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Identification of urine microorganisms by genomic and proteomic analysis
No full textU identifikaciji bakterija koji su najčešći uzročnici infekcija mokraćnoga sustava najčešće se koriste klasične
medicinsko-mikrobiološke metode. Glavni nedostatak tih metoda je njihova dugotrajnost. Upravo iz toga razloga
kontinuirano se istražuju mogućnosti bržih i učinkovitijih postupaka za određivanje broja i vrste mikroorganizama.
U ovom doktorskom radu istraživane su mogućnosti upotrebe masene spektrometrije (MS) i sekvenciranja gena za
16S rRNA u svrhu identifikacije bakterija iz mokraće. Za identifikaciju mikroorganizama izoliranih iz mokraće
ispitanika sa simptomima cistitisa, kao kontrola koristila se klasična mikrobiološka dijagnostika nakon koje se na
istim uzorcima provodila analiza mikrobioma i metaproteoma. Analiza mikrobioma obuhvaćala je identifikaciju
gena za 16S rRNA, dok se analizom metaproteoma provedenoga na MALDI-TOF MS/MS (engl. matrix assisted laser
desorption ionization-time of flight tandem mass spectrometry) pokušala postići rezolucija na nivou soja. Cilj ovoga
rada bio je dizajnirati i ispitati metodu MS-a za izravnu, brzu i pouzdanu identifikaciju mikroorganizama u uzorcima
mokraće ispitanika kod kojih je klasičnim mikrobiološkim metodama dokazana prisutnost mikroorganizama >105
CFU/ml te je usporediti s rezultatima dobivenim genomskom analizom mikroorganizama mokraće. Također, cilj
rada bio je pratiti promjene sastava mokraćne mikrobiote izazvane cistitisom i dinamiku njihove promjene uslijed
antibiotske terapije. Istraživanje je obuhvatilo analizu ukupno 396 uzoraka mokraće prikupljenih u KB Dubrava.
Osim toga, analizirano je dodatnih osam uzoraka mokraće istoga ispitanika koji je bio na antimikrobnoj terapiji s
ciljem praćenja promjena u mokraćnoj mikrobioti, te 40 uzoraka kultura četiri najčešća uropatogena. Rezultati
ovoga istraživanja pokazali su da se koristeći masenu spektroskopiju mogu identificirati bakterije u
monomikrobnim kulturama na razini roda. Međutim, ukoliko se radi o polimikrobnim kulturama MS ne daje
pouzdane rezultate identifikacije. Sekvenciranjem gena za 16S rRNA postignuta je taksonomska kategorizacija
uropatogena do razine roda (44 %) i obitelji (56 %), dok identifikacija na razini vrste nije postignuta. Također,
utvrđeno je da antibiotska terapija ima snažan utjecaj na dinamiku promjena sastava mokraćne mikrobiote, te da
je trajanje terapije iznimno važan terapijski parametar, kao i početni izbor lijeka.The bacteria that are the most prevalent causes of urinary tract infections are typically identified using standard
microbiological procedures. The biggest downside of these approaches is that they take a long time to complete.
As a result, researchers are always looking for new ways to determine the quantity and kind of microorganisms
faster and more efficiently. The possibility of utilizing mass spectrometry (MS) and sequencing of 16S rRNA genes
to detect bacteria from urine were studied in this doctoral thesis. Classical microbiological tests were utilized to
identify bacteria isolated from the urine of patients with cystitis symptoms, after which microbiomes and
metaproteom were analyzed. Microbiome investigation included identifying genes for 16S rRNA, while MALDI-TOF
MS/MS (matrix aided laser desorption ionization-time of flight tandem mass spectrometry) analysis of the
metaproteome tried to acquire strain-level resolution. The aim of the study was to design and test an MS method
for direct, rapid, and reliable identification of microorganisms in urine samples of patients whose presence of
microorganisms > 105 CFU / ml was confirmed by traditional microbiological methods, and to compare the results
with those of genomic analysis of urine microorganisms. Also, the aim of the study was to monitor changes in the
composition of the urinary microbiota caused by cystitis and the dynamics of their change due to antibiotic
therapy. The research included the analysis of a total of 396 urine samples collected through four phases in KB
Dubrava. In addition, 40 culture samples from the four most frequent uropathogens were studied, as well as 8
urine samples from the same person who had been on antibiotic therapy to monitor changes in the urinary
microbiota. The findings of this study revealed that mass spectroscopy can be used to identify bacteria in
monomicrobial cultures at the genus level. Mass spectroscopy, on the other hand, does not yield good
identification results in polymicrobial cultures. The 16S rRNA gene provided taxonomic categorization of
uropathogens down to the genus (44 %) and family (56 %) levels, but not species level identification. It was
discovered that monitoring the urine microbiota during antibiotic therapy has a substantial influence on the
dynamics of changes in its composition, and that the duration of therapy, as well as the initial drug choice, is an
extremely essential therapeutic parameter
Farmakogenetika inhibitora protonske pumpe
No full textCilj istraživanja: Cilj ovog rada je utvrditi utjecaj genetičkog polimorfizma CYP2C19 na farmakokinetiku inhibitora protonske pumpe (IPP) te prikazati utjecaj različitih varijanti ovog gena na ishode liječenja.
Materijali i metode: Pretraživanjem znanstvene literature detaljno je opisan utjecaj polimorfizma CYP2C19 na IPP-e i ishode liječenja ovisno o fenotipu. Pretraživanjem terapijskih smjernica stručnih farmakogenomskih društava, pregledno su prikazane preporuke o prilagodbi farmakoterapije farmakogenomskim analizama.
Rezultati: Polimorfizam gena CYP2C19 utječe na farmakoterapiju s IPP-ima. Fenotip sporog i intermedijarnog metabolizatora povezuje se s boljim terapijskim ishodom u odnosu na normalne, brze i ultra brze metabolizatore. Zbog povišene razine IPP-a u serumu ti pacijenti kod kronične terapije mogu razviti više nuspojava. Primjena IPP-a s drugim lijekovima - supstratima, inhibitorima ili induktorima enzima CYP2C19 - dovodi do različitog terapijskog ishoda ovisno o fenotipu.
Zaključak: Doziranje IPP-a prema genotipu CYP2C19 može pomoći u individualizaciji farmakoterapije s IPP-ima i boljem terapijskom ishodu.Objectives: The aim of this study was to determine the influence of CYP2C19 genetic polymorphism on the pharmacokinetics of proton pump inhibitors (PPI) and to show the influence of different variants of this gene on treatment outcomes.
Materials and methods: By reviewing scientific literature the effect of CYP2C19 polymorphism on PPI and phenotype-dependent treatment outcomes was described in detail. By searching through therapeutic guidelines of professional pharmacogenomic societies the recommendations on the adaptation of pharmacotherapy to pharmacogenomic analyzes were clearly presented.
Results: Polymorphism of the CYP2C19 gene affects pharmacotherapy with PPIs. The slow and intermediate metabolizer phenotype is associated with a better therapeutic outcome compared to normal, fast and ultrafast metabolizers. Due to elevated serum PPI levels these patients may develop more side effects with chronic therapy. Administration of PPIs with other drugs, substrates, inhibitors or inducers of CYP2C19 enzymes leads to a different therapeutic outcome depending on the phenotype.
Conclusion: Dosing of PPIs according to the CYP2C19 genotype may help to individualize pharmacotherapy with PPIs and improve the therapeutic outcome
Sadržaj i sastav eteričnog ulja u komercijalnim uzorcima kamilice (Matricaria recutita L.)
No full textKamilica je jedna od najduže poznatih i najcjenjenijih ljekovitih biljaka, a među širokim spektrom farmakološki i klinički dokazanih učinaka posebno se ističe primjena zbog protuupalnih i spazmolitičkih svojstava. Terapijski učinak cvjetova uglavnom se pripisuje flavonoidima i sastavnicama eteričnog ulja pa je i farmaceutska kakvoća droge Matricariae flos prema Europskoj farmakopeji definirana njihovim sadržajem. Dosadašnja istraživanja ukazala su da je sadržaj i sastav eteričnog ulja kamilice vrlo promjenjiv i da na njih utječe veći broj čimbenika, pa se uslijed velike popularnosti nameće pitanje kakvoće komercijalno dostupnih fitopreparata kamilice. S obzirom na široku primjenu kamilice u obliku najdostupnijeg čaja i njihov veliki izbor na hrvatskom tržištu kao i razlike s obzirom na oblik, proizvođače, porijeklo, regulatorni status i mjesto kupovine, cilj ovog specijalističkog rada bio je prikupiti komercijalno dostupne uzorke kamiličinog čaja i provesti određivanje sadržaja i sastava eteričnog ulja kao važnih pokazatelja kakvoće i njome uvjetovane djelotvornosti droge. Rezultati fitokemijskih istraživanja ukazali su na značajne razlike u sadržaju eteričnog ulja u kamiličinom cvijetu s tržišta, koji su se kretali u rasponu od 0,7 mL do 5,0 mL eteričnog ulja/kg biljne droge. Samo su tri uzorka droge Matricariae flos in toto udovoljavala farmakopejskom zahtjevu za sadržajem najmanje 4 mL/kg eteričnog ulja što ukazuje da velika većina kamiličinog cvijeta dostupnog na hrvatskom tržištu nije farmaceutske kakvoće. Metodom plinske kromatografije spregnute s tandemskom spektrometrijom masa (GC-MS/MS) odijeljeno je i identificirano 37 sastavnica kamiličinog eteričnog ulja. Glavne sastavnice su oksidirani sesviterpenski spojevi α-bisabolol oksid A (13,5-41,9 %) i α-bisabolol oksid B (7,0–31,8 %). Ostale značajnije zastupljene sastavnice su cis-spiroeter (4,5 – 18,0 %) i α-bisabolon oksid A (6,2–12,2 %) te trans-β-farnezen (0,8–6,5 %) i kamazulen (0,6 – 5,8 %).
Usporedna analiza pokazala je da uzorci cjelovitog cvijeta općenito sadrže eterično ulje ujednačenijeg sastava u odnosu na usitnjen cvijet prisutan na tržištu u obliku filter vrećica kod kojih su uočene veće razlike u sadržaju dviju glavnih sastavnica. Eterično ulje iz kamiličinog cvijeta in toto sadržavalo je između 27,2 % i 41,9 % α-bisabolol oksida A, α-bisabolol oksida B u rasponu od 21,1 % do 27,8 % te je bilo bogatije kamazulenom (3,1-5,8 %) u odnosu na eterično ulje kamilice iz filter vrećica (0,6-3,6 %). Rezultati provedene usporedne analize tržišnih uzoraka kamiličinog čaja upućuju na veću kvalitetu cvijeta kamilice in toto i samim time na nužnost korištenja tog oblika u ljekovite svrhe. Rad također ističe važnost i nužnost provođenja kontrole kakvoće biljnih droga i pripravaka kako bi se pacijentima osigurala primjena fitopreparata farmaceutske kvalitete što predstavlja imperativ suvremene, racionalne fitoterapije i pridonosi jačaju njihova povjerenja u fitoterapiju općenito.Chamomile is one of the longest known and most valued medicinal plants and among the wide range of pharmacologically and clinically proven effects, its use stands out due to its anti-inflammatory and antispasmodic properties. The therapeutic effect of chamomile flower is mainly attributed to the flavonoids and essential oil constituents, so the pharmaceutical quality of the herbal drug Matricariae flos, according to the European Pharmacopoeia, is defined by their contents. Previous research has shown that the content and composition of chamomile essential oil is very variable and is influenced by a number of factors, so due to its great popularity, the question of the quality of commercially available chamomile preparations arises. Given the wide use of chamomile in the form of the most available herbal tea and their large selection on the Croatian market as well as differences in relation to form, producers, origin, regulatory status, and place of purchase, the goal of this specialist thesis was to collect commercially available samples of chamomile tea and determine the content and composition of essential oil as important indicators of the quality and related effectiveness of the herbal drug. Conducted phytochemical studies revealed significant differences between chamomile flowers from the market related to the content of essential oil, which were between 0.7 and 5.0 mL of essential oil per kg of herbal drug. Only three analysed samples of the herbal drug Matricariae flos in toto met the pharmacopoeial requirement of the content of at least 4 mL/kg of essential oil, indicating that the vast majority of chamomile herbal teas available on the Croatian market are not of pharmaceutical grade. Using the method of gas chromatography coupled with tandem mass spectrometry (GC-MS/MS), 37 components of chamomile essential oil were separately identified. The main components are the oxidized sesquiterpene compounds α-bisabolol oxide A (13.5 – 41.9%) and α-bisabolol oxide B (7.0 – 31.8%). Other
significant ones are cis-spiroether (4.5 – 18.0%), α-bisabolon oxide A (6.2 – 12.2%), trans-β-farnesene (0.8 – 6.5%) and chamazulene (0.6 – 5.8%).
Comparative analysis showed that whole flower samples generally contain essential oil having more uniform composition compared to samples present on the market in the form of filter bags, where larger oscillations in the content of the two main components were observed. Essential oils of market samples of chamomile flowers in toto contained α-bisabolol oxide A in the range from 27.2% to 41.9%, and α-bisabolol oxide B from 21.1% to 27.8%, respectively. Also, those essential oils were richer in camazulene (3.1 - 5.8%) compared to the chamomile essential oil from filter bags (0.6 - 3.6%). The results of the comparative analysis of market samples of chamomile tea point to the higher quality of the chamomile flower in toto, suggesting the necessity of using this form for medicinal purposes. The thesis also highlights the importance and necessity of quality control of herbal drugs and preparations in order to ensure the use of pharmaceutical-quality phytopreparations for patients, which represents the imperative of modern, rational phytotherapy and contributes to strengthening their trust in phytotherapy in general
Ispitivanje propusnosti različitih tipova zaštitnih maski za vijabilne čestice plijesni u zraku
No full textThe beginning of the COVID-19 pandemic resulted in global
application of face masks and respirators as a common control
measure in reducing the risk of infection and disease transmission. Consequently,
the efficacy of the. masks and respirators in mitigating negative health
impact related to the inhalation of various airborne particles were investigated.
Given the widespread distribution, public health and economic significance,
molds certainly represent a part of the aerial ecosystem that is important to
explore. Therefore, in this paper, we examined the permeability of a cotton mask,
surgical mask, FFP2 and FFP3 respirators far indoor and outdoor aeromycota by
using air sampling device and appropriate agar plates. The results of quantitative
analysis have shown that in both cases the FFP2 mask best retains viable mold
particles (93-95%) in accordance with a declared regulation and the certificate
due. Although a respirator type FFP3 mask should have retained the mycoparticles
to an even greater extent, this study showed up to 11 % lower efficiency
compared to a certified filtration percentage of 99%. The surgical mask was the
least effective and retained 30-80% less of the viable mold particles. lnterestingly,
the reverse of the surgical mask retained as much as 89% of viable mold
particles. Such results are in line with the recommendation to wear a surgical
mask to reduce the spread of a potentially infectious aerosol. The cotton mask
had no significant impact on the retention of airborne molds so the protective
role of such is questionable.
The molds belonging to Cladosporium, Aspergillus and Penicillium were the
most common in indoor air. While cotton and surgical masks similarly filtered
different genera of molds, in the airsamples taken through the FFP2 and FFP3
respirators only molds from the genus Cladosporium were detected. For a precise
interpretation of the results of this work, a study should be carried out using
sterile filters more suitable for the air sampling device, and correspond to the
surgical, FFP2 and FFP3 masks in their properties. The proposed research method
can also be optimized for testing new materials with more efficient retention
properties for the infectious and/or allergenic particles and molds, and as such
would provide more effective protection to the target groups of patients
Association between TNF-α gene polymorphism and efficiency of therapy with the TNF-α antagonists infliximab and adalimumab and development of antibodies to those drugs
No full textAntagonisti faktora nekroze tumora α (engl. Tumor Necrosis Factor, TNF-α) učinkoviti su u liječenju
autoimunih reumatoidnih i upalnih bolesti crijeva, ali se čak u 30 % bolesnika ne postiže remisija
bolesti. Cilj istraživanja bio je ispitati postoji li razlika u kliničkom i biokemijskom odgovoru na terapiju
anti-TNF-α protutijelima ovisno o polimorfizmima gena TNF-α na položajima -238 G/A (rs361525) i -
308 G/A (rs1800629).
U istraživanje je bilo uključeno 112 bolesnika od čega 66 s upalnim bolestima crijeva te 46 bolesnika s
autoimunim reumatoidnim bolestima. Na terapiji infliksimabom (IFX) bilo je ukupno je 73 bolesnika, a
39 na terapiji adalimumabom (ADM). Bolesnici su praćeni 6 do 12 mjeseci od početka biološke terapije.
Svim je bolesnicima određena koncentracija C reaktivnog proteina (CRP), lijekova IFX i ADM i
protutijela na te lijekove kao i genotip polimorfizama rs361525 i rs1800629 gena TNF-α. Bolesnicima s
upalnim bolestima crijeva određena je i koncentracija fekalnog kalprotektina (fKal), dok je onima s
autoimunim reumatoidnim bolestima klinički odgovor praćen ocjenama aktivnosti reumatoidnih
bolesti.
Ni koncentracije IFX i ADM kao ni pojavnost i koncentracije protutijela na studirane lijekove nisu se
razlikovale ovisno o genotipovima polimorfizama rs361525 i rs1800629 gena TNF-α. Koncentracija CRP
nakon 12 mjeseci terapije bila je viša u bolesnika s genotipom GG nego u onih s genotipom GA na
položaju -238 gena TNF-α, dok nije bilo razlike u koncentraciji CRP kod različitih genotipova na položaju
-308 gena TNF-α. Koncentracija fKal nije se razlikovala ovisno o genotipu polimorfizama rs361525 i
rs1800629 gena TNF-α. Remisija je postignuta kod 63 % bolesnika, neovisno o genotipu studiranih
polimorfizama. Bolesnici s autoimunim reumatoidnim bolestima genotipa GG u oba ispitivana
polimorfizma imali su statistički značajno bolji odgovor na terapiju u odnosu na bolesnike s genotipom
GA ili AA. Univarijatnom regresijskom analizom pokazano je da je postizanje terapijske koncentracije
IFX i ADM izglednije kod muškaraca, a pojava protutijela na lijekove manje izgledna. U bolesnika s RA
izglednija je pojava protutijela na lijekove, a manje izgledno je postizanje terapijske koncentracije
lijekova, dok kod ostalih bolesti univarijatnom regresijskom analizom nisu dobiveni statistički značajni
omjeri izgleda. Remisiju bolesti može predvidjeti koncentracija CRP 6 i 12 mjeseci nakon terapije, dok
se klinički odgovor na terapiju ne može predvidjeti ne temelju genotipa studiranih polimorfizama.Tumor necrosis factor α (TNF-α) inhibitors are effective in the treatment of autoimmune rheumatoid
disease (ARD) and inflammatory bowel diseases (IBD), but almost 30 % of patients do not achieve
remission of the disease.
Objectives of the study were to examine the association of genotypes of -238 G/A (rs361525) and -308
G/A (rs1800629) polymorphisms in TNF-α gene with the clinical and biochemical response to the
therapy.
The study included 112 patients, of which 66 with IBD and 46 patients with ARD. There was a total of
73 patients on infliximab (IFX) therapy and 39 on adalimumab (ADM) therapy. Patients were followed
for 6 to 12 months from the start of biologic therapy. All patients were tested for reactive protein C
(CRP), IFX and ADM, and antibodies to these drugs, as well as the genotype polymorphisms rs361525
and rs1800629 of the TNF-α gene. Patients with IBD were also tested for fecal calprotectin (fCal) levels,
while those with ARD had a clinical response followed by assessments of rheumatoid disease activity.
Concentrations of IFX and ADM after at least 6 months of therapy did not differ depending on
genotypes TNF-α gene polymorphisms -238 G/A and -308 G/A. The incidence of antibody
development, as well as the concentration of anti-drug antibodies, did not differ depending on tested
polymorphisms. After 12 months of therapy, CRP concentration was higher in patients with GG than
in patients with GA genotype in the -238 position of the TNF-α gene. fCal concentration did not differ
depending on the studied polymorphisms. Remission was achieved in 63 % of patients, with no
difference depending on the genotypes. Patients with ARD carrying the GG genotypes in both
positions, -238 and -308, had a significantly better response to the therapy compared to patients with
GA or AA genotypes. The univariate logistic regression analysis has shown that males are more likely
to achieve therapeutic levels of IFX and ADM and less likely to develop antibodies to drugs. The studied
polymorphisms were not factors that can predict the clinical response to the therapy.
Genotyping of polymorphisms -238 G/A and -308 G/A in the TNF-α gene before the introduction of IFX
and ADM therapy does not contribute to the prediction of clinical outcomes monitored by blood
concentration of drugs and antibodies to the drugs, or clinical remission of IBD or ARD
Transformation pathway of drug models in chlorinating conditions. Quantum-chemical study
No full textLijekovi nakon uporabe bivaju eliminirani iz organizma i kao takvi dospijevaju u otpadne vode i
dezinfekcijske bazene. Prilikom obrade takvih voda najkorištenija metoda je kloriranje raznim
klorirajućim specijama među kojima je najučestalija hipokloritna kiselina i plinoviti klor. U
reakcijama s klorirajućim specijama metaboliti lijekova, među kojima su nama najzanimljiviji oni
koji sadrže amino skupinu, nastaju N-kloramini koji su reaktivniji, toksičniji i perzistentniji oblici.
Sudbine N-kloraminskih specija smo proučavali putem Hoffman-Löffler-Freytag (HLF) reakcije.
Računato je koji su produkti vjerojatniji s obzirom na energetske barijere reakcija te stabilnost
produkata.
Mehanizmi ovih reakcija proučavani su kvantno-kemijskim modelima kojima su se računale
energije produkata, reaktanata i prijelaznih stanja te se putem IQmol programa vizualizirale
strukture. Kvantno kemijski izračuni izvedeni su korištenjem programskog paketa Orca. Orca nudi
najsuvremenije metode u područjima funkcionala gustoće (DFT – Density Functional Theory) kao
i metode temeljene na valnim funkcijama.
Rezultati dobiveni u ovom radu pokazuju da se N-klorirani derivati pregrađuju u N-radikale koji se
putem intramolekulskog prijenosa vodika pregrađuju u stabilnije C-radikale koji se kloriraju i pod
utjecajem baze cikliziraju u piperidinske i pirolidinske sustave dajući spojeve novih karakteristika.
Na kraju reakcije ostajemo s pirolidinskim (ili piperidinskim) prstenom i trimetilamin
hidrokloridnom soli.After use, drugs are eliminated from the body and as such end up in wastewater and disinfection
pools. When treating such waters, the most used method is chlorination with chlorinating spices,
among which hypochlorous acid and chlorine gas are most common. In reactions with chlorinating
species, drug metabolites, among which the most interesting are those containing an amino group,
N-chloramines are formed which are more reactive, toxic and persistent forms.
The fate of N-chloramine species was studied by Hoffman-Löffler-Freytag (HLF) reactions. It was
calculated which products are more likely given the barrier energy response and the stability of
products.
The mechanisms of these reactions have been studied by quantum chemical models that calculate
the energy of products, reactants and transition states, and structures are visualized through the
IQmol program. Quantum chemical calculations were performed using the Orca software package.
Orca offers state-of-the-art methods in the field of functional density theory (DFT - Density
Functional Theory) as well as methods based on wave functions.
The results obtained in this paper show that N-chlorinated derivatives are converted into Nradicals
which are converted into more stable C-radicals by intramolecular hydrogen transfer
which are then chlorinated and cyclized under the influence of base into piperidine and pyrrolidine
systems giving compounds of new characteristics. At the end of the reaction we are left with a
pyrrolidine (or piperidine) ring and trimethylamine hydrochloride salt
Influence of sex hormones on the development of mental disorders in women
No full textSpolni hormoni imaju značajni utjecaj na sveopće fizičko i psihičko stanje žene. Kroz cijeli reproduktivni život, počevši od
menarhe pa do ulaska u menopauzu, žene osjećaju intenzivne promjene koncentracija progesterona i estrogena. Dobro
opisani učinci na periferne ciljne organe praćeni su i djelovanjem hormona unutar središnjeg živčanog sustava gdje
reguliraju različite procese. Spolni hormoni utječu na prilagodbu mozga tijekom bitnih hormonskih tranzicija, npr. tijekom
trudnoće ili menopauze, ali i na mjesečnoj bazi uobičajenim fluktuacijama tijekom menstruacijskog ciklusa. Primjerice, tada
su strukturalne promjene najočitije u hipokampusu, amigdali, ali i temporalnim i parijetalnim regijama mozga u obliku
promjena volumena sive tvari. Osim strukturalnih, funkcionalne promjene uključuju utjecaj na različite neurotransmitorske
sustave, posebice monoaminske. To se povezuje s određenim rizikom za nastanak mentalnih poremećaja. Estrogen se ističe
svojim neuroprotektivnim djelovanjem, uz povoljne učinke na podizanje razine serotonina i dopamina. Nagli pad razina
estrogena povezuje se s poremećajima raspoloženja i smanjenjem kognitivnih sposobnosti u postmenopauzi. Progesteron
također ima modulatorne uloge u središnjem živčanom sustavu, preko svog aktivnog metabolita alopregnanolona koji
pozitivnom modulacijom GABA-A receptora ispoljava pozitivno djelovanje na regulaciju raspoloženja. Nagli pad
koncentracija progesterona, odnosno alopregnanolona u posljednoj fazi lutealnog perioda pokazuje korelaciju s
intenziviranjem negativnih simptoma raspoloženja kod žena s PMS-om ili PMDD-om. Egzogeni hormoni, poput
kombinacija estrogena i progestina koje se koriste u svrhu kontracepcije ili za smanjenje simptoma menopauze pokazuju
različite učinke na mentalno zdravlje i ponašanje žena. Dok je u adolescenata primjena hormonskih pripravaka povezana s
povećanim rizikom od depresije, kod žena u menopauzi primjena kombiniranih hormona povezana je s pozitivnim
djelovanjem na raspoloženje i kognitivne funkcije, premda su rezultati kontradiktorni. Iako promjene spolnih hormona
tijekom menstruacijskog ciklusa utječu na funkcioniranje različitih organskih sustava, njihov doprinos uglavnom je
zanemaren prilikom psihofarmakološke terapije, velikim dijelom i zbog nedostatka podataka i jasnih smjernica temeljenih na
dokazima. Za sada je najviše podataka prikupljeno o povezanosti fluktuacija spolnih hormona i primjene selektivnih
inhibitora ponovne pohrane serotonina i benzodiazepina. Daljnja istraživanja nužna su za kvalitetniju terapiju prilagođenu
svakoj pacijentici, a uzevši u obzir i njezin hormonalni status, kada je to primjenjivo.Sex hormones have a significant impact on the physical, as well as the mental state of women. During their whole
reproductive life, starting ftom the menarche up until reaching menopause, women experience intense changes of
progesterone and estrogen concentrations. Well described effects of these hormones on their peripheral target tissues are
acompanied with their effects upon the central nervous system where they regulate multiple different processes. Sex
hormones influence the brain's adaptation capabilities during pivotal hormonal transitions such as pregnancy or menopause,
however their effects during monthly fluctuations within the menstrual cycle can not be neglected. For instance, the most
apparent structural changes during the menstrual cycle happen in the hippocampus, amygdala, temporal and parietal regions
of the brain with changes in gray matter volume. In addition to the structural aspect, functional changes include alterations of
multiple neurotransmission systems with emphasis on the monoamine system. Thic could potentially be related to the risk of
developing mental disorders. Estrogen is considered to have a neuroprotective role with beneficial effects of elevating the
levels of serotonine and dopamine. A sudden drop in estrogen levels is associated with negative mood disorders and
decreasing cognitive cpabilities during menopause. Progesterone also has a modulatory role in the central nervous system,
mainly through its active metabolite allopregnanolone which exerts a positive effect on mood regulation via positive
modulation of GABA – A receptors. An abrupt decrease in progesterone or allopregnanolone in the laste phase of the luteal
period is associated with intensifying negative mood symptoms in women with PMS or PMDD. Exogenous hormones, such
as combined estrogen and progesterone medications used for contraceptive purposes or for reducing menopausal symptoms
demonstrate different effects on women's mental health and behaviour.While in adolescents the use of hormonal preparations
increased the risk of depression, in menopausal women the use of combined hormones is associated with positive effects on
mood and cognitive function, however the evidence is not unanimous. Even though changes in sex hormones during the
menstrual cycle affect multiple organ systems, their contribution is largely dismissed during psychopharmacological therapy,
in large due to lacking data and no clear evidence based guidelines. So far, the most data has been collected regarding sex
hormone fluctuations and the use of selective serotonine reuptake inhibitors as well as benzodiazepines. Further research is
needed in order to provide patient tailored therapy, taking hormonal status into account
Određivanje cinka, bakra i selena u pseudožitaricama metodom induktivno spregnute plazme s masenom spektrometrijom
No full textPseudograins are a group of grains with a better nutritional profile than traditional grains such as corn, rice, or wheat. When it
comes to the macronutrients, they are superior compared to other ingredients.
They represent the source of biologically valuable amino acids, lipids and indigestible carbohydrates, which serve as prebiotic. Moreover, they have essential micronutrient composition, including trace elements – zinc, copper, and selenium.
These elements were quantitatively determined in pseudograins such as buckwheat,
quinoa, amaranth, and millet by the Inductive Coupled Plasma Mass Spectrometry
(ICP-MS). Herein we report the results obtained. All examined pseudograins contain a substantial amount of zinc, copper and selenium. A significant amount of copper is present in the buckwheat (0.59 ± 0.00 mg/100g) and selenium in amaranth (31.73 ± 2.43 mg/100g), which makes over 40% of the Recommended Daily Allowance (RDA). These microelements have an irreplaceable role in the physiological functioning of our organism, and their lack or excess can lead to numerous pathological conditions. Therefore, the pseudograins are an excellent source of these microelements and should be included in the everyday diet
Life quality of adjuvant endocrine therapy in patients who suffered from hormone dependent breast cancer
No full textU hormonski ovisnom tipu ranog raka dojke visoko preživljenje je posljedica vrlo učinkovitog endokrinog liječenja.
Međutim, dugotrajno AEL koje obuhvaća aromatazne inhibitore (anastrozol, letrozol i ekesemestan) i tamoksifen dovodi
do brojnih nuspojava koje su posljedica antiestrogenskog djelovanja tih lijekova. U premenopauzalnih žena nuspojave
AEL mogu biti jače izražene zbog nagle i snažne supresije estrogena uslijed intenzivne endokrine terapije. Prema
podacima iz literature nuspojave AEL utječu na kvalitetu života i adherenciju pacijentica. Obzirom da se radi o kroničnoj
terapiji koja se uzima kroz razbolje od 5 do 10 godina, vrlo je bitno identificirati žene s visokim rizikom za pojavu
određenih nuspojava te one kod kojih se očekuju teži oblici nuspojava. Mnoge od najčešćih nuspojava moguće je ublažiti
nefarmakološkim i farmakološkim pristupima s ciljem održavanja visoke adherencije i ustrajnosti u liječenju obzirom
da su oni nužan preduvjet za smanjenje rizika od povrata bolesti i visoku stopu preživljenja ove skupine pacijentica.
Cilj ovog diplomskog rada bio je istražiti vrstu, učestalost i težinu nuspojava koje se javljaju pri AEL žena koje su
bolovale od ranog raka dojke. Nadalje, ovim istraživanjem istražen je i utjecaj komedikacije GnRH na vrstu, prevalenciju
i težinu nuspojava AEL. Sudionice ovog istraživanja bile su isključivo žene koje su bolovale od hormonski ovisnog
karcinoma dojke stadija I-III te koje su započele AEL barem tri mjeseca prije ispunjavanja upitnika. Uključeno je 329
pacijentica prosječne životne dobi 57 godina. Ispitanice na tamoksifenu imale su statistički značajno veću prevalenciju
krvožilnih (navale vrućine, hladan znoj i noćno znojenje) i vaginalnih (vaginalni iscjedak, vaginalna iritacija) nuspojava
u odnosu na ispitanice na AI, dok su ispitanice na AI imale statistički značajno veću prevalenciju i jače bolove u kostima.
Također, komedikacija GnRH uz AEL značajno je pridonijela prevalenciji i težini nuspojava u odnosu na liječenje samo
endokrinim lijekovima. Nadalje, prevalencija i težina svih najčešćih nuspojava, osim bolova u kostima, bila je veća u
žena liječenih kombinacijom GnRH + AEL. Istraživanje ovog tipa prvi je puta provedeno na populaciji pacijentica
oboljelih od hormonski ovisnog karcinoma dojke u Hrvatskoj te može doprinijeti boljem razumijevanju čimbenika koji
doprinose adherenciji. Identifikacija subpopulacije žena s najvećim rizikom od teških nuspojava AEL važna je kako bi
se razvile specifične intervencije i intenzivirala farmaceutska skrb za žene čija će kvaliteta života vjerojatno biti značajno
narušena tijekom AEL i posljedično kod kojih postoji rizik od neadherencije i neustrajanja u kroničnom liječenju.In hormone type of early breast cancer, high survival is the result of very effective endocrine treatment options. However,
long-term adjuvant endocrine therapy (AET) which includes aromatase inhibitors (anastrozole, letrozole, and
exemestane) and tamoxifen leads to a number of side effects resulting from the antiestrogenic effects of these drugs. In
premenopausal women, the side effects of AET may be even more pronounced due to a sudden and strong estrogen
suppression which is the consequence of intensive endocrine therapy. According to the literature, the side effects of AET
affect the quality of life and adherence of patients. Since AET is a chronic therapy taken through the period from 5 to
10 years, it is very important to identify women at high risk for certain side effects and the women who are expected to
have more severe forms of certain side effects. Many of the most common side effects can be alleviated by nonpharmacological
and pharmacological approaches with an aim of maintaining high adherence and persistence as they
are necessary for reducing the risk of disease recurrence and high survival rates of this group of patients.
The aim of this diploma thesis was to investigate the type, frequency and severity of side effects that occur due to AET
in women suffering from early breast cancer. Furthermore, this study also investigated the impact of gonadotropinreleasing
hormone (GnRH) comedication on the type, prevalence, and severity of side effects that occur in AET.
Participants in this study were women who suffered from stage I-III hormone-dependent breast cancer and who started
AET at least three months before completing the questionnaire. This research included 329 women with an average age
of 57 years. Subjects on tamoxifen had a statistically significant higher prevalence of vascular (hot flashes, cold sweat
and night sweats) and vaginal (vaginal discharge, vaginal irritation) side effects compared to subjects on AI, while
subjects on AI had a statistically higher prevalence of stronger bone pain. Also, the comedication with GnRH and AET
significantly contributed to the prevalence and severity of side effects compared to treatment with endocrine drugs alone.
Furthermore, the prevalence and severity of all the most common side effects, except bone pain, was higher in women
treated with the GnRH + AET combination. This type of research was conducted for the first time on the population of
patients with hormone positive breast cancer in Croatia and can contribute to a better understanding of adherence factors.
The identification of the subpopulation of women with the highest risk of severe AET side effects is important as to
target specific interventions and intensify pharmaceutical care for women whose quality of life is likely to be
significantly impaired during AET and consequently at risk of nonadherence and failure in chronic treatment
Impact of BMP1-3 on expression of Col1A1, TGFβ and decorin on dermal scarring in rats
No full textUvod: BMP1-3 ostvaruje profibrotični učinak kroz povećanu ekspresiju i taloženje ECM-a, što može rezultirati estetski vidljivim ožiljkom. Smatra se da je za profibrotični učinak BMP1-3 dijelom odgovorno pridruženo smanjenje ekspresije dekorina, te povećana ekspresija Col1A1 i TGFβ. Ovaj rad ispituje učinak poliklonskih protutijela razvijenih na BMP1-3 na ekspresiju Col1A1, TGFβ-1 i dekorina u ožiljkastom tkivu in vivo koristeći različite koncentracije i načine primjene protutijela na eksperimentalnom modelu štakora.
Metode: Iz dobivenih homogenata, nakon tretmana različitim dozama i načinom primjene BMP1-3 polyAb i BMP1-3, izolira se RNA i provodi se analiza genske ekspresije Col1A1, TGFβ i dekorina lančanom reakcijom polimeraze u stvarnom vremenu.
Rezultati: Primjenom BMP1-3 polyAb subkutano u tri koncentracijske razine, nije pokazana razlika u ekspresiji između tretiranih i kontrolnih skupina u svakoj grupi kao i između grupa tretiranih različitim dozama antitijela. Za grupe tretirane intravenski BMP1-3 polyAb i subkutano BMP1-3 proteinom, ekspresija tretirane strane nije statistički značajno promijenjena u odnosu na kontrolnu. Zaključak: Moguće je da BMP1-3 polyAb značajnije utječe na posttranslacijsku modifikaciju, a manje na razini transkripcije kolagena, TGFβ i dekorina. Unatoč tome što razlika ekspresije između tretiranih i kontrolnih skupina nije pokazana, potrebno je uzeti u obzir rezultate histološke analize koja slijedi, te na taj način interpretirati potencijalnu važnost primjene BMP1-3 polyAb na smanjenje veličine kožnog ožiljka u štakora.Introduction: BMP1-3 achieves a profibrotic effect through increased ECM expression and deposition, which can result in an aesthetically visible scar. The profibrotic effect of BMP1-3 is thought to be partly caused by the combined decrease in decorin expression and increased expression of Col1A1 and TGFβ. This research explores the effect of polyclonal antibodies developed on BMP1-3 on the expression of Col1A1, TGFβ-1 and decorin in scar tissue in vivo using different concentrations and methods of antibody application in an experimental model using rats. Methods: After rat treatment with different doses and methods of application of BMP1-3 polyAb and BMP1-3, RNA was isolated from the obtained skin tissue homogenates and analysis of gene expression of Col1A1, TGFβ and decorin was performed by real-time polymerase chain reaction. Results: Administration of BMP1-3 polyAb subcutaneously at three concentration levels did not result in different gene in expression between treated and control side of body in each group of animals, as well as between groups treated with different antibody doses. For the groups treated with BMP1-3 polyAb intravenously and BMP1-3 protein subcutaneously, gene expression in the treated group was not statistically significantly changed when compared to the control group. Conclusion: It is possible that BMP1-3 polyAb shows a more significant effect on posttranslational modifications instead to the transcription of collagen, TGFβ and decorin genes. Despite the lack of a difference in expression between the treated and control groups , it is necessary to take into account the results obtained by future histological analysis, and interpret the potential importance of BMP1-3 polyAb to reduce skin scar size in rats accordingly