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Epidemiološke studije dovele su u vezu prenatalno izlaganje efektima imune aktivacije izazvane virusnim, bakterijskim ili parazitskim infekcijama sa povećanim rizikom od nastanka neurorazvojnih poremećaja poput shizofrenije. Ova saznanja dovela su do razvoja animalnih modela prenatalne imune aktivacije sa ciljem da se u njima modeluju simptomi i patofiziološki mehanizmi relevantni za određena neurorazvojna oboljenja. Utvrđeno je da primena lipopolisaharida (LPS), imunogene komponente ćelijskog zida gram-negativnih bakterija, gravidnim ženkama glodara izaziva febrilni odgovor i indukciju više citokina, čime utiče na balans pro- i antiinflamatornih medijatora koji je neophodan za pravilan razvoj mozga fetusa.U proučavanju etiologije shizofrenije akcenat je nedavno pomeren ka ispitivanjima poremećaja GABA-ergičkog sistema, a deficiti GABA-ergičke transmisije koji su zabeleženi kod pacijenata obolelih od shizofrenije nađeni su i u modelima prenatalne primene LPS-a gravidnim ženkama pacova. Od posebnog značaja za ispitivanja predstavljena u ovoj disertaciji stoje informacije da se vreme primene LPS-a u našem istraživanju poklapa sa periodom prvobitne ekspresije α5GABAA receptora u fetusnom mozgu pacova, kao i da prenatalna primena LPS-a u tim danima gestacije rezultira smanjenjenjem GABA-ergičke transmisije u hipokampusu potomaka u periodu preadolescencije. Otkrivanje ranih poremećaja u razvoju CNS-a leži u osnovi strategije prevencije razvoja shizofrenije i srodnih poremećaja, koja podrazumeva farmakološko delovanje na neurorazvojne promene u nastanku, pre ispoljavanja prvih simptoma.U ovoj studiji, LPS (serotip O111:B4, Escherichia coli) je primenjivan gravidnim ženkama Wistar pacova 15. i 16. dana gestacije u dozi od 100 μg/kg. Prenatalna inflamacija je detektovana kroz porast nivoa citokina TNF-α u krvi majke i placentalnom tkivu, i povećanje koncentracije IL-6 u krvi majke i amnionskoj tečnosti, dok fetusna neuroinflamacija posredovana ovim citokinima nije potvrđena, Epidemiological studies have linked the exposure to the effects of maternal immune activation induced by viral, bacterial or parasitic infections, with the emergence of schizophrenia and several other neurodevelopmental disorders. These findings led to the development of animal models of prenatal immune activation designed to model symptoms and pathological mechanisms relevant to certain neurodevelopmental disorders. It has been shown that administration of lipopolysaccharide (LPS), an immunogen component of the cell wall of gram-negative bacteria, to pregnant rodents causes febrile response and cytokine induction, thus affecting the balance between pro- and anti-inflammatory mediators which is necessary for regular development of the fetal brain.Within the studying of etiology of schizophrenia, a focus of investigation has recently been shifted to abnormalities observed in GABA-ergic system, and deficits of GABA-ergic transmission recorded in schizophrenia patients have also been found in rats tested in models of prenatal LPS administration. Some GABA-related findings are of special interest for investigation presented in this dissertation: the time of LPS administration in our protocol is the very time of primary expression of α5GABAA receptors in rat fetal brain, and prenatal LPS administration the selected days of gestation results in a decrease of GABA-ergic transmission in the hippocampus of preadolescent offspring. The discovery of early disturbances in the development of CNS underlies the strategy for prevention of schizophrenia and related disorders, which implies a pharmacological treatment of neurodevelopmental changes at their occurrence, before the manifestation of first symptoms.In this study, LPS (serotype O111:B4, Escherichia coli) was administered to pregnant Wistar rats at 15th and 16th day of gestation, at the dose of 100 μg/kg. Prenatal inflammation was detected via the elevation of TNF-α concentration in maternal blood and placenta, and IL-6 con

Poremećaji raspoloženja, uključujući i depresiju, predstavljaju ozbiljne zdravstvene probleme i prema podacima Svetske zdravstvene organizacije do 2020. godine postaće vodeći uzrok radnog onesposobljavanja na globalnom nivou. Poznato je da je hiperaktivnost osovine hipotalamus-hipofiza-nadbubreg (HPA) čest pratilac depresivnih poremećaja, kao i da je hronična izloženost stresu vodeći faktor rizika u razvoju ovih bolesti. Jedan od najvećih problema farmakoterapije depresije predstavlja prilično veliki procenat neadekvatnog odgovora pacijenata na terapiju selektivnim inhibitorima preuzimanja serotonina (SSRI), koji predstavljaju lekove prvog izbora. Stoga, identifikacija biomarkera povoljnog odgovora na terapiju atnidepresivima, kao i pronalaženje eventualnog dodatnog tretmana koji bi povećao verovatnoću dobrog odgovora na terapiju od velikog je kliničkog značaja. Poslednjih godina pokazano je da hormon oksitocin učestvuje u modulaciji ponašanja i raspoloženja kao i da ima ulogu u adaptaciji organizma na hronični stres. Cilj istraživanja obuhvaćenih ovom doktorskom disertacijom bio je da se ispita uticaj oksitocina na ponašanje i parametre aktivnosti HPA osovine u modelu hroničnog stresa/depresije indukovane dugotrajnom primenom kortikosterona kod pacova Wistar soja. Takođe, cilj je bio i da se u navedenom modelu ispita efekat dodatnog tretmana oksitocinom uz antidepresiv citalopram, lek iz grupe SSRI. Da bi se realizovali postavljeni ciljevi, istraživanja su podeljena u tri faze. U prvoj fazi, ispitivan je uticaj različite dužine tretmana kao i različitih doza oksitocina na ponašanje i nivo biogenih amina u plazmi pacova. U drugoj eksperimentalnoj fazi, ispitivan je uticaj tretmana oksitocinom u dozi 10 IU/400 μL, s.c., tokom 14 dana na ponašanje i parametre aktivnosti HPA osovine u modelu hroničnog stresa/depresije izazvane primenom kortikosterona u dozi 100 mg/L, per os, tokom 21. dana..., Mood disorders, with depression leading the way, are severe health problems and according to the World Health Organization, depression is becoming the leading cause of disability worldwide. It is known that depressive disorders are frequently accompanied with hyperactivity of the Hypothalamic-Pituitary-Adrenal (HPA) axis, as well as that the chronic stress is one of the most important risk-factors for its development. One of the most important problems of depressive disorders pharmacotherapy is that fairly large percentage of patients does not respond adequately to the therapy with selective serotonin reuptake inhibitors (SSRI), which are the first-line treatment drugs. Therefore, the identification of biomarkers of favorable response to antidepressant therapy, as well as discoveries of potential additional treatments, which would increase the probability of favorable response to the primary therapy is of the major clinical importance. In recent years, it has been shown that the hormone oxytocin modulates mood and behavior, and mediates adaptation feedback-response against chronic stress. The aim of the doctoral dissertation research was to evaluate the influence of oxytocin on the behavior and parameters of HPA axis activity, in the model of the long-term corticosterone administration-induced depression-like symptoms in adult male Wistar rats. Furthermore, the aim was to examine the potential beneficial effect of administering oxytocin alongside citalopram, an antidepressant from SSRI group, in this animal model. In order to fulfil these aims, the experimental work has been conducted in three phases. In the first phase, the effects of different treatment durations and dosages of oxytocin on behavior and plasma levels of biogenic amines were evaluated. In the second experimental phase, the effects of 14-day long oxytocin treatment (10 IU/400 μL, s.c.) on behavior and HPA axis activity in the model of chronic stress/depression induced by 21-day long corticosterone ad

Epidemiološke studije dovele su u vezu prenatalno izlaganje efektima imune aktivacije izazvane virusnim, bakterijskim ili parazitskim infekcijama sa povećanim rizikom od nastanka neurorazvojnih poremećaja poput shizofrenije. Ova saznanja dovela su do razvoja animalnih modela prenatalne imune aktivacije sa ciljem da se u njima modeluju simptomi i patofiziološki mehanizmi relevantni za određena neurorazvojna oboljenja. Utvrđeno je da primena lipopolisaharida (LPS), imunogene komponente ćelijskog zida gram-negativnih bakterija, gravidnim ženkama glodara izaziva febrilni odgovor i indukciju više citokina, čime utiče na balans pro- i antiinflamatornih medijatora koji je neophodan za pravilan razvoj mozga fetusa. U proučavanju etiologije shizofrenije akcenat je nedavno pomeren ka ispitivanjima poremećaja GABA-ergičkog sistema, a deficiti GABA-ergičke transmisije koji su zabeleženi kod pacijenata obolelih od shizofrenije nađeni su i u modelima prenatalne primene LPS-a gravidnim ženkama pacova. Od posebnog značaja za ispitivanja predstavljena u ovoj disertaciji stoje informacije da se vreme primene LPS-a u našem istraživanju poklapa sa periodom prvobitne ekspresije α5GABAA receptora u fetusnom mozgu pacova, kao i da prenatalna primena LPS-a u tim danima gestacije rezultira smanjenjenjem GABA-ergičke transmisije u hipokampusu potomaka u periodu preadolescencije. Otkrivanje ranih poremećaja u razvoju CNS-a leži u osnovi strategije prevencije razvoja shizofrenije i srodnih poremećaja, koja podrazumeva farmakološko delovanje na neurorazvojne promene u nastanku, pre ispoljavanja prvih simptoma. U ovoj studiji, LPS (serotip O111:B4, Escherichia coli) je primenjivan gravidnim ženkama Wistar pacova 15. i 16. dana gestacije u dozi od 100 μg/kg. Prenatalna inflamacija je detektovana kroz porast nivoa citokina TNF-α u krvi majke i placentalnom tkivu, i povećanje koncentracije IL-6 u krvi majke i amnionskoj tečnosti, dok fetusna neuroinflamacija posredovana ovim citokinima nije potvrđe, Epidemiological studies have linked the exposure to the effects of maternal immune activation induced by viral, bacterial or parasitic infections, with the emergence of schizophrenia and several other neurodevelopmental disorders. These findings led to the development of animal models of prenatal immune activation designed to model symptoms and pathological mechanisms relevant to certain neurodevelopmental disorders. It has been shown that administration of lipopolysaccharide (LPS), an immunogen component of the cell wall of gram-negative bacteria, to pregnant rodents causes febrile response and cytokine induction, thus affecting the balance between pro- and anti-inflammatory mediators which is necessary for regular development of the fetal brain. Within the studying of etiology of schizophrenia, a focus of investigation has recently been shifted to abnormalities observed in GABA-ergic system, and deficits of GABA-ergic transmission recorded in schizophrenia patients have also been found in rats tested in models of prenatal LPS administration. Some GABA-related findings are of special interest for investigation presented in this dissertation: the time of LPS administration in our protocol is the very time of primary expression of α5GABAA receptors in rat fetal brain, and prenatal LPS administration the selected days of gestation results in a decrease of GABA-ergic transmission in the hippocampus of preadolescent offspring. The discovery of early disturbances in the development of CNS underlies the strategy for prevention of schizophrenia and related disorders, which implies a pharmacological treatment of neurodevelopmental changes at their occurrence, before the manifestation of first symptoms. In this study, LPS (serotype O111:B4, Escherichia coli) was administered to pregnant Wistar rats at 15th and 16th day of gestation, at the dose of 100 μg/kg. Prenatal inflammation was detected via the elevation of TNF-α concentration in maternal blood and placenta, and IL-6 c

Preeclampsia is a pregnancy-specific disorder clinically characterized by hypertension and proteinuria that occurs after 20 weeks of gestation. Affecting 5% of pregnancies, it remains one of the leading causes of both maternal and fetal morbidity and mortality worldwide. Preeclampsia covers a spectrum of conditions, with eclampsia (its convulsive form) and HELLP syndrome representing its most severe forms. Despite recent advances in the field of angiogenesis and anti-angiogenesis in preeclampsia, urine and serum measurements of circulating angiogenic proteins have not provided a reliable screening tool for preeclampsia with current techniques. Emerging evidence suggests that podocyte plays a critical role in the evolution of kidney injury in this disorder. Studies of human tissue show that the expressions of podocyte-specific proteins (including nephrin and synaptopodin) are severely affected by preeclampsia. In addition, the detection of podocyte products and live podocytes in the urine (podocyturia) may serve as clinically useful tools for prediction and diagnosis of preeclampsia. Identification of podocytes using the techique of culturing and staining of urinary sediments is time consuming and requires special expertise. To overcome these limitations, a new technique using Mass spectrometry was developed that allows to confirm the presence of urinary podocytes trough identification of the podocyte-specific proteins. In addition, it was shown that women with preeclamptic pregnancies demonstrate signs of small vessel disease and less favorable cardiovascular risk profile both at the time of delivery and years after their affected pregnancies. One possible mechanism for this relationship is that hypertensive pregnancy disorders (preeclampsia, in particular) and CVD share several common risk factors (obesity, diabetes mellitus, and renal disease) or, alternatively, hypertension in pregnancy may induce long-term metabolic and vascular abnormalities that may increase a, Preeklampsija je oboljenje koje se javlja u trudnoći i klinički se karakteriše pojavom hipertenzije i proteinurije nakon dvadesete nedelje trudnoće. Javlja se u 7 – 10% svih trudnoća i čini vodeći uzrok mortaliteta i morbiditeta trudnica i fetusa. Klinička slika ovog oboljenja varira od lakih do najtežih formi, koje mogu da se manifestuju pojavom konvulzija tj. razvojem eklampsije, kao i razvojem hemolize, poremećaja funkcije jetre i koagulacije u okviru tzv. HELP sindroma. Uprkos nedavnom napretku u razumevanju uloge proteina angiogeneze u patofiziologiji preeklampsije, postojeći dokazi iz kliničkih studija još uvek su nedovoljni za korišćenje u ranom otkrivanju trudnoća koje su pod rizikom za razvoj preeklampsije. Prvi objavljen rad iz serije radova o dijagnostičkom i prognostičkom značaju podociturije kod žena sa preeklampsijom pokazao je da je pojava proteinurije u preeklampsiji povezana sa podociturijom, odnosno pojavom i gubitkom glomerularnih epitelnih ćelija (podocita) u mokraći, kao i sa promenama u ekspresiji strukturnih proteina (nefrina i sinaptopodina) ovih ćelija. Ovi klinički podaci uputili su na zaključak da se podociturija javlja pre proteinurije i hipertenzije, te da može da posluži kao rani pokazatelj i dijagnostički marker ovog oboljenja. S obzirom da je tehnika identifikacije podocita koja se bazira na kulturi sedimenta urina komplikovana i da zahteva posebnu obučenost za interpretaciju rezultata, u nastavku studije razvijena je nova tehnika identifikacije podocita koja se bazira na masnoj spektrometriji. Ovom tehnikom, potvrđeno je da se podociturija moze dijagnostikovati identifikacijom peptida koji je specifičan za podocin...

Intrauterusni zastoj rasta (IUZR) je jedan od vodećih uzroka perinatalnog morbiditeta i mortaliteta. Hipertenzija, insulinska rezistencija (IR), dijabetes mellitus tip 2 (T2DM), metabolički sindrom (MS), nizak rast i osteoporoza se dovode u vezu sa IUZR. Skorašnje kliničke i eksperimentalne studije su rasvetlile ulogu koju masno tkivo igra u razvoju insulinske rezistencije i MS kao posledica fetalnog programiranja in utero Cilj ove studije je bio da ispita da li je koncentracija adipokina u krvi pupčanika (P) i u trećem danu (d3) povezana sa usporenim fetalnim rastom i nivoom lipida kod blizanaca sa IUZR. Testirana je povezanost nivoa leptina i adiponektina sa somatskim parametrima i IR na roĎenju i u d3 kod diskordantnih i konkordantnih blizanaca. U studiju je uključeno 36 diskordantnuh (razlika u poroĎajnoj telesnoj masi-TM≥20% računato u odnosu na većeg blizanca) i 42 konkordantna para blizanaca (razlika u TM≤10%), roĎenih≥32 gestacionih nedelja (GN). TM manjeg blizanca je bila ispod 10. percentila (IUZR blizanac) udruženo sa abnormalnim protocima u umbilikalnoj arteriji. Iz venske krvi iz pupčanika kao i iz venske krvi uzete u trećem danu pre jela (d3) su odreĎivani nivoi hormona (leptin, adiponektin, insulin) i bihemijski parametri (glukoza, ukupni holesterol-TC, high density lipoprotein holesterol –HDL C, low density lipoprotein holesterol-LDL C i trigliceridi-TG). Indeksi body mass index-BMI, ponderalni indeks-PI, homeostasis model assesment insulin resistance index-HOMA IR, TG/HDL C i glukoza/insulin (G/I) su izračunati a poslednja tri predstavljaju markere insulinske rezistencije/senzitivnosti. Rezultati: U diskordantnoj grupi nivoi leptina i leptina/TM u krvi iz pupčanika i d3 bili su uporedivi izmeĎu IUZR i blizanaca sa odgovarajućim rastom (appropriate for gestational age-AGA). Kada smo poredili blizance roĎene posle 35 GN koncentracije leptina su bile značajno niže kod IUZR blizanaca u d3 (p=0,011). Nivoi leptina i L/TM u d3 su bili značajno viši kod di, Intrauterine growth restriction (IUGR) is one of the leading causes of perinatal morbidity and mortality. Hypertension, insulin resistance (IR), type 2 diabetes mellitus (T2DM), metabolic syndrome (MS), short stature and osteoporosis were found to be associated with IUGR. The recent clinical and experimental studies have highlighted the role of adipose tissue (AT) in the development of insulin resistance and MS as consequences of fetal programming in utero. The aim of this study was to explore whether adipokines concentrations in cord blood (CB) and on day3 (d3) were related to impaired fetal growth and lipids in IUGR twins. The relationship between leptin and adiponectin levels with somatic parameters and IR at birth and on d3 in discordant and concordant twins were tested. Patients and methods: 36 discordant (birth weight BW discordance ≥20% calculated in relation to the heavier cotwins) and 42 concordant (birth weight discordance ≤10%) twin pairs≥32 gestational weeks (GW) were included. BW of the smaller twins was less than 10th percentile (IUGR twins) with abnormal umbilical artery Doppler velocimetry. Umbilical venous CB and venous blood samples on d3 were obtained from each pair of twins in the fasting state both for hormone determination (leptin, adiponectin and insulin) and biochemical analysis (glucose, total cholesterol-TC, high density lipoprotein cholesterol –HDL C, low density lipoprotein cholesterol-LDL C and triglyceride-TG). Indices body mass index-BMI and ponderal index- PI,. homeostasis model assessment insulin resistance index HOMA IR, TG/HDL C and glucose/insulin (G/I) ratio were calculated as a markers of insulin resistance/sensitivity. Results: Within the discordant group leptin and leptin/PTM levels in cord blood and on d3 were comparable between AGA (appropriate for gestational age) twins and IUGR twins. When we compared late preterm and term twins (≥35 GW) on d3 leptin concentration was significantly lower in IUGR twins (p=0,011). Leptin lev

This study shows modelling developed during the first year of the SmartNet project. In particular, it presents a mathematical model for aggregation of curtailable generation and sheddable loads. The model determines the quantity and the cost of the flexibility provided by the flexible resources based on their physical and dynamic behaviours. The model also proposes a bidding strategy in order to translate the aggregated behaviour into market bids.

Aging is inevitable, and as the percentage of elderly in the population increases it becomes more important to understand physiological mechanisms associated with the normal aging process so the quality of life can be sustained. Maintaining physiological functions or 'health' in aging population will help to reduce the burden on the medical systems. In this work, we briefly consider, in the light of up-to-date scientific data and hypotheses, some key questions on the biology and physiology of aging: what is it and why does it happen. Prospects for delaying and impeding the aging process are disputed as well., Starenje je neizbežno i kako zastupljenost starih osoba u populaciji raste, razumevanje fizioloških mehanizama uključenih u proces normalnog starenja ima sve veći značaj u cilju održavanja kvaliteta života u starosti. Takođe, očuvanje fizioloških funkcija ili 'zdravlja' starih ljudi smanjiće pritisak na zdravstvene sisteme i troškove. U ovom radu, u svetlu najnovijih naučnih podataka i hipoteza, sažeto se razmatraju neka ključna pitanja u vezi biologije i fiziologije starenja: šta je starenje i zašto se ono događa, kao i mogućnosti odlaganja i usporavanja starenja.

In order to provide a morphometrical description of the changes in the aged rat thymus and to relate them to apoptotic and proliferative activity of thymocytes, the thymuses from 3- and 18-month-old male Wistar rats and the percentages of bromodeoxyuridine-incorporating and apoptotic cells in cultures of thymocytes were assessed by stereological analysis and flow cytometry, respectively. In old rats the volume of lymphoepithelial thymic tissue is markedly reduced, reflecting a sharp decrease in the total number of thymocytes. A reduction in the proliferative capacity of thymocytes and increase in their susceptibility to apoptosis are, most likely, primarily responsible for a 7-fold reduction in thymic cellularity in old animals. Furthermore, only the volume of cortical compartment was affected by aging, while that of medulla, despite of reduced cellularity, was not significantly altered. The loss of functional tissue in aged thymus is compensated by a substantial increase in the volume of inter-lobular connective and adipose tissue, so the thymic weight remained unaltered in old rats. These results suggest that thymus of aged Wistar rats exhibits morphological characteristics similar to those found in aged human thymus and thus may serve as an animal model for further investigations of thymus-related changes in immunological aging.

In order to examine the influence of chronic alpha(1)-adrenergic receptor (alpha(1)-AR) blockade on the thymus structure and T-cell maturation, peripubertal and adult male rats were treated with urapidil (0.20 mg/kg BW/d; s.c.) over 15 consecutive days. Thymic structure and phenotypic characteristics of the thymocytes were assessed by stereological and flow cytometry analysis, respectively. In immature rats, treatment with urapidil reduced the body weight gain and, affecting the volume of cortical compartment and its cellularity decreased the organ size and the total number of thymocytes compared to acre-matched saline-injected controls. The percentage of CD4+8- single positive (SP) thymocytes was decreased, while that of CD4-8+ was increased suggesting, most likely, a disregulation in final steps of the positively selected cells maturation. However alpha(1)-AR blockade in adult rats increased the thymus weight as a consequence of increase in the cortical size and cellularity. The increased percentage of most immature CD4-8- double negative (DN) cells associated with decreased percentage of immature CD4+8+ double positive (DP) thymocytes suggests a decelerated transition from DN to DP stage of T-cell development. As in immature rats, the treatment in adult rats evoked changes in the relative numbers of SP cells, but contrary to immature animals, favoring the maturation of CD4+8- over CD4-8+ thymocytes. These results demonstrate that: i) chronic blockade of alpha(1)-ARs affects both the thymus structure and thymocyte differentiation, ii) these effects are age-dependent, pointing out to pharmacological manipulation of alpha(1)-AR-mediated signaling as potential means for modulation of the intrathymic T-cell maturation.

Ethane dimethanesulphonate (EDS), an alkylating agent, caused marked atrophy of the adrenal cortex of adult male rats, in addition to its toxic effect on testicular Leydig cells. The aim of this work was to examine whether a 9-day treatment with ACTH (40 IU/kg/d), isoproterenol (120 mg/kg/d) or dexamethasone (0.25 mg/kg/d), which started 4 days prior to intraperitoneal administration of a single dose of EDS (75 mg/kg), affected the morphological changes in the adrenal cortex evoked by EDS alone. The animals were killed 15 days after EDS injection. Stereological analysis revealed that both ACTH and isoproterenol almost completely prevented cortical atrophy induced by EDS. They also considerably stimulated corticosterone secretion in EDS-injected animals. By contrast, in dexamethasone-suppressed rats, the deleterious effect of EDS on adrenocortical cells was augmented. The volume and cellularity of all cortical zones were reduced, but the remaining cells of the zona reticularis displayed considerable hypertrophy which was probably responsible for the maintenance of corticosterone secretion. These results clearly demonstrate that both ACTH and b adrenoceptor stimulation have protective action against the toxic effects of EDS on rat adrenal cortex, whereas dexamethasone exerts an opposite influence., Alkilirajući agens etandimetansulfonat (EDS), pored toksičnog delovanja na Lajdigove ćelije semenika, izaziva izraženu atrofiju kore nadbubrežne žlezde odraslih pacova. U ovom radu je ispitivan uticaj devetodnevnog tretmana sa ACTH (40 IU/kg/d), izoproterenolom (120 mg/kg/d) ili deksametazonom (0.25 mg/kg/d) na morfološke promene kore nadbubrega koje izaziva jedna intraperitonealna injekcija EDS (75 mg/kg). Tretmani su započeli 4 dana pre davanja EDS i nastavljeni su još 5 dana, a životinje su žrtvovane 15 dana posle aplikacije EDS. U prisustvu ACTH ili izoproterenola ne ispoljavaju se promene u stereološkim parametrima kore nadbubrega koje izaziva EDS. Oba tretmana značajno povećavaju i koncentraciju kortikosterona u serumu. Deksametazon, međutim, pojačava toksične efekte EDS; zapremina svih zona kore i broj parenhimskih ćelija u zonama su smanjeni, ali preostale ćelije retikularne zone pokazuju značajnu hipertrofiju, koja je verovatno odgovorna za održavanje sekrecije kortikosterona kod ovih životinja. Rezultati rada pokazuju da se toksični efekti EDS na koru nadbubrega mogu sprečiti visokim nivoom ACTH ili stimulacijom b adrenalinskih receptora, a potencirati egzogenim glukokortikoidom.

UVOD: Trudnice sa urođenom trombofilijom imaju veći rizik za razvoj venskih tromboembolijskih komplikacija, spontanih i habitualnih pobačaja, peeklampsije, intrauterusnog zastoja u rastu ploda i abrupcije posteljice. Etiopatogeneza obstetričkih komplikacija kod trombofilije nije jasno definisana, što je i jedan od razloga povremenih neuspeha terapije. Ključni faktor za normalan razvoj trudnoće je kontakt između fetalne i maternalne cirkulacije, kao i ravnoteža između koagulacije i fibrinolize u posteljici na nivou hemohorionske membrane. Najčešće se govori o trombozi fetoplacentne cirkulacije kao uzroku obstetričkih komplikacija kod trudnica sa urođnom trombofilijom. S obzirom na značajan broj neuspelih trudnoća i uz primenjenu antikoagulantnu terapiju, evidentno je da postoje i drugi uzroci opstetričkih komplikacija u trudnoćama sa naslednom trombofilijom. Obstetričke komplikacije tokom drugog i trećeg trimestra kod trudnica sa trombofilijom su slične komplikacijama preeklampsije. Kod trudnica sa preeklampsijom je dokazan porast koncentracije reaktivnih kiseoničkih vrsta kao i smanjena aktivnost enzima zaštite od oksidacionih oštećenja, što za posledicu ima endotelijalnu disfunkciju, neadekvatnu invaziju trofoblasta i hipoperfuziju posteljice što pojačava oksidativni stres. Hipoteza studije bi bila, da je u trudnoćama sa naslednom trombofilijom oksidativni stres uzrok komplikacija. CILJ RADA: Uticaj primene LMWH kod pacijentkinja sa opterećenom akušerskom anamnezom i dokazanom urođenom trombofilijom na broj živorođene dece i pojavu komplikacija u trudnoći (spontani pobačaj, intrauterusna smrt ploda, abrupcija posteljice, PE, IUGR, VTE). Ispitati i uporedi aktivnost antioksidativnog enzimskog zaštitnog sistema u krvi trudnica obolelih od trombofilije i zdravih trudnica nakon porodjaja. METODOLOGIJA: Longitudinalnom studijom je obuhvaćeno 60 trudnica koje su bile hospitalizovane i kontrolisane u GAK “Narodni Front” u Beogradu u toku 2013 godine, a kod kojih je dijagn, BACKGROUND: Pregnant women with inherited trombophylia have a higher risk for developing venous embolic complications, spontaneous and habitual miscarriages, preeclamspia, IUGR, and placental abruption. Genesis of obstetric complications is not clearly defined, and as such may present one of the reasons for therapy failure. The key for the development of a normal pregnancy is the contact between the fetal and maternal circulation, as is the balance between coagulation and fibrinolysis in the placenta at the chorionic membrane level, Usualy we target fetoplacental thrombosis, as the main cause for obstetrical complication in pregnant women with congenital thrombophilia. Considering the number of unsuccesfull pregnancies, even when using anticoagulant therapy, it becomes evident that other causes exist for obstetric complications in pregnancies with inherited trombophylia. Obstetric complications during the second and third trimester, in pregnancies with inherited thrombophilia are similair to eclamptic complications, An elevated level of reactive oxygen is found in pregnant patients with preeclampsia, and an impaired enzyme protection from oxidative damage, which effect in endothelial dysfunction, less than adequate trophoblast invasion and a hypoperfussion of the placenta, which all increase oxidative stress. THE GOALS: To examine the influence of LMWH application in patients with inherited trombophylia on the number of live born children and number of manifest complkications in pregnancy (spontaneous abortion, intrauterine fetal death, placental abruption, PE, IUGR, VTE). To investigate the activity of enzyme antioxidative protection system in patients with trombophylia and to compare with healthy patients after live birth. METHODS: Through this longitudinal study 60 gravide patients were followed. These patients were hospitalized and/or controlled in GAK “Narodni Front” in Beograd during 2013., with a diagnosis of inherited trombophylia prior to pregnancy. For all

Uvod: Cilj ovog istraživanja je mogućnost predikcije razvoja preeklampsije (PE), intrauterusnog zastoja u rastu ploda (IUZR), abrupcije placente (AP) i intrauterusne smrti ploda (FMU) pojedinačnom i kombinovanom upotrebom niskih vrednosti plazma-proteina-A povezanog sa trudnoćom (PAPP-A) i slobodne beta-subjedinice humanog-horionskog-gonadotropina (free-βHCG), kao i visokih srednjih vrednosti doplerskog pulsatilnog-indeksa (PI) uterinih arterija u prvom trimestru trudnoće. Metodologija: Serumski PAPP-A, free-βHCG i srednji doplerski-PI su određivani tokom 11-13+6 nedelja gestacije kod normotenzivnih nulipara sa jednoplodnom trudnoćom. Pacijentkinje su ispunjavale minimum jedan od tri navedena kriterijuma: ekstremno niske vrednosti PAPP-A (PAPP-A≤0.52MoM), free-βHCG (free-βHCG≤0.56MoM) i ekstremno visok srednji doplerski-PI (PI≥2.52). Rezultati: Od 85 trudnica, njih 14 (16.5%) je razvilo PE , 14 (16.5%) IUZR, 7 (8.2%) AP i 1 (1.2%) FMU. ROC-analiza je identifikovala PAPP-A i PI, kao kontinualne varijable, sa značajnom prediktivnom moći za razvoj PE (p=0.001; p=0.002), IUZR (p=0.045; p=0.004) i AP (p=0.009; p=0.011). Ista analiza je utvrdila da free-βHCG nema prediktivnu moć za razvoj PE (p=0.709), IUZR (p=0.142) i AP (p=0.141). Kombinovani prediktivni model kategorijalnih varijabli (PAPP-A≤0.52MoM+PI≥2.52) je pokazao značajnu prediktivnu moć za razvoj PE (OR=5.83, 95%CI=1.217-27.297, p=0.027), ali ne i zarazvoj IUZR (OR=2.171, 95%CI=0.622-7.576, p=0.224) i AP (OR=5.143, 95%CI=0.591-44.742, p=0.138). Zaključak: Ova istraživanje je pokazalo da niske vrednosti PAPP-A i povišene sdrednje vrednosti doplerskog-PI prvog trimestra trudnoće, kao pojedinačne varijable, imaju značajan prediktivni kapacitet za razvoj PE, IUZR i AP. Ekstremno niske vrednosti PAPP-A i ekstremno visoke srednje vrednosti 6 doplerskog-PI u kombinovanom prediktivnom modelu prvog trimestral trudnoće, pokazuju značajnu prediktivnu moć za razvoj PE...

Contemporary lifestyle is commonly associated with chronic stress, an environmental factor contributing to development of various psychological and somatic disorders. Increased levels of glucocorticoids, observed in the chronic stress, induce the production of reactive oxygen species leading to genotoxicity. The aim of this study was to investigate whether chronic administration of oxytocin (OXY) 10 IU/400 mu L/day, s.c., for 14 days, a hormone presumed to exert antioxidant effect, may prevent DNA damage in the comet assay of peripheral blood lymphocytes of Wistar rats treated chronically with corticosterone (CORT) 100 mg/L ad libitum, per os, for 21 days, as well as, to influence some plasma oxidative stress parameters, i.e. levels of total lipid hydroperoxide (LOOH), and malondialdehyde (MDA), and the activity of antioxidative enzyme superoxide dismutase (SOD). Even though there was no reduction in overall number of damaged cells after oxytocin treatment only, the marked increase in total comet score (TCS) after incubation with H2O2 in CORT group compared to controls, was absent in the CORT + OXY experimental group. Furthermore, significant decrease of highly damaged cells compared to corticosterone group was noted. Chronic oxytocin administration thus protected lymphocytes from high intensity damage that leads to cellular death. In addition, treatment with OXY along with CORT, significantly decreased concentration of LOOH in plasma, and increased SOD compared to CORT treatment only. This finding corresponds well with current reports on beneficial effects of OXY in conditions of HPA axis hyperactivity, and supports the hypothesis of OXY-mediated antioxidant action.

Background: Physical exercise activates the hypothalamopituitary-adrenal (HPA) axis and induces the body's inflammatory response. Due to contemporary dietary habits and increased energy expenditure, athletes are susceptible to depletion of magnesium ions. The aim of our study was to investigate, through assessment of plasma ACTH, serum IL-6, and salivary/serum cortisol levels, if chronic magnesium supplementation might reduce damaging stress effects in amateur rugby players. Methods: Rugby players (N=23) were randomly assigned to intervention and control group. Basal samples were collected before intervention group started a 4-week-long supplementation with magnesium (500 mg Mg/d). Blood and saliva sampling were done a day before the match (Day-1), on the morning of competition (Game), and during a six-day-long recovery period (Day1, Day3 and Day6). ACTH, serum/salivary cortisol, IL-6 and total/differential leukocytes counts were determined at each time point. Results: There was a statistically significant increase in ACTH concentration in intervention group compared to control group, while reductions in cortisol concentrations between the two groups were the greatest at Day-1 (p lt 0.01) and at the day of competition (Game) (p lt 0.01). Our results revealed that magnesium completely abolished the increase in IL-6 level noted in control group on Day1 and Day3 vs. Day-1 (p lt 0.01) and also diminished the rise in neutrophil/lymphocyte ratio in intervention group vs. control group (p lt 0.01). Conclusions: These results suggest the possibly important influence magnesium supplementation might have on the change of parameters of HPA axis activity and reduction of immune response activation following strenuous physical exercise such as a rugby game.

Sedentary lifestyle is highly associated with increased risk of cardiovascular disease, obesity, and type 2 diabetes. It is known that regular physical activity has positive effects on health; however several studies have shown that acute and strenuous exercise can induce oxidative stress and lead to DNA damage. As magnesium is essential in maintaining DNA integrity, the aim of this study was to determine whether four-week-long magnesium supplementation in students with sedentary lifestyle and rugby players could prevent or diminish impairment of DNA. By using the comet assay, our study demonstrated that the number of peripheral blood lymphocytes (PBL) with basal endogenous DNA damage is significantly higher in rugby players compared to students with sedentary lifestyle. On the other hand, magnesium supplementation significantly decreased the number of cells with high DNA damage, in the presence of exogenous H2O2, in PBL from both students and rugby players, and markedly reduced the number of cells with medium DNA damage in rugby players compared to corresponding control nonsupplemented group. Accordingly, the results of our study suggest that four-week-long magnesium supplementation has marked effects in protecting the DNA from oxidative damage in both rugby players and in young men with sedentary lifestyle.

The usage of alcohol is widespread, but the effects of acute alcohol ingestion on exercise performance and the stress hormone axis are not fully elucidated.We studied 10 healthy white men, nonhabitual drinkers, by Doppler echocardiography at rest, spirometry, and maximal cardiopulmonary exercise test (CPET) in two visits (2-4 days in between), one after administration of 1.5g/kg ethanol (whisky) diluted at 15% in water, and the other after administration of an equivalent volume of water. Plasma levels of NT-pro-BNP, cortisol, and adrenocorticotropic hormone (ACTH) were also measured 10min before the test, at maximal effort and at the third minute of recovery. Ethanol concentration was measured from resting blood samples by gas chromatography and it increased from 0.00 +/- 0.00 to 1.25 +/- 0.54 parts per thousand (P lt 0.001). Basal echocardiographic and spirometric parameters were normal and remained so after acute alcohol intake, whereas ACTH, cortisol, and NT-pro-BNP nonsignificantly increased in all phases of the test. CPET data suggested a trend toward a slight reduction of exercise performance (peak VO2=3008 +/- 638 vs. 2900 +/- 543ml/min, ns; peak workload=269 +/- 53 vs. 249 +/- 40W, ns; test duration 13.7 +/- 2.2 vs. 13.3 +/- 1.7min, ns; VE/VCO2 22.1 +/- 1.4 vs. 23.3 +/- 2.9, ns). Ventilatory equivalent for carbon dioxide at rest was higher after alcohol intake (28 +/- 2.5 vs. 30.4 +/- 3.2, P=0.039) and maximal respiratory exchange ratio was lower after alcohol intake (1.17 +/- 0.02 vs. 1.14 +/- 0.04, P=0.04). In conclusion, we showed that acute alcohol intake in healthy white men is associated with a nonsignificant exercise performance reduction and stress hormone stimulation, with an unchanged exercise metabolism.

Background: Periodontitis is considered to be a risk factor for preterm birth. Mechanisms have been proposed for this pathologic relation, but the exact pathologic pattern remains unclear. Therefore, the objective of the present study is to evaluate levels of four major labor triggers, prostaglandin E-2 (PGE(2)), interleukin (IL)-1 beta, IL-6, and tumor necrosis factor (TNF)-alpha, in gingival crevicular fluid (GCF) and serum samples between women with preterm birth (PTB) and full-term birth (FTB) and correlate them with periodontal parameters. Methods: PGE(2), IL-1 beta, IL-6, and TNF-alpha levels were estimated using enzyme-linked immunosorbent assays in GCF and serum samples collected 24 to 48 hours after labor from 120 women (60 FTB, 60 PTB). Results: Women with PTB exhibited significantly more periodontitis, worse periodontal parameters, and increased GCF levels of IL-6 and PGE(2) compared with the FTB group; there were no significant differences in serum levels of measured markers. GCF levels of IL-1 beta, IL-6, and PGE(2) and serum levels of TNF-alpha and PGE(2) were significantly higher in women with periodontitis compared with periodontally healthy women. Serum levels of PGE(2) were positively correlated with probing depth (PD) and clinical attachment level (CAL) as well as with GCF levels of TNF-alpha in women with PTB. Conclusions: Women with PTB demonstrated worse periodontal parameters and significantly increased GCF levels of IL-6 and PGE(2) compared with those with FTB. Based on significant correlations among serum PGE(2) and PD, CAL, and GCF TNF-alpha in PTB, periodontitis may cause an overall increase of labor triggers and hence contribute to preterm labor onset.