of this study confirm the role of ADAR1 during HSV-1 infection and pointing towards ADAR1 as a potential target to boost antiviral immune response

Roles of ADAR1 protein in herpes simplex virus 1 replication

Infekcija virusom herpes simpleksa 1 (HSV-1) uzrokuje nekoliko bolesti, u rasponu od kožnih, oralnih i genitalnih infekcija do fatalnog encefalitisa (1). Unatoč napretku protuvirusnih terapija koje su značajno smanjile morbiditet i mortalitet HSV-a kod imunokompromitiranih osoba, i dalje je od velikog interesa pobliže razumijevanje elemenata koji pridonose virulenciji HSV-1. Iz tog razloga postoji velika potreba za detaljnom analizom, različitih faktora domaćina koje virus koristi za promicanje infekcije kao i faktora obrane koji djeluju protivno HSV-1 infekciji (2). Jedan od potencijalnih faktora koji utječe na HSV-1 virulenciju je adenozin deaminaza koja djeluje na RNA (ADAR1). Njegova funkcija A-u-I uređivanja dvolančanih RNA nedavno je prepoznata kao ključan proces u označavanju dsRNA kao vlastite, prevenirajući tako aktivaciju urođenog imunološkog odgovora te djelujući na razvoj i ishod imunološki posredovanih bolesti i infekcija. Prethodna istraživanja pokazala su da, ovisno o specifičnim interakcijama virusa i domaćina, ADAR1 može djelovati protuvirusno, ali i provirusno. Do danas, njegova uloga u HSV-1 infekciji nije istražena, stoga je cilj ovog rada bio odrediti utjecaj ADAR1 enzima na replikaciju HSV-1. U svrhu ostvarenja tog cilja korištene se stanice s utišanom ekspresijom ADAR1 te stanice negativne kontrole, kod kojih je praćena razina faktora urođenog imunološkog odgovora i virusnih proteina. Dobiveni rezultati ukazuju na protuvirusni učinak ADAR1 tijekom rane faze HSV-1 infekcije s obzirom da se njegovim utišavanjem značajno povećala razina neposredno ranih virusnih proteina te faktora uređenog imunološkog odgovora eIf-2α, čija aktivnost potiče ekspresiju virusnih gena. S druge strane, utišavanje ekspresije ADAR1 nije dovelo do značajne promjene u replikaciji virusa između ispitivanih stanica, stoga je pretpostavljeno da njegova protuvirusna aktivnost nema dovoljno snažan učinak koji bi uzrokovao veći poremećaj u replikaciji HSV-1. Zaključno, rezultati ovog rada potvrđuju ulogu ADAR1 tijekom HSV-1 infekcije te ukazuju na ADAR1 kao potencijalnu metu za pojačavanje protuvirusnog imunološkog odgovora.Herpes simplex virus type-1 (HSV-1) infection can cause several diseases, ranging from cutaneous, oral and genital infections to fatal encephalitis (1). Despite advances in antiviral therapies that have significantly reduced HSV morbidity and mortality, a closer understanding of the elements contributing to HSV-1 virulence remains of great interest. For this reason, there is a great need for a detailed analysis of the host factors that the virus uses to promote infection as well as defense factors that act against HSV-1 infection (2). One of the potential factors affecting HSV-1 virulence is ADAR1. A-to-I editing by ADAR1 has recently been recognized as a key process in marking dsRNA as self, thus preventing activation of the innate immune response and affecting the development and outcome of immune-mediated diseases and infections. Previous research has shown that depending on different virus-host combinations, ADAR1 can have both antiviral and proviral effects. To date, its role in HSV-1 infection has not been evaluated, therefore the aim of this study was to investigate the role of ADAR1 in HSV-1 infection. To achieve this goal, cells with downregulated ADAR1 expression and negative control cells were used to examine the level of innate immune factors and viral proteins. The obtained results indicate the antiviral effect of ADAR1 during the early phase of HSV-1 infection since its downregulation significantly increased the level of immediate-early viral proteins and translation initiation factor eIf-2α, which promotes the expression of viral genes. On the other hand, we did not observe a difference in virus replication when ADAR1 was downregulated, therefore this data suggests that its antiviral activity is not strong enough to cause HSV-1 replication defect. In summary, the results of this study confirm the role of ADAR1 during HSV-1 infection and pointing towards ADAR1 as a potential target to boost antiviral immune response

INFANTILNA FORMA POMPEOVE BOLESTI

Pompeova bolest je rijetko autozomno recesivno nasljedno metaboličko oboljenjeuzrokovano nedostatkom enzima kisele alfa glukozidaze usljed mutacije GAA gena.Karakteriše se nakupljanjem glikogena u lizozomima svih ćelija, posebno ćelija mišića,jetre, srca i mozga. Simptomi bolesti mogu se javiti u različitoj dobi i mogu biti različitetežine, što najviše zavisi od prirode mutacije i rezidualne enzimske aktivnosti. Najteži jeinfantilni oblik kod koga rano nastaju kardiomegalija, hepatomegalija, hipotonija i mišićnaslabosti, i kod koga do smrtnog ishoda dolazi u toku prve godine života. Od 2006.godine dostupno je i odobreno liječenje Pompeove bolesti enzimskom supstitucionomterapijom. Uspješnost ovog vida liječenja najviše zavisi od stadija bolesti u vrijeme započinjaliječenja, genotipa i CRIM statusa. Većinom pacijenti sa CRIM negativnim statusomimaju loš odgovor na liječenje, više komplikacija i samim tim lošiju prognozu.U ovom radu smo prikazali prvi slučaj infantilne forme Pompeove bolesti koju smoliječili enzimskom supstitucionom terapijom u našoj zdravstvenoj ustanovi. Pompeovabolest se kod ovog pacijenta prvo manifestovala hipertrofičnom kardiomiopatijom iimala je brzu progresiju sa razvojem hepatomegalije, teške hipotonije, mišićne slabostii konačno srčane i respiratorne slabosti. Enzimsku supstitucionu terapijou pacijent jepočeo da prima u dobi od 3 mjeseca. Odgovor na terapiju je bio loš i pacijent je umrou dobi od 6 mjeseci.Smatramo da bi prepoznavanje ove bolesti u ranijoj dobi i započinjanje liječenja prijerazvoja kliničkih simptoma vjerojatno dalo bolji rezultat liječenja i produžilo životnivijek oboljelih od Pompeove bolesti