Occurrence of Hepatocellular Carcinoma in Patients with Chronic hepatitis C Treated with Direct-Acting Antiviral Therapy

Poznato je kako oboljeli od kronične bolesti jetre učestalije obolijevaju od hepatocelularnog karcinoma. Premda se RNA molekula hepatitis C virusa uspješno eliminira iz cirkulacije direktnodjelujućim antivirusnim lijekovima, HCV RNA može ostati i dalje prisutna u jetrenom tkivu ili perifernim mononuklearnim stanicama te je taj entitet poznat kao okultni HCV. Postoje brojne nedoumice povezane s ponovnom pojavom HCC-a nakon provedenog liječenja DAA terapijom jetrenih stanica kronično zaraženih HCV-om, a jedan od glavnih čimbenika rizika koji dovodi do de novo HCC-a je pojava kroničnosti HCV-a u stanicama jetre. Mnoge studije provedene su s ciljem istraživanja promjena jetrenih stanica inficiranih HCV-om u HCC. Međutim, još uvijek nisu u potpunosti jasni molekularni mehanizmi koji vode do progresije kronične HCV infekcije u HCC i učinak HCV-a na promjenu DNA ploidnosti, što dovodi do ponovnog povratka HCC-a nakon liječenja DAA terapijom. Stoga je cilj ovoga članka razmotriti čimbenike rizika koji bi mogli dovesti do razvoja HCC-a nakon liječenja HCV-a upotrebom DAA terapije, poput uloge ciroze jetre, promjene DNA ploidnosti, reaktivacije virusa hepatitisa B, kao i okultne HCV infekcije.Patients with chronic liver disease are known to be more likely to develop hepatocellular carcinoma (HCC). Although direct-acting antivirals have proven successful in eliminating the hepatitis C virus RNA from blood circulation, the HCV RNA can still remain present in liver tissue or peripheral blood mononuclear cells – a condition known as occult HCV infection. There have been numerous concerns related to the recurrence of HCC after DAA treatment of hepatocytes infected with chronic HCV. One of the major risk factors leading to de novo HCC is the chronicity of HCV in liver cells. Moreover, numerous studies investigated the change of HCV-infected hepatocytes into HCC. However, the molecular mechanisms leading to the progression of chronic HCV infection into HCC, as well as the effect of HCV on the alteration of DNA ploidy that leads to recurrence of HCC after DAA treatment, are still unclear. Therefore, this article examines the risk factors that could lead to the development of HCC after treatment of HCV with DAAs, such as the role of liver cirrhosis, reactivation of hepatitis B virus, alteration of DNA ploidy and occult HCV infection

Occurrence of Hepatocellular Carcinoma in Patients with Chronic hepatitis C Treated with Direct-Acting Antiviral Therapy

Poznato je kako oboljeli od kronične bolesti jetre učestalije obolijevaju od hepatocelularnog karcinoma. Premda se RNA molekula hepatitis C virusa uspješno eliminira iz cirkulacije direktnodjelujućim antivirusnim lijekovima, HCV RNA može ostati i dalje prisutna u jetrenom tkivu ili perifernim mononuklearnim stanicama te je taj entitet poznat kao okultni HCV. Postoje brojne nedoumice povezane s ponovnom pojavom HCC-a nakon provedenog liječenja DAA terapijom jetrenih stanica kronično zaraženih HCV-om, a jedan od glavnih čimbenika rizika koji dovodi do de novo HCC-a je pojava kroničnosti HCV-a u stanicama jetre. Mnoge studije provedene su s ciljem istraživanja promjena jetrenih stanica inficiranih HCV-om u HCC. Međutim, još uvijek nisu u potpunosti jasni molekularni mehanizmi koji vode do progresije kronične HCV infekcije u HCC i učinak HCV-a na promjenu DNA ploidnosti, što dovodi do ponovnog povratka HCC-a nakon liječenja DAA terapijom. Stoga je cilj ovoga članka razmotriti čimbenike rizika koji bi mogli dovesti do razvoja HCC-a nakon liječenja HCV-a upotrebom DAA terapije, poput uloge ciroze jetre, promjene DNA ploidnosti, reaktivacije virusa hepatitisa B, kao i okultne HCV infekcije.Patients with chronic liver disease are known to be more likely to develop hepatocellular carcinoma (HCC). Although direct-acting antivirals have proven successful in eliminating the hepatitis C virus RNA from blood circulation, the HCV RNA can still remain present in liver tissue or peripheral blood mononuclear cells – a condition known as occult HCV infection. There have been numerous concerns related to the recurrence of HCC after DAA treatment of hepatocytes infected with chronic HCV. One of the major risk factors leading to de novo HCC is the chronicity of HCV in liver cells. Moreover, numerous studies investigated the change of HCV-infected hepatocytes into HCC. However, the molecular mechanisms leading to the progression of chronic HCV infection into HCC, as well as the effect of HCV on the alteration of DNA ploidy that leads to recurrence of HCC after DAA treatment, are still unclear. Therefore, this article examines the risk factors that could lead to the development of HCC after treatment of HCV with DAAs, such as the role of liver cirrhosis, reactivation of hepatitis B virus, alteration of DNA ploidy and occult HCV infection

Pharmacogenomics: Sex Differences and Application in Pediatrics

Pharmacogenomics is a promising field which increasingly influences medicine and biomedical research in many areas. The aim of this article is to review recent advancements in the understanding of genetic polymorphisms and their influence on interindividual variability in drug response. Also, the main variabilities in drug response according to sex differences will be discussed. The translation of pharmacogenomics into the clinical routine as well as the challenges of achieving the goal of personalized medicine are also discussed. The role of pharmacogenetic tests in pediatrics has not been well defined yet, but it is clear that those tests could help in resolving some issues regarding the administration of drugs to children. At the conclusion, the foremost ethical, social and regulatory issues regarding the translation of pharmacogenomics into clinical practice and future perspectives in the field will be discussed

Učinak hipertireoze i antitiroidne terapije na koštanu gustoću - patofiziološki mehanizmi te kliničko značenje

Graves’ disease is an autoimmune disease characterized by excessive thyroid hormone production. One of the consequences of that state can be a decrease in bone mineral density (BMD). Graves’ disease is often treated with antithyroid drugs (ATD) as first line therapy, which can lead to disease remission. Moreover, recent data show that improvement in BMD can be expected. However, vitamin D deficiency can coexist along with Graves’ disease, which is also involved in the process of bone remodeling. It is still not known whether lower values of vitamin D can contribute to onset of Graves’ disease and if its supplementation might be helpful in therapy for hyperthyroidism. In the past couple of decades, osteopenia and osteoporosis have become a major health burden not only in post-menopausal women but also as a result of other diseases, leading to extensive research into various pathophysiological mechanisms responsible for bone remodeling. The Wnt (wingless integrated) signaling pathway is a very important factor in bone homeostasis, especially the canonical pathway. Present data indicate that stimulation of the Wnt pathway leads to bone mass increase and, in contrast, its inhibition leads to bone mass decrease. Hence, inhibitors of the canonical Wnt pathway became the focus of interest, in particular sclerostin and dickkopf 1 (DKK1). Hyperthyroidism and osteopenia/osteoporosis are quite common today and can coexist together or as separate entities. In this article, we aimed to give an overview of possible associations and potential mutual pathophysiological mechanisms.Gravesova bolest je autoimuna bolest karakterizirana prevelikom proizvodnjom hormona štitnjače. Jedna od posljedica toga stanja može biti sniženje mineralne gustoće kosti. Liječi se antitireoidnim lijekovima kao prvim izborom čime se može postići remisija bolesti. Postizanjem remisije, može se očekivati i poboljšanje mineralne gustoće kosti. No, uz Gravesovu bolest, može postojati i snižena vrijednost vitamina D koji je također važana za procese pregradnje kosti. Još je uvijek otvoreno pitanje mou li snižene vrijednosti vitamina D pridonijeti nastanku Gravesove bolesti i da li bi njegova supstitucija mogla pomoći u liječenju hipertireoze. Kako je smanjena mineralna gustoća kosti danas rasprostranjena širom svijeta, u prošlim desetljećima počeo se istraživati Wnt put. Ovaj put vrlo je važan za homeostazu kosti, osobito njegov dio koji se naziva kanonički put u kojem sudjeluju i sklerostin i dickkopf 1 kao inhibitori. Svi spomenuti čimbenici, odnosno stanja, danas su učestala i mogu postojati zajedno i odvojeno. Ovim člankom pokušali smo dati pregled moguće veze između njih

Influence of Caffeine on Crystallization and Amelioration of Oxidative Stress on in vitro Model of Urolithiasis

Urolithiasis is a disease characterized by formation of solid crystals within the urinary tract. Kidney stone formation is still not clear but it is mostly composed of calcium oxalate which can produce free radicals that are toxic to renal tubular cells. Oxidative stress is an important contributory mechanism in cell damage and is associated with a number of disorders. Several studies have shown antioxidative effects of caffeine, proposing its possible role in stopping the formation of calcium oxalate stones in urinary tract. Hence, the aim of this study was to evaluate the toxic effects of calcium oxalate monohydrate crystals (COM) on renal epithelial cell line; Madin-Darby canine kidney cells subtype I (MDCK I) and Epithelial-like pig kidney cell line (LLC-PK1), and to determine possible inhibition of COM that caused oxidative stress by antioxidant treatment with caffeine in different concentrations in a cell culture model of urolithiasis

Urolithiasis and osteoporosis: clinical relevance and therapeutic implications

Nekoliko kliničkih i epidemioloških istraživanja otkrila su povećanu koštanu pregradnju i nižu koštanu masu u bolesnika s urolitijazom. Gubitak koštane mase posebno je uočen kod idiopatske kalcijske urolitijaze. Međutim, patogenetski mehanizmi i čimbenici povezani s gubitkom koštane mase u ovih bolesnika su još uvijek nepoznati. Ograničenje kalcija u prehrani, povećani unos soli i životinjskih proteina, polimorfizam receptora za vitamin D su vjerojatni rizični čimbenici. Uloge proupalnih citokina, osteopontina i prostaglandinom posredovane resorpcije kostiju još treba istražiti. Dokazano je da pozitivan utjecaj u prevenciji i liječenju osteoporoze i urolitijaze imaju nadomjesci kalcija i prehrana s povećanim unosom kalcija s kalijevim alkalijama. Tiazidski diuretici smanjuju hiperkalciriju u bubrežnim tubulima, te dodatno promoviraju diferencijaciju osteoblasta. Konačno, bisfosfonati, uobičajena terapija osteoporoze, imaju potencijal za inhibiciju stvaranja kalcijskih kamenaca, dok se pozitivan učinak antioksidansa treba još detaljno istražiti.Several clinical and epidemiological studies revealed increased bone turnover and lower bone mass in patients with urolithiasis. Bone mass loss is particularly evident in idiopathic calcium stone formers. However, pathogenetic mechanisms and factors implicated in bone loss in these patients are still unknown. Dietary calcium restriction, increased intake of salt and animal proteins, vitamin D receptor polymorphisms are likely risk factors, while role of inflammatory cytokines, osteopontin and prostaglandin mediated bone resorption is yet to be determined. Regarding treatment and prevention, it has been proven that calcium supplements and high calcium diet with the addition ot potassium alkali have an important role in prevention and treatment of both, urolithiasis and osteoporosis. Thiazide diuretics reduce hypercalciuria in renal tubules, and in addition promote osteoblast differentiation. Finally, bisphosphonates, a commonly used drugs in treatment of osteoporosis, show the potential to inhibit calcium stone formation, whereas a possible protective effect of antioxidants in bone loss and renal injury needs to be investigated further

Urolithiasis and osteoporosis: clinical relevance and therapeutic implications

Nekoliko kliničkih i epidemioloških istraživanja otkrila su povećanu koštanu pregradnju i nižu koštanu masu u bolesnika s urolitijazom. Gubitak koštane mase posebno je uočen kod idiopatske kalcijske urolitijaze. Međutim, patogenetski mehanizmi i čimbenici povezani s gubitkom koštane mase u ovih bolesnika su još uvijek nepoznati. Ograničenje kalcija u prehrani, povećani unos soli i životinjskih proteina, polimorfizam receptora za vitamin D su vjerojatni rizični čimbenici. Uloge proupalnih citokina, osteopontina i prostaglandinom posredovane resorpcije kostiju još treba istražiti. Dokazano je da pozitivan utjecaj u prevenciji i liječenju osteoporoze i urolitijaze imaju nadomjesci kalcija i prehrana s povećanim unosom kalcija s kalijevim alkalijama. Tiazidski diuretici smanjuju hiperkalciriju u bubrežnim tubulima, te dodatno promoviraju diferencijaciju osteoblasta. Konačno, bisfosfonati, uobičajena terapija osteoporoze, imaju potencijal za inhibiciju stvaranja kalcijskih kamenaca, dok se pozitivan učinak antioksidansa treba još detaljno istražiti.Several clinical and epidemiological studies revealed increased bone turnover and lower bone mass in patients with urolithiasis. Bone mass loss is particularly evident in idiopathic calcium stone formers. However, pathogenetic mechanisms and factors implicated in bone loss in these patients are still unknown. Dietary calcium restriction, increased intake of salt and animal proteins, vitamin D receptor polymorphisms are likely risk factors, while role of inflammatory cytokines, osteopontin and prostaglandin mediated bone resorption is yet to be determined. Regarding treatment and prevention, it has been proven that calcium supplements and high calcium diet with the addition ot potassium alkali have an important role in prevention and treatment of both, urolithiasis and osteoporosis. Thiazide diuretics reduce hypercalciuria in renal tubules, and in addition promote osteoblast differentiation. Finally, bisphosphonates, a commonly used drugs in treatment of osteoporosis, show the potential to inhibit calcium stone formation, whereas a possible protective effect of antioxidants in bone loss and renal injury needs to be investigated further

Rizični čimbenici i koštana masa u bolesnika s recidivirajućom urolitijazom: presječno istraživanje na 144 ispitanika

Patients with urolithiasis, particularly hypercalciuria, may have reduced bone mineral density (BMD). There are numerous risk factors contributing to reduction of BMD such as advanced age, sedentary life-style, smoking, low calcium intake, etc. The aim of our study was to investigate the association of lifestyle risk factors and daily intake of milk and dairy products with determinants of BMD in a group of recurrent calcium stone formers (RSF) compared with healthy subjects (HS). The study was carried out at the De-partment of Mineral Research, Faculty of Medicine in Osijek, Croatia. The study included 144 subjects, i.e. 56 RSF and 78 HS. BMD was assessed by dual-energy x-ray absorptiometry. A standard self-reported questionnaire was used to collect data on lifestyle risk factors. Current dietary intake was assessed by personal interview that included questions about milk and dairy product intake. Low BMD was observed in 44.64% of RSF and 35.90% of HS. RSF consumed significantly less milk and dairy products than HS. Calcium restriction in dietary recommendations might be unnecessary due to the impact on bone mineral loss in RSF and dual-energy x-ray absorptiometry should be included in the routine evaluation of RSF.Bolesnici s urolitijazom, osobito oni s hiperkalciurijom, imaju smanjenu koštanu mineralnu gustoću (bone mineral density, BMD). Rizični čimbenici gubitka koštane mase su uznapredovala dob, sjedilački način života, pušenje i smanjen unos kalcija. Cilj našeg istraživanja bio je ustanoviti povezanost rizičnih čimbenika i dnevnog unosa mlije-ka i mliječnih prerađevina s odrednicama BMD u bolesnika s recidivirajućom kalcijskom urolitijazom te ih usporedi-ti sa zdravim ispitanicima. Istraživanje je provedeno na Zavodu za mineralni metabolizam Medicinskog fakulteta u Osijeku. U istraživanju su sudjelovala 144 ispitanika, od čega 56 bolesnika s recidivirajućom kalcijskom urolitija-zom i 78 zdravih ispitanika. BMD je određen metodom dvoenergetske apsorpciometrije X zraka (DXA). Podatci o čimbenicima rizika dobiveni su anketnim upitnikom, a unos hrane je ocijenjen osobnim intervjuom koji je uključi-vao pitanja o unosu mlijeka i mliječnih proizvoda. Snižen BMD zabilježen je u 44,64% bolesnika s recidivirajućom urolitijazom i u 35,90% zdravih ispitanika. Bolesnici s recidivirajućom urolitijazom konzumirali su znatno manje mlijeka i mliječnih proizvoda u odnosu na zdrave ispitanike. Nepotrebna je preporuka smanjenog unosa kalcija bolesnicima s recidivirajućom urolitijazom zbog utjecaja na gubitak koštane mase, a DXA treba biti dio rutinske procjene bolesnika s recidivirajućom urolitijazom

The potential and properties of aboveground biomass of willow clones

Provedeno je terensko istraţivanje različitih klonova vrba s ciljem utvrĎivanja ukupne nadzemne biomase u periodu mirovanja vegetacije. Na terenu je obavavljeno odreĎivanje mase posječenih stabalaca i uzorkovanje kolutova,a nakon toga je u laboratoriju gravimetrijskom analizom odreĎena vlaga i gustoća u trenutku sječe i nominalna gustoća, odnosno preračun i iskaz standardno suhe biomase. Osim toga odreĎen je i maseni odnos drva i kore na pojedinim uzorcima te je odreĎen maseni udio pepela i kore, odnosno drva na prethodno pripremljenim laboratorijskim uzorcima sukladno HRN EN normama za čvrsta biogoriva. Matematičko statističkim analizama je odreĎena razlika u prinosu biomase izmeĎu pojedinih klonova, razlike u postotnom udjelu kore izmeĎu pojedinih klonova te razlike u udjelu pepela drva i kore kao i izmeĎu pojedinih klonova. Rezultati istraţivanja će posluţiti pri izboru odgovarajućih klonova vrba za podizanje kultura kratkih ophodnji za proizvodnju energijskoga drva s naglaskom na postizanje optimalne količine i kakvoće proizvedenog biogoriva

Antioxidant Pre-Treatment Reduces the Toxic Effects of Oxalate on Renal Epithelial Cells in a Cell Culture Model of Urolithiasis

Urolithiasis is characterized by the formation and retention of solid crystals within the urinary tract. Kidney stones are mostly composed of calcium oxalate, which predominantly generates free radicals that are toxic to renal tubular cells. The aim of the study is to explore possible effects of antioxidant pre-treatment on inhibition of oxidative stress. Three cell lines were used as in vitro model of urolithiasis: MDCK I, MDCK II and LLC-PK1. Oxidative stress was induced by exposure of cells to sodium oxalate in concentration of 8 mM. In order to prevent oxidative stress, cells were pre-treated with three different concentrations of l-arginine and vitamin E. Oxidative stress was evaluated by determining the expression of superoxide dismutase (SOD), osteopontin (OPN), and by the concentration of glutathione (GSH). In all three cell lines, pre-treatment of antioxidants increased cell survival. Positive correlation of SOD and OPN expression as well as GSH concentration was observed in all groups of cells. Our results indicate that an antioxidant pre-treatment with l-arginine and vitamin E is able to hamper oxalate-induced oxidative stress in kidney epithelial cells and as such could play a role in prevention of urolithiasis