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Analiza polimorfizama gena za CD86, CTLA-4, TNF i IL-10 kod bolesnika sa pemfigusom u Srbiji | Analysis of polymorphism in CD86, CTLA4, TNF and IL10 genes in Serbian patients with pemphigus | Uvod: Oboljenja iz grupe pemfigusa - pemfigus vulgaris (PV) i pemfigus foliaceus (PF) su autiomunska bulozna oboljenja kože i sluznica. U patogenezi su od značaja autoantitela na dezmogleine i druge molekule koja dovode do akantolize i formiranja intraepidermalnog rascepa. Za aktivaciju autoreaktivnih T-ćelija u pemfigusu neophodno je prepoznavanja dezmogleinskih peptida i angažovanje CD28 molekula, koji je najznačajniji kostimulatorni receptor u aktivaciji naivnih T ćelija. CD28 molekul se vezuje za B7 familiju molekula kao što su CD80 i CD86. Pored toga, B7 molekuli mogu da aktiviraju inhibitorni receptor na T-ćelijama, CTLA-4, koji kontroliše mehanizam održavanja tolerancije na sopstvene peptide. Na značaj genetskih faktora u patogenezi pemfigusa ukazuju prethodna istraživanja kojima su definisani određeni genetski faktori kao što su i polimorfizmi pojedinačnih nukleotida u genima molekula od značaja za patogenezu pemfigusa. Ciljevi istraživanja: Odrediti distribuciju alela u genima za molekule CD86, CTLA-4, TNF i IL-10 kod pacijenata sa PV i PF, kao i kod zdravih osoba (dobrovoljni davaoci krvi) u Srbiji, ispitati da li je neki od ispitivanih polimorfizama faktor rizika za nastanak oboljenja (PV i PF) i uporediti ih sa podacima iz literature koji su dobijeni ispitivanjem istih polimorfizama kod geografski i etnički različitih populacija. Pacijenti i metode: Istraživanje je obuhvatilo 61 bolesnika sa pemfigusom od kojih je PV imalo 48, a PF 13 bolesnika i 486 zdravih osoba-kontrola (dobrovoljni davaoci krvi). Dijagnoza pacijenata sa pemfigusom postavljena je na osnovu kliničke slike i testa direktne imunofluorescencije (DIF test). Za detekciju i analizu polimorfizama gena za CD86, CTLA-4, TNF i IL-10 korišćene su komercijalne optimizovane smeše specifičnih oligonukleotida i TaqMan proba obeleženih FAM i VIC fluorohromima i to: CD86 rs1129055, CTLA4 rs733618 i rs5742909, TNF rs1800629 i rs361525 i IL-10 rs1800896 i rs1800871 (PE, Applied Biosystems). Amplifikacija fragmenata DNK Real-time PCR metodom vršena je pomoću navedenih smeša komercijalnih oligonukleotida i Maxima™ Probe qPCR 2X Master Mix, (Fermentas) uzimajući u obzir preporuke proizvođača reagenasa... | Introduction: Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are rare autoimmune blistering diseases with presumed T cell dependent pathology. Activation of naïve T cells is dependent on antigen recognition, subsequent signaling through the T cell receptor complex (signal 1), and various other interactions of T cells with antigen presenting cells that may be collectively designated as signal 2, which is unconditionally required for T cell activation both in response to infection and to autoantigens. Among the best described interactions contributing to signal 2 are those mediated by B7 family molecules such as CD80 and CD86 with their ligands, CD28, providing activation signals, and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), conferring inhibition. Single nucleotide polymorphisms (SNPs) within genes encoding those molecules may alter the signaling process. It is not known whether functional genetic polymorphisms within genes encoding the aforementioned proteins may increase risk for developing PV and PF and, if so, whether they might serve as biomarkers for susceptibility to these diseases. Aims of the investigation: To examine functional single nucleotide polymorphisms within CD86 (rs1129055), CTLA4 (rs733618 and rs5742909), TNF (rs1800629 andrs361525), and IL-10 (rs1800896 and rs1800871) genes in 61 pemphigus patients and 486 healthy controls, and to compare results in Serbian pemphigus patients and healthy controls with results obtained in different populations groups. Patients and methods: Our study included 61 pemphigus patients, among them 48 with PV and 13 with PF, treated at the Dermatovenereology Clinics of the Clinical Centre of Serbia. Patients were stratified according to clinical presentation of the disease as a PV or PF patients. Diagnosis in all patients was established by merging clinical findings, histopathologic analysis, and the results of direct immunofluorescence tests. Blood samples from 486 healthy blood donors were obtained from the National Blood Transfusion Institute... | false |
Dinamičko ponašanje pametnih tankozidnih kompozitnih struktura | Dynamic behavior of smart thin-walled composite structures | Ova
doktorska
disertacija
bavi
se
optimizacijom
i
aktivnim
prigušenjem vibracija pametnih tankozidnih kompozitnih struktura pomoću
piezoelektričnih aktuatora i senzora. Razvijen je matematički model pločaste
kompozitne strukture sa integrisanim aktuatorima i senzorima. Problem je
definisan metodom konačnih elemenata bazirane na teoriji smicanja trećeg
reda. Konstitutivne jednačine i veza između pomeranja i deformacija su
linearne. U daljem radu, predstavljen je problem određivanja optimalnih
veličina, položaja i orijentacija aktuator – senzor parova, a zatim su
definisane funkcija cilja i ograničenja. Takođe, izvršena je sinteza metode
konačnih elemenata i optimizacije rojem čestica i primenom definisanih
kriterijuma optimizacije, izvršena je optimizacija veličine, položaja i
orijentacije
pet
aktuator-senzor
parova
na
kvadratnim
uklještenim
kompozitnim pločama sa sledećim konfiguracijama slojeva: (90°/0°/90°/0°)S,
(90°/0°/90°/0°/90°/0°/90°/0°) i (45°/-45°/45°/-45°/45°/-45°/45°/-45°). Aktuatori i
senzori, koji se razmatraju u ovoj disertaciji, jednakih su dimenzija, isto su
orijentisani i nalaze se na suprotnim stranama ploče: aktuator na gornjoj
strani, a senzor na donjoj strani ploče. Radi prevazilaženja problema prilikom
sinteze konvencionalnih upravljačkih algoritama koji se javljaju usled
stohastične prirode vibracija, predstavljen je optimizovani samopodešavajući
fazi-logički upravljački sistem. Glavna ideja ovog upravljačkog sistema je
praćenje amplitude i samopodešavanje ulaznih skalirajućih faktora na osnovu
amplitude. Funkcije pripadnosti su parametrizovane, a optimalna kombinacija
parametara nađena je pomoću optimizacije rojem čestica na osnovu definisanih
kriterijuma optimizacije. Razmatrana su dva principa zaključivanja: Mamdani
princip zaključivanja i Takagi-Sugeno-Kang princip zaključivanja nultog reda.
Numerički primeri su dati za kompozitnu konzolu i kompozitnu uklještenu
ploču za slobodne i prinudne vibracije. Za konzolu razmatrana je jedno-ulazno-
jedno-izlazna („Single input – single output“, „SISO“) konfiguracija, a za ploču
više-ulazno-više-izlazna („Multiple inputs – multiple outputs“, „MIMO“)
konfiguracija. Izvršeno je poređenje performansi prilikom upotrebe
različitih principa fazi zaključivanja, kao i poređenje optimizovanog
samopodešavajućeg fazi-logičkog upravljačkog sistema sa linearno-kvadratnim
regulatorom. | This doctoral dissertation deals with optimization and active vibration
suppression of smart thin-walled composite structures by using piezoelectric actuators
and sensors. Mathematical model of plate composite structure with integrated actuators
and sensors is developed. The problem is formulated using the finite element method
based on the third order shear deformation theory. Constitutive equations and the strain
- displacement relations are linear. In further work, the problem of determination of
optimal sizes, positions and orientations of actuator – sensor pairs are presented and,
after that, objective functions and constraints are defined. Also, the integration of finite
element method and particle swarm optimization is performed and using defined
optimization criteria, the optimization of sizes, positions and orientations of five
actuator – sensor pairs on square cantilever composite is performed. The cantilever
composite
plates
have
following
orientation
of
layers:
(90°/0°/90°/0°)S,
(90°/0°/90°/0°/90°/0°/90°/0°) и (45°/-45°/45°/-45°/45°/-45°/45°/-45°). Actuators and
sensors considered in dissertation are collocated. In order to overcome problems during
conventional control algorithm synthesis which occur due to vibration’s stochastic
nature, the optimized self-tuning fuzzy logic controller is presented. The main idea of
proposed controller is amplitude monitoring and self-tuning of input scaling factors
based on amplitude. Membership functions are parameterized and optimal combination
of parameters are found by using the particle swarm optimization method based on
previously defined optimization criteria. Two inference methods are considered: the
Mamdani and zero-order Takagi-Sugeno-Kang inference methods. Numerical studies
are provided for composite cantilever beam and composite cantilever plate for both free
and forced vibrations. Single-input single-output (SISO) configuration is considered for
the cantilever beam and multiple-input multiple-output (MIMO) configuration is
considered for cantilever plate. Comparisons of control performances for these two
types of inference methods as well as optimized self-tuning fuzzy logic controller with
linear quadratic regulator are performed. | true |
Oksidativni stres i ravnoteža bioelemenata kod pacijentkinja u postupku vantelesnog oplođenja | Oxidative stress and trace elements balance in patients during in vitro fertilization cycles | Uvod: Oksidativni stres dešava se usled neuravnoteženog odnosa pro-oksidanata i antioksidanata u prilog poslednjih. Odnos može biti poremećen zbog povećane koncentracije reaktivnih kiseoničnih vrsta (ROS) i/ili umanjene antioksidativne odbrane. Normalne fiziološke funkcije, uključujući proces signalizacije ćelija, proliferacije i diferencijacije, zavise od prisustva određenih koncentracija ROS. U reproduktivnom traktu, fiziološki nivoi ROS neophodni su ne samo za ovulaciju, već i za interakciju oocita-spermatozoid, fertilizaciju, implantaciju i rani razvoj embriona. Ipak, povećana produkcija ROS može da ošteti prirodnu antioksidativnu odbranu organizma, remeteći mikrosredinu u reproduktivnom traktu i normalne fiziološke reakcije. Razumevanje uloge ROS u ženskom infertilitetu i dalje je nepotpuno. Činjenica da su oksidativni i antioksidativni sistem prisutni u različitim ženskim reproduktivnim tkivima sugeriše da infertilitet i određenja reproduktivna oboljenja mogu biti uzrokovana, makar delimično, oksidativnim stresom. Već godinama se sve više smatra da oksidativni stres (OS) ima negativan uticaj na reproduktivne sposbnosti i muškaraca i žena. Doprinos OS patogenezi infertiliteta sve se obimnije ispituje u oblasti muškog infertiliteta, posebno u pogledu uticaja na različite aspekte kvaliteta spermatozoida. Cilj: Ciljevi ove studije bili su da se kod pacijenata uključenih u postupak VTO ispita uticaj različitih protokola kontrolisane ovarijalne stimulacije (KOS), doze gonadotropina, promene koncetracija parametara OS pre stimulacije i posle stimulacije na ishod IVF postupka. Takođe smo ispitivali povezanost promene koncentracije parametara oksidativnog stresa, poremećaja ravnoteže bioelemenata i uticaj toksičnih metala kod žena na ishod IVF postupka kod žena, dok smo kod muških partnera ispitivali povezanosti promene koncentracija parametara oksidativnog stresa, poremećaja ravnoteže bioelemenata i uticaj toksičnih metala sa parametrima spermograma i ispitivali uticaj parametara spermograma na ishod postupka... | Background: Oxidative stress occurs due to the unbalanced relationship pro-oxidants and antioxidants in favor of the latter. The relationship can be disrupted due to the increased concentration of reactive oxygen species (ROS) and / or reduced antioxidant defense. Normal physiological functions, including the process of cell signaling, proliferation and differentiation, depend on the presence of certain concentrations of ROS. In the reproductive tract, physiological levels of ROS are essential not only for ovulation, but also for oocyte-sperm interaction, fertilization, implantation and early embryo development. However, the increased production of ROS can damage the body's natural antioxidant defenses, disrupting microenvironment in the reproductive tract and normal physiological reactions. Understanding the role of ROS in the female and male infertility is still incomplete. The fact that the oxidative stress and antioxidant system are present in a different female reproductive tissues suggests that infertility and other reproductive disorders can be caused, at least in part, by oxidative stress. It is considered that oxidative stress (OS) has a negative impact on the reproductive abilities of both men and women. Contribution of OS in pathogenesis of infertility is extensively investigated in the field of male infertility, particularly in terms of impact on different aspects of sperm quality. Objective: The aims of this study were to investigate the effect of different protocols of controlled ovarian stimulation (COS), doses of gonadotropins, changes in OS parameters OS prior to stimulation and after stimulation on IVF outcome. We also examined the association between the changes of OS parameters and trace elements in women on IVF outcome in women, while on male partners we examined the association between oxidative stress parameters and trace elements and semen parameters as well as the influence of semen parameters on IVF outcome. Design and Methods: The study included 107 consecutive women and 52 men involved in the process of in vitro fertilization (IVF) at the Department of Obstetrics and Gynecology, Clinical Center of Serbia. Women were divided into three groups... | false |
Uloga kanabinoidnih CB1 receptora u patogenezi nealkoholne masne bolesti jetre izazvane dijetom bogatom mastima kod miševa | The role of cannabinoid CB1 receptors in pathogenesis of nonalcoholic fatty liver disease induced by high fat diet in mice | Nealkoholna masna bolest jetre (NAFLD) obuhvata širok spektar bolesti jetre, od inicijalne steatoze do steatohepatitisa, koji može dalje da progredira do fibroze i ciroze jetre, uz mogućnost razvoja hepatocelularnog karcinoma. Ključnu ulogu u patogenezi NAFLD, na samom početku, ima insulinska rezistencija (IR) u masnom tkivu, koja povećava lipolizu i dopremanje masnih kiselina (MK) u jetru, a takođe utiče i na posrast de novo sinteze MK u heptocitima. Tako, najpre dolazi do razvoja steatoze, koja povećava osetljivost hepatocita na oštećenje dejstvom faktora aktivacije inflamatorne kaskade i fibrogeneze, dovodeći do dalje progresije bolesti u steatohepatitis i fibrozu jetre. Među ovim faktorima najznačajniji su oksidativni/nitrozativni stres, mitohondrijalna disfunkcija, lipotoksičnost, proinflamatorni citokini, kao i disbalans produkcije adipokina. Dosadašnja eksperimentalna i klinička istraživanja ukazala su na značajnu ulogu endokanabinoidnog sistema (ES) u razvoju NAFLD. U našoj studiji korišćena je dijeta bogata mastima (HFD, engl. high fat diet), koja izaziva strukturne, funkcionalne i metaboličke promene u jetri miševa slične ispoljavanjima NAFLD i metaboličkog sindroma u ljudi (porast nivoa oksidativnog i nitrozativnog stresa u hepatocitima, razvoj dislipidemije, IR, hepatičke steatoze, inflamacije i fibroze). Ciljevi ove disertacije su bili: da se ispita uloga kanabinoidnih CB1 receptora u patogenezi NAFLD sa posebnim osvrtom na ulogu u razvoju oksidativnog/nitrozativnog stresa, uticaj na kapacitet antioksidativne zaštite, kao i koncentraciju Zn, Cu, Mn i Fe u tkivu jetre; da se ispita uticaj CB1 receptora na lipidni status, profil MK u jetri (palmitinska, stearinska, oleinska, linoleinska i arahidonska kiselina), kao i adipokine (leptin, apelin, rezistin i visfatin) i proinflamatorne citokine (IL-6 i IFN-γ) u masnom tkivu i jetri; da se ispita uticaj blokade CB1 receptora na glikemiju, koncentraciju insulina i HOMA indeks. NAFLD je izazvana mužjacima miševa C57BL/6 soja, uzrasta 8 nedelja, primenom HFD. Pre samog eksperimenta sve životinje (n=40) bile su hranjene kontrolnom dijetom... | Non alcoholic fatty liver disease (NAFLD) encompasses a wide range of liver diseases from initial steatosis to steatohepatitis, which may further progress to liver fibrosis or cirrhosis and potentially develop hepatocellular carcinoma. At the very beginning, insulin resistance (IR) in adipose tissue has the key role in the NAFLD pathogenesis, increasing lipolysis and supply of fatty acids (FA) to liver and also affecting the increase of de novo synthesis of FA in hepatocytes. In this manner steatosis occurs first, increasing the sensitivity to the damage occurred due to the factors which activate inflammatory cascade and fibrogenesis and lead to further progression of the disease towards steatohepatitis and liver fibrosis. The most significant among these factors are oxidative/nitrosative stress, mitochondrial dysfunction, lipotoxicity, proinflammatory cytokines, as well as the adipokine production imbalance. Previous experimental and clinical research has emphasized the considerable role of the endocannabinoid system (ECS) in the development of NAFLD. In our study we used high fat diet (HFD) which causes structural, functional and metabolic changes in mouse liver similar to the manifestations of NAFLD and metabolic syndrome in humans (increased level of oxidative and nitrosative stress in hepatocytes, development of dyslipidemia, IR, hepatic steatosis, inflammation and fibrosis). The goals of this thesis were: to test the role of cannabinoid CB1 receptors in the pathogenesis of NAFLD with particular overview of their role in the development of oxidative/nitrosative stress, impact on the capacity of antioxidative protection, as well as Zn, Cu, Mn and Fe concentrations in liver tissue; to test the impact of CB1 receptors on the lipid profile, FA profile in liver (palmitic, stearic, oleic, linoleic and arachidonic), as well as adipokines (leptin, apelin, resistin and visfatin) and proinflammatory cytokines (IL-6 and IFN- γ) in adipose tissue and liver; to test the impact of blocking CB1 receptors on glycemia, insulin concentration and HOMA-IR index. HFD was applied on 8 weeks old male mice of C57BL/6 strain, which caused NAFLD to occur. Before the very experiment all the animals (n=40) were fed a control diet... | false |
Značaj ranog predviđanja akutnog oštećenja bubrega kod bolesnika sa sepsom posle hirurških intervencija | Significance of early prediction of acute kidney injury in surgical patients with sepsis | Uvod: Akutno oštećenje bubrega u sepsi (S-AOB) značajno utiče na morbiditet i
mortalitet hirurških bolesnika sa sepsom.
Cilj: Cilj naše studije je bio da se ispitaju vrednosti novih biomarkera bubrežnog
oštećenja, inflamacije i oksidativnog stresa kod septičnih hirurških bolesnika sa S-AOB
kao i da se evaluira njihov značaj kao dijagnostičkih, prediktivnih i prognostičkih
biomarkera S-AOB i sepse.
Bolesnici i metode: U ovoj prospektivnoj observacionoj studiji je poređeno 53
abdominalnih hirurških bolesnika obolelih od sepse, od čega 37 sa S-AOB i 16 bez S-
AOB, sa kontrolnom grupom operisanih (n = 53) i kontrolnom grupom neoperisanih (n
= 53) bolesnika sličnih po godinama, polu, komorbiditetima i tipu hirurške intervencije.
Uzorci krvi i urina su uzimani pri prijemu u jedinicu intenzivnog lečenja i 24, 48, 72 i
96 sati kasnije od septičnih bolesnika i jednom od bolesnika kontrolnih grupa. U
prikupljenim uzorcima su merene vrednosti standardnih biomarkera bubrežne funkcije
kao i novih biomarkera bubrežnog oštećenja, inflamacije i oksidativnog stresa. Skorovi
težine bolesti su računati svakog dana posmatranja za sve bolesnike.
Rezultati: Septični bolesnici sa S-AOB su imali statistički značajno različite vrednosti
novih biomarkera bubrežnog oštećenja, inflamacije i oksidativnog stresa u poređenju sa
septičnim bolesnicima bez S-AOB i kontrolnim grupama. Vrednosti ovih biomarkera se
nisu značajno menjale tokom 96 sati. Nađena je značajana korelacija između vrednosti
novih biomarkera bubrežnog oštećenja, inflamacije, oksidativnog stresa i vrednosti
standardnih biomarkera bubrežne funkcije i skorova težine bolesti. Pojedinačno ili u
kombinaciji, ispitivani biomarkeri su bili dobri dijagnostički, prediktivni i prognostički
biomarkeri S-AOB i sepse.
Zaključci: Novi biomarkeri bubrežnog oštećenja, inflamacije i oksidativnog stresa su
potencijalno dobri dijagnostički, prediktivni i prognostički biomarkeri S-AOB i sepse. | Introduction: Sepsis-associated acute kidney injury (SA-AKI) severely impacts morbidity
and mortality in the surgical patients with sepsis.
Aim: The aim of our study was to investigate the levels of the novel biomarkers of kidney
injury, inflammation and oxidative stress in the septic surgical patients with SA-AKI and to
evaluate their diagnostic, predictive and prognostic value in SA-AKI and sepsis.
Patients and methods: This prospective observational study compared 53 major
abdominal surgery patients with sepsis divided into SA-AKI (n = 37) and non-SA-AKI (n
=16) groups to 50 operated controls and 50 not-operated controls matched by age, gender,
comorbidities and type of surgery. Blood and urine samples from the septic patients were
collected on admission to Intensive Care Unit and 24 h, 48 h, 72 h and 96 h later and once
from the controls. Standard and novel biomarkers of kidney function and injury,
inflammation and oxidative stress were measured. Disease severity scores were calculated
for all patients daily during the entire observational period.
Results: The septic patients with SA-AKI had altered levels of the novel biomarkers of
kidney injury, inflammation and oxidative stress compared to the septic patients without
sepsis and control groups. The levels of these biomarkers did not change significantly over
96 h. The novel biomarkers of kidney injury, inflammation and oxidative stress
significantly correlated with the standard biomarkers of kidney function and disease
severity scores. These biomarkers, independently or in combination, were good diagnostic,
predictive and prognostic biomarkers of SA-AKI and sepsis.
Conclusions: The novel biomarkers of kidney injury, inflammation and oxidative stress
could serve as potential diagnostic, predictive and prognostic biomarkers of SA-AKI and
sepsis. | true |
Analiza kliničkih imunoseroloških osobenosti bolesnika sa krioglobulinemijom: doprinos utvrđivanju fenotipova | Analysis of clinical and immunoserological characteristics of patients with cryoglobulinemia:importance for phenotype definition | Uvod: Krioglobulini su serumski imunoglobulini koji precipitiraju na temperaturi nižoj od 370C i ponovo rastvaraju zagrevanjem seruma. Najčešće se povezuju sa prisustvom infekcije, autoimunskih i malignih bolesti ili je uzrok nejasan (esencijalna krioglobulinemija). Krioglobulinemije se klasifikuju u tri tipa na osnovu imunohemijskog sastava krioprecipitata. Tip I sastavljen je od jednog monoklonskog imunoglobulina, dok su tip II i III sastavljeni od imunskih kompleksa, u čijem se sastavu nalazi imunoglobulin sa aktivnošću reumatoidnog faktora (RF), te se zovu mešoviti krioglobulini. Kod tipa II RF je monoklonski, dok je kod tipa III poliklonski. Kod krioglobulinemije tipa II i III (mešovite krioglobulinemije - MC) taloženje imunskih kompleksa u zidu krvnog suda može da dovede do vaskulitisnog procesa uz zahvatanje malih krvnih sudova, kapilara i postkapilarnih venula, a nekada i krvnih sudova srednjeg kalibra, pri čemu histološki nalaz odgovara leukocitoklazijskom vaskulitisu. U kliničkom smislu, vaskulitis se manifestuje artralgijama, malaksalošću kao i lezijama pre svega na koži, bubrezima, perifernom nervnom sistemu, ali i bilo kom drugom organu. Najveći broj do sada objavljenih istraživanja odnosi se na MC u hroničnoj infekciji virusom hepatitisa C (HCV). Podaci u literatuti o esencijalnoj krioglobulinemiji/vaskulitisu su vrlo oskudni, dok se tek u poslednje vreme daje se nešto veći značaj tzv. neinfektivnom krioglobulinemijskom vaskulitisu. Hronična antigenska stimulacija, povećan nivo citokina i faktora stimulacije B limfocita (B lymphocyte stimulator-BLyS), aktivacija sistema komplementa, neki su od pretpostavljenih mehanizama značajnih u patogenezi krioglobulinemijskog vaskulitisa, koja ostaje nepotpuno razjašnjena. Ciljevi istraživanja: ispitati kliničke i imunoserološke karakteristike bolesnika sa krioglobulinemijom u odnosu na prisustvo i težinu kliničke slike vaskulitisa, kao i etiologiju krioglobulinemije; ispitati kvantitativne i kvalitativne karakteristike krioglobulina (tip krioglobulina, prisustvo RF i M komponente u krioprecipitatu); ispitati učestalost esencijalne u odnosu na sekundarne krioglobulinemije, kao i njene kliničke i imuno serološke karakteristike; utvrditi značaj količine i sastava krioglobulina, koncentracije C3 i C4, anti C1q antitela i BLyS u serumu, za procenu aktivnosti, praćenje i prognozu esencijalnog, sekundarnog krioglobulinemijskog vaskulitisa, kao i krioglobulinemije bez manifestacija vaskulitisa... | Introduction: Cryoglobulins (cryoG) are serum immunoglobulins (IG) that precipitate at temperatures lower than 370C and redissolve after rewarming. Their occurrence is most often associated with various infections, autoimmune and malignant disorders, or the cause of it remains obscure (essential cryoglobulinemia (EMC). Three basic types are recognized according to the clonality and type of immunoglobulins. Type I consists of monoclonal IG, generally either IgM or IgG, while in Type II cryoglobulins are a mixture of monoclonal IgM and polyclonal IgG. Type three cryoglobulis are mixture polyclonal IgM and IgG. The IgM component of type II cryoglobulins has rheumatoid factor activity. In Type II cryoglobulina (CG) RF is of monoclonal, whilst in Type III CG of polyclonal variety. Types II and III are referred to as mixed mixed cryoglobulinemias (MC). MC deposits of immune complexes in walls of blood vessels might lead to vasculitis of small (capillaries and post capillary venules) and medium blood vessels, giving the hystologic picture of leukocytoclastic vasculitis. Clinically, this inflammation is manifested as arthralgias, fatigue, and lesions mainly in skin, kidneys and peripheral nerves, however, any organ system can be involved. Most of the so far reported clinical and laboratory investigations deal with mixed CG in chronic hepatitis C virus (HCV) infection while the data concerning essential CG vasculitis (CV) are scarce. Only recently, so-called noninfectious CV has attracted more attention of the medical community. Chronic antigenic stimulation, increased cytokine and growth factor (BLyS) levels and complement activation may are implicated in the pathogenesis of CV, etiology of which remains largely unknown. Objectives: To investigate clinical and imunoserologic characteristics of patients with CG and their relation to presence and clinical manifestations of vasculitis, as well as to the etiology of CG; explore quantitative and qualitative characteristics of cryoG; to analyze a ratio between ECG and secondary CG in 201 consecutive patients with CG; to see whether clinical manifestations and laboratory data in patients with ECG vasculitis differ from those in secondary CG at its presentation and in relapse; to determine whether quantity and structure of CG and serum concentrations of C3 and C4 complement components, anti-C1q antibody and BLyS, have value in estimation, follow-up and prognosis of secondary essential CV, as well as CG without clinically apparent vasculitis... | false |
Karakterizacija materijala SPM tehnikom i njeno unapređenje primenom analize uticaja defekata sondi | SPM characterization of materals and its improvements by probe defects analysis | Jedna od najperspektivnijih tehnika za ispitivanje sastava, strukture i svojstava materijala
je mikroskopija sondama za skeniranje (SPM), odnosno njene komponente mikroskopija
tunelovanjem elektrona (STM) i mikroskopija atomskim silama (AFM). Ovim metodama
se rutinski postiže nanometarska i atomska rezolucija. Posebno istaknuta prednost metode
je da ne postoje ograničenja u smislu porekla i sastava uzoraka, te je moguće ispitivanje
organskih i neorganskih materijala. Ova tehnika se primenjuje u savremenim
multidisciplinarnim istraživanjima u oblasti medicine, farmacije, stomatologije, nauke o
materijalima, itd, i to za ispitivanje bioloških uzoraka, hemijskih jedinjenja,
farmaceutskih proizvoda, veštačkih tkiva, materijala za implantologiju, i svih ostalih
materijala čija nanotehnološka svojstva imaju uticaj na primenu u navedenim naučnim
oblastima. Međutim, snimci dobijeni pomoću AFM-a su samo aproksimacije površina
uzoraka, jer sonde nemaju ni savršenu veličinu ni geometriju, usled čega dolazi do pojave
artefakata koji se definišu kao karakteristike koje se pojavljuju na snimku a koje nisu
prisutne na ispitivanom uzorku. Ovi efekti izazvani konvolucijom između sonde i uzorka
mogu do izvesne mere da budu korigovani matematičkom manipulacijom topografskim
podacima. Metodologija koja je u ovom radu korišćena se zasniva na algebri skupova i
osnovnim alatima matematičke morfologije. Iskorišćeni su matematički algoritmi za
“slepu rekonstrukciju” vrhova sondi, a potom je izvršena dekonvolucija, da bi se otkrili
delovi površine uzorka koji u realnosti nisu bili dostupni. Granica realnog vrha sonde se
izračunava iz slike pomoću morfoloških ograničenja koja su inherentna u procesu
snimanja. Rezultat se dobija u vidu snimka rekonstruisane površine uzorka iz dobijenih
snimaka, uz pomoć rekonstrukcije vrha sonde kojom je uzorak sniman. | One of the most perspective available technique for investigation of the composition,
structure and properties of materials, is scanning probe microscopy (SPM), respectively
its components scanning tunneling microscopy (STM) and atomic force microscopy
(AFM). The advantage of the method is that they have no restrictions related to origin
and composition of the material, and its possibilities to investigate vide variety of
materials. This technique is used in multidisciplinary research in the field of medicine,
pharmacy, dentistry, material science, etc., for study of biological samples, chemical
compounds, pharmaceutical products, artificial tissues, implantology materials, and all
other materials that have nanotechnological impact on application in these scientific
fields. However, images obtained by AFM represent only approximation of the sample
surfaces. This is because the probes have not perfect size and geometry, which leads to
the appearance of artifacts. They are defined as characteristics that appear on the image
and are not present on the sample. These effects caused by convolutions between the
probe and sample can be corrected to a certain extent by mathematical manipulation of
topographic data. The methodology used in this paper is based on algebra of sets, and
basic tools of mathematical morphology. Mathematical algorithms for the "blind
reconstruction" of the tip were used, and then in order to detect the parts of the sample
surface which is not available in real-time scanning deconvolution was applied. The limit
of the real probe tip is calculated from the image, using the morphological limitations
inherent in the recording process. The result acuired as an image of the reconstructed
surface out of the used images, with the reconstruction of the real tip. | true |
Analiza prediktivnih faktora ishoda lečenja hipertrofične stenoze pilorusa primenom rastvora atropin sulfata | Analysis of predictive factors for treatment outcome of hypertrophic pyloric stenosis by using a solution of atropine sulfate. | Hipertrofična stenoza pilorusa (HSP) je najčešći razlog za hiruršku intervenciju u
uzrastu novorođenčeta i mladog odojčeta. Ekstramukozna piloromiotomija je zlatni standard
u lečenju HSP, a medikamentozni tretman primenom atropin sulfata je jedina neoperativna
metoda kojom se postiže visok procenat izlečenja, pa je u nekim zemljama i uvedena kao
prva linija terapije. Suštinski značaj neoperativnog tretmana je neizlaganje novorođenog
deteta stresu uzrokovanim hirurškom intervencijom i opštom anestezijom. Ovom studijom je
urađena procena uticaja različitih režima oralne primene atropina na njegovu efikasnost u
lečenju HSP, uz definisanje prediktivnih faktora i analizu njihovog uticaja na ishod
medikamentoznog tretmana. Urađeno je i poređenje efikasnosti konzervativnog tertmana sa
operativnim.
Metode. Studijom je obuhvaćeno 100 bolesnika lečenih zbog HSP na Univerzitetskoj dečjoj
klinici (UDK) u Beogradu, u periodu od 2006 - 2016. godine. Klinički pregled, laboratorijske
analize i ehosonografija abdomena, urađeni su kod svih ispitanika na prijemu. Njih 55 (55%),
operisano je odmah nakon postavljanja dijagnoze. Kod preostalih 45 (45%) ispitanika lečenih
konzervativno, atropin sulfatom, analizirana je efikasnost konzervativnog tretmana, s
posebnim naglaskom na efekat doziranja leka i uz definisanje potencijalnih prediktivnih
faktora negativnog ishoda. Procena uspešnosti lečenja analizirana je upotrebom deskriptivnih
statističkih
metoda
uz
korišćenje
modela
multivarijantne
logističke
regresije.
Rezultati. Grupa ispitanika lečenih medikamentozno, obuhvata 45 bolesnika, od kojih je 36
(80%, p= 0.0008) uspešno izlečeno, bez potrebe za hirurškom intervencijom i bez
komplikacija. Od opserviranih parametara, pokazalo se da u pogledu polne zastupljenosti,
uzrasta, porođajne telesne mase, telesne težine na prijemu, trajanja simptoma, kao i dužine i
debljine pilorusnog mišića nema statistički značajnog pojedinačnog uticaja na uspeh
medikamentoznog lečenja. Ispitanici kod kojih je primenjeno progresivno povećanje doze
atropina imaju 18 puta veci rizik da će biti operisani. Ispitanici koji su na prijemu imali
hipohloremijsku alkalozu imaju 15 puta veći rizik, dok ispitanici koji su imali više od 5
povraćanja u prva tri dana od početka primene atropina imaju 9 puta veći rizik da će biti
operisani. Preostalih 55 pacijenata uspešno je izlečeno hirurškom intervencijom (100%) uz
6,3% postoperativnih komplikacija od kojih se u 3,2% radilo o insuficijentnoj
piloromiotomiji, a, koje su takođe uspešno izlečene peroralnom administracijom atropina,
tako da reintervencije nisu bile potrebne.
Zaključak. Visoka stopa uspešnosti bez štetnih efekata oralno primenjenog atropina, čini ga
prihvatljivom alterantivom piloromiotomiji u lečenju HSP, posebno u slučajevima sa
kontraindikacijama za opštu anesteziju. Pokazalo se da je primena inicijalno visokih doza
efikasnija u odnosu na postepeno povećavanje oralne doze atropin sulfata. Hipohloremijska
alkaloza i kontinuirano povraćanje, smatraju se potencijalnim prediktivnim faktorima
negativnog ishoda atropinskog tretmana. Peroralno ordiniran atropin kod dece sa
insuficijentnom piloromiotomijom, treba da bude terapija izbora. | Infantile hypertrophic pyloric stenosis (IHPS) is the most common cause
for surgery in the newborn and young infant. Extramucosal pyloromyotomy is the gold
standard treatment of IHSP, but treatment with atropine sulphate has also leeds to a successful
outcome and in some countries it was introduced as the first line of therapy. Conservative
treatment of IHPS is of great importance because it saves a newborn from stress caused by
surgery and general anesthesia. This study evaluates the impact of various oral administration
regimens of atropine on its efficacy in treating IHPS with defining predictive factors and
analyzing their impact on the outcome of atropine treatment. A comparison of the efficiency
of the conservative tertment with the pyloromyotomy was also performed.
Methods. The study included 100 patients treated for IHSP at the University Chidren´s
Hospital in Belgrade in the period from 2006 - 2016. Clinical examination, laboratory
analysis and ultrasonography were performed in all patients on admission. Fifty-five of them
(55%) underwent surgery immediately after diagnosis was set. The remaining 45 (45%)
patients were treated conservatively by atropine sulfate. We analyzed the efficacy of that
treatment, with different drug dosage regimens and with definition of potential predictive
factors of the negative outcome. Evaluation of the treatment was also analyzed by descriptive
statistical methods and multivariate logistic regression model.
Results. Group of patients, conservatively treated, included 45 patients, of whom 36 (80%,
p=0,0008) were successfully cured, without the need for surgery and without complications.
It has been shown that in terms of sex prevalence, age, birth weight, body weight on
admission, duration of symptoms, pyloric muscle thickness and length, there is no statistically
significant individual effect on the success of atropine treatment. Patients who received
progressively increased dose of atropine have an 18 times higher risk of surgery, patients who
have hypochloremic alkalosis have a 15 times higher risk, while others, who vomited more
than 5 times within the first three days of therapy are 9 times more likely to be surgically
treated. The remaining 55 patients were successfully treated by surgical intervention (100%)
with 6.3% of postoperative complications, of which 3.2% were insufficient pyloromyotomy.
They were successfully treated by orally administered atropine, so reintervention was not
necessary.
Conclusion. High success rate and no side effects represent an orally administered atropine
treatment as a suitable alternative for management of IHPS, especially in cases of risk or
contra-indications for general anesthesia Administration of initially high doses has been
shown to be more effective in relation to gradually increased oral doses of atropine sulfate.
Hypochloremic alkalosis and continued vomiting are considered as potential predictive
factors of negative outcome of atropine treatment. Orally administered atropine in children
with insufficient pyloromyotomy should be a therapy of choice. | true |
Ispitivanje povezanosti zdravstvene pismenosti i kvaliteta života kod pacijenata sa srčanom insuficijencijom | Exploring the Importance of Health Literacy for the Quality of Life in Patients with Heart Failure | Kao i kod svih drugih hroničnih nezaraznih bolesti, adekvatna
zdravstvena pismenost igra ključnu ulogu u donošenju ispravnih odluka
prilikom
lečenja
srčane
insuficijencije.
Pacijenti
sa
srčanom
insuficijencijom i nižom zdravstvenom pismenošću imaju lošiji kvalitet
života.
Ciljevi: Ciljevi ove doktorske disertacije su: 1) procena zdravstvene
pismenosti i kvaliteta života ispitanika lečenih od srčane insuficijencije u
Kliničko-bolničkom centaru „Bežanijska kosa―; 2) utvrđivanje faktora koji su
povezani sa zdravstvenom pismenošću; i 3) ispitivanje povezanosti između
zdravstvene pismenosti i različitih domena kvaliteta života ispitanika.
Metod: Studija preseka sprovedena je kod 200 pacijenata sa srčanom
insuficijencijom u državnoj univerzitetskoj bolnici u Beogradu. Za
ispitivanje zdravstvene pismenosti koristili smo Evropski upitnik za procenu
zdravstvene pismenosti, HLS-EU-47. Kvalitet života je meren sa generičkim SF-
36 i specifičnim Minesota upitnikom. Za procenu sociodemografskih
karakteristika primenjen je opšti upitnik. Podaci su analizirani metodama
deskriptivne i analitičke statistike.
Rezultati: Više od polovine ispitanika (64%) imalo je ograničenu
zdravstvenu pismenost. Najniža vrednost prosečnog indeksa zdravstvene
pismenosti (28,01±9,34) bila je u okviru dimenzije prevencije bolesti, gde je
najveći broj ispitanika pokazao ograničenu zdravstvenu pismenost (70%).
Ispitanici su imali lošiji kvalitet života u fizičkoj dimenziji, dok su
najbolje vrednosti kvaliteta života identifikovane u emotivnoj ulozi i
društvenom funkcionisanju. Zdravstvena pismenost je bila visoko statistički
značajan i nezavistan prediktor kvaliteta života (fizičkog, mentalnog i
ukupnog kvaliteta života).
Zaključak: Poboljšanje zdravstvene pismenosti može dovesti do boljih odluka u
lečenju bolesti i kvaliteta života kod pacijenata sa srčanom insuficijencijom. | As with all other chronic noncommunicable diseases, adequate health
literacy plays a key role in making the right decisions in the treatment of heart failure.
Patients with heart failure and a lower health literacy have a reduced quality of life.
Оbjectives: The aims of this study were to: 1) assess the health literacy and quality of
life of patients treated for heart failure at the Clinical Center ―Bežanijska Kosa‖; 2)
identify the factors associated with health literacy; and 3) investigate the connection
between health literacy and various domains of patients’ quality of life.
Methods: A cross-sectional study among 200 patients with heart failure was conducted
at a state university hospital in Belgrade, Serbia. The European Health Literacy
Questionnaire, HLS-EU-Q47, was used to assess health literacy. Quality of life was
measured with the generic SF-36 and the Minnesota Living with Heart Failure
Questionnaire; and Sociodemographic Questionnaire. Descriptive and analytical
statistical analysis was applied.
Results: More than half of the respondents (64%) had limited health literacy. The
lowest mean health literacy index (28.01±9.34) was within the disease prevention
dimension, where the largest number of respondents showed limited health literacy
(70%). Our patients had a poorer quality of life in the physical dimension, and the best
scores were identified in the emotional role and social functioning. Health literacy was
highly statistically significant and an independent predictor of quality of life (physical,
mental, and total quality of life).
Conclusion: Improving health literacy can lead to better decisions in the treatment of
disease and quality of life in heart failure patients. | true |
Uticaj stavova studenata medicine prema statistici na sticanje kompetencija iz oblasti biostatike: multicentrična studija i meta-analiza | The importance of medical students' attitudes towards statistics for acquiring competence in biostatistics: multi-site study and meta-analysis | Nakon saznanja da osnovne greške u analizi podataka doprinose
neponovljivosti rezultata istraživanja mnogih publikovanih studija, u
naučnoj zajednici prepoznata je potreba za boljim razumevanjem
statističkih analitičkih metoda. Cilj ove studije je da se ispitaju stavovi
studenata prema statistici u različitim edukativnim okruženjima, prate
njihove promene i uticaj na postignuća iz biostatistike. Takođe,
sproveden je sistematski pregled literature u cilju pronalaženja naučnih
dokaza radi pružanja podrške pedagoškim odlukama koje se odnose na
podučavanje studenata medicine iz oblasti primenjene statistike.
Metod
Upitnik za procenu stavova studenata prema statistici (eng. Survey of
Attitudes Towards Statistics – SATS – 36) je korišćen za anketiranje
studenata medicine na tri fakulteta Zapadnog Balkana, koji su pohađali
obavezni predmet iz biostatistike. Prethodno je urađena validacija i
kulturološka adaptacija upitnika na srpski jezik. Sistematski pregled
literature sproveden je pretraživanjem publikacija objavljenih od 1994.
godine u sledećim bazama podataka: Scopus, Web of Science, Science
Direct, Medline i APA. Urađena je i meta-analiza koeficijenata korelacije
skorova SATS komponenti i postignutih rezultata iz statistike. Zbirne
procene su izračunate korišćenjem modela slučajnih efekata.
Rezultati
Korišćenjem upitnika SATS – 36 anketiran je 461 student. Većina
studenata je imala pozitivne stavove prema statistici. Predznanje iz
matematike
i
prosečna
ocena
na
studijama
povezani
su
u
multivarijantnom regresionom modelu sa “sposobnošću razumevanja”,
nakon
prilagođavanja
za
godine
starosti,
pol
i
kompjuterske
sposobnosti. Rezultati uparenih podataka studenata (n=90) praćenih
pre i posle nastave pokazali su značajne pozitivne promene za
komponente “sposobnost razumevanja”, “afekat” i “napor”. Vrednost
komponente “sposobnost razumevanja” je pokazala najveći porast
(M=0.48, SD=0.95). Takođe, pronađena je pozitivna korelacija između
vrednosti komponente “sposobnost razumevanja” i postignutih rezultata
tokom nastave (r=0.41; p<0.001), koja je potvrđena i rezultatima meta-
analize (r=0.37; 95% CI 0.32–0.41).
Zaključak
Subjektivni stavovi studenata o sposobnosti razumevanja statistike na
početku kursa iz biostatistike, koji su bili direktno povezani sa znanjem
iz matematike, uticali su na njihove stavove na kraju kursa koji su, s
druge strane, imali uticaj na postignute rezultate. Ovakav nalaz ukazuje
na značaj pozitivnih promena ne samo u razumevanju statistike, već i
studentske
percepcije
stečenih
kompetencija
tokom
kursa
iz
biostatistike. | The scientific community increasingly is recognizing the need to bolster
standards of data analysis given the widespread concern that basic
mistakes in data analysis are contributing to the irreproducibility of
many published research findings. The aim of this study was to
investigate students’ attitudes towards statistics within a multi-site
medical educational context, monitor their changes and impact on
student achievement. In addition, we performed a systematic review to
better support our future pedagogical decisions in teaching applied
statistics to medical students.
Methods
A validated Serbian Survey of Attitudes Towards Statistics (SATS-36)
questionnaire
was
administered
to
medical
students
attending
obligatory introductory courses in biostatistics from three medical
faculties. A systematic review of peer-reviewed publications was
performed through searches of Scopus, Web of Science, Science Direct,
Medline, and APA databases through 1994. A meta-analysis was
performed for the correlation coefficients between SATS component
scores and statistics achievement. Pooled estimates were calculated
using random effects models.
Results
SATS-36 was completed by 461 medical students. Most of the students
held positive attitudes towards statistics. Ability in mathematics and
grade point average were associated in a multivariate regression model
with the Cognitive Competence score, after adjusting for age, gender
and computer ability. The results of 90 paired data showed that Affect,
Cognitive Competence, and Effort scores demonstrated significant
positive changes. The Cognitive Competence score showed the largest
increase (M=0.48, SD=0.95). The positive correlation found between the
Cognitive Competence score and students’ achievement (r=0.41;
p<0.001), was also shown in the meta-analysis (r=0.37; 95% CI 0.32–
0.41).
Conclusion
Students' subjective attitudes regarding Cognitive Competence at the
beginning of the biostatistics course, which were directly linked to
mathematical knowledge, affected their attitudes at the end of the
course that, in turn, influenced students' performance. This indicates
the importance of positively changing not only students’ cognitive
competency, but also their perceptions of gained competency during the
biostatistics course. | true |
Uticaj ekspresije gena za humani koncentrativni nukleozidni transporter 3 i prisustva alela CYP2B6*6 na odgovor na terapiju fludarabinom i ciklofosfamidom kod bolesnika sa hroničnom limfocitnom leukemijom | Association of human concentrative nucleoside transporter 3 gene expression and CYP2B6*6 аllele with the response to fludarabine plus cyclophosphamide in chronic lymphocytic leukemia patients | Hemioterapija na bazi fludarabina i ciklofosfamida predstavlja osnov lečenja
pacijenata sa hroničnom limfocitnom leukemijom (HLL) mlađe životne dobi i bez značajnih
komorbiditeta. Kod nekih pacijenata efekat terapije može biti uslovljen aberantnom
ekspresijom i/ili mutacijama gena koji utiču na farmakodinamiku i farmakokinetiku
antileukemijskih lekova. Sa druge strane, ustanovljeni su brojni kliničko-laboratorijski i
molekularno-genetički markeri prognoze koji su značajni u predikciji kliničkog toka,
prvenstveno vremena do prve terapije (time to first treatment, TTFT) i ukupnog
preživljavanja (overall survival, OS). Oni se poslednjih godina u cilju jačanja prognostičke
vrednosti kombinuju unutar različitih prognostičkih modela, među kojima su za predikciju
TTFT naročito relevantni Skor rizika od progresije (Progression.Risk Score, PRS) i Skor MD
Anderson centra za kancer iz 2011 (MD Anderson Cancer Center 2011 score, MDACC
2011), dok je za predviđanje OS najznačajniji Internacionalni prognostički indeks za HLL
(The International Prognostic Index for CLL, CLL-IPI). Cilj rada je da se ispita uticaj
farmakogenetike, tačnije ekspresije gena SLC28A3 koji kodira hCNT3 protein, jedan od
transportera za fludarabin, i varijantnog alela CYP2B6*6 gena za citohrom P450 2B6, koji
učestvuje u metabolizmu ciklofosfamida, na ishod lečenja FC protokolom kod pacijenata sa
HLL-om. Takođe, cilj je da se u grupi ovih pacijenata utvrdi vrednost skorova CLL-IPI, PRS
i MDACC 2011 u predikciji TTFT, OS, vremena bez progresije (progression free survival,
PFS) i odgovora na terapiju. Konačno, ispitaće se veza farmakogenetičkih karakteristika i
skorova.
Metodologija: U studiju je uključeno 57 pacijenata sa HLL-om koji su lečeni FC
protokolom, većinom u prvoj liniji. Pacijenti su stratifikovani prema skorovima CLL-IPI,
PRS i MDACC 2011, nakon čega je ispitana njihova prognostička vrednost u pogledu TTFT,
odgovora na terapiju, PFS i OS. Imajući u vidu da je gubitak funkcije TP53 gena jedan od
glavnih uzroka rezistencije na konvencionalnu hemioterapiju, za potrebe farmakogenetičke
analize iz kohorte su isključeni pacijenti sa mutacijom i/ili delecijom TP53, čime otklonjena
je mogućnost da su ove aberacije uticale na ishod lečenja pacijenata. Detekcija CYP2B6*6
varijantnog alela je izvršena reakcijom lančanog umnožavanja DNK (Polymerase Chain
Reaction, PCR) i direktnim sekvenciranjem. Ekspresija SLC28A3 je merena u
mononuklearnim ćelijama izolovanim iz uzoraka periferne krvi HLL pacijenata uzetih pre
započinjanja terapije FC protokolom, metodom kvantitativnog PCR na matrici dobijenoj
reverznom transkripcijom (Quantitative Reverse Transcriptase Polymerase Chain Reaction,
qRT-PCR).
Rezultati: Kod pacijenata koji nisu reagovali na terapiju FC protokolom (ishod lečenja
stabilna bolest ili progresija) detektovani su značajno viši nivoi iRNK SLC28A3 gena u
odnosu na pacijente koji su postigli parcijalnu ili kompletnu remisiju (p=0.01). Pacijenti koji
su visoko eksprimirali SLC28A3 imali su skoro 10 puta veću šansu da ne odgovore na
terapiju FC u odnosu na pacijente sa niskom ekspresijom (OR=9.8, p=0.046). Nije pokazano
da postoji povezanost nivoa ekspresije SLC28A3 sa PFS i OS. Prisustvo alela CYP2B6*6,
detektovano kod 24 pacijenta (54.6%), nije bilo značajno povezano sa odgovorom na FC, kao
ni PFS i OS. Pacijenti sa višim vrednostima skorova CLL-IPI, PRS i MDACC 2011 su imali
značajno kraće vreme do prve terapije u odnosu na pacijente koji su imali niže vrednosti
skorova (p=0.002, p=0.019 i p<0.001, redom). U multivarijantnoj analizi, MDACC 2011 i
CLL-IPI su zadržali značajnost u pogledu predikcije TTFT (p=0.001 i p=0.018, redom), dok
PRS nije bio značajan. CLL-IPI je jedini pokazao značajnost u predikciji OS (p=0.005 u
univarijantnoj i p=0.013 u multivarijantnoj analizi) i PFS (p=0.036), dok je PRS bio samo
granično značajan u predikciji OS (p=0.052). MDACC 2011 nije pokazao statističku
značajnost u pogledu predikcije OS i PFS, dok nijedan od ispitivanih prognostičkih modela
nije imao prediktivnu vrednost u pogledu odgovora na terapiju. Takođe, nije utvrđeno da
postoji veza između vrednosti ispitivanih skorova i ekspresije SLC28A3.
Zaključak: Rezultati ovog rada su pokazali da je nivo ekspresije SLC28A3 značajan
prediktor odgovora na FC kod pacijenata sa funkcionalnim TP53 genom. Varijantni alel
CYP2B6*6 u ovoj studiji nije ispoljio značaj u terapijskom ishodu. Sa druge strane,
prognostički modeli CLL-IPI, PRS i MDACC 2011 pokazali su značajan potencijal u
predviđanju TTFT, uprkos tome što su pacijenti iz naše kohorte imali više pokazatelja
agresivnije bolesti u odnosu na opštu HLL populaciju. CLL-IPI je pokazao prognostičku
vrednost i u slučaju predikcije PFS i OS. Povezanost između ispitivanih prognostičkih
skorova i ekspresije SLC28A3 u ovoj studiji nije detektovana, što ukazuje na to da ovi
rizikofaktori odražavaju potpuno različite aspekte bolesti i njenog lečenja. U našoj studiji,
ekspresija SLC28A3 se pokazala kao striktno prediktivni marker, čiji je efekat bio ograničen
na terapijski odgovor i nije se dalje odrazio na preživljavanje. Validacija na većim kohortama
i standardizacija metoda merenja ekspresije SLC28A3 su neophodne kako bi se potvrdila
prediktivna moć ovog molekularnog markera i njegova primenljivost za stratifikaciju
pacijenata u svakodnevnoj kliničkoj praksi. | Fludarabine plus cyclophosphamide (FC) chemotherapy is the basis of
treatment protocols used in management of chronic lymphocytic leukemia (CLL). In some
patients, response to therapy may be affected by aberrant function of genes involved in
pharmacokinetics and pharmacodynamics of the drugs. On the other hand, numerous
clinical, biological and genetic prognostic markers which predict the clinical course of CLL,
primarily time to first treatment (TTFT) and overall survival (OS) have been established. In
recent times, they have been combined to make different prognostic models in order to
enhance their prognostic value. The most relevant prognostic models used for prediction of
TTFT are the Progression-Risk Score (PRS), and the MD Anderson Cancer Center Score
2011 (MDACC 2011), while CLL-International Prognostic Index (CLL-IPI), although the
most powerful for prediction of OS, is also being used to estimate TTFT. The aim of this
research was to assess the impact of pharmacogenetic variability, namely expression of
SLC28A3 gene and the presence of CYP2B6*6 variant allele, on the FC treatment efficacy.
Also, one of the objectives was to investigate CLL-IPI, PRS, and MDACC 2011 prognostic
values regarding TTFT, first line treatment response, progression-free survival (PFS) and OS.
Finally, the association of pharmacogenetics and prognostic models was investigated.
Methods: Fifty-seven CLL patients treated with FC, most of them in the first treatment line,
were enrolled in this study. Patients were stratified according to the prognostic models CLL-
IPI, PRS and MDACC 2011 and their prognostic significance regarding TTFT, treatment
response, PFS and OS was examined. Considering the fact that the loss of TP53 gene
function is one of the main causes of chemoresistance, patients with mutated and/or deleted
TP53 were excluded from pharmacogenetic analyses, thus eliminating the possibility of its
influence on the treatment outcome. CYP2B6 genotyping was performed by polymerase chain
reaction (PCR) and direct sequencing. SLC28A3 expression was measured by quantitative
reverse-transcriptase polymerase chain reaction (qRT-PCR).
Results: Significantly higher pretreatment levels of SLC28A3 mRNA were detected in
patients who failed to respond to FC in comparison to patients who achieved complete and
partial response (p=0.01). SLC28A3 high-expressing cases were almost ten times more likely
not to respond to FC than low-expressing cases (OR=9.8; p=0.046). However, association of
SLC28A3 expression with PFS and OS was not observed. CYP2B6*6 allele, detected in 24
(54.6%) of patients, exerted no association with the attainment of response to FC, as well
with PFS and OS. Patients with higher risk scores according to CLL-IPI, PRS, and MDACC
2011 underwent treatment significantly earlier than patients with lower risk scores (p=0.002,
p=0.019, and p<0.001, respectively). In multivariate analysis, MDACC 2011 and CLL-IPI
retained their significance regarding TTFT (p=0.001 and p=0.018, respectively), while PRS
did not. CLL-IPI was the only significant predictor of OS both at the univariate (p=0.005)
and multivariate (p=0.013) levels, as well as of PFS (p=0.036). PRS exhibited borderline
significance only in prediction of OS (p=0.052), while MDACC 2011 was not able to predict
either PFS or OS. All three examined prognostic models failed to predict treatment response.
In addition, the association between the level of risk and SLC28A3 expression was not
detected.
Conclusion: The results of this study demonstrate that SLC28A3 expression is a significant
predictor of FC efficacy in CLL patients with intact TP53. CYP2B6*6 variant allele did not
exhibit association with response to FC. On the other hand, CLL-IPI, PRS, and particularly
MDACC 2011 were able to predict TTFT, despite the fact that the patients in our cohort
exhibited features of more aggressive disease than expected in general CLL population. In
addition, CLL-IPI was also predictive of PFS and OS. No association between SLC28A3
expression and prognostic scores was detected in this study, implying that they reflect
completely different aspects of CLL and its treatment. In our study, SLC28A3 expression
emerged as a strictly predictive marker, whose effect was restricted to the treatment period,
without further impact on survival. Validation on larger cohorts and standardization of
expression measurement methods are warranted in order to confirm predictive value and
applicability of this molecular marker for pretreatment stratification of CLL patients in daily
clinical practice. | true |
Faktori rizika, prognostički faktori i kvalitet života u obolelih od malignih tumora usne šupljine i ždrela | Risk factors, prognostic factors and quality of life of patients with malignant tumours of the oral cavity and pharynx | aligni tumori predstavljaju značajan medicinski problem i imaju veliki socijalno-ekonomski značaj. Česta su oboljenja u svim delovima sveta i zabrinjavajuća je sve veća učestalost malignih tumora i pomeranje starosne granice ka mlađim populacionim grupama. Među uzrocima smrtnosti nalaze se u svetu i kod nas na drugom mestu posle oboljenja kardiovaskularnog sistema. Značajna nova otkrića u oblasti dijagnostike i terapije su dovela do bitnog povećanja dužine preživljavanja obolelih što je aktuelizovalo pitanje kvaliteta života obolelih. Lečenje obolelih od malignih tumora usne šupljine i ždrela je složen medicinski i psihosociološki problem, zato što su operacije ovih tumora mutilantne i bitno menjaju način i kvalitet života; bolest kao takva uslovljava smanjenje radne sposobnosti, a nakon lečenja je neophodna kompletna psihološko-socijalna i fonijatrijska rehabilitacija. U cilju podizanja kvaliteta života obolelih i lečenih od malignih tumora usne šupljine i ždrela potrebna je sistematska, multidisciplinarna rehabilitacija bolesnika i edukativna adaptacija njegove okoline. Ispitivanje faktora rizika za nastajanje ovih malignih tumora omogućava nova saznanja koja se koriste pre svega u prevenciji bolesti. Praćenje dužine preživljavanja daje smernice u planiranju terapijskih modaliteta. Cilj rada je bio da se analizira kretanje obolevanja i umiranja od malignih tumora usne šupljine i ždrela tokom trinaest godina na području centralne Srbije; da se ispita kvalitet života obolelih od ovih malignih tumora u odnosu na demografske karakteristike, težinu kliničke slike i psihosocijalne parametre; da se identifikuju potencijalni faktori rizika za nastanak malignih tumora usne šupljine i ždrela i da se analizira trogodišnje preživljavanje obolelih. Metod. Analiza obolevanja od malignih tumora usne šupljine i ždrela je vršena korišćenjem podataka Instituta za javno zdravlje Srbije ,, Dr Milan Jovanović –Batut“ u Beogradu, a podaci o umrlima su dobijeni iz nepublikovanog materijala Zavoda za statistiku... | Introduction. Malignant tumours represent a significant medical problem, with a considerable socio-economic impact. The disease is common in all parts of the world, with a worrying tendency of prevalence of malignant tumours and lowering of the age limit to include younger population groups. It is the second leading cause of death, both globally and in our country, after cardiovascular disease. Major new diagnostic and therapeutic discoveries resulted in a significantly enhanced length of survival for patients, which brought to the fore quality of life issues for patients. The treatment of patients with malignant tumours of the oral cavity and pharynx is a complex medical and psycho-social problem, as surgical treatment of these tumours tends to cause disfiguring and significantly alters the way and quality of life; the disease in itself causes reduced working abilities, and a full psycho-social and phoniatric rehabilitation is required once treatment is completed. Improving the quality of life of diseased and treated patients with malignant tumours of the oral cavity and pharynx requires systematic, multi-disciplinary rehabilitation of patient and an educational adaptation of his/her environment. Research into risk factors for the development of these malignant tumours provides new insights which are primarily used in prevention of disease. Monitoring of the length of survival provides guidelines for planning treatment modalities. The goal of this paper was to analyse incidence and mortality rates for malignant tumours of the oral cavity and pharynx over the thirteen years in central Serbia; to investigate the quality of life of patients with this type of malignant tumour in relation to demographic characteristics, severity of clinical presentation and psycho-social parameters. To identify potential risk factors for developing malignant tumours of the oral cavity and pharynx and to analyse a three-year survival period of patients... | false |
Ehokardiografska procena mehanike miokarda kod bolesnika sa dijabetesom tipa dva | Echocardiographic evaluation of myocardial mechanics in patients with diabetes typ two | Diabetes mellitus tip 2 (DM) ima značajan uticaj na morfologiju i funkciju leve komore
nezavisno od drugih faktora rizika i komorbiditeta kao što su hipertenzija (HTA) i koronarna
bolest (AP). Cilj rada je bio da se ispitaju mogućnosti dopunskih i strain ehokardiografskih
parametara u otkrivanju dijabetesne kardiomiopatije (DCM) u odnosu na klasične, da se proceni
prediktivna vrednost pojedinih parametara na razvoj neželjenih događaja, i prediktivna vrednost
strain i strain rate analiza kod asimptomatskih pacijenata sa DM i mikroalbuminurijom.
Metod: Ispitivano je 210 pacijenata sa DM i to: (grupa I:70 samo DM, grupa II:70 DM i AP i
grupa III:70 DM i HTA), i 80 zdravih dobrovoljaca bez DM koji su služili kao kontrolna grupa.
Svim pacijentima određivani su klasični faktori rizika, rađena laboratorijska ispitivanja, testovi
na mikroalbuminuriju, pregled očnog dna, klinički pregled, ergo test, klasična ultrazvučna
merenja, tkivni Doppler, longitudinali, cirkumferencijalni strain i strain rate. Kontrolna
ultrazvučna merenja rađena su nakon godinu dana.
Rezultati: u poređenju sa kontrolama pacijenti u grupi I imali su povećanu masu leve komore
(LK),oštećenu relaksaciju LK, nižu ejekcionu frakciju (EF), frakciono skraćenje (FS) i manju
ekskurziju mitralnog anulusa (MAPSE). Prisustvo HTA dodatno oštećuje EF, FS i MAPSE i
pogoršava dijastolnu disfunkciju.Maksimalni globalni longitudinalni strain (Slong) i rani
dijastolni strain rate (SRlong E) sniženi su u grupi I u odnosu na kontrole, dok je
cirkumferencijalni strain (Scirc) smanjen samo ako je DM udružen sa HTA ili AP.
Prediktivna vrednost u predviđanju neželjenih događaja postoji za: EF, indeks mitralnog protoka
(E/A), indeks volumena leve pretkomore (LAVindeks; ml/m2), vreme deceleracije E talasa
(EDT), brzinu propagacije mitrlanog protoka (Vp),MAPSE, Slong, SRlong E, Scirc.
Zaključak: DM je nezavistan determinator morfologije i funkcije leve komore što se može
dokazati primenom klasične i strain rate ehokardiografije. Ove promene ne pokazuju jasnu
korelaciju sa trajanjem DM, metaboličkom kontrolom i mikrovaskularnim komplikacijama. | Diabetes mellitus type 2 (DM) has a significant impact on the morphology and
left ventricular function independent of other risk factors and co-morbidities such as
hypertension (HTA) and coronary heart disease (AP).The aim of this study was to examine the
possibility of additional strain and echocardiographic parameters in the detection of diabetic
cardiomyopathy (DCM) in relation to classical, to assess the predictive value of the parameters
on the development of adverse events, and the predictive value of strain and strain rate analysis
in asymptomatic patients with DM and microalbuminuria.
Method: 210 patients with DM divided in: (group I: 70 DM Group II: 70 DM and AP and Group
III: 70 DM and HTA), and 80 healthy subjects without DM who served as a control group. All
patients were determined by conventional risk factors, conducted laboratory tests, tests for
microalbuminuria, fundus examination, clinical examination, ergo test, conventional ultrasonic
measurements, tissue Doppler, longitudinal, circumferential strain and strain rate. Control
ultrasound measurements were made after one year.
Results: Compared with control group, patients in group I had increased mass of the left
ventricle (LK), damaged LK relaxation, lower ejection fraction (EF), fractional shortening (FS)
and mitral annular plane excursion (MAPSE). The presence of HTA further damaged EF, FS and
MAPSE and deteriorating diastolic disfunction. Peak global longitudinal strain (Slong) and early
diastolic longitudinal strain rate (SRlong E) decreased in group I compared to controls, while the
circumferential strain (Scirc) reduced only if DM is associated with hypertension or AP.
The predictive value in predicting adverse events exist for: EF, the index of the mitral flow (E /
A), left atrial volume index (LAV index), E wave deceleration time (EDT), the speed of
propagation of mitral flow (Vp), MAPSE, Slong, SRlong E, Scirc.
Conclusion: DM is an independent determinant of morphology and function of the LK which
can be proved by applying classical and strain rate echocardiography. These changes do not
show a clear correlation with the duration of DM, metabolic control and microvascular
complications. | true |
Relacije različitih vrsta plesova i ritmičke gimnastike | Relations between different types of dances and rhythmic gymnastics | Veliki broj različitih umetničkih sportova kao što su ples, ritmička gimnastika,
sinhrono plivanje, umetničko klizanje, predstavljaju sa kineziološke strane najkreativnije
sportske disciplina, a sa druge strane veliki problem prilikom ujednačavanja kriterijuma za
takmičarske pravilnike.
Problem ovog istraţivanja koje je obuhvatilo: plesačice sportskog plesa (20), plesačice
narodnog plesa (20), balerine (20) i ritmičke gimnastičarke (20), u ukupnom broju od 80
ispitanica, proistekao je iz dileme koliko različiti plesovi, kao prvenstveno umetničke
aktivnosti, imaju sportsko-kineziološke karakteristike, kao što su neke kondicione sposobnosti
iz prostora fitnes statusa. Koliko su, i u kakvim relacijama, te sposobnosti sa muzikalnošću i
ritmom, kao i mentalno-motoričkim potencijalom. Isto tako vaţno pitanje je i da li različite
vrste plesa i ritmička gimnastika imaju zajedničke regulativne mehanizme koji su zaduţeni za
kontrolu motoričkog odgovora, i da li različite kretne strukture uz različitu muziku formiraju
posebne obrasce mentalno-motoričkog ponašanja, kao što su ritam i koordinacija. Problem je
predstavljao i genetski potencijal nekih mentalnih sposobnosti, ritma, koordinacije i
muzikalnosti i koliko je on izraţen i značajan u različitim vrstama plesa i ritmičkoj gimnastici.
Neke morfološke karakteristike, kao što su telesna teţina i potkoţno masno tkivo, i uopšte
konstitucija, odnosno telesna kompozicija, svakako imaju uticaja na izvoĎenje kretnih
struktura u različitim vrstama plesa i ritmičkoj gimnastici, kao i na funkcionalnu sposobnost i
ukupan fitnes status. Ovde je vaţno pitanje da li su ti uticaji jednako značajni u različitim
plesovima i ritmičkoj gimnastici. Najzad, značajan problem u ovom istraţivanju je i u
pretpostavci koliko su neke komponente muzikalnosti i fitnes statusa uslovljene specifičnim
veţbanjem različitih kretnji uz muziku.
Predmet istraţivanja je funkcionalna analiza različitih vrsta plesa (sportski ples,
narodni ples i balet) i njihova relacija sa ritmičkom gimnastikom.
Cilj istraţivanja je bio da se utvrdi relacija fitnes statusa, muzikalnosti, ritma i
mentalno-motoričkog potencijala, različitih vrsta plesova i ritmičke gimnastike.
Posebna paţnja u ovom istraţivanju posvećena je funkcionalnoj analizi različitih vrsta
plesa: sportskog plesa, narodnog plesa, baleta, kao i ritmičke gimnastike. Ovo se, pre svega,
odnosi na pretpostavku da efikasnost u ovim aktivnostima, po hijerarhiji, zavisi najpre od
kvaliteta mišićne aktivnosti, kontraktilnih svojstava, njihovih biohemijskih i elektrohemijskih
procesa, mentalno – motoričkih i intelektualnih sposobnosti i stanja mehanizama koji regulišu
ove procese. Efikasnost se postiţe samo u uslovima kada su ostale komponente sloţenog
sistema motoričkog funkcionisanja (nervni sistem, koštano – zglobni sistem, antropometrijske
karakteristike, kardiovaskularni sistem, respiratorni, digestivni, endokrini sistem, itd.) u
optimalnom stanju. Dakle, funkcionalna analiza se u ovom istraţivanju odnosi na integralne
meĎuzavisne regulativne funkcije koje leţe u osnovi specifičnih kretnih struktura
(koordinacije) u različitim vrstama plesa i ritmičkoj gimnastici, a odnose se pre svega na fitnes
status, muzikalnost, ritam i mentalno – motoričke funkcije.
Funkcionisanja centralnog nervnog sistema pri sprovoĎenju motoričkih zadataka u
osnovi fenomenološke i strukturalne modele objašnjava se funkcionalnim hijerarhijskim
mehanizmima različitog nivoa. Najviši nivo u ovoj funkcionalnoj hijerarhiji ima hipotetski
centralni regulacioni ureĎaj koji kontroliše i koordinira funkcije regulativnih mehanizama ne
samo motoričkog, nego i kognitivnog i konativnog prostora. Ovo se pokazalo i u ovom
istraţivanju. Mehanizam za regulaciju kretanja je odgovoran za manifestacije koordinacije,
pokretljivost i ritma pa otuda je i dobijena njihova meĎusobna veza u ovom istraţivanju.
Rezultati govore u prilog ovoj teorije jer su se ritmičke gimnastičarke zbog svojih specifično
sportsko kinezioloških karakteristika pokazale kao dominantnije u odnosu na plesačice
sportskog plesa, plesačice narodnog plesa i balerine. Najveće vrednosti se uočavaju u
testovima pokretljivosti, testovima za procenu snage, mišićne izdrţljivosti, muzikalnosti i kod
testova za procenu koordinacije. Ovakvi rezultati svakako se mogu pripisati selekciji koja je
zbog svoje rane specijalizacije veoma bitna za specifičan sport kao što je ritmička gimnastika.
Tajming koji je deo funkcije regulatora kretanja je odgovoran za manifestacije
ritmičkih struktura, a pošto je povezan sa motoričkom memorijom i inteligencijom, otuda i
povezanost motorike sa ritmičkim pamćenjem i mentalnim potencijalom. Mehanizam za
energetsku regulaciju je pored repetitivne, izometrijske i eksplozivne snage (koje su
procenjivane u ovom istraţivanju u okviru fitnes statusa) je odgovoran za funkcionalni
kardiorespiratorni i metabolički odgovor organizma na bilo koje motoričke zahteve pre svega
kontrolom vegetativnih funkcija. Vegetativne funkcije su odgovorne i za odrţavanje dobro
izbalansirane unutrašnje ravnoteţe organizma pa time i na koncentraciju i odrţanje paţnje. U
ovom istraţivanju je dobijena pozitivna veza izmeĎu parametara za procenu funkcionalnog
statusa, ritmičkog pamćenja, mentalnih greški i koordinacije u ritmu u čemu je generator
povezanosti upravo regulator organskih funkcija.
Ovo znači da bi se bez funkcionalne analize interakcijskih i integralnih uticaja
motoričkih regulatora i kognitivnih procesora u konkretnom tipu plesa, gubila velika količina
relevantnih informacija u razumevanju uzroka i prirode povezanosti fitnes statusa,
muzikalnosti i mentalnog potencijala.
Prilikom pokušaja ispitivanja, utvrĎivanja i analize integralnog antropološkog
funkcionisanja ljudskog organizma gotovo je nemoguće izolovano posmatrati bilo koju
antropološku karakteristiku jer je svaka u sloţenim sveproţimajućim odnosima sa svakom
drugom. Ovo istraţivanje je to potvrdilo, a takoĎe je pokazalo da su se manifestne varijable za
procenu više različitih prostora u različitim vrstama plesova različito ponašale i da su na prvi
pogled nelogično bile povezane, jer su pripadale različitim prostorima. Ovakvu pojavu nije
moguće objasniti sa stanovišta strukturalne analize nego isključivo dubljom funkcionalnom
analizom latentnih regulativnih mehanizama u centralnom nervnom sistemu. Na osnovu
različitih istraţivanja faktorskog pristupa, moguće je samo formulisati tzv. strukturalne
modele, ali je bilo kakva valjana interpretacija rezultata nemoguća bez funkcionalnih hipoteza,
odnosno dubljih analiza uzročnika povezanosti pojavnih oblika i pokušaja sinteze dobijenih
rezultata u kojima su osnovni generatori u stvari funkcionalni regulacioni procesi različitog
nivoa i širine. U ovom istraţivanju se pokazalo da specifično motoričko funkcionisanje kakvo
je u svakom od četiri relativno različita ispitana područija, sportski ples, narodni ples, balet i
ritmička gimnastika, i adaptacije koje ono posledično ostavlja, zavisi od funkcija regulativnih
mehanizama koji pripadaju različitim antropološkim prostorima. Ovo znači da definitivno
motorički prostor nije moguće sagledati bez istovremene analize kognitivnih i konativnih
funkcija. Sloţene meĎusobne interakcije primećuju se posebno u povezanosti motorike,
morfologije, muzikalnosti i mentalnih potencijala. Ovo je u stvari zajedničko "gnezdo" gde je
u centru motoričko funkcionisanje a ton, boju i karakter mu daju funkcije mentalnih i
konativnih regulatora.
Dobijeni rezultati ukazuju na pojavu koja zavreĎuje paţnju i dublju analizu, kao što su
naizgled nelogične povezanosti varijabli različite prirode. Funkcionalnom analizom je
svakako moguće doći do samog "epicentra" te povezanosti. | A vast number of different artistic sports such as dance, rhythmic gymnastics,
synchronised swimming and figure skating are kinesiologically speaking the most creative
sports disciplines but on the other hand, they pose a great problem when standardizing the
criteria for competition rulebooks.
The subject matter of this research comprising: dancesport female dancers (20), folk
dance female dancers (20), balerinas (20) and rhythmic female gymnasts (20), 80 female
respondents in total, arose from the dilemma regarding the extent to which different dances, as
primarily artistic activities, have sporting and kinesiological features such as some fitness
abilities in the area of fitness status as well as regarding the level and nature of relations
between these abilities with musicality and tempo and between musicality and mental and
motor potential. It is equally important to find out whether different types of dance and
rhythmic gymnastics have common regulatory mechanisms which govern the control of motor
response and whether different movement structures to different music form specific patterns
of mental and motor behaviours such as rhythm and coordination. The subject matter also
included the genetic potential of some mental abilities, rhythm, coordination and musicality
and how prominent and significant it was for different types of dance and rhythmic
gymnastics. Some morphological characteristics such as body weight and subcutaneous
adipose tissue and body composition in general most certainly have influence on the
performance of movement structures in different types of dance and rhythmic gymnastics as
well as on the functional ability and the overall fitness status. The key question here is
whether those influences are equally significant for different dances and rhythmic gymnastics.
Finally, a significant topic of this research is also the assumption of the extent to which some
components of musicality and fitness status depend on specific exercise of different
movements to the music.
The research subject matter is the functional analysis of different types of dance
(dancesport, folk dance and ballet) and their relation to rhythmic gymnastics.
The aim of this research was to determine the relation between the fitness status,
musicality, rhythm and mental and motor potential of different types of dance and rhythmic
gymnastics.
In this research, a special focus was put on the functional analysis of different dance
types: dancesport, folk dance, ballet and rhythmic gymnastics. This primarily refers to the
assumption that efficiency in these activities by hierarchy chiefly depends on the quality of
muscle activity, contractile properties, their biochemical and electrochemical processes,
mental, motor and intellectual abilities and the state of mechanisms regulating these processes.
Efficiency is achieved only when other components of the complex motor functioning system
(nervous system, osteoarticular system, anthropometric characteristics, cardiovascular system,
respiratory, digestive and endocrine systems etc.) are in optimal condition. Therefore, the
functional analysis in this research refers to the integral inter-dependent regulatory functions
which underlie specific movement structures (coordination) in different types of dance and
rhythmic gymnastics and which refer to the fitness status, musicality, rhythm and mental and
motor functions.
Functioning of the central nervous system while conducting motor tasks is at the core
of phenomenological and structural models and it is explained by functional hierarchical
mechanisms of different levels. The highest level in this functional hierarchy has got a
hypothetical central regulatory device controlling and coordinating functions of regulatory
mechanisms of not only motor but also cognitive and conative spaces. This was confirmed in
this research too. The mechanism for regulating the movement is responsible for manifestation
of coordination, mobility and rhythm so this is how their mutual relation was obtained in this
paper in the first place. The results speak in favour of this theory since female rhythmic
gymnasts proved to be more dominant compared to dancesport female dancers, folk female
dancers and balerinas due to their specifically athletic kinesiological features. The largest
values are detected in mobility tests, tests for evaluating the strength, muscular endurance, and
musicality and in tests for coordination evaluation. Such results can most certainly be
attributed to the selection which, due to its early specialisation, is extremely important for
specific sports such as rhythmic gymnastics.
As a segment of movement regulator`s function, timing is responsible for
manifestation of rhythmic structures and since it is connected to motor memory and
intelligence, it results in the connection between motor skills and rhythmic memory and
mental capacity. In addition to the repetitive, isometric and explosive strength (evaluated in
this research within the fitness status), the mechanism for energy regulation is responsible for
functional cardiorespiratory and metabolic response of organism to any motor requirement
primarily by controlling the vegetative functions. Vegetative functions are also responsible for
maintaining the well-balanced inner equilibrium of the body and thus maintaining the
concentration and attention focus. In this research, a positive correlation between parameters
for evaluating the functional status, rhythmic memory, mental errors and coordination in
rhythm was obtained with the regulator of organic functions being the actual correlation
generator.
This means that without the functional analysis of interactive and integral effects of
motor regulators and cognitive processes in a specific dance type, a vast amount of relevant
information would be lost in trying to understand the cause and nature of the correlation
between the fitness status, musicality and mental capacity.
When attempting to test, identify and analyse integral anthropological functioning of
the human body, it is almost impossible to analyse separately any anthropological
characteristic since they all have a complex pervading relation with one another. This research
confirmed this and also proved that manifestation variables for evaluation of several different
spaces in different types of dance behaved differently and that at the first glance, they seemed
illogically related to each other since they belonged to different spaces. This phenomenon is
impossible to explain from the aspect of structural analysis since it solely requires deeper
functional analysis of latent regulatory mechanisms in the central nervous system. Based on
various studies of factorial approach, it is only possible to define so-called structural models
but any proper interpretation of results is impossible without functional hypotheses, or in-
depth analyses of relation causes of manifestations and without attempts to unify obtained
results in which basic generators are actually functional regulatory processes of different level
and view. In this research, it was confirmed that specific motor functioning (which seemed as
such in all four relatively different analysed areas: dancesport, folk dance, ballet and rhythmic
gymnastics) and adaptation which it inevitably results in, depend on functions of regulatory
mechanisms belonging to different anthropological spaces. This definitely means that motor
space cannot be analysed without simultaneous analysis of cognitive and conative functions.
Complex mutual interactions are particularly noticeable in the relations between motor skills,
morphology, musicality and mental capacity. This is actually a common “cluster” with motor
functioning in the centre of it and with a tone, colour and character provided by the functions
of mental and conative regulators.
The obtained results indicate the phenomenon which deserves attention and deeper
analysis just as those apparently illogical relations of variables different in nature. Most
certainly, it is possible to get to the very “epicentre” of this relation by means of functional
analysis. | true |
Phylogenetic analysis and molecular characterization of human immunodeficiency virus in Serbia | Filogenetska analiza i molekularna karakterizacija virusa humane imunodeficijencije u Srbiji | Virus humane imunodeficijencije (HIV) je retrovirus koji uzrokuje sindrom
stečene imunodeficijencije. Od početka epidemije pre 35 godina, ovim virusom
je inficirano više od 78 miliona ljudi a preko 30 miliona je umrlo. Visoka
genetička varijabilnost i brza evolucija HIV-a su ključni uzroci opstanka i
globalnog širenjaepidemije. HIV je filogenetski klasifikovan u dva tipa: HIV-1 i
HIV-2. Visoki diverzitet HIV-1 ogleda u postojanju četiri grupe (M, N, O, P) od
kojih su virusi grupe M uzročnici globalne HIV-1 pandemije. Grupa M virusa je
podeljena u više filogenetski različitih podtipova (A-D, F-H, J i K), pod-
podtipove (A1, A2, F1 i F2) i cirkulišuće rekombinantne forme. Distribucija
podtipova u svetu je složena i dinamična sa regionalnim HIV-1 epidemijama
unutar globalnog diverziteta. Molekularna filogenetska analiza, metod za
rekonstrukciju evolutivnih odnosa između nukleotidnih sekvenci, je tehnika za
proučavanje varijabilnosti virusa i dinamike transmisije unutar regionalnih
populacija. Procenjuje se da kod blizu polovine inficiranih osoba HIV infekcija
nije dijagnostikovana, zbog čega je identifikacija puteva transmisije izuzetno
značajna u cilju javno zdravstvenog nadzora. U ovom istraživanju primenjene
su savremene filogenetske metode u analizi HIV-1 sekvenci izolata iz Srbije u
cilju karakterizacije molekularne epidemiologije i dinamike transmisije, što je
ključno za bolje razumevanje karakteristika aktuelne HIV-1 epidemije u Srbiji.
FILOGENETSKA ANALIZA I MOLEKULARNA KARAKTERIZACIJA VIRUSA HUMANE
IMUNODEFICIJENCIJE U SRBIJI
Ciljevi
Ciljevi ovog istraživanja bili su određivanje aktuelne distribucije podtipova
HIV-1 u Srbiji. Ciljevi su obuhvatili i analizu transmisionih lanaca kao i
filogenetsko datiranje epidemije za najzastupljenije HIV-1 podtipove u Srbiji.
Istraživanje je takođe obuhvatilo analizu učestalosti i svojstava izmena
nukleotidne sekvence genoma koje su odraz trajanja HIV-1 infekcije i interakcije
virusa i domaćina.
Materijal i metode
U istraživanje su uključeni HIV-1 seropozitivni pacijenti praćeni u odeljenju za
HIV/AIDS, Klinike za infektivne i tropske bolesti, Kliničkog centra Srbije, u
Beogradu. Uzorci krvi od 155 pacijenata uključenih u studiju uzimani su u
periodu od 2008. do 2013. godine, a dodatno su u istraživanje uključene 162
sekvence sojeva iz Srbije deponovane u NCBI bazi podataka, koje su generisane
u periodu od 1997. do 2007. godine. Sekvence pol i env gena umnožene su
metodom reakcije lančane polimerizacije u dva kruga (engl. „nested
polymerase chain reaction“-nested PCR). DNK sekvence svih pozitivnih PCR
produkata su analizirane filogenetskim i drugim bioinformatičkim metodama.
Identifikacija podtipova i cirkulišućih rekombinantnih formi izvršena je
pomoću REGA alata za genotipizaciju kao i filogenetskom analizom pol
sekvenci. Ukupno, 304 virusne sekvence analizirane su različitim filogenetskim
softverskim paketima, u zavisnosti od postavljenog cilja. Konstrukcija
filogenetskih stabala je urađena primenom različitih filogenetskih metoda,
uključujući metode Bajesove statistike, korišćenjem kompjuterskih programa
MEGA, Paup i MrBayes. Filogenetska analiza urađena je na osnovu
nukleotidnog substitucionog modela izabranog na osnovu skora verovatnoće
pomoću Jmodeltest programa. U cilju identifikacije transmisionih lanaca,
definisanih kao skup virusnih varijanti koje potiču od istog soja, primenjeni su
REZIME
višestruki strogo definisani kriterijumi zasnovani na nukleotidnoj distanci i
statističkoj podršci filogenetskom grupisanju. Primenjene su različite analize
koje se zasnivaju na Bajesovoj statistici u cilju filogenetskog datiranja epidemije
za najzastupljenije HIV-1 podtipove u Srbiji. Bioinformatički pristup, zasnovan
na analizi učestalosti pojave istovremenog prisustva različitih baza na istoj
poziciji u genomu, poslužio je kao molekularni marker u proceni rane (kraće od
godinu dana) ili hronične (duže od godinu dana) HIV-1 infekcije. Posebno je
analiziran nukleotidni sastav i izmena kodona na poziciji 245 RT produkta pol
gena HIV-1 kao i povezanost promena sa dužinom trajanja infekcije i
filogenetskim grupisanjem.
Rezultati
Rezultati ovog istraživanja su pokazali da je među HIV-1 inficiranim osobama u
Srbiji dominantan podtip B virusa, sa prevalencijom od 90,8% (129/142), dok je
prevalencija drugih podtipova iznosila 9,2% (13/142). Filogenetskom analizom,
u koju su uključene 304 virusne sekvence, identifikovano je prisustvo većeg
broja transmisionih klastera i jedna transmisiona mreža. Sve sekvence u okviru
transmisionih klastera i transmisione mreže identifikovane su kao podtip B.
Ukupno, 42,2% (116/275) virusnih sekvenci pol gena podtipa B pokazalo je
lokalno filogenetsko grupisanje, dok je 57,8% (159/275) sekvenci filogenetski
pomešano sa izolatima iz Evrope i Amerike, što ukazuje na višestruko poreklo
HIV-1 epidemije u Srbiji. Većina sekvenci unutar filogenetski grupisanih
sekvenci 82,7% (96/116), poticala je od pacijenata iz Beograda, muškog pola,
kojima je najverovatniji način izlaganja HIV infekciji bio seksualni kontakt
(muškarci koji imaju seksualne odnose sa muškarcima – MSM). Analizom je
procenjeno da najraniji zajednički predak transmisione mreže, sačinjene od 45
virusnih sekvenci, potiče iz 1994. godine (95% IP : 1982–2000.). Procenjeno
poreklo najvećeg transmission klastera sačinjenog od 11 virusnih sekvenci,
dominanto izolovanih iz pacijenata koji su prijavili homoseksualni odnos kao
FILOGENETSKA ANALIZA I MOLEKULARNA KARAKTERIZACIJA VIRUSA HUMANE
IMUNODEFICIJENCIJE U SRBIJI
rizik infekcije, je znatno kasnije 2004. godina (95% IP: 2002–2006.). Analiza
porekla podtip G sekvenci izolata iz Srbije pokazala je da je naraniji predak
poreklom iz 1991 (95% IP: 1979–2000.). Filogenetsko istraživanje jednog
transmisionog klastera u kontekstu forenzičke analize pokazalo je da ispitivani
uzorci formiraju jasno izdvojen transmisioni lanac, u prilog a priori hipotezi o
njihovoj epidemiološkoj povezanosti. Međutim, uprkos utvrđenoj topologiji
filogenetskog stabla i parafiliji sekvenci subjekta 1 u odnosu na subjekte 2 i 3,
dobijeni rezultati ne mogu sa sigurnošću da dokažu neposrednu transmisiju
virusa između dva subjekta, kao ni smer transmisije. Analiza učestalosti pojave
istovremnog prisustva različitih baza na istoj poziciji u genomu, na osnovu
usvojene granice od 0,47% za ukupno 54% ispitanih virusnih sekvenci podtipa
B ukazivala je na trajanje infekcije kraće od godinu dana. Na poziciji 245
produkta RT gena u najvećem procentu 61% (168/275) identifikovana je
aminokiselina divljeg soja virusa, aminokiselina valin (V), dok je 36.7%
(101/275) na toj poziciji imalo aminokiselinsku izmenu. Najzastpljenija
promena aminokiselina na poziciji 245 produkta RT gena bila je metionin (M)
22.9% (63/275), zatim glutaminska kiselina (E) 7.7% (20/275), glutamin (Q)
5.5% (15/275), i ostale. Veoma visoka prevalenca, 93.6% (41/45), promene
aminokiseline na ispitivanoj poziciji pronađena je u okviru sekvenci koje su
obuhvađene transmisionom mrežom, dok je jednaka prevalence ove substitucije
pronađena među sekvencama rane i hronične infekcije.
Zaključak
Dobijeni rezultati doprinose stvaranju detaljne i jasne slike kompleksne HIV-1
epidemije u Srbiji. HIV-1 epidemijom u Srbiji i dalje dominira podtip B virusa,
ali sa promenom distribucije drugih podtipova kroz godine, pojavom novih
podtipova i povećanjem diverziteta među njima. U ovom istraživanju
okarakterisani su lanci transmisije podtip B virusa u Srbiji, dominantno
povezani sa seksulanom transmisijom MSM kontaktom. Pokazano je da je
REZIME
širenje HIV-1 epidemije unutar lokalnih transmisionih mreža počelo početkom
devedesetih godina, dok je širenje među pacijentima mlađeg uzasta, iz
Beograda, sa MSM kontaktom kao rizikom za transmisiju virusa počelo znatno
kasnije i predstavlja najskoriju epidemiju. Na slučaju jednog transmisionog
klastera ispitana je forenzička primena filogenetske analize. Analiza dužine
trajanja infekcije, pokazala je statističi značajno veću zastupljenost rane infekcije
u periodu od 2008. do 2013. godine. Ista prevalenca substitucije na kodonu 245
među sekvencama rane i hronične infekcije, uz visoku prevalencu iste
substitucije u okviru sekvenci transmisione mreže, ukazuje na ranu fiksaciju
ove promene nastale HLA selektivnim pritiskom. Pronađena je značajno viša
prevalenca substitucije na kodonu 245 u odnosu na preliminarne rezultate
frekvence alela HLA B* 57-01 među HIV-1 inficiranim pacijentima iz Srbije. | Human immunodeficiency virus (HIV) is a retrovirus, the causative agent of
Acquired immunodeficiency syndrome (AIDS). Since the beginning of the
epidemic over 35 years ago, more than 78 million people have been infected so
far and over 30 million have died. The high genetic variability and rapid
evolution of HIV have been critical to its persistence and spread throughout the
world. HIV-1 and HIV-2 comprise two distinct types of HIV. HIV-1 has
diversified extensively into numerous genetic forms, including four groups (M,
N, O, P), of which group M is causing the pandemic of HIV infection and AIDS.
Group M viruses are further classified in multiple phylogenetically distinct
subtypes (A-D, F, G, H, J and K), sub-subtypes (A1, A2, F1 and F2) and
numerous recombinant forms. The global distribution of HIV-1 is complex and
dynamic with regional epidemics representing only a subset of the global
diversity. Molecular phylogenetic analysis, a method of reconstructing
evolutionary relationships between nucleotide sequences, is one of the
strategies for studying viral diversity and transmission dynamics. It is
estimated that around half of HIV infected people are undiagnosed, making
identification of transmission networks important for targeted public health
intervention programs. In this doctoral dissertation modern phylogenetic
techniques were used to identify HIV-1 sequences from Serbia, to characterize
PHYLOGENETIC ANALYSIS AND MOLECULAR CHARACTERIZATION OF HUMAN
IMMUNODEFICIENCY VIRUS IN SERBIA
the molecular epidemiology and transmission dynamics which is crucial to
understand the actual characteristics of the Serbian HIV-1 epidemic.
The Aims of the Study
The aims of this research were to determine the current prevalence and
distribution of HIV-1 subtypes in Serbia. The objectives also included
identification of local transmission networks and reconstruction of the history
of the introduction of founder strains. Different molecular footprints on HIV-1
sequences and their association with duration of infection and phylogenetic
clustering were also investigated.
Materials and Methods
The study enrolled HIV-1 seropositive patients attending the HIV/AIDS
Center, University Hospital for Infectious and Tropical Diseases, Clinical Centre
of Sebia, Belgrade. Blood samples from 155 patients were collected from 2008 to
2013, whereas 162 HIV-1 sequences from Serbian isolates deposited in the NCBI
database, dating from 1997 to 2007, were also included in the study. Nested-
PCR (Polymerase chain reaction) method was used for amplification of the pol
and env gene of HIV-1. All positive PCR products were directly sequenced and
further analyzed by different phylogenetic and other bioinformatics approach.
HIV-1 subtypes and circulating recombinant forms (CRF) were identified both
by REGA subtyping tool and phylogenetic analysis of the pol gene sequences.
Overall, 304 sequences were analysed with different phylogenetic software
packages, depending on specific objective. Phylogenetic trees reconstruction
was performed using different methods including Bayesian inference of
phylogeny as well as dedicated softwares such as MEGA, PAUP and MrBayes.
All analyses were performed under nucleotide substitution model that was
chosen based on the likelihood scores obtained by jModeltest. In order to
SUMMARY
identify transmission clusters, defined as viral lineages derived from the same
variant in the Serbian population, we applied different series of rigorous criteria
sets, based on genetic distance and bootstrap support. A different approach,
based on Bayesian phylogenetic inference, has been employed here to elucidate
the ancestry of HIV-1 clades. A bioinformatics approach was used to estimate
the duration of infection by calculating the fraction of ambiguous nucleotides in
the sequence as a delimiter for more recent (less than 1 year) versus chronic
infection (longer than 1 year). By analyzing complete dataset of subtype B
sequences, prevalence of amino acid (aa) substitutions at 245 codon, and
association with duration of infection and phylogenetic clustering, were
investigated.
Results
Results of this study showed that among HIV-1 infected patients in Serbia
subtype B predominated 90.8% (129/142), while the prevalence of non B
subtypes was 9.2% (13/142). Phylogenetic analyses, that included 304 viral
sequences, revealed a number of transmission clusters that accomplished all
predefined criteria sets, along with one large transmission network. All
sequences within transmission clusters and transmission network were
identified as subtype B sequences. In total, 42.2% (116/275) of viral pol gene
sequences were found within local phylogenetic clusters, while 57.8% (159/275)
were found intermixed in the phylogenetic tree with sequences sampled Europe
and America, indicative of multiple subtype B introductions. The majority of
clustering sequences 82.7% (96/116) were from male patients living in Belgrade
that predominantly reported MSM (men who have sex with men) as
transmission category. The tMRCA (time of the Most Recent Common
Ancestor) inferred for the local subtype B transmission network composed of 45
sequences was in 1994 (95% Higher Posterior Density (HPD): 1982–2000).
Estimated temporal origin for the largest local subtype B, MSM associated
PHYLOGENETIC ANALYSIS AND MOLECULAR CHARACTERIZATION OF HUMAN
IMMUNODEFICIENCY VIRUS IN SERBIA
transmission cluster composed of 13 sequences was much more recent, 2004
(95% HPD: 2002–2006). The early nineties were found to be temporal origin of
subtype G in Serbia, 1991 (95% HPD: 1979–2000). Results of the phylogenetic
exploration of one particular transmission cluster in a forensic context have
shown query samples to form a well-supported transmission chain, in support
of the a priori hypothesis of their epidemiological linkage. However, in spite of
the cluster topology with paraphyly of subject 1 sequences to those of subjects 2
and 3, this finding is not sufficient to unambiguously prove the transmission
event and its direction. Based on the threshold of 0.47% ambiguous bases per
sequence a total of 55.1% of samples (114/207) were classified as a recent
infection, of duration of less than 1 year, whereas among subtype B samples this
percentage was 54% (58/180). The predominant aa at RT codon 245 was the
wild type valine (V), found in 61% (168/275), hence 36.7% (101/275) contained
mutation at this position. The most common substitution at RT codon 245 was
methionine (M) 22.9% (63/275), followed by glutamic acid (E) 7.2% (20/275),
glutamine (Q) 5.4% (15/275) and others. Very high prevalence 93.6% (41/45) of
aa substitutions at the investigated position was found among sequences from
transmission network.
Conclusions
Results obtained in this research, enable drawing a more comprehensive and
dynamic picture of the HIV-1 epidemic Serbia. HIV epidemics in Serbia
continues to be dominated with subtype B, but with changes in distribution of
non B subtypes over time, the emergence of new non B subtypes and increased
genetic diversity among them. In this study we characterized a chain of
ongoing subtype B HIV-1 transmission spanning the period of 16 years. Results
of this research showed that the most encountered risk factor for infection with
subtype B virus was the MSM transmission. Furthermore, transmission clusters
were highly associated with MSM rather than other transmission risks. Our
SUMMARY
data support the need for increased public health interventions targeting MSM.
This research indicated that local epidemic spread within transmission
networks and outside the firstly implicated IDUs community dating from the
beginning of the nineties, while epidemic spread of HIV subtype B among
MSMs represents the most recent HIV-1 epidemic in Serbia. Based on
transmission clusters analyses forensic application of phylogenetics was also
explored. Estimation of the duration of infection, based on the ambiguous
nucleotides sequence content, suggested an increasing proportion of recent
infections, significantly higher in the second half of the study period. Equal
prevalence of RT 245 substitutions in samples from recent and chronic HIV
infection, together with high prevalence of this polymorphism in sequences
within transmission network, might suggest early fixation of an HLA induced
selective imprint, during intra-host viral evolution. Significantly higher
prevalence of RT 245 substitution, compared to the preliminary reports of the
HLA-B*57-01 allele frequency in HIV infected population in Serbia, was found. | true |
Uticaj operativne metode na ishod hirurškog lečenja sindaktilije šake kod dece | The impact of operative technique on the outcome of the hand syndactyly surgical treatment in children | Sindaktilija predstavlja jednu od najčešćih anomalija šake. Definiše se kao postojanje urođeno
sraslih prstiju i spada u grupu poremećaja u diferencijaciji. Može se javiti kao izolovana pojava
ili u sklopu više od 28 različitih sindroma. U toku proteklih dvesta godina opisane su brojne
hirurške tehnike za rešavanje ovog urođenog deformiteta šake.
CILJ RADA
Cilj našeg rada je bio: evaluacija ishoda lečenja pacijenata operisanih klasičnom tehnikom sa
transplantatima i dece operisane tehnikom privremene tkivne ekspanzije bez primene kožnih
transplantata i poređenje uspešnosti lečenja ovih metoda.
METODE ISTRAŽIVANJA
Naša studija je obuhvatila decu sa sindaktilijom šake koja su u periodu od 2006 do 2014
operisana i nadgledana najmanje godinu dana od operacije. Svi ispitanici su u podeljeni u dve
grupe. Prva grupa dece operisana je na klasičan način uz korišćenje transplantata kože (31
dete), a u drugoj grupi je primenjenena tehnika privremene tkivne ekspanzije i lokalnih
režnjeva bez kožnih transplantata (30 dece). Svi pacijenti su operisani u uslovima opšte
anestezije. Analiza ishoda lečenja učinjena jeprema Weberovoj deskriptivnoj metodi i
funkcionalni rezultati su određivani kao : dobri, zadovoljavajući i loši. Istovremeno vršeno je i
poređenje uspešnosti lečenja u dve ispitivane grupe.
REZULTATI
Od ukupnog broja pacijenata (61) uzrasta šest meseci do šest godina (prosečno 17 meseci) bilo
je 42 dečaka i 19 devojčica. Imali smo 39 kompletnih i 22 nekompletne sindaktilije.
Mekotkivna spojenost prstiju je evidentirana kod 53 pacijenta, a koštana kod osmoro dece.
Najčešće su bili zahvaćeni leva šaka i treći interdigitalni prostor. Udružene anomalije su se
javile kod 30 pacijenata i to najčešće u vidu Polandovog sindroma. Komplikacije su se javile
kod osam pacijenata u prvoj grupi i kod jednog deteta u drugoj. Rezultati u prvoj grupi su bili
dobri kod 15, zadovoljavajući kod 11 pacijenata i loši kod pet ispitanika. U drugoj grupi ishod
lečenja je bio dobar kod 24 dece, zadovoljavajući kod pet pacijenata i loš kod jednog deteta.
ZAKLJUČAK
Vrsta hirurške tehnike ima veliki uticaj na konačan ishod lečenja dece sa sindaktilijom šake.
Značajno bolji rezultati su postignuti primenom operativne metode bez transplantata u odnosu
na metodu sa transplantatima. Hirurška procedura sa privremenom ekspanzijom kože i lokalnim
režnjevima bez kožnih transplantata predstavlja novi pristup u rešavanju sindaktilija šake koja u
većini slučajeva daje dobre funkcionalne i estetske rezultate. | INTRODUCTION: Syndactyly is one of the most common congenital anomaly of the hand in
children. Fingers are webbed with functional limitations and an abnormal appearance. In most
cases it presents an isolated malformation, while less frequently it is combined with other
congenital abnormalities. A great number of syndactyly release techniques have been described
over last two centuries.
OBJECTIVES: The aim of our study is outcome assessment of congenital syndactyly surgery:
using temporarytissue expansion of the dorsal hand and local flaps, without skin grafts and
classical technique dividing fingers using skin grafts.
METHODS: Our study included children with congenital hand syndactylydividing in two
groups, treated in period from 2006-2014by operative technique with temporarytissue expansion
of the dorsal hand skin and local flaps, without skin grafting in one group and classical technique
using skin grafts in another. In all cases surgery was performed under general anesthesia.
According to Weber’sdescriptive method, the functional outcome at the end ofthefollow-up
period was categorized as good, fair or bad. All patients were evaluated for associated anomalies.
RESULTS: Sixtyone children (42 males, 19 females), aged from 6 months to 6 years (mean age
17 months), were operatedby one of the previously described techniques. There were 39 cases
with complete syndactyly and 22 with the incomplete, mostly involving left hand and the third
web. There were 53 patients with the simple syndactyly and eight cases with bone fussion.
Associated anomalies were diagnosed in 30 patients mostly with Sy Poland. First group included
31 operated children while second group involved 30 patients. The follow up period ranged from
one to five years, mean duration 33months. The functional results in the first group were: good in
15patients, fair in 11 and bad in five case. In the second group outcome were: good in 24
children and fair in five patients.
CONCLUSION: The type of operative technique has a great influence on final outcome in
syndactyly management. We got mutch better results using procedure without skin grafts, than
classical operative method. Surgical procedure with temporarytissue expansion of the dorsal
hand skin and local flaps, without skin grafting is effective method of congenital syndactyly
treatment in children with good functional and aesthetic results. The advantages of this technique
are the reduction of surgery duration andavoiding certain complications, such as web hair growth
and hyperpigmentation involving skin grafts. | true |
Prediktivni faktori maligniteta kod bolesnika sa oksifilnim tumorom štitaste žlezde | Malignancy predictors for patients with oxyphile tumors of the thyroid gland | Uvod: Za razliku od većine drugih karcinoma štitaste ţlezde, oksifilni karcinomi se vrlo
teško preoperativno dijagnostikuju vizualizacionim metodama ili punkcionom biopsijom s
obzirom na to da je ćelijska morfologija oksifilnih adenoma i karcinoma vrlo sliĉna, a
invaziju kapsule ili krvnih sudova, koja karakteriše oksifilne karcinome, nije moguće
citološki dokazati. U ovoj studiji ispitali smo moguće prediktivne faktore maligniteta kod
bolesnika sa oksifilnim tumorom štitaste ţlezde u cilju pravilne selekcije pacijenata za
operativnu terapiju i izvoĊenja odgovarajućeg tipa operacije.
Cilj: Prvi cilj je bio da se ispitaju epidemiološke i kliniĉke karakteristike operisanih
pacijenata sa oksifilnim tumorom štitaste ţlezde. Drugi se odnosio na odreĊivanje
prediktivnih faktora za pojavu oksifilnog karcinoma.
Metode: U okviru ove retrospektivne kohortne studije analizirane su epidemiološke i
kliniĉke karakteristike pacijenata sa oksifilnim tumorima štitaste ţlezde. Podaci su
prikupljeni iz istorija bolesti za 256 pacijenata koji su u periodu od 1999. do 2008. godine
operisani zbog oksifilnog tumora štitaste ţlezde u Centru za endokrinu hirurgiju Kliniĉkog
centra Srbije u Beogradu. Operisani pacijenti su na osnovu histopatološkog nalaza podeljeni
u dve grupe ispitanika: pacijente sa oksifilnim adenomom i pacijente sa oksifilnim
karcinomom. Za svakog ispitanika su prikupljeni sledeći podaci: demografske karakteristike,
navike, izloţenost zraĉenju, duţina trajanja bolesti štitaste ţlezde pre operacije, liĉna i
porodiĉna anamneza, laboratorijski, histopatološki kao i ehotomografski nalazi. U statistiĉkoj
analizi podataka korišćeni su χ kvadrat test, univarijantna i multivarijantna regresiona analiza.
7
Rezultati: Oksifilni karcinom imalo je 114 bolesnika (32 muškarca, 82 ţene, proseĉne
starosti 52,1 godina, a opseg godina kretao se od 26 do 89), a adenoma 142 pacijenta (16
muškaraca i 126 ţena, proseĉne starosti 52,9 godina, a opseg godina kretao se od 15 do 77).
Rezultati univarijantne regresione analize pokazali su da su muški pol, koncentracije
tireoglobulina jednake ili veće od 300 ng/ml i veliĉina tumora preko 3cm znaĉajno ĉešće bili
prisutni kod pacijenata sa oksifilnim karcinomom, a Hašimoto tiroiditis i pozitivna AntiTPO
antitela znaĉajno reĊe, u poreĊenju sa osobama koje su operisane zbog oksifilnog adenoma.
Prema rezultatima multivarijantne regresione analize jedini znaĉajni nezavisni prediktor
maligniteta je koncentracija tireoglobulina jednaka ili veća od 300 ng/ml (OR=5,88, CI 2,78-
12,05, p=0,001).
Zaključak: Osobe sa oksifilnim karcinomom, u poreĊenju sa osobama koje su imale
oksifilne adenome, znaĉajno su ĉešće bili muškarci, ĉešće su imale vrednosti titra
tireoglobulina veće od 300ng/ml i ĉešće su imale dijametar tumora veći od 3cm, a reĊe su
imale pozitivne vrednosti titra antiTPOAt i reĊe su imale Hašimotov tiroiditis. Jedini
nezavisni znaĉajni prediktor oksifilnih karcinoma je vrednost tireoglobulina veca od 300
ng/ml. U cilju sagledavanja nezavisnih prediktora maligniteta kod pacijenata sa oksifilnim
tumorom štitaste ţlezde neophodna su dalja multicentriĉna istraţivanja. | Introduction: In contrast to the majority of other thyroid carcinomas it still seems difficult to
establish a correct preoperative diagnosis for oxyphile carcinomas of the thyroid considering
the fact that the cell morphology of oxyphile adenomas and carcinomas is similar and that
capsular and vascular invasion, which are features of oxyphile carcinomas, cannot be
determined by cytology findings. In this study we sought for predictive factors of oxyphile
carcinoma in order to enable a surgeon to indicate operative treatment and to perform an
adequate operation for each patient with an oxyphile neoplasm of the thyroid.
Objectives: The goals of this survey were to investigate epidemiological and clinical
characteristics of patients operated for oxyphile tumors of the thyroid gland, to determine
malignancy predictors for oxyphile carcinoma and to highlight their importance.
Methods: In this retrospective study we have analyzed medical files of all patients with
oxyphile tumors of the thyroid operated between 1999 and 2008 in the Center for endocrine
surgery of the Clnical Center of Serbia in Belgrade. A total of 256 patients were included in
this study, which were, on the basis of their definite histopathological diagnosis, divided into
oxyphile adenomas and oxyphile carcinomas. The following data were collected for each
patient: demographic data, smoking habits, radiation exposure, preoperative duration of
illness, personal and familiar medical history, laboratory data, histopathological and
sonographic findings. The results of our survey were statistically analyzed by χ square test,
univariate and multivariate logistic regression.
9
Results: In 114 patients we found oxyphile carcinoma (32 males, 82 females, average age
52,1 years, range 26 – 89 years) and in 142 patients oxyphile adenoma (16 males, 126
females, average age 52,9 years, range 15 – 77). The results of the univariate analysis showed
that male gender, Thyroglobulin concentrations equal and higher than 300ng/ml and tumor
diameter over 3cm were significantly and more frequently present in patients with oxyphile
carcinoma compared to patients with oxyphile adenoma while coexistent Hashimoto
thyreoiditis and positive AntiTPO Antibodies appeared significantly less frequent in the
carcinoma group. The parameter with a p value <0,1 in the univariate test, were then
reexamined through multivariate regression analysis in which elevated preoperative
Thyroglobulin concentrations (≥ 300ng/ml) were the only independent predictor of
malignancy for patients with oxyphile tumors of the thyroid gland (OR=5,88, CI 2,78-12,05,
p=0,001).
Conclusion: According to our results preoperative Thyroglobulin levels equal and over
300ng/ml showed as an independent predictive factor for oxyphile carcinomas of the thyroid
gland. In order to gain further conclusions considering the predictive factors for malignancy
in patients with oxyphile tumors of the thyroid it would be necessary to analyze a higher
number of such patients which could only be possible through a large multicentric study. | true |
Procena strukturnih i funkcionalnih promena nervnog sistema kod pacijenata sa Gošeovom bolešću tipa 1 | Assessment of structural and functional changes of the nervous system in patients with type 1 Gaucher disease | Cilj ove studije preseka je da se pruže dokazi o funkcionalnim promenama u
centralnom nervnom sistemu obolelih od Gošeove bolesti tipa 1 (GB1) bez
kliničkih neuroloških manifestacija, i da se utvrdi da li postoje i strukturne
promene.
Metodologija: U istraživanje je uključeno 28 pacijenata sa GB1 i isti broj
zdravih ispitanika sparenih po polu, godinama života i dominantnoj ruci.
Katalitička aktivnost β-glikocerebrozidaze u leukocitima periferne krvi
utvrđena je spektrofluorometrijskim metodom. Analiza gena GBA1 izvedena je
direktnim sekvenciranjem. Procena funkcionalnih promena nervnog sistema
obavljena je 18F-FDG-PET snimanjem po protokolu za statičke studije mozga.
Kvantitativna obrada pojedinačnih nalaza i kvantitativna grupna analiza
obavljene su metodom statističkog parametarskog mapiranja funkcionalnih slika.
Evaluacija promena u funkcionisanju mozga obavljena je i primenom fMR na
skeneru jačine magnetnog polja 3 T korišćenjem 32-kanalne zavojnice za glavu.
Protokol akvizicije sastojao se od brze gradijent eho akvizicije sa preparacijom
magnetizacije. Procenjivanje promena u debljini moždane kore uz kvantifikovanje
zapremina pojedinih formacija mozga vršeno je korišćenjem tehnika kortikalnog
mapiranja, kao i tehnike morfometrije zasnovane na poređenju voksela. Snimljeni su
somatosenzorni potencijali izazvani električnom stimulacijom n. medianus-a obe
ruke. Nadražajima trajanja 0,2 ms delovalo se na frekvenciji od 5 Hz. Polni
hormoni mereni su radioimunološki metodom, korišćenjem gama scintilacionog
brojača.
Rezultati: Kod obolelih od GB1, detektovana je nova mutacija c.968A>G u
egzonu 7 gena GBA1. Posle 18F-FDG-PET snimanja, karakterističan obrazac
regionalnog hipometabolizma glikoze u mozgu dobijen je grupnom SPM analizom za
p < 0,001 bez korekcije za višestruka poređenja. Značajno niža aktivacija mozga
tokom fMR pri izvođenju motoričkog zadatka utvrđena je u šest klastera.
Signifikantno manja debljina korteksa posle korekcije Monte Carlo Null Z sa
značajnošću p < 0,001 konstatovana je u pet klastera u levoj hemisferi i jednom
klasteru u desnoj hemisferi mozga. Signifikantno manja zapremina utvrđena je
samo u putamenu, levo p < 0,03 a desno p < 0,01. Kod zdravih muškaraca, značajna je
negativna povezanost centralnog vremena sprovođenja SSEP (N20-N13) sa
testosteronom (r = - 0,571, p = 0,085), a kod obolelih sa estradiolom (r = - 0,8220,
p = 0,007). Kod zdravih žena, signifikantna je pozitivna korelacija latence N13 i
estradiola (r = + 0,783, p = 0,037), a kod obolelih negativna korelacija latence N9 i
estradiola (r = - 0,789, p = 0,035).
Zaključak: U GB1 bez kliničkih neuroloških manifestacija, funkcionalne
i strukturne promene postoje i u CNS-u. Na nivou CNS-a postoji seksualni
diverzitet: polni hormoni su na različite načine povezani s ovom bolešću kod
žena i muškaraca. | The aim of this cross-sectional study is to provide evidence of functional changes
of the central nervous system in patients with type 1 Gaucher disease (GD1) without
clinical neurological manifestations, and to determine if there are structural changes.
Methodology: The catalytic activity of β-glucocerebrosidase in peripheral blood
leukocytes was determined using the spectrofluorometric method. Direct sequencing of the
GBA1 gene was also performed. Computerized tomographic recording using the 18F-FDG-
PET was performed to assess central nervous system functional changes during rest.
Quantitative processing of individual findings and quantitative group analysis were done
using statistical parametric mapping of functional images. Evaluation of changes in brain
functioning was also carried out using fMRI on a scanner with a magnetic field strength of
3 T employing a 32-channel head coil. The acquisition protocol consisted of a quick
gradient echo acquisition with the preparation of magnetization. Assessment of changes in
cortical thickness, with the volume quantifications of individual brain formations, was
performed using cortical mapping techniques and morphometry based on voxel-based
morphometry. Somatosensory evoked potentials (SSEP) were recorded after electrical
stimulation of the median nerve in both arms. Stimuli of 0.2 ms duration, at a frequency of
5 Hz, wеre used. Sex hormones were measured using radioimmunoassay method with
gamma scintillation counter.
Results: In patients with GD1, a novel mutation c.968A>G in exon 7 of the GBA1
gene was detected. After 18F-FDG-PET recording, the characteristic pattern of regional
glucose hypometabolism in the brain was obtained by group SPM analysis for p < 0.001
without correcting for multiple comparisons. While performing movement exercises, a
significantly lower brain activation in the six clusters was observed on fMRI. Following a
Monte Carlo Null Z correction, a significantly lower cortex thickness p < 0.001 was seen in
five clusters in the left hemisphere, and one cluster in the right hemisphere of the brain.
Significantly smaller volume was observed only in both putamens, with values being on the
left p < 0.03, and on right p < 0.01. In healthy men, there was a significant negative
correlation observed between the central conduction time of SSEP (N20-N13) with
testosterone (r = - 0.571, p = 0.085). Interestingly, a negative correlation was also observed
in male patients with оestradiol (r = - 0.8220, p = 0.007). In healthy women, there is a
positive correlation between N13 latency and оestradiol (r = + 0.783, p = 0.037), while a
negative correlation between N9 latency and оestradiol in diseased women (r = - 0.789,
p = 0.035).
Conclusion: In GD1 patients without clinical neurological manifestations,
functional and structural changes exist in the CNS. At the level of the CNS, gender
discrepancies are observed; sex hormones appear to function in different ways based on
gender in both healthy and diseased groups. | true |
Povezanost rane primarne perkutane koronarne intervencije sa mortalitetom i kvalitetom života bolesnika sa infarktom miokarda sa elevacijom ST segmenta | Connetion of early primary perutaneous oronary intervention with mortality and quality of life of patients with myoardial infarction with ST segment elevation | Primena reperfuzione terapije se preporučuje za pacijente sa infarktom miokar-
da sa ST segment elevacijom (STEMI), a vremenski interval kašnjenje sistema je predlože-
no kao merilo indeksa kvaliteta pružanja medicinske nege u lečenju pacijenata sa STEMI
primarnom perkutanom koronarnom intervencijom (pPCI). Međutim, posmatranje vre-
mena od pojave simptoma do primene pPCI (ukupno ishemijsko vreme (TD)) je rele-
vantnije, jer oštećenje miokarda počinje sa pojavom simptoma. Do sada nije sprovedena
slična studija u Srbiji koja bi povezala TD sa lošim ishodima kod pacijenata sa STEMI
lečenim pPCI.
Cilj: Ova studija je imala za cilj procenu ishoda i kvaliteta života kod pacijenata sa
STEMI u odnosu na TD u dugoročnom praćenju.
Metode: Analizirali smo 507 pacijenata sa STEMI koji su lečeni primenom pPCI. Paci-
jenti su klasifikovani prema trajanju TD na pacijente kod kojih je intervencija primenjena
u prva četiri sata od početka simptoma i pacijenata kod kojih je intervencija primenjena
nakon četiri sata od početka simptoma. Tokom 48-mesečnog praćenja upoređivali smo
osnovne karakteristike, kliničke nalaze, ishode i kvalitet života kod ovih pacijenata.
Rezultati: Pacijenti sa STEMI kod kojih je pPCI primenjena nakon 240 minuta od
početka simptoma imaju značajno veću incidencu dijabetes melitusa i zastupljenost žen-
skog pola u odnosu na pacijente kod kojih je pPCI primenjena u intervalu kraćem od 240
minuta. U ostalim demografskim, kliničkim i angiografskim varijablama nije bilo razlike.
Četvorogodišnja opšta smrtnost u celoj grupi ispitanika je iznosila 18,74% (95 pacijena-
ta), zabeležili smo značajne razlike u stopi smrtnosti između ispitivanih grupa (12,6%
naspram 23,3% p = 0,002). U multivarijantnoj analizi nakon prilagođavanja za druge fak-
tore mortaliteta, TD> 240 min. je ostao nezavisni prediktor mortaliteta (OR 2,087 95% CI
(1.002-4.345) p = 0,049) tokom praćenja. Osim TD, nezavisni prediktori za smrtnost su
bili: dijabetes melitus, starost, trosudovna koronarna bolest, prethodna revaskularizacija
i srčana insuficijencija (Killip≥2). Nezavisni prediktori za kvalitet života povezan sa zdra-
vljem su bili starost, pol, dijabetes melitus i arterijska hipertenzija. U našoj studiji TD nije
bio povezan sa kvalitetom života.
Zaključak: kašnjenje sa priemnom pPCI više od 240 minuta povezano je sa mortalitetom.
Smanjenje totalnog ishemijskog vremena je presudno za pacijente sa STEMI lečenim pPCI.
Povećani napori u organizaciji zbrinjavanja pacijenata sa STEMI su od suštinskog značaja za
smanjenje kašnjenja sa primneom pPCi i povećanja efikasnosti primenjene terapije. | Timely reperfusion therapy is recommended for patients with ST seg-
ment elevation myocardial infarction(STEMI), and system delay has been proposed as a
performance measure in treatment of patients with primary percutaneous coronary in-
tervention (pPCI). However, focusing on the treatment delay (total ischemic time (TD))
is more relevant, since myocardial impairment starts with symptoms onset. No previous
studies have demonstrated the association between TD and outcome in patients with STE-
MI treated with pPCI in Serbia.
Objective: This study aimed at evaluating long term outcomes and quality of life in
patients with STEMI according to the TD.
Methods: We analyzed 507 patients with STEMI who were admitted for pPCI. The
patients were classified according to the duration of TD into patients with symptom onset
to balloon time less than 240 minutes and the patients who had the pPCI intervention four
hours after the symptoms onset. During the 48-month follow up we compared baseline
characteristics, clinical findings, outcomes and quality of life among these patients.
Results: Patients with STEMI undergoing primary percutaneous coronary intervention
with symptom onset to balloon time more than 240 minutes had higher incidence of diabe-
tes mellitus and there were more patients of female sex compared to patients treated earlier.
In other baseline and angiographic variables two groups were similar. Four year mortality
in entire cohort was 18,74% (95 patients), and we recorded significant differences in morta-
lity between groups (12,6% vs 23,3% p=0,002). In multivariable analysis adjusted for other
predictors for mortality, TD>240 min. was independent predictor for mortality (OR 2.087
95%CI(1.002-4.345) p=0,049) during the follow up. Besides treatment delay, independent
predictors for mortality were: diabetes mellitus, age, three vessel coronary artery disease, pri-
or revascularization and heart failure (Killip≥2). Independent predictors for HRQoL were
age, sex, diabetes mellitus and arterial hypertension. TD was not associated with HRQoL.
Conclusion: More than 240 minutes treatment delay was associated with mortality.
The reduction of treatment delay is crucial for patients with STEMI treated with pPCI.
Joint actions in organization and care of patients with STEMI are essential to increase
treatment efficacy and reduce adverse outcomes. | true |
Ispitivanje ekspresije proteina ćelijskog ciklusa kod bolesnika sa karcinomom bubrežnih ćelija | The analysis of cell cycle proteins expression in patients with renal cell carcinoma | Karcinom bubrežnih ćelija je najčešći maligni tumor bubrega, naročito muške populacije. U
odnosu na klasifikaciju, koja obuhvata brojne histološke varijante, kao i činjenicu da ne
postoji specifičan tumor marker, cilj ove doktorske disertacije bio je da se analizira
imunohistohemijska ekspresija odabranih proteina koji regulišu ćelijski ciklus (ciklina A,
ciklina B, ciklina D1, p16 i p57) u uzorcima iz tumora nakon nefrektomije na Klinici za
urologiju Kliničkog centra Srbije i odeljenju urologije Kliničko-bolničkog centra „Dr Dragiša
Mišović“ u Beogradu u periodu od 2010. do 2013. godine, da se ispita metodom qRT-PCR
ekspresija gena koji kodiraju ove proteine (CCNA, CCNB, CCND, CDKN2A, CDKN1C) na
DNK izolovanoj iz parafinskih kalupa, kao i da se ispita međusobna korelacija dobijenih
rezultata u odnosu na kliničko-morfološke parametre (pol, starost, nuklearni gradus, stadijum
bolesti, veličinu tumora, preživljavanje). Ova retrospektivna studija uključivala je 74 pacijenta
sa, u proseku, tumorom srednje veličine, svetloćelijskim histološkim tipom, nižim gradusom i
nižim TNM stadijumom bolesti. Imunohistohemijski metod je pokazao visok nivo ekspresije
ciklina A kod starijih pacijenata ženskog pola, sa većim dijametrom tumora, višim gradusom i
višim TNM stadijumom, bez statističke značajnosti, i značajnu ekspresiju u papilarnom
histološkom tipu i kod pacijenata sa smrtnih ishodom. Ekspresija CCNA je pokazala
normalan nivo ili duplikaciju jednako u grupi visokog gradusa. Ekpresija ciklina D1 opada sa
povećanjem starosne kategorije i dimenzije tumora, slična je kod višeg i nižeg stadijuma,
razlika prema gradusu je blizu konvencionalnog nivoa značajnosti. Najveći procenat
pacijenata koji ima ekspresiju ciklina D1>10% su oni sa svetloćelijskim tipom, što je
statistički značajno. Ekspresija CCND je pokazala značajnost koja je blizu konvencionalne
kod papilarnog histološkog tipa- trećina bolesnika imala je deleciju gena. Ekspresija
p16>10% je pronađena kod svih pacijenata sa papilarnim RCC (p<0.001). Ekspresija p16 je
pokazala trend rasta sa povećanjem starosne kategorije i dimenzija tumora. Broj umrlih bio je
veći u grupi pacijenata sa p16>10%, i to je zanimljiv rezultat, jer je p16 tumor supresor.
Razlika u ekpresiji CDKN2A je na konvencionalnom nivou značajnosti (isključeni pacijenti
sa duplikacijom), postoji statistički značajna razlika između tri grupe ekspresije CDKN2A
gena (delecija i normalan nalaz) u korelaciji sa histološkim tipom. Smrtni ishod je bio manje
učestao kod pacijenata sa delecijom, bez statističke značajnosti. Pacijenti sa normalnom
ekspresijom CDKN1C uglavnom su imali p57 >5% (jedan slučaj sa duplikacijom i p57<5%).
Medijana p57 je bila dvostruko veća kod muškog pola, i taj je rezultat bio blizu
konvencionalnog nivoa značajnosti. Medijana p57 bila je veća kod starijih i većih dimenzija
tumora, kao i kod pacijenata sa smrtnim ishodom, ali bez statističke značajnosti. Ekspresija
p57>5% bila je blizu konvencionalnog nivoa značajnosti kod tumora većih od 7cm, sa
svetloćelijskim histološkim tipom i smrtnim ishodom. Grupa sa normalnom ekspresijom
CDKN1C imala je lošiji klinički ishod. Urađena je Koksova univarijabilna regresiona analiza
kliničkih karakteristika i rezultati su jasni –prediktori preživljavanja su starost, dimenzije
tumora i stadijum bolesti. Koksova univarijabilna regresiona analiza ekspresije ispitivanih
gena i proteina je pokazala da ciklin A može biti prediktor smrtnog ishoda kod bolesnika sa
karcinomom bubrežnih ćelija. Backward metoda multivarijabilne regresije pokazala je da su
značajni prediktori preživljavanja starost, gradus, stadijum bolesti i ekpresija ciklina A.
Ovakvi rezultati ekspresije ciklina A, ciklina D1 i CDKN2A ukazuju na značaj daljih
istraživanja uloge ćelijskog ciklusa u nastanku bolesti i kliničkom ishodu kod bolesnika sa
karcinomom bubrežnih ćelija. | Renal Cell Carcinoma is the most common renal malignant tumor, especially within male
population. According to renal cell carcinoma classification, which considers many
histological variants and the fact there is no specific tumor marker, the aim of this doctoral
dissertation was to analyze the immunohistochemical expression of cell cycle regulatory
proteins (cyclin A, cyclin B, cyclin D1, p16 and p57) in tumor samples after nephrectomy on
Urology Clinic of Clinical Center of Serbia and Urology department of Clinical-hospital
Center „Dr Dragisa Misovic“ in Belgrade from 2010 to 2013, to analyze qRT-PCR expression
of genes encoding these proteins (CCNA, CCNB, CCND, CDKN2A, CDKN1C) on DNA
isolated from paraffin blocks, and to correlate the results in relation to clinical-pathological
parameters (sex, age, nuclear grade, stadium, tumor size and survival). This retrospective
study included 74 patients with in average middle-sized tumors, clear cell histological type,
low-grade and low TNM stadium. Immunohistochemical method showed high level of cyclin
A expression in older, female patients, with large tumor size, high grade, and high TNM
stadium, without statistical significance, and significant expression in papillary histological
type and in patients with deadly outcome. CCNA expression had normal expression level and
duplication equally in the group with high-grade RCC. Cyclin D1 expression was lower
contrary to tumor size and age, it is alike in lower and higher stadium, but difference
according to grade was near to conventional level of significancy. Most patients with cyclin
D1>10% expression had clear cell type, which was statistically significant. CCND expression
was near to conventional significancy in papillary histological type- third of patients had
deletion of CCND gene. p16>10% expression was found in all the patients with papillary
RCC (p<0.001). p16 expression was higher in older patients and bigger tumor size. We had
more patients with deadly outcome in group with p16>10%, and this is an interesting result,
considering p16 is tumor suppressor protein. The difference in CDKN2A expression had
conventional level of significance (patients with duplication were excluded), there is a
statistically significant difference between three groups of CDKN2A gene expression
(deletion and normal result) correlated to histological type. Deadly outcome was less often in
patients with gene deletion, without statistical significance. Patients with normal CDKN1C
expression mostly had p57>5% (one case with duplication and p57<5%). p57 median was
duplicated within male population, and this result was near to conventional level of
significance, median p57 was higher in older patients with large tumor size with deadly
outcome, but these results were not significant. Expression p57>5% was near to conventional
level of significance in tumors larger than 7cm, with clear cell histological type and deadly
outcome. Group with normal expression CDKN1C had worse clinical outcome. Cox
univariable regression was done for clinical-morphological parameters, and the results were
clear- survival predictors are age, tumor size, grade and stadium. Cox univariable regression
for gene and protein expression showed that cyclin A can be deadly outcome predictor or
survival predictor in patients with renal cell carcinoma. Backward method of multivariable
regression showed that survival predicor are age, stadium and cyclin A expression. These
results of cyclin A, cyclin D1 and CDKN2A expression indicate the importance of further
research of cell cycle role in cancer development and clinical outcome in patients with renal
cell carcinoma | true |
Naponi i deformacije struktura kompleksne geometrije cevovodne armature | Stresses and strains of geometrically complex structures of pipeline fittings | Dosadašnja istraživanja u oblasti opreme pod pritiskom, odnosno merenja i određivanja
napona i deformacija struktura kompleksne geometrije su se oslanjala na analitičke
proračune najčešće bazirane na teoriji ljuski, numeričke proračune upotrebom
računarskih softvera i konvencionalne eksperimentalne metode. Kao jedan od najčešćih
zaključaka u svojim radovima, istraživači su naveli nepostojanje adekvatnih
eksperimentalnih rezultata u postojećoj literaturi, odnosno iskazali potrebu za detaljnom
eksperimentalnom analizom kritičnih mesta za koje nije moguće precizno odrediti
veličine pomeranja, deformacija ili napona upotrebom analitičkih obrazaca ili
numeričkih modela.
Ograničenja korišćenih eksperimentalnih metoda su se ogledala u više aspekata. Prvo,
za analizu geometrijskih diskontinuiteta, najčešće su korišćene standardizovane
epruvete sa pripremljenim diskontinuitetima i ispitivane na zatezanje. Na osnovu
dobijenih rezultata su pravljeni dijagrami sa faktorima koncentracije napona, koji su
kasnije primenjivani na probleme geometrijski kompleksnih struktura. Ovakav pristup
je davao samo okvirna rešenja, koja nisu bila dovoljno precizna i tačna. Drugo,
eksperimenti su sprovođeni konvencionalnim metodama. Ograničenje konvencionalnih
metoda je lokalno merenje, odnosno dobijanje vrednosti merenih veličina samo u jednoj
tački. Treće, merenja su vršena samo u blizini geometrijskih diskontinuiteta, a ne na
samim spojevima geometrijskih oblika, tako da nije bilo moguće merenje najvećih
vrednosti deformacija.
Jedan od ciljeva ove teze je upravo taj da prevaziđe navedene eksperimentalne
probleme, odnosno da pokaže da je moguće primeniti relativno novu metodu digitalne
korelacije slika na slučajeve ispitivanja struktura kompleksne geometrije u oblasti
cevovodne armature. Metoda korelacije digitalnih slika, prevazilazi ograničenja metode
mernih traka, kao najčešće korišćene konvencionalne metode i omogućava merenje
Naponi i deformacije struktura kompleksne geometrije cevovodne armature
iii
celih polja pomeranja i deformacija. Jednim eksperimentalnim merenjem se dobija
veliki broj podataka koja zamenjuje više desetina/stotina mernih traka i značajno
smanjuje vreme pripreme eksperimenta, a samim tim i troškove. S druge strane, kako se
metodom konačnih elemenata dobija kompletno polje pomeranja i deformacija, sama
verifikacija numeričkog modelase mnogo jednostavnije sprovodi poređenjem sa
rezultatima koji su predstavljeni na isti način. Eksperimentalno merenje celih polja
deformacija omogućuje precizno određivanje mesta kritičnih, odnosno najvećih
deformacija, kao i pravce glavnih deformacija koje omogućava bolju teorijsku analizu
kompleksnih struktura.
Numerički proračunski model je izrađen spajanjem karakterističnih poprečnih preseka
ispitivanih kućišta ventila. Numerički proračuni urađeni su u softverskom paketu za
proračun metodom konačnih elemenata – ABAQUS. Metoda konačnih elemenata je
odabrana kao metod u ovom istraživanju zato što je pomoću MKE moguće opisati šta se
dešava u određenoj zoni geometrijskih diskontinuiteta koja nije dostupna za snimanje,
tj. analizirani su naponi koji se javljaju kako na definisanim mernim mestima, tako i na
mestima koja nisu obuhvaćena eksperimentalnom analizom.
Struktura kompleksne geometrije na kojoj je izvršeno ispitivanje u okviru doktorske
disertacije je kućište ravnog zapornog ventila. Eksperimentalno istraživanje je
sprovedeno na tri ravna zaporna ventila DN32, PN6 i to za dva slučaja opterećenja:
opterećenje unutrašnjim pritiskom do 30 bar i aksijalnom silom od 30 kN koja deluje u
pravcu ose ventila (sabijanje). Eksperiment je izvršen na četiri merna mesta koja se
nalaze na karakterističnim pozicijama na kućištu ventila. Za sva četiri merna mesta su
prikazane eksperimentalne vrednosti polja pomeranja i deformacija. Za određivanje
polja deformacija i pomeranja korišćena je oprema za trodimenzionalno merenje
deformacija i softverski sistem Aramis, proizvođača GOM. Sistem za 3D optičko
merenje pomeranja i deformacija je baziran na metodi digitalne korelacije slika. Sistem
omogućava 3D grafičko predstavljanje izmerenih rezultata. Za primenu sistema za
optičko merenje deformacija na problemima kompleksnih struktura, definisane su i
razvijene odgovarajuće procedure ispitivanja (operacije pre ispitivanja, u toku
ispitivanja i posle ispitivanja i obrada rezultata). Podaci dobijeni eksperimentalnim
Naponi i deformacije struktura kompleksne geometrije cevovodne armature
iv
putem su, korišćenjem regresione analize, opisani odgovarajućim analitičkim obrascima
koji prikazuju zavisnosti pomeranja/deformacija i dužine karakterističnih preseka za
definisane preseke na kućištu ravnog zapornog ventila. Dokazano da je ponašanje
kućišta ventila u toku izlaganja aksijalnom silom linearno. | Previous studies in the field of pressure equipment, i.e. measuring and determining
stress and strain of geometrically complex structures, have relied on analytical
calculations based on shell theory, numerical calculations using computer software and
conventional experimental methods. As one of the most often conclusions in their work,
the researchers indicated the lack of adequate experimental data in the available
literature, i.e. expressed the need for detailed experimental analysis of critical areas
where is not possible to precisely determine displacement, strain and stress values using
analytical or numerical models.
Limitations of used experimental methods were recognized in several aspects. First,
standardized specimens with discontinuities were used for analysis of geometrical
discontinuities and tensile testing. Based on the results of tensile testing, stress
concentration factors were plotted on diagrams and later used to solve problems on
geometrically complex structures. This approach gave only approximate solutions that
are not sufficiently precise and accurate. Second, experiments were conducted using
conventional methods. Limitation of conventional methods is local measurement, i.e.
experimental values are measured only in a single point. Third, measurements were
carried out close to the geometrical discontinuity, rather than on the actual intersection
of geometrical shapes, so it was not possible to measure highest strain values.
One of the goals of the thesis is exactly that to overcome abovementioned experimental
problems, i.e. to show that is possible to implement relatively new digital image
correlation method on testing geometrically complex structures in the field of pipeline
fittings. Digital image correlation method overcomes limitations of strain gauge, as the
strain gauge is most commonly used conventional method that enables full-field
displacement and strain measurement. One experimental measurement enables
acquisition of large datasets that replaces dozens/hundreds of strain gauges and
Naponi i deformacije struktura kompleksne geometrije cevovodne armature
vi
significantly reduces experiment preparation time and therefore the costs. On the other
hand, as finite element method calculates full displacement and strain fields, numerical
model verification is easily carried out by comparing to experimental results presented
in the same manner. Full strain field experimental measurement allows accurate
determination of critical areas, i.e. areas with highest strain values, as well as principle
stress directions that enables better theoretical analysis of complex structures.
Numerical model was created by connecting characteristic cross-sections of the tested
valve housings. Numerical calculations were performed using software for Finite
Element Analysis – ABAQUS. Using Finite Element Method (FEM), it is possible to
better understand behavior of structures with geometrical discontinuities that cannot be
experimentally tested, i.e. it is possible to analyze stresses on predefined measuring
areas, as well as on areas that cannot be experimentally tested.
Geometrically complex structure tested in the dissertation is globe valve housing.
Experimental analysis was performed on three globe valve housings DN32, PN6 for two
loading types: internal pressure up to 30 bar and axial force of 30 kN acting in the
direction of valve symmetry axis (compression). Experiment is conducted on four
measuring areas that are located on the characteristic positions on the valve housing.
Displacement and strain fields were measured using system for three-dimensional
optical strain measurement and software Aramis, by GOM manufacturer. System for
three-dimensional optical displacement and strain measurement is based on Digital
Image Correlation method. System enables 3D graphical presentation of measured
results. For application of system for 3D optical strain measurement on complex
structure problems, appropriate procedures are defined and developed (operations
before testing, during testing and after testing and result processing). Experimental data
are described with analytical equations that represent dependence of displacement/strain
and section length for defined sections on globe valve housing. It is proven that valve
housing behavior during axial loading is linear.
Naponi i deformacije struktura kompleksne geometrije cevovodne armature
vii | true |
Ispitivanje polimorfizama eNOS gena kao faktora rizika za razvoj retinopatije prevremeno rođene dece | Investigation of enos gene polymorphisms as a risk factors for the development of retinopathy of prematurity | Uvod: Retinopatija prematuriteta (ROP) je oboljenje mrežnjače oka prevremeno roñene
dece i osnovni je uzrok teškog oštenja vida u detinjstvu. Genetička istraživanja ROP
usmerena su ka otkrivanju varijanti gena odgovornih za razvoj teških formi ROP-a.
Cilj ove studije bio je da ispita učestalost genotipova i alela polimorfizama T-786C i
4a/4b gena za endotelnu azot oksid sintetazu (eNOS) u populaciji prevremeno roñene
dece kao i povezanost ispitivanih polimorfnih varijanti sa nastankom teškog stepena
retinopatije. Takoñe, cilj ove studije je ispitivanje kliničkih faktora rizika udruženih sa
nastankom teškog stepena ROP-a.
Metodologija: Istraživanje je uključilo 239 prevremeno roñene dece. Na osnovu
sprovedenog oftalmološkog skrininga prevremeno roñena deca su podeljena u dve grupe.
ROP grupa je obuhvatila 113 dece kod kojih je stepen ROP-a zahtevao oftalmološku
terapiju, a kontrolnu grupu činilo je 126 dece bez terapije. DNK je izolovana iz brisa
bukalne sluznice prevremeno roñene dece a ispitivanje polimorfizama vršeno je PCR
metodom.
Rezultati: Ispitivanje polimorfizma T-786C pokazalo je da je 39,1% dece homozigotno
za češći alel T (genotip TT), 52,3% su heterozigoti (genotip CT) i 8,6% homozigoti za
reñi alel C (genotip CC). Učestalost C alela je 34,8%. Učestalost genotipova T-786C
polimorfizma u grupi sa ROP-om je: 40,0% TT genotipa, 51,7% CT genotipa i CC
genotipa 8,3%. U kontrolnoj grupi učestalost TT genotipa je 38,2%, CT genotipa 52,9% i
CC genotipa 8,8%. Učestalost C alela u ROP grupi je 34,2%, a 35,3% u kontrolnoj grupi.
Ispitivanjem polimorfizma 4a/4b utvrñeno je da je 65,3% dece homozigotno za češći alel
4b (genotip bb), 31,2% su heterozigoti (genotip ab) i 3,5% homozigoti za reñi alel 4a
(genotip aa). Učestalost 4a alela je 19,1%. Učestalost 4a/4b polimorfizma u grupi sa
ROP-om je: genotipa 4bb 60,2%, genotipa 4ba 34,9% i 4aa genotipa 4,9%. U kontrolnoj
grupi učestalost genotipa 4bb je 70,1%, genotipa 4ba 27,6% i 4aa genotipa 2,3%.
Učestalost 4a alela u ROP grupi je 22,3%, a 16,1% u kontrolnoj grupi. Razlika u
VI
učestalosti genotipova i alela eNOS T-786C i eNOS 4a/4b polimorfizama izmeñu ROP i
kontrolne grupe nije statistički značajna.
Prevremeno roñena deca nosioci 4aa genotipa imaju nižu nedelju gestacije,
telesnu masu i Apgar skor, a veći broj dana provedenih na terapiji O2 u odnosu na decu
koja imaju druge genotipove (4bb i 4ba). Srednje vrednosti NG ispitivane po recesivnom
modelu se statistički značajno razlikuju, tj. nosioci 4aa genotipa imaju značajno niže
srednje vrednosti NG nego nosioci 4bb i 4ba genotipa. Multivarijantna linearna
regresiona analiza sa polom, TM i Apgar skorom kao kovarijatama nije pokazala
asocijaciju 4a/4b genotipa sa vrednostima NG kod ispitivane prevremeno roñene dece.
Multivarijantna regresiona analiza je pokazala da su nezavisni faktori rizika za razvoj
ROP-a: niska nedelja gestacije, niska telesna masa na roñenju, pneumonija, sepsa,
intraventrikularna hemoragija i nekrotični enterokolitis.
Zaključak: Kod prevremeno roñene dece u našoj sredini, T-786C i 4a/4b polimorfizmi
eNOS gena ne predstavljaju faktor rizika za nastanak teške forme ROPa. Nezavisni
faktori rizika za razvoj ROP-a su: niska nedelja gestacije, niska telesna masa na roñenju,
pneumonija, sepsa, intraventrikularna hemoragija i nekrotični enterokolitis. | Introduction: Retinopathy of prematurity (ROP) is a disease of the retina of premature
infants and is the main cause of severe visual impairment in childhood. Genetic studies of
ROP are directed towards to discovering variants of genes responsible for the
development of severe forms of ROP.
The aim of this study was to determine the frequency of genotypes and allele of
polymorphisms T-786C and 4a/4b genes for endothelial nitric oxide synthase (eNOS) in
the population of premature infants as well as the correlation between the polymorphic
variants and the development of severe degree of retinopathy. The goal of this study was
to evaluate clinical risk factors associated with the occurrence of severe degree of ROP.
Methodology: The study included 239 premature infants. On the basis of conducted
ophthalmological screening premature infants were divided into two groups. ROP group
consisted of 113 children in whom the degree of ROP demanded ophthalmological
therapy, and the control group consisted of 126 children without therapy. DNA was
isolated from the buccal mucosa swabs of premature infants and the examination of
polymorphisms was performed by PCR method.
Results: Examination of T-786C polymorphism has shown that 39.1% of children are
homozygous for common allele T (TT genotype), 52.3% are heterozygous (genotype CT)
and 8.6% are homozygous for rare allele C (genotype CC) . The frequency of C allele is
34.8%. The frequency of genotypes T-786C polymorphism in the group with ROP is
40.0% TT genotype, 51.7% CT genotype and CC genotype 8.3%. In the control group the
frequency of TT genotype is 38.2%, 52.9% CT genotype and CC genotype is 8.8%. The
frequency of C allele in the ROP group is 34.2% and 35.3% in the control group. By
examination of polymorphism 4a/4b we found that 65.3% of children are homozygous for
common allele 4b (genotype bb), 31.2% are heterozygous (genotype ab) and 3.5% are
homozygous
for
rare
allele
4a
(genotype
aa).
The
frequency
of
4a allele is 19.1%. The frequency of 4a/4b polymorphism in the ROP group is
VIII
4bb genotype 60.2%, 34.9% 4b genotype and genotype 4a 4.9%. In the control group,
genotype frequency of 4bb is 70.1%, 27.6% 4b genotype and genotype 4a 2.3%. The
frequency of allele 4a in the ROP group is 22.3% and 16.1% in the control group. The
difference in the frequency of genotypes and alleles of eNOS T-786C and eNOS 4a/4b
polymorphisms between the ROP and the control group is not statistically significant.
Premature infants the carriers of 4aa genotype have a lower week of gestation, the body
weight and Apgar score, a greater number of days spent on the O2 therapy compared to
children who have other genotypes (4bb and 4ba). Mean values of the NG examined by
recessive model are statistically significantly different, ie. 4aa genotype carriers had a
significantly lower mean values than the NG holders of 4bb and 4ba genotype.
Multivariate linear regression analysis to gender, TM and the Apgar score as covariates
did not show an association of 4a/4b genotype with the values of NG in the examined
premature infants. Multivariate regression analysis showed that the independent risk
factors for the development of ROP are: low weeks of gestation, low birth weight,
pneumonia, sepsis, intraventricular hemorrhage and necrotizing enterocolitis.
Conclusion: In preterm infants in our midst, T-786C and 4a/4b eNOS gene
polymorphisms do not represent a risk factor for severe form of ROP. Independent risk
factors for developing the ROP are: low weeks of gestation, low birth weight, pneumonia,
sepsis, intraventricular hemorrhage and necrotizing enterocolitis. | true |
Povezanost samopoimanja sa kvalitetom života i životnim navikama kod osoba sa oštećenjem vida | Correlations of self-concept with quality of life and life habits in persons with visual impairment | Samopoimanje, kvalitet života i životne navike su definisani
preko domena povezanih sa određenim oblastima funkcionisanja u
svakodnevnom životu i nekim životnim ulogama, stoga je moguće da
interferiraju.
Ovo istraživanje ima za cilj utvrđivanje samopoimanja kod odraslih
sa oštećenjem vida (OV) i osoba iz opšte populacije i njegove
povezanosti sa kvalitetom života i životnim navikama.
Uzorak je činilo 175 ispitanika: osobe sa OV (N=92) oba pola, stare
od 19 do 65 godina (AS=35,10, SD=10,78) i osobe iz opšte populacije
(N=83) kao kontrolna grupa ujednačena sa ispitanicima sa OV prema
uzrastu i polu.
Za prikupljanje podataka o nezavisnim varijablama korišćen je
Demografski upitnik konstruisan za potrebe ovog istraživanja.
Pomenuti konstrukti ispitivani su sledećim skalama: Tenesi skala za
procenu samopoimanja (The Tennessee Self-Concept Scale – TSCS:2, 2nd edition;
Fitts &Warren, 2003); Sveobuhvatna skala kvaliteta života (Comprehensive
Quality of Life Scale – ComQOL-A5, 5th edition; Cummins, 1997) i skraćena
forma Skale životnih navika(The Assessment of Life Habits general short form
– LIFE-H 3.1; Fougeyrollas & Noreau, 2003).
Ispitujući samopoimanje, uočili smo da najviše rezultate imaju
slabovidi ispitanici. Što se tiče kvaliteta života, primetno je da
slepe osobe imaju značajno lošiji objektivni kvalitet života u
poređenju sa osobama iz kontrolne grupe. Poređenje postignuća osoba sa
oštećenjem vida pokazalo je da slabovide osobe realizuju više životnih
navika u odnosu na slepe. Kada govorimo o odnosu samopoimanja,
kvaliteta života i životnih navika, korelaciona analiza je pokazala da
između ispitivanih konstrukata postoje niske do umerene značajne
korelacije.
Bez obzira na to što postoje dokazi da prisustvo OV može da izazove
određene teškoće, nije neophodno da ono uzrokuje i probleme u kvalitetu
života, socijalnoj participaciji ili u oblasti samopoimanja. | Self-concept, quality of life and life habits are defined through domains
connected with certain areas of everyday functioning and with some social
roles, so it could be that they interfere.
This research has a goal to determine self-concept in visually impaired
(VI) adults and adults from typical population and to check its correlations with
quality of life and life habits.
The sample included total of 175 respondents: VI persons (N=92) of both
gender, between age 19 to 65 and a control group of persons from typical
population (N=83) equal with VI respondents by age and gender.
For collecting data on the control variables, in our study we used a
demographic questionnaire designed for this study. The above mentioned
constructs were examined by following instruments: Tennessee Self-Concept Scale
(TSCS:2, 2nd edition; Fitts & Warren, 2003), Comprehensive Quality of Life Scale
(ComQOL-А5, 5th edition; Cummins, 1997) and The Assessment of Life Habits
general short form (LIFE-H 3.1; Fougeyrollas & Noreau, 2003).
Examining the self-concept, we noticed that respondents with low vision
have the highest scores. As for the quality of life, it is evident that blind people
from our study have significantly poorer objective quality of life comparing the
control group. A comparison of the achievements of VI people showed that
respondents with low vision accomplish more life habits than their blind
counterparts. When we are talking about the relationship between self-concept,
quality of life and life habits, correlation analysis showed the existence of low to
moderate correlations between tested constructs.
Regardless of the evidence that existence of VI can cause certain
difficulties, it is not necessary that it causes problems in the domains of quality
of life, social participation or self-concept. | true |
Model za restrukturiranje poštanske mreže u ruralnim oblastima u funkciji održivog razvoja | A model for public postal network reorganization in rural areas as a function of sustainable development | Koncept univerzalne poštanske usluge menjao se paralelno sa razvojem i napretkom
ljudskog društva. Ovaj pojam danas prevazilazi svoju primarnu ulogu povezivanja na svim
nivoima društva i postaje usluga od opšteg društvenog interesa kroz koju se ostvaruju
širi društveni ciljevi. Zbog svoje važnosti koja se ogleda u specifičnoj socijalnoj
vrednosti kako za fizička, tako i za pravna lica i društvenoj ulozi u ostvarenju
Globalnih ciljeva, pozitivnog uticaja na životnu sredinu, tradicionalnu saradnju sa
drugim državnim organima, jačanja patriotizma, sigurnosti i bezbednosti, postoji
potreba da se ovaj humani koncept zaštiti i održi naročito u nerazvijenim i
devastiranim oblastima i posebno za najosetljivije grupe stanovništva. Pored toga,
poštanski saobraćaj kroz realizovane usluge postaje svojevrstan indikator ekonomske i
društvene aktivnosti područja i sa specifičnim robnim i novčanim tokovima daje širu
sliku o životu i radu ljudi u određenoj oblasti.
Proces transformacije poslovanja imenovanog poštanskog operatora, kao ekskluzivnog
davaoca univerzalne poštanske usluge, na liberalizovanom tržištu zahteva utvrđivanje
efikasnosti poslovnih procesa i racionalizaciju troškova. Shodno tome, imajući u vidu
da bi trebalo postići dva suprotstavljena cilja, efikasnost i dostupnost,
redefinisanje ili reorganizacija poštanske mreže predstavlja veoma složen i osetljiv
zadatak. Održivi poslovni model IPO zahteva precizno definisanje neophodnih
kriterijuma za određivanje neprofitabilnih JPM u različitim oblastima, dok humani
koncept UPU zahteva prepoznavanje važnosti razlika u funkcionisanju i održivosti
lokalnih zajednica i potrebama najugroženije populacije.
Predmet doktorske disertacije je utvrđivanje specifičnosti u potražnji i zadovoljenju
potreba korisnika poštanskih usluga u ruralnim područjima. Cilj je da se utvrde
zakonitosti karakteristične za ruralna područja i da se na osnovu dobijenih rezultata,
uzimajući u obzir specifičnosti lokalnih zajednica i značaj poštanskih usluga za njihovo
održanje, definiše metodologija održivosti koncepta univerzalne poštanske usluge u
ovim oblastima. Analizom iskustava svetskih poštanskih uprava može se utvrditi da su
se atributi UPU menjali i prilagođavali nacionalnim specifičnostima u skladu sa
preuzetim međunarodnim obavezama i nacionalnim zakonodavstvom. Postoji trend
zatvaranja stalnih JPM, ali su posledice na lokalnu zajednicu velike i poštanske uprave
pokušavaju da pronađu alternativna rešenja ili uvedu ciljane mere kako bi taj proces
minimalno ugrozio posmatrano područje i njegove stanovnike.
Istraživanje u radu se bazira na utvrđivanju socijalne vrednosti poštanske mreže i
poštanskih usluga u ruralnim oblastima. Kroz istraživanje se utvrđuju obrasci
korišćenja poštanskih usluga i navike korisnika (pravnih i fizičkih lica) koje se
zasnivaju na karakterističnom stilu života i rada. Ovo istraživanje je od značaja jer
su doneseni zaključci u skladu sa drugim istraživanjima u oblasti, posebno imajući u vidu
osetljive kategorija stanovnika – stanovništvo smanjene mobilnosti, niže platežne
moći, starijih korisnika... Značajne promene demografske strukture i promene u
okruženju utiču i na potražnju za poštanskim uslugama na način da se postojeća ponuda
mora prilagoditi zahtevima novih korisnika.
Kvalitativno istraživanje atributa poštanskih usluga može ukazati na smernice u
daljem razmatranju promene UPU i njenom prilagođavanju korisnicima, dok kvantitativno
istraživanje vrednosti poštanske mreže daje precizan podatak o važnosti poštanske
infrastrukture i njene dostupnosti za korisnike.
U ranijim istraživanjima utvrđeno je da postoji potreba za optimizacijom poštanske
mreže i u naučnoj i stručnoj literaturi postoje različiti pristupi za utvrđivanje
minimalnog/optimalnog broja stalnih JPM na određenom području, Kroz različite
metodologije dobija se broj JPM koje treba da budu zatvorene ili da im se promeni način
poslovanja. Predloženi model u ovom radu na osnovu prethodno definisanih kriterijuma
v
proračunava potreban broj JPM, ali i jednoznačno određuje koje JPM treba zatvoriti
kako bi ukupan negativan efekat na lokalnu zajednicu i privrednu aktivnost bio najmanji
mogući. U model se, kao jedan od parametara, pored efikasnosti JPM, broja pravnih lica,
rastojanja do alternativne JPM, uvodi i socijalni kriterijum, odnosno broj lica iz
osetljivih kategorija koja bi najviše bila pogođena promenom načina poslovanja ili
zatvaranjem jer bi takva promena uticala na povećanje troškova, stvaranje negativnih
ekoloških efekata, gubljenje socijalnog čvorišta, a nekada i smanjenom mogućnošću ili
nemogućnošću da se realizuje tražnja za poštanskim uslugama. | Concept of the universal postal service has been changing parallelly with the development and
advancement of the human society. Today, this term overcomes its primary role of connecting the
society on every level and becomes a service of common social interest through which broader
social goals are achieved. Because of its importance which reflects in the specific social value for
individuals as well as legal entities, and the social role with achieving Global goals, positive
influence on the environment, traditional collaboration with other state organs, strengthening of
patriotism, safety and security, it is necessary to protect and preserve this humane concept,
especially in the underdeveloped and devastated areas and for the most sensitive parts of the
population. Apart from that, postal traffic, through realized services, becomes a kind of an indicator
of the economic and social activity of an area and, through specific ware and monetary flows
provides
a
wider
picture
about
life
and
work
of
people
in
a
given
area.
Business transformation process of the designated postal operator, as an exclusive provider of the
universal postal service on the liberalized market demands determination of the efficiency of the
work processes and rationalization on the expenses. Following that, and bearing in mind that two
opposing goals, efficiency and accessibility, should be reached, redefining or reorganizing of the
postal network shows to be a very difficult and sensitive task. Sustainable business model DPO
requires precise defining of the required criteria for determining unprofitable PNUs in different
areas, while the humane USO concept demands the recognition the importance of the differences of
the functioning and sustainability of the local communities and needs of the most endangered
populace.
The subject of the doctor dissertation is the determination of the specifics of the demands and
coverage of needs of the users of the postal services in the rural areas. The goal is to determine
regularities characteristic for the underdeveloped areas and, based on the received results, taking in
consideration the specifies of the local communities and the importance of the postal services for
their sustention, define the methodology of the sustainability of the universal postal service concept
in these areas. By analyzing the experiences of the world's postal managements it is apparent that
the USO attributes were changed and adjusted to the national specifics in accordance with the
accepted international compliances and national legislations. There is a trend of closing permanent
PNUs, but the consequences for the local community are significant, and postal managements are
trying to find alternative solutions or introduce aimed measures so the mentioned process would
minimally threaten the observed area and its inhabitants.
Work research is based on determining of the social values of the postal networks and postal
services in the rural areas. Through research, postal service usage and user (legal entities and
individuals) habits patterns are determined, which are based on the characteristic work and life
style. This research is significant because received conclusions are in accordance with other
research in the area, bearing especially in mind sensitive categories of the inhabitants - populace
with reduced mobility, lower economical status, elderly... Significant changes of the demographic
structure and in the environment influence also the demand for postal services in a way so that the
existing supply must adjust to the requirements of the new users.
Qualitative research of the postal service attributes may point to guidelines in further consideration
of the changes to USO and its adjustment to the users, while quantitative research of the postal
network values provides precise data about the importance of the postal infrastructure and its user
availability.
In the previous research, it is determined that there is a need for the optimization of the postal
network, and in the scientific and professional literature offers different approaches for determining
minimal/optimal number of permanent PNU in a given area. Through different methodologies, it is
possible to get a number of PNUs which need to be closed or which business methods needs to be
changed. Suggested model in this work based on previously defined criteria calculates the required
PNU number, but also unambiguously determines which PNUs need to be closed so the total
negative effect to the local community and economic activity would be the lowest possible one. In
this model, as one of the parameters, beside the efficiency of the PNU, number of the legal entities,
vii
distance from the alternative PNUs, a new, social criteria is introduced, by which is meant the
number of individuals from sensitive categories who would be influenced the most by the business
change or closure, because such change would influence the increase of expenses, creation of
negative ecological effects, loss of social hubs, and sometimes even reduced possibility or
impossibility to realize the request for the postal services. | true |
Analiza patomorfoloških, patofizioloških i kliničkih karakteristika stenozantno-okluzivne i aneurizmatske bolesti infrarenalnog dijela aorte | Analysis of pathomorphological, pathophysiological and clinical features of steno-occlusive and aneurysmal disease of the infrarenal part of aorta | Stenozantno-okluzivne promjene na aortoilijačnom segmentu (SOBA) uglavnom nastaju kao posljedica degenerativnih i inflamatornih aterosklerotskih promjena na zidu krvnog suda. U zadnje vrijeme sve je veći broj dokaza o inflamatornoj komponenti aterogeneze (Mulenix 2005; Zhongzhi, 2017). Aneurizmatska bolest aorte (ANBA) je lokalizovano trajno proširenje aorte čiji je dijametar bar 50% veći od normalnog promjera. ANBA je nedovojlno jasne etiologije. Opisani su najčešći uzroci: poremećaji vezivnog tkiva (Ehlers-Danlosov sindrom, Marfanov sindrom), degenerativni procesi, infekcija, inflamatorni arteritisi, disekcija itd (Davidović 2015; Humphrey 2012). Iako ima dosta podataka o značaju genetskih faktora koji determinišu i aterosklerozu i aneurizmatsku bolest, sve više je radova o značaju metaloproteinaza (Shapiro 1999) za nastanak i komplikacije ANBA. CILJ RADA: Cilj rada je da se uporede imunohistohemijski parametri, patomorfološke osobenosti, klinička slika i način liječenja bolesnika sa ANBA i obolelih od SOBA radi bolje determincije ova dva patološka stanja infrarenalnog segmenta abdominalne aorte MATERIJAL I METODE: Sprovedene su dvije studije: retrospektivna (72 bolesnika sa ANBA i 59 bolesnika sa SOBA) i prospektivna (30 ANBA i 30 SOBA bolesnika) u UKC RS Banjaluka (Klinika za vaskularnu hirurgiju) u periodu od 3 godine (1. 4. 2010 - 1. 4. 2013) . Retrospektivnom studijom su ispitivane demografske karakteristike (distribucija bolesnika po polu, životnom dobu), anamnestički podaci (klaudikacije, bolovi), faktori rizika i štetne navike (pušenje, alkoholizam), prateća oboljenja, laboratorijski nalazi (lipidni status), objektivni klinički nalaz pulsni status) , dopler indeksi i EHO ultrazvučni nalaz aorte, angiografija, metode hirurškog liječenja i rezultati neposrednog ishoda liječenja po ispitivanim grupama (ANBA i SOBA). Prospektivnom studijom su praćeni klinički (distribucija bolesnika po polu, životnoj dobi, kliničkoj slici, pulsnom statusu, dopler indeksima, kolor dupleks skenu aorte, angiografskom nalazu, diabetes mellitusu, hipertenziji, hiperlipidemiji, pušenju, alkoholizmu, sesilnom načinu života, hroničnoj opstruktivnoj bolesti pluća, hroničnoj renalnoj insuficijenciji, koronarnoj bolesti, cerebrovaskualrnim bolestima i vrsti operativnog zbrinjavanja) , laboratorijski (vrijednosti C-reaktivnog proteina, fibrinogena, homocisteina α 1 antitripsina), histološki (isječci zida infrarenalne aorte bojeni hemotoksilin-eozin i detektovani kristali holesterola, kalcifikacija, inflamatornog infiltrata) i imunohistohemijski parametri (koncentracije metaloproteinaza 2 i 9 (MMP-2 i MMP-9) i tkivnih inhibitora metaloproteinaza 2 i 9 (TIMP 1, TIMP 2) na 5 μm isječcima zida abdominalne aorte složenom tehnikom reakcije antigena i monoklonskih antitijela) kod bolesnika sa ANBA i SOBA... | Steno-occlusive changes in the aortoilliac segment (AIOD) mainly occur due to degenerative and inflammatory atherosclerotic changes on the blood vessel wall. Lately, there has been increasing evidence suggesting the inflammatory component of atherogenesis (Mulenix 2005; Zhongzhi, 2017). Aneurysmatic aortic disease (AAA) is a localized permanent enlargement of the aorta whose diameter is at least 50% greater than the normal diameter. AAA does not have an undeniably clear etiology. The most common causes are: connective tissue disorders (Ehlers-Danlos syndrome, Marfan syndrome), degenerative processes, infections, inflammatory arteritis, dissection, etc. (Davidović 2015; Humphrey 2012). Although there is substantial data about the significance of genetic factors that determine both atherosclerosis and aneurysmal disease, more and more papers focus on the importance of metalloproteinases (Shapiro 1999) for the onset and complications of AAA. AIM OF WORK: The aim of the paper is to compare the immunohistochemical parameters, the pathomorphological characteristics, the clinical presentation, and the method of treating the patients with AAA and patients with AIOD, for better determination of these two pathological conditions of the infrarenal segment of the abdominal aorta. MATERIAL AND METHODS: Two studies were carried out: retrospective (72 patients with AAA and 59 patients with AIOD) and prospective (30 AAA and 30 AIOD patients) in UKC RS Banja Luka (Department of Vascular Surgery) for a period of 3 years (1.4 2010 - 1. 4. 2013). The retrospective study examined the demographic characteristics (distribution of patients by gender, age), anamnestic data (claudication, pain), risk factors and harmful habits (smoking, alcoholism), accompanying comorbidities, laboratory findings (lipid profile), objective clinical finding (pulse status), Doppler indexes and ECHO ultrasound findings of the aorta, angiography, methods of surgical treatment and results of immediate outcome of treatment by examined groups (AAA and AIOD)... | false |
Estimation of the predictive role of presenting symptoms in establishing the diagnosis of idiophatic intracranial hypertension, course and outcome of the disease | Procena prediktivne uloge prezentujućih simptoma i postavljanje dijagnoze idiopatske intrakranijalne hipertenzije, tok i ishod bolesti | Idiopatska intrakranijalna hiprtenzija (IIH) je retko oboljenje koje karakteriše
povišen intrakranijalni pritisak (IKP) bez jasno detektabilnog uzroka. Kliničko
ispoljavanje IIH je varijabilno a bolest se najčešće manifestuje glavoboljom i edemom
papile optičkog živca. Ostale simptome čine tranzitorne vizuelne opskuracije (TVO),
zamagljen vid, duple slike usled lezije VI kranijalnog živca, zujanje u ušima,
vrtoglavica, mučnina, bol u vratu, teškoće sa pamćenjem i koncentracijom.
Dijagnostički značaj različitih prezentujućih simptoma i znakova bolesti nije dovoljno
ispitan. Aktuelni dijagnostički kriterijumi za IIH nisu bazirani na kliničkoj prezentaciji
bolesti, i za razliku od prethodnih ne zahtevaju postojanje simptomatologije povišenog
IKP. Imajući u vidu nisku prevalenciju IIH, u literaturi nema dovoljno podataka o toku i
dugoročnom ishodu bolesti.
Ciljevi: Ciljevi istraživanja su a) utvrđivanje prezentujućih simptoma i znakova bolesti
kod osoba kod kojih je dijagnoza IIH postavljena prema aktuelnim dijagnostičkim
kriterijumima, b) uvrđivanje korelacije prezentujućih simptoma i znakova IIH sa
rezultatima dijagnostičkih procedura: vrednostima IKP, prisustvom edema papile
optičkog živca i neuroradiološkim znacima intrakranijalne hipertenzije, c) utvrđivanje
korelacije prezentujućih simptoma i znakova IIH sa kliničkim tokom i ishodom bolesti.
Metodologija: Ova kohortna studija je sprovedena u dva tercijarna centra: Klinici za
neurologiju Kliničkog centra Srbije u Beogradu i Danskom centru za glavobolje bolnice
Rigshospitalet, u Glostrupu. U istraživanje je uključeno 286 bolesnika koji su
konsekutivno upućivani od strane neurologa ili oftalmologa pod sumnjom na IIH u
periodu od januara 2007. do marta 2016. godine. Istraživanje je sprovedeno u dve faze.
U prvoj fazi su klinički podaci prospektivno prikupljani od svih ispitanika sa ciljem da
se ustanove prezentujući simptomi i znaci IIH. Klinički intervju i detaljan semi-
strukturisani uputnik sastavljen za potrebe ovog istraživanja je korišćen za prikupljanje
demografskih podataka, karakteristika prezentujućih simptoma, podataka o korišćenju
lekova pre pojave bolesti i komorbiditetima. Svim ispitanicima je urađen neurološki i
neurooftalmološki pregled, merenje IKP i neuroimidžing. U drugi deo istraživanja
uključeno je 182 bolesnika sa IIH koji su praćeni od strane neurologa i oftalmologa bar
godinu dana nakon postavljanja dijagnoze. Period praćenja je bio između 12 i 144
meseci. Tok i ishod bolesti su procenjeni retrospektivnom analizom specijalističkih
izveštaja sa kontrolnih pregleda. Analiziran je prediktivni značaj simptoma i znakova
bolesti za postavljanje dijagnoze i ishod IIH i utvrđeni su nezavisni prediktori.
Rezultati: Dijagnoza IIH je potvrđena kod 219 (76.6%) bolesnika. Češće je potvrđena
kod bolesnika sa većim indeksom telesne mase (BMI) (p=0.032) i kod onih koji su
upućeni od strane oftalmologa a ne neurologa (83.6% vs. 69.8%, p=0.029). Duple slike
(p=0.033), TVO (p=0.006), zujanje u ušima (p=0.013) i bol u vratu (p=0.025) su čeće
prijavljivali ispitanici sa IIH, a kod njih je takođe pregledom češće uočen edem papile
vidnog živca i lezija VI kranijalnog živca. Multivarijantnom analizom je edem papile
izdvojen kao samostalan prediktor IIH (p<0.001). Glavobolja je bila najčešči simptom
IIH, prisutna kod 90.8% pacijenata na početku bolesti. Defekti vidnog polja koji su
nastali kao posledica IIH nađeni su kod 75% pacijenata, a edem papile kod 93.3%.
Postojala je značajna korelacija između vrednosti IKP i prisustva edema papile vidnog
živca, lezije VI kranijalnog živca, TVO i duplih slika. Ustanovljena je povezanost
između prisustva edema papile vidnog živca i znakova povišenog IKP na MR mozga.
Mlađi uzrast na početku bolesti bio je povezan sa višim vrednostima IKP, kao i
kliničkom prezentacijom u vidu glavobolje, zujanja u ušima, duplih slika usled lezije VI
kranijalnog živca, mučnine i povraćanja. Nađena je značajna korelacija oštećenja vida
(snižena oštrina vida, duple slike i defekt vidog polja bar na jednom oku) u vreme
postavljanja dijagnoze sa BMI. Kompletna remisija simptoma i znakova IIH je
potvrđena kod 72 (39.6%) bolesnika na poslednjoj kontroli. Više vrednosti IKP i
glavobolja koja je dostigla maksimalnu jačinu unutar jednog dana su univarijantnom
analizom izdvojeni kao pozitivni prediktori remisije, dok su bol u vratu na početku
bolesti (HR=4.959, CI 2.438-10.087, p<0.001), kao i odsustvo fonofobije (HR=0.230,
CI 0.106-0.501, p<0.001) i teškoća sa koncentracijom (HR=0.360, CI 0.186-0.697,
p=0.002) potvrđeni kao nezavisni prediktori remisije multivarijantnom analizom.
Relapsni tok bolesti je imalo 34 (18.7%) pacijenata. Glavobolja kao prvi simptom
bolesti, pojava fotofobije, teškoće sa koncentracijom i pamćenjem, obostrano očuvana
oštrina vida u vreme postavljanja dijagnoze kao i vrednost IKP izdvojeni
univarijantnom analizom su bili povezani sa relapsnim tokom bolesti, ali ni jedan od
ovih prediktora nije dostigao značajnost u multivarijantnoj Cox regresionoj analizi.
Refraktorna IIH ustanovljena je kod 76 (41.7%) pacijenata na kraju praćenja. Viši BMI,
komorbidna depresija i empty sella znak na MR pregledu glave su pozitivno korelirali
sa refraktornom bolešću, dok je negativna povezanost uočena sa konstantnom
glavoboljom čeone lokalizacije i vrtoglavicom. Stariji uzrast na početku bolesti
(HR=1.066, CI 1.025-1.110, p=0.002), glavobolja koja se pogoršava na fizičku
aktivnost (HR=7.525, CI 2.505-22.604, p<0.001) i oštećenje vidnog polja koje
prevazilazi proširenu slepu mrlju (HR=2.550, CI 1.166-5.581, p=0.019) čine nezavisne
pozitivne prediktore refraktorne IIH, dok je stežuća glavobolja (HR=0.179, CI 0.073-
0.437, p<0.001) identifikovana kao negativan prediktor.
Zaključci: Iako studije koje su istraživale IIH opisuju obilje prezentujućih simptoma,
naši rezultati ukazuju na to da simptomi nemaju dijagnostičku vrednost. Edem papile
optičkog živca je najpouzdaniji klinički znak za predikciju tačne dijagnoze IIH kod
osoba kod kojih se sumnja na ovu bolest. Prediktori povoljnog ishoda IIH su bol u vratu
na početku bolesti, odsustvo fonofobije i teškoća sa koncentracijom, dok kasniji početak
bolesti, pojačanje glavobolje na napor i oštećenje vidnog polja koje prevazilazi
proširenu slepu mrlju na inicijalnom oftalmološkom pregledu predviđaju refraktornu
bolest. | Idiopathic intracranial hypertension (IIH) is a rare disease characterized
by increased intracranial pressure (ICP) in the absence of any other detectable cause.
Clinical presentation of IIH is variable, with the most frequent finding of papilledema
and headache. Other symptoms include transient visual obscurations (TVO), blurred
vision, double vision due to sixth nerve palsy, tinnitus, dizziness, nausea, neck pain,
disturbed concentration and memory impairment. The diagnostic value of this variety of
presenting symptoms and clinical findings has been scarcely investigated. Current
diagnostic criteria for IIH are not based on clinical presentation of the disease, and
unlike former criteria do not include specific symptoms of raised ICP. Low prevalence
of IIH results in insufficient data regarding the course and long-term outcome of the
disease.
Objectives: The main aims of the study are to a) characterize the presenting symptoms
and signs of IIH defined according to the existing diagnostic criteria, b) analyze the
correlation of presenting symptoms and signs with the results of diagnostic procedures:
ICP measurement, presence of papilledema, and neuroimaging markers of raised
intracranial pressure c) investigate the correlation of presenting symptoms and signs
with the course and disease outcome.
Methods: This cohort study was conducted in two tertiary centers: Neurology Clinic of
the Clinical Center of Serbia and the Danish Headache Center-Rigshospitalet, Glostrup.
The study included 286 patients that were consecutively referred by attending
neurologist and ophthalmologist for the evaluation of possible IIH from January 2007 to
March 2016. The study was conducted in two phases. At first, clinical data were
prospectively collected from all study participants in order to evaluate the presenting
symptoms and signs of IIH. Clinical interview and a comprehensive semi-structured
questionnaire designed for the study was used to collect the demographic data,
characteristics of presenting symptoms, medication use prior to disease onset and the
presence of comorbid disorders. Neurological and neuro-ophthalmological examination,
ICP measurement and neuroimaging were performed in all participants. In the second
phase of the study were included 182 patients with IIH who were followed by
neurologist and ophthalmologists at least one year after the confirmation of diagnosis.
The duration of follow-up ranged from 12 to 144 months. A retrospective chart review
was performed in order to identify the course and outcome of the disease. Clinical
symptoms and findings that predict the diagnosis and outcome of IIH were analyzed and
independent predictors were estimated.
Results: The diagnosis of IIH was confirmed in 219 (76.6%) patients. It was more often
confirmed in patients with higher body mass index (BMI) (p=0.032) and if the patient
was referred by an ophthalmologist than if the referral was from a neurologist (83.6%
vs. 69.8%, p=0.029). Double vision (p=0.033), TVO (p=0.006), tinnitus (p=0.013), and
neck pain (p=0.025) were presenting symptoms more frequently reported by patients
with IIH diagnosis; papilledema (p<0.001) and sixth nerve palsy (p=0.010) were also
noted significantly more often in this patients. Papilledema was extracted by
multivariate analysis as an independent predictor of IIH diagnosis (p<0.001). Headache
was the most common symptom of IIH reported by 90.8% of patients at presentation.
Visual field defects resulting from IIH were found in 75% of patients at baseline, while
papilledema was noted in 93.3% of IIH patients. There was a significant correlation
between the presence of papilledema, sixth nerve palsy, TVO and double vision, with
the ICP values. A positive relationship was found between the presence of MRI markers
of raised ICP and papilledema in IIH. Younger age at disease onset has been associated
with the higher values of ICP and the presence of headache, tinnitus, double vision due
to sixth nerve palsy, nausea and vomiting at presentation. A significant positive
correlation of visual impairment (decreased visual acuity, double vision, and visual field
defect at least on one eye) at the time of diagnosis was found with BMI. Full remission
of symptoms and signs of IIH was documented in 72 (39.6%) patients at the final
follow-up visit. Higher ICP and headache reaching maximum intensity within one day
were extracted as positive predictors of remission by univariate analysis, while the
presence of neck pain at the disease onset (HR=4.959, CI 2.438-10.087, p<0.001) and
the absence of phonophobia (HR=0.230, CI 0.106-0.501, p<0.001) and concentration
difficulties (HR=0.360, CI 0.186-0.697, p=0.002) at baseline were identified by
multivariate analysis. Relapsing course of the disease was identified in 34 (18.7%)
patients. Headache announcing IIH, the occurrence of photophobia, concentration and
memory problems, preserved visual acuity bilaterally at the time of diagnosis as well as
ICP value derived from univariate analysis were associated with relapsing IIH course,
but none of the predictors reached statistical significance in multivariate Cox regression
analysis. Refractory IIH was identified in 76 (41.7%) patients at the end follow-up.
Higher BMI, comorbid depression, and empty sella sign on MRI scanning were
positively associated with refractory disease in univariate analysis, while constant
headache of frontal localization and dizziness showed a negative correlation. Older age
at onset (HR=1.066, CI 1.025-1.110, p=0.002), aggravation of headache by physical
activity (HR=7.525, CI 2.505-22.604 p<0.001), visual field defect beyond enlarged
blind spot at baseline (HR=2.550, CI 1.166-5.581, p=0.019) were extracted as positive
independent predictors of refractory IIH, while pressing headache (HR=0.179, CI
0.073-0.437, p<0.001) is identified as a negative predictor.
Conclusions: Although studies investigating IIH report an abundance of presenting
symptoms, our results indicate that these symptoms are not diagnostic for IIH.
Papilledema is the most reliable clinical sign predicting the correct IIH diagnosis in
patients with suspected IIH. The predictors of favorable IIH outcome are neck pain at
the disease onset and the absence of phonophobia and concentration difficulties, while
the refractory disease is more likely to occur in older patients in whom headache
aggravates by physical activity, and visual field defect exceeds an enlarged blind spot at
the baseline eye examination. | true |
Procena efektivnosti hirurškog lečenja katarakte merenjem kvaliteta života operisanih bolesnika | Effectiveness assessment of the cataract surgical treatment by measuring the quality of life of operated patients | Cilj: Da se testira validnost i pouzdanost „National Eye Institute Visual Functioning Questionnaire“ (NEI VFQ-25). Da se izvrši procena kvaliteta ţivota kod najĉešćih oftalmoloških oboljenja i da se proceni efektivnost hirurške korekcije katarkte merenjem kvaliteta ţivota operisanih bolesnika. Metode: Srpska verzija NEI VFQ-25 upitnika je prevedena u skladu sa meĊunarodno prihvaćenim standardima. Sa ciljem da se proceni pouzdanost i validnost prevedene verzije NEI VFQ-25 upitnika koristili smo uzorak od 105 pacijenata sa ĉetiri razliĉite oftalmološke bolesti. Kronbah alfa koeficijent je korišćen za procenu unutrašnje konzistentnosti svake subskale. Za procenu test-retest pouzdanosti korišćen je koeficijent interklasne korelacije. Test-retest podaci su prikupljeni od kliniĉki stabilnih pacijenata sa kataraktom u razmaku od dve nedelje. Za procenu psihometrijskih karakteristika upitnika takoĊe je primenjena i Raš analiza. Za procenu kvaliteta ţivota povezanog sa vidom korišćena je srpska verzija NEI VFQ-25 upitnika. Deskriptivna analiza i analiza generalizovane linearne procene jednaĉine su korišćeni za merenje promena u kvalitetu ţivota povezanim sa vidom nakon hirurgije katarakte. Rezultati: Pacijenti su za potrebe lingvistiĉke validacije upitnika podeljeni u ĉetiri grupe. Prvu grupu su ĉinili pacijenti sa kataraktom i bilo ih je 40 (38.1%), potom pacijenti sa dijabetiĉkom retinopatijom (DR) 31 (29.5%), senilnom degeneracijom ţute mrlje (ARMD) 22 (21.0%) i glaukomom 12 (11.4%). Ukupni index skor u NEI FQ-25 se kretao od 65.3 do 67.8 uz srednju vrednost od 67.4±15.0. Evaluacija validnosti Srpske verzije NEI VFQ-25 je data kao „multi-trait-multi-method matrix“ metoda. Sva pitanja su prošla test konvergentne i diskriminantne validnosti. Za konkurentnu validnost, detektovana je snaţna Spirmanova korelacija izmeĊu skorova većine NEI VFQ-25 subskala i sliĉnih domena u sklopu SF-36. Raš analiza je pokazala dobru preciznost instrumenta, ali i postojanje misfiting ajtema, i multidimenzionalnost. Proseĉna vrednost kompozitnog skora pre operacije je iznosila 73.1 (SD, 18.8). Nakon operacije katarakte na lošijem oku, došlo je do povećanja vrednosti kompozitnog skora u proseku za 20.2 taĉke na 93.3 (SD, 11.6)... | Purpose: To test the validity and reliability of the Serbian version of the intervieweradministered format of the National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25). To asses vision related quality of life and health related quality of life in most common ophthalmic deseases and to measure effectivness of catarct surgery throu quality of life assessment. Methods: The Serbian version of NEI VFQ-25 was translated in accordance with standard methods that have been adopted internationally. In order to assess the reliability and validity of the translated NEI VFQ-25, we used a sample of 105 patients with four different chronic ocular diseases. Cronbach’s alpha coefficient was used to assess internal consistency for each subscale. To assess test–retest reliability, intraclass correlation coefficients were used. The test–retest data were obtained from clinically stable patients with age-related cataracts, in surveys performed 2 weeks apart. Rasch analysis was also applied as a modern methods of psychometric assessment of the questionnaire. Vision-related quality of life was assessed using the NEI VFQ-25. Descriptive analyses and a generalized linear estimating equation analysis were undertaken to measure change in vision related quality of life after surgery. Results: Four groups of patients were studied and the most prevalent were patients with cataract 40 (38.1%), followed by diabetic retinopathy 31 (29.5%), age related macular degeneration 22 (21.0%) and glaucoma 12 (11.4%). The overall index score on the NEI VFQ- 25 ranged from 65.3 to 67.8 with a mean of 67.4 ± 15.0. Cronbach's alpha coefficient (index of internal consistency reliability) ranged from 0.592 to 0.889 for the subscales. Evaluation of the validity of the Serbian version of NEI VFQ-25 is presented in the multi-trait–multimethod matrix and all items passed the convergent and discriminant validity tests. Rasch analysis showed a good measurement precision, but also demonstrated misfitting items and multidimensionality of the questionnaire. The average value of a composite score before surgery was equal to 73.1 (SD, 18.8). After cataract surgery on the worse eye, there was an increase in the value of the composite score by an average of 20.2 points on 93.3 (SD, 11.6)... | false |
Uticaj genskog polimorfizma za angiotenzin konvertujući enzim, matriksnu metaloproteinazu 3, endotelnu azot oksid sintetazu, interleukine 6 i 10 i faktor nekroze tumora na kardiovaskularni morbiditet i mortalitet bolesnika na hemodijalizi | Influence of gene polymorphisms for angiotensine converting enzyme, matrix metalloproteinase 3, endothelial nitric oxidase, interleukins 6 and 10 and tumor necrosis factor on cardiovascular morbidity and mortality in hemodialysis patients | Kardiovaskularne bolesti (KVB) su glavni uzrok morbiditeta (Mb) i mortaliteta (Mt)
bolesnika u terminalnoj fazi hronične bubreţne slabosti (HBS). Godišnja stopa Mt usled KVB
iznosi 9%, što je 10-20 puta više nego u opštoj populaciji nakon prilagoĎavanja za starost, pol,
rasu i diabetes mellitus. Visoka incidenca smrti od infarkta miokarda kod bolesnika srednje
ţivotne dobi na hroničnoj hemodijalizi (HD) zapaţena je još ranih ’70- tih godina i objašnjena je
hipotezom o “akcelerirajućoj aterosklerozi”, koja je i danas podjednako aktuelna. Klasični faktori
rizika kao što su starija ţivotna dob, hipertenzija, dislipidemija, dijabetes melitus, fizička
neaktivnost i pušenje nisu mogli zadovoljavajuće objasniti visoku prevalencu koronarne bolesti u
HBS. Kasnija istraţivanja su pokazala da se ubrzana aterogeneza kod bolesnika sa HBS
pojavljuje usled sinergizma mehanizama koji obuhvataju malnutriciju, inflamaciju, oksidativni
stres i genetske komponente.
Zbog toga u poslednje vreme paţnju mnogih istraţivača privlače takozvani netradicionalni faktori
rizika, u koje se od skora pored vrednosti ukupnog homocisteina, lipoproteina a (Lp(a)), infekcija
Herpesvirusima i Chlamidiom pneumonie, ubraja i polimorfizam gena za različite proteine koji
učestvuju u genezi ateroskleroze. Tokom proteklih nekoliko godina najveći broj ovih istraţivanja
bavio se polimorfizmima za različite gene endotelne disfunkcije i gene inflamatornog odgovora
(angiotenzin konvertujući enzim (ACE) i matriksne metaloproteinaze (MMP), endotelna azot
oksid sintetaza (eNOS), interleukin-6 (IL-6), interleukin-10 (IL-10), faktor nekroze tumora
(TNF)).
Cilj ove studije bio je analiza kardiovaskularnog morbiditeta i ukupnog i kardiovaskularnog
mortaliteta u odnosu na genski polimorfizam za ACE, MMP-3, eNOS, Il-10, IL-6 i TNF kod
bolesnika koji se leče hroničnim hemodijalizama, kao i da se odredi koji od navedenih genskih
polimorfizama ima najviše uticaja na pojavu kardiovaskularnih dogaĎaja u navedenoj populaciji .
Metod: Ovom studijom obuhvaćeno je ukupno 315 bolesnika koji se nalaze na hroničnom
programu lečenja hemodijalizama duţe od šest meseci u Kliničkom odeljenju za bolesti bubrega i
poremećaje metabolizma sa dijalizom Kliničko-bolničkog centra „Zvezdara“ u Beogradu. Svi
bolesnici imali su tri hemodijalizna tretmana nedeljno u trajanju od 4-5 sati. Uzorak venske krvi
uziman je na redovnoj dijalizi i upućivan na genotpizaciju. Tokom istrazivanja prekinuto je
praćenje 21 bolesnika, te je krajnji broj bolesnika bio 294. Praćenje je za 21 bolesnika prekinuto
jer je 7 bolesnika prešlo u drugi dijalizni centar, kod 10 bolesnika je uraĎena transplantacija
bubrega, 3 bolesnika su prešla na drugu metodu zamene bubreţne funkcije (peritoneumska
dijaliza), dok je jedan bolesnik ušao u remisiju osnovne bolesti i prekinuo lečenje dijalizama.
Kod 201 bolesnika iz ove grupe je odreĎivan genski polimorfizam za IL-10, IL-6 i TNF, dok je
kod 200 bolesnika odreĎivan genski polimorfizam za MMP-3, ACE i eNOS, pri čemu su svi
ispitivani genski polimorfizmi odreĎivani kod 85 ispitanika. Deo genetskih analiza (MMP3, ACE
i eNOS) radjen je u laboratoriji odeljenja za Citogenetiku i prenatalnu dijagnostiku KBC
“Zvezdara”, a drugi deo (IL-10, IL-6, TNF) u laboratoriji Instituta za imunologiju Kliničkog
centra Srbije.
Retrospektivni deo studije obuhvatao je prikupljanje podataka o kardiovaskularnom morbiditetu
iz istorija bolesti (preleţani akutni infarkt miokarda, cerebrovaskularni insult, prisustvo
ishemijske bolesti srca, poremećaja srčanog ritma, hipertenzije, prisustvo hipertrofije leve
komore i periferne vaslukarne bolesti) i ispitivanje njegove povezanosti sa genetskim
polimorfizmom. Prospektivni deo studije podrazumevao je praćenje bolesnika uperiodu od 5
godina i analizu mortaliteta shodno genskom polimorfizmu.
Rezultati: U odnosu na gen za IL-6 utvrĎena je statistički značajna povezanost sa koronarnom
arterijskom bolešću i cerebrovaskularnim insultom, a heterozigoti za ovaj gen pokazali su
značajno niţi rizik za nastanak cerebrovaskularnog insulta u odnosu na CC homozigote. Značajna
povezanost pronaĎena je izmeĎu IL-10 genskog polimorfizma i infarkta miokarda kod bolesnika
na hemodijalizi, dok su GG homozigoti za ovaj gen imali 5 puta niţi rizik za nastanak koronarne
bolesti u odnosu na AA homozigote. Nosioci A alela za TNF genski polimorfizam pokazali su 6
puta viši rizik za nastanak hiperlipidemije.
Ukupni petogodišnji mortalitet u odnosu na IL-10 genski polimorfizam najviši je meĎu GG
homozigotima, a najveći kardiovaskularni mortalitet imali su AA homozigoti. U odnosu na IL-6
genski polimorfizam najkraće ukupno preţivljavanje registrovano je meĎu GC heterozigotima,
dok u odnosu na kardiovaskularni mortalitet nije bilo većih razlika meĎu pojedinim
genotipovima. Bolesnici sa GG genotipom za TNF genski polimorfizam imali su najlošije
preţivljavanje, dok u ukupnom mortalitetu nije bilo razlika meĎu genotipovima.
U odnosu na MMP3 genski polimorfizam rezultati su pokazali statistički značajnu povezanost sa
koronarnom arterijskom bolešću i srčanim aritmijama, a rizik za ove dve bolesti značajno je viši
meĎu heterozigotima za ovaj gen u odnosu na 6A homozigote. Homozigoti 5A/5A za ovaj gen
imali su najviši ukupni, kao i kardiovaskularni mortalitet ali bez statističke značajnosti.
Rezultati našeg istraţivanja pokazali su statistički značajnu povezanost I/I genotipa za ACE gen
sa nastankom srčanih aritmija. Ukupni mortalitet najviši je meĎu I/D heterozigotima dok su D/D
homozigoti imali najkraće kardiovaskularno preţivljavanje.
U odnosu na eNOS genski polimorfizam TT homozigoti pokazali su duplo viši rizik za koronarnu
arterijsku bolest. Ukupni i kardiovaskularni mortalitet najviši je meĎu TT homozigotima.
Zaključak: Pretpostavka je da ispitivani genski polimorfizmi u kombinaciji sa spoljašnjim
faktorima ili u specifičnim udruţenim dejstvom sa drugim genima mogu imati značajnog uticaja
na kardiovaskularni morbiditet i mortalitet. Stoga, za definitivni zaključak potrebno je još mnogo
dodatnih ispitivanja. | Introduction:Cardiovascular disease (CVD) is leading cause of morbidity and death in
haemodialysis patients. The risk for developing cardiovascular event is 10-20 folds higher in
patients with end stage renal desease (ESRD) than in the general population, after adjustment for
age, gender, race and diabetes mellitus. High mortality rate in hemodialysis patients was
observed in early ’70ies and was explained with “accelerated atherosclerosis” hypothesis.
Traditional risk factors (elderly patients, hypertension, dislipidaemia, diabetes, sedentary life
style and smoking), could not explain high prevalence of cardiovascular disease in haemodialysis
patients. That why recent reports have suggested a role of non-traditional risk factors in
pathogenesis of CVD, such as malnutrition, inflammation, oxidative stress, homocysteine levels,
Lp(a), infections with Herpes and Chlamidia pneumoniae and gene polymorphism of proteins
involved in pathogenesis of atherosclerosis. For the last few years investigators were focused on
genes of endothelial dysfunction (ACE, MMP3, eNOS) and genes of inflammatory response (Il/6,
IL/10, TNF). Gene polymorphism includes egzistance of two or more variant of one gene when
frequency of its rarest allele in population is more than 1%.
The aim of this study was to analyse cardiovascular morbidity and overall and cardiovascular
mortality regarding the gene polymorphisms for ACE, MMP3, eNOS, IL-10, IL-6 and TNF in
patients on chronic dialysis and to detect which gene polymorphism has the highest impact on
cardiovascular events in henodialysis patients.
Methods: The study included 315 patients on regular hemodialysis longer than 6 months in
University Clinical Center „Zvezdara“, Belgrade. All patients had 3 dialysis sessions weekly in
duration of 4/5 hours. Venous blood sample was collected in midweek dialysis and was sent for
genotyping.
During the research, 21 patients was droped out from the study, 7 due to transferring to another
dialysis center, 10 of them due to renal transplantation, 3 were switched to peritoneal dialysis and
one had a remmision. Genotyping for IL-10, IL-6 and TNF was done in 201 of 315 patients ,
while genetic analysis for MMP3, eNOS and ACE were done in 200 patients. All genetic analysis
were performed in 85 patients.
Genetic analysis for ACE, MMP3 and eNOS were performed in Department for gentic and
prenatal diagnostics of “Zvezdara” University Clinical Center , while genetic analysis for IL-10,
IL-6 and TNF were performed at Institute for immunology Faculty of Medicine, Belgrade
University.
Retrospective analysis included data collection from the patients history regarding cardiovascular
morbidity (myocardial infarction, cerebrovascular accident, coronary artery disease, heart
arrhythmia, hypertension, left ventricular hypertrophy, peripheral artery disease). Collected data
were analysed regarding genetic polymorphisms. The prospective part of this study included 5
years follow-up in order to analyse CV morbidity and all-cause and CV mortality regarding
MMP3 gene polymorphism.
Results: Regarding IL-6 gene polymorphism there were significant correlation with coronary
artery disease and cerebrovascular accident, while heterozygots for IL-10 gene had significantly
lower risk for developing cerebrovascular accident regarding the CC homozygots. Our results
showed significant correlation between gene polymorphism for IL-10 and myocardial infarction,
while GG homozygots showed 5 fold lower risk for developing coronary artery disease.
Heterozygots for IL-10 gene showed significantly lower incidence of cardiovascular events
(p=0.05) and more than twice lower risk for developing of myocardial infarction, but
experienced twice higher risk for left ventricular hypertrophy regarding GG homozygots. Also, A
allele carriers for TNF experienced 6 fold higher risk for development of hyperlipidemia.
Overall mortality rate was highest in GG homozygots for IL-10, while highest cardiovascular
mortality experienced AA hopmozygots for this gene. Regarding the IL-6, the lowest survival
had heterozygots, while there was no significant difference between different genotypes
regarding cardiovascular mortality rate. Homozygots GG for TNF gene had lowest
cardiovascular survival rate, while there were no difference regarding overall mortality rate.
Result of our study showed statistically significant correlation between MMP3 gene
polymorphism and coronary artery disease and heart arrhythmia and risk for this conditions was
higher in heterozygots for MMP3 gene regarding 6A homozygots. Homozygots 5A/5A had the
highest overall and cardiovascular mortality rate.
Regarding ACE gene polymorphism, I/I homozygots had statistically significant correlation with
development of heart arrhythmia. Overall mortality was highest among I/D heterozygots while
D/D homozygots had shortest cardiovascular survival.
Homozygots TT for eNOS gene had twice higher risk for coronary artery disease. Overall and
cardiovascular mortality rate was the highest among TT homozygots for eNOS gene.
Conclusion: So far, it was shown that certain genes in interaction with other genes and
enviromental factors may cause some of cardiovascular diseases. We will need longer follow-up
in order to get definitive conlusion about influence of gene polymorphism on cardiovascular
morbidity. | true |
Uticaj infekcije virusom humane imunodeficijencije na genetičku varijabilnost kliničkih izolata BK i JC poliomavirusa | The influence of human immunodeficiency viral infection on the genetic variability of clinical isolates of BK and JC polyomaviruses | Uticaj infekcije virusom humane imunodeficijencije na genetičku
varijabilnost kliničkih izolata BK i JC poliomavirusa
Uvod
Seroepidemiološke studije pokazuju da je između 27% i 80% humane
populacije inficirano sa dva poliomavirusa BK virusom (BKV) i JC virusom (JCV).
Posle primarne asimptomatske infekcije, koja se obično dešava u toku ranog
detinjstva, oba virusa uspostavljaju latenciju u ćelijama bubrega i gornjih partija
urinarnog trakta. Sporadična asimptomatska reaktivacija oba virusa se dešava kod
0.5-20% imunokompetentnih seropozitivnih osoba. Međutim, kod
imunosuprimiranih osoba njihova reaktivacija može dovesti do nastanka životno
ugrožavajućih oboljenja. Reaktivacija JCV, pre svega kod pacijenata sa T ćelijskom
imunodeficijencijom, dovodi do litičke infekcije oligodendrocita u centralnom
nervnom sistemu (CNS) i nastanka progresivne multifokalne leukoencefalopatije
(PML), dok reaktivacija BKV dovodi do nastanka hemoragijskog cistitisa i
poliomavirus-udružene nefropatije. Pre epidemije AIDS-a, limfoproliferativna
oboljenja su bila vodeći uzrok reaktivacije JCV i BKV, dok danas HIV infekcija
predstavlja najčešći uzrok reaktivacije JCV i nastanka PML. Očigledno je da
imunosupresija predstavlja fundamentalni predisponirajući faktor za nastanak
PML, poliomavirus-udružene nefropatije i hemoragijskog cistitisa. Ipak, ova
oboljenja ne nastaju kod svih imunosuprimiranih osoba, tako da se smatra da i
drugi faktori, poput genetičke varijabilnosti BK i JC virusa, mogu doprineti
njihovom nastanku.
Ciljevi
Ciljevi ovog istraživanja bili su: da se odredi prevalenca izlučivanja BKV i JCV
u urinu HIV-inficiranih pacijenata i pacijenata kontrolne grupe i ispita moguća
povezanost virurije u grupi HIV-inficiranih sa demografskim, virusološkim i
citološkim parametrima kao i sa stadijumima bolesti i vrstom primenjene terapije;
da se utvrdi distribucija genotipova i subtipova, struktura nekodirajućeg
regulatornog regiona kao i prisustvo mutacija u VP1 regionu JCV i BKV u obe grupe
ispitanika.
Metodologija
U istraživanje su uključeni uzorci urina 114 HIV-inficiranih pacijenta i 120
zdravih osoba. Semi-nested i nested-PCR metodom su umnoženi fragmenti VP1
gena i NCRR JCV i BKV, a PCR produkti su zatim direktno sekvencirani. Upotrebom
odgovarajućih bioinformatičkih alata vršena je filogenetska analiza sekvenci. Za
statističku obradu podataka korišćen je SPSS program ver. 20.
Rezultati
Učestalost BK virurije kod HIV-inficiranih pacijenata iznosila je 50,8%, dok
je u kontrolnoj grupi ispitanika iznosila 7,5%. Utvrđena je visoko statistički
značajna razlika u učestalosti BK virurije između dve ispitivane grupe (p=0,0001).
JC virurija je češće otkrivana kod HIV-inficiranih pacijenata (43,8% kod HIV-
inficiranih vs. 30,8% ispitanika kontrolne grupe; p=0,039). Utvrđena je statistički
značajna razlika u stepenu BKV virurije među CDC kliničkim kategorijama
(p=0,019) gde je BK virurija značajno češća među HIV-inficiranim pacijentima koji
pripadaju C kliničkoj kategorije (64,4%) u odnosu na one koje pripadaju A+B
kategoriji. U obe grupe ispitanika su otkrivena dva subtipa BKV: I i IV. S druge
strane, distribucija JCV se razlikovala među isputivanim grupama. U kontrolnoj
grupi ispitanika najčešći genotipovi JCV su bili genotip 1, 2 i 4, dok je u grupi HIV-
inficiranih dominantan genotip bio 2 praćen genotipovima 1 i 4. Kod HIV-
inficiranih pacijenata, najveći broj nesinonimnih nukleotidnih izmena otkriven je u
okviru BC receptorskog domena VP1 gena BKV, dok su kod ispitanika kontrolne
grupe sve nesinonimne nukleotidne izmene otkrivene van receptorskih domena u
okviru β-ploča. Statistički visoko značajna razlika je utvrđena u distribuciji
mutacija u BC receptorskom domenu VP1 gena BKV između HIV-inficiranih
pacijenata i ispitanika kontrolne grupe (p=0,0004). Svi HIV-inficirani pacijenti koji
su imali mutacije u VP1 genu BKV imali su broj CD4+ ćelija manji od 200 po ml
krvi. Struktura NCRR svih izolata JCV i BKV odgovara arhetip varijanti NCRR JCV tj.
BKV. dN i dS vrednosti DE receptorskih domena JCV i BC receptorskog domena
BKV kod HIV-inficiranih pacijenata su bile nekoliko puta više od dN i dS vrednosti
za protein kodirajuće sekvence VP1 regiona JCV tj. BKV, ukazujući da je ovaj deo
genoma pod većim uticajem selekcionog pritiska imunskog odgovora.
Zaključak
Imunosupresija predstavlja jako bitan faktor za reaktivacija BKV i JCV i
dovodi do povećanja nivoa virusne replikacije. Povećan nivo replikacije BKV je
povezan sa češćom pojavom mutacija u okviru BC receptorskog domena, a mutacije
u BC receptorskom domenu mogu dovesti do izmene tropizma i stvaranja novih
agresivnijih varijenti BKV. Ova studija je pokazala da evropski, evroazijski i indijski
tipovi JCV cirkulišu u Srbiji i takva distribucija je u skladu sa poreklom i istorijom
srpskog naroda. Selektivni pritisak zbog imunosupresivnog stanja dovodi do
promene u distribuciji JCV genotipova. Imajući na umu da je genotip 2 tzv.,
“nepovoljni” genotip najčešći genotip kod HIV-inficiranih pacijenata u ovom
istraživanja, pacijenti koji imaju HIV/poliomavirus koinfekciju treba da budu pod
češćim i redovnijm nadzorom kako bi se modulacijom imunosupresivne terapije
smanjila mogućnost za reaktivaciju JCV i nastanak PML-a. | The influence of human immunodeficiency viral infection on the genetic
variability of clinical isolates of BK and JC polyomaviruses
Introduction
Seroepidemiologic studies have shown that between 27% and 80% of
human population is infected with two human polyomaviruses BK virus (BKV) and
JC virus (JCV). After primary asymptomatic infection, which usually occurs during
early childhood, both viruses establish latency in the cells of the kidney and upper
parts of the urinary tract. Sporadic asymptomatic reactivations of both viruses
occur in 0,5-20% of seropositive immunocompetent individuals. However, in
immunosuppressed patients reactivation of the viruses can lead to the
development of serious and life threatening diseases. Reactivation of JCV, primarily
in patients with T cell immunodeficiency, leads to lytic infection of
oligodendrocytes in the central nervous system (CNS) and the development of
progressive multifocal leukoencephalopathy (PML), while reactivation of BKV is
associated with hemorrhagic cystitis and polyomavirus-associated nephropathy.
Before the AIDS epidemic, lymphoproliferative diseases were the leading cause for
reactivation of JCV and BKV while nowdays HIV infection is the most common
cause for reactivation of JCV and the development of PML. It is evident that
immunosuppression is a fundamental predisposing factor for developing PML,
polyomavirus-associated nephropathy and hemorrhagic cystitis. However, these
diseases do not affect all immunosuppressed individuals, suggesting that other
factors, such as genetic variability of BK and JC viruses, can contribute to their
occurrence.
Objectives
The objectives of this research were to determine the prevalence of BKV and
JCV viruria in HIV-infected patients and patients of the control group and critically
evaluate the relationship between viruria and demographic, virological and
cytological parameters as well as the stages of the disease and the applied therapy;
also, to determine the distribution of genotypes and subtypes, the structure of non-
coding regulatory region and the presence of mutations in the VP1 region of JCV
and BKV in both groups of patients.
Methodology
The survey included urine samples of 114 HIV-infected patients and 120
healthy donors. Semi-nested and nested-PCR methods were used for amplification
of the VP1 gene and NCRR of JCV and BKV. After visualisation of PCR products of
appropriate length in 2% agarose gel under the UV light, all posititive PCR products
were directly sequenced. Phylogenetic analysis of sequences was performed by
using appropriate bioinformatics tools. For statistical analysis SPSS program ver.
20 was used.
Results
The frequency of BK viruria in HIV-infected patients was 50.8%, while it
was 7.5% in the control group subjects. There was high statistically significant
difference in the frequency of BK viruria between two study groups (p=0.0001). JC
viruria was also more often detected in HIV-infected patients (43.8% in HIV-
infected vs. 30.8% in the control group; p=0.039). There was statistically
significant difference in frequency of BKV viruria among HIV-infected patients
belonging to different CDC clinical categories (p=0.019). BK viruria was more
common among HIV-infected patients who belonged to the C clinical category
(64.4%) compared to those belonging to category A+B. In both groups two
subtypes of BKV were identified: I and IV. On the other hand, the distribution of JCV
genotypes was different among studied groups. In the control group the most
common genotypes of JCV were 1, 2 and 4, while among HIV-infected patients
dominant genotype was 2 followed by genotypes 1 and 4. In HIV-infected patients,
the majority of non-synonymous alterations were detected within the BC loop of
the BKV VP1, while in the control group all non-synonymous alterations were
detected outside of the receptor loops in the β-sheets that connect the loops. The
higher frequency of mutations in the BC loop of VP1 protein was identified among
the BKV isolates from HIV-infected patients and there was statistically significant
difference between HIV-infected patients and healthy subjects (p=0.0004). All
mutations in the VP1 protein of BKV isolates from HIV-infeted patients were
detected among patiebts with CD4+ cell counts less than 200cell/mm3. The
structures of BKC and JCV NCRR found in the urine samples of patients infected
with HIV and healthy donors showed a pattern identical to the archetype structure,
except for some point mutations. dS and dN values of the DE and BC loop of JCV
and BKV in HIV-infected patients were several times higher compared with the dS
and dN values of the VP1 gene region, indicating that this part of the genome is
under the more selective pressure.
Conclusion
Immunosuppression is a very important factor for the reactivation of BKV
and JCV, and leads to increased levels of viral replication. Increased levels of
replication of BKV are associated with a higher incidence of mutations in the BC
loop, and mutations in the BC loop may lead to changed tropism and generatinon of
new more aggressive variations of BKV. This study showed that European, Eurasian
and Indian types of JCV circulate in Serbia and such distribution is in accordance
with the origin and history of the Serbian people. The selective pressure due to the
immunosuppressive state leads to changes in the distribution of JCV genotypes.
Having in mind that “unfavorable” genotype 2 is the most common genotype in
HIV-infected patients of this study, it could be concluded that patients who have
HIV/polyomavirus coinfection should be under more frequent supervision in order
to reduce the potential risk for reactivation of JCV and the emergence of PML by
modulatating immunosuppressive therapy. | true |
Procena kvaliteta života kod žena u reproduktivnom periodu lečenih zbog patoloških promena grlića materice | Quality of life assessment in women of reproductive age treated for pathological changes in the uterine cervix | Učestalost pojave displazije grlića materice pokazuje porast, naročito
kod žena u reproduktivnom periodu. Pravovremeno lečenje ovih promena je
značajno za smanjenje učestalosti pojave invazivnog karcinoma grlića materice, a
ispitivanje kvaliteta života povezanog sa zdravljem (HRQoL) nakon lečenja
displazije doprinosi unapređenju ishoda lečenja. I pored toga, u kliničkoj praksi kod
nas nisu zaživeli adekvatni instrumenti za ispitivanje HRQoL ovih žena. Pored same
bolesti i njenog hirurškog lečenja, na HRQoL žena u reproduktivnom periodu
hirurški lečenih zbog patoloških promena grlića materice mogu uticati i dugoročne
posledice lečenja na reproduktivnu funkciju, mogući infertilitet i povišen rizik
perinatalnog morbiditeta i mortaliteta. Pored toga, lečenje može dovesti do
značajnih promena u psihičkoj sferi i seksualnosti.
Ciljevi: Primarni cilj istraživanja bila je psihometrijska validacija srpske
verzije instrumenta za ispitivanje HRQoL žena sa cervikalnom displazijom FACIT-
CD (Functional Assessment of Chronic Ilness Therapy-Cervical Dyplasia). Drugi cilj
bilo je ispitivanje HRQoL žena u reproduktivnom periodu lečenih ekscizionim
hirurškim metodama zbog skvamozne intraepitelne lezije (SIL) FACIT-CD
upitnikom, SF-36v2 upitnikom, Bekovim upitnikom za anksioznost (BAI) i Bekovim
upitnikom za depresiju (BDI), posebno u odnosu na reproduktivne karakteristike
ispitanica: paritet i zainteresovanost za reprodukciju.
Pacijenti i metode: Istraživanje je sprovedeno kao studija preseka i
obuhvatilo je žene operisane iz dijagnostičkih ili terapijskih razloga dve i više godina
pre uključivanja u studiju, kod kojih je histološki potvrđeno postojanje SIL.
Kriterijumi za isključivanje iz studije bili su postojanje invazivne promene grlića,
naknadni tretman grlića, kao i postojanje drugih patoloških promena na genitalnim
organima i/ili hroničnih oboljenja koja mogu remetiti HRQoL. Prikupljeni su
sociodemografski i klinički podaci ispitanica, a HRQoL je procenjivan FACIT-CD, SF-
36v2, BAI i BDI upitnicima.
Rezultati: Srpska verzija FACIT-CD upitnika je pokazala zadovoljavajuće
psihometrijske karakteristike. Cronbach alfa koeficijent za celu skalu iznosio je
0.710. Ispitivanje validnosti je potvrdilo originalnu petofaktorsku strukturu
upitnika, uz delimično preklapanje sa originalnim domenima upitnika. Dokazane su
brojne signifikantne pozitivne korelacije između skorova srodnih domena
generičkog upitnika SF-36v2 i FACIT-CD skale, kao i signifikantne negativne
korelacije između skorova FACIT-CD skale i skorova BAI i BDI. Najniže FACIT-CD
skorove imale su nulipare zainteresovane za reprodukciju, što ukazuje da ove
pacijentkinje imaju značajno narušen HRQoL nakon hirurškog lečenja patoloških
promena grlića materice, kako u poređenju sa ženama koje nisu zainteresovane za
dalju reprodukciju, tako i u poređenju sa onima koje jesu zainteresovane, a već su
ostvarile fertilnu sposobnost, što je u skladu sa hipotezom istraživanja. HRQoL ovih
žena bio je takođe značajno lošiji i u domenu emocionalnog stanja (EWB) ispitivanog
FACIT-CD upitnikom. U odnosu na ostale ispitivane parametre, prosečne vrednosti
FACIT-CD skorova su bile signifikantno niže kod neudatih žena, onih sa manjim
brojem ukupnim porođaja i onih sa strahom za reproduktivnu sposobnost u
trenutku operacije. HRQoL ispitivanih pacijentkinja meren FACIT-CD skalom nije se
značajno razlikovao u odnosu na gradus SIL i vrstu hirurškog lečenja.
Zaključak: Kulturološki adaptirana srpska verzija FACIT-CD upitnika
predstavlja adekvatnu meru HRQoL žena u reproduktivnom periodu hirurški
lečenih zbog patoloških promena grlića materice. Izvršena kulturološka adaptacija i
psihometrijska validacija FACIT-CD skale omogućava dalje istraživanje HRQoL kod
žena u reproduktivnom periodu lečenih zbog patoloških promena grlića materice u
srpskoj populaciji, kao i internacionalno poređenje dobijenih rezultata. Prema
rezulatima ovog istraživanja, nulipare zainteresovane za reprodukciju imaju
dugoročno značajno narušen HRQoL. HRQOL nije se razlikovao u odnosu na gradus
SIL i vrstu hirurške ekscizije primenjene za lečenje. | The incidence of cervical dysplasia is growing, particularly in
women of reproductive age. Timely treatment of these changes is important for
reducing the incidence of invasive cervical cancer, and the investigation of health
related quality of life (HRQoL) following dysplasia treatment contributes to a better
treatment outcome. Nevertheless, adequate instruments for studying HRQoL in
women are still not widely used in our clinical practice. Apart from the disease itself
and its surgical treatment, the HRQoL in women of reproductive age that were
surgically treated can be influenced by the long-term consequences of the treatment
on the reproductive function, possible infertility, and increased risk of perinatal
morbidity and mortality. Moreover, treatment may lead to significant changes in the
psychological field and in sexuality.
Aims: The primary aim of our research was psychometric validation of the
Serbian version of the HRQoL assessment instrument for women with cervical
dysplasia - FACIT-CD (Functional Assessment of Chronic Illness Therapy-Cervical
Dysplasia). The secondary aim was the evaluation of the HRQoL in women of
reproductive age treated by excisional surgical methods for squamous
intraepithelial lesion (SIL), using the FACIT-CD questionnaire, the SF-36v2
questionnaire, the Beck’s anxiety inventory (BAI), and the Beck’s depression
inventory (BDI), particularly in relation to the reproductive characteristics of the
participants: parity and fertility interest.
Patients and methods: Research was conducted as a cross-sectional study,
and it encompassed women operated for diagnostic or therapeutic reasons two and
more years prior to study enrollment, in whom SIL was histologically confirmed.
The exclusion criteria were: the presence of invasive disease, repeated cervical
treatment, the presence of other pathological changes on the reproductive organs
and/or chronic diseases that could impair the HRQoL. The data on socio-
demographic and clinical characteristics of the participants were collected, and the
HRQoL was assessed using the FACIT-CD, SF-36v2, BAI and BDI questionnaires.
Results: The Serbian version of the FACIT-CD questionnaire exhibited
appropriate psychometric characteristics. The Cronbach's alpha coefficient for the
entire scale was 0.710. Validity evaluation confirmed the original five-factor
structure of the questionnaire, with partial overlapping with the original domains.
Numerous significant positive correlations between the scores of the corresponding
domains of the generic questionnaire SF-36v2 and the FACIT-CD scale were
documented, as well as significant negative correlations between the FACIT-CD
scale and both the BAI and BDI scores. The lowest FACIT-CD scores were found in
the nulliparas interested in fertility, which indicates significant impairment of
HRQoL in these patients compared to those who were not interested in further
reproduction, or to those who were interested and parous, thus confirming the
research hypothesis. The HRQoL in nulliparous women interested in reproduction
was also significantly impaired in the domain of emotional well-being (EWB),
evaluated by the FACIT-CD questionnaire. In relation to the other evaluated
parameters, the average values of the FACIT-CD scores were significantly lower in
single women, in those with a lower total number of deliveries, and in those with
fertility concerns at the time of surgery. The HRQoL in the investigated patients,
measured with the FACIT-CD scale, was not significantly different in relation to the
SIL grade and type of surgical treatment.
Conclusion: The transculturally adapted Serbian version of the FACIT-CD
questionnaire represents an adequate measure for the HRQoL in women of
reproductive age surgically treated for pathological changes in the uterine cervix.
The performed cross-cultural adaptation and psychometric validation of the FACIT-
CD scale enables further evaluation of the HRQoL in women of reproductive age
treated for pathological changes in the uterine cervix in the Serbian population as
well as international comparison of the obtained data. As documented by this
research, the nulliparas interested in reproduction have long-standing HRQoL
impairment. The HRQoL was not affected by the SIL grade and the type of surgical
excision used for treatment. | true |
Odgovor alveolo-kapilarne membrane na kontinuiranu fizičku aktivnost kod vrhunskih sportista sa različitom adaptacijom respiratornog sistema | Alveolo-capillary membrane response on continuous physical activity in elite athletes with various adaptations of the respiratory system | Uvod: Difuzijski kapacitet pluća za ugljen monoksid (DLCO ili transfer faktor)
definiše se kao količina gasa ugljen monoksida (CO) koja prolazi kroz alveolo-
kapilarnu membranu tokom jednog minuta pri razlici pritiska od 1 kPa. DLCO zavisi od
difuzijskog kapaciteta alveolarne membrane, krvnog volumena u alveolarnim
kapilarama i brzini vezivanja CO sa oksihemoglobinom. Sposobnost respiratornog
sistema da izvrši ovu razmenu određena je strukturnim i funkcionalnim svojstvima
samih pluća. Ranije studije su pokazale da intenzivna, dugotrajna fizička aktivnost kod
sportista dovodi po povećanja DLCO.
Ciljevi istraživanja: U ovom radu ciljevi istraživanja bili su: da se ispita uticaj
redovne, programirane i kontrolisane specifične fizičke aktivnosti na odgovor alveolo-
kapilarne membrane u miru, kod sportista i zdravih ljudi, razlika u disajnim
volumenima između fizički aktivnih (sportista) i neaktivnih, zdravih ljudi u miru i uticaj
antropometrijskih parametara na njih i DLCO, a potom da se ispita uticaj intenziteta i
učestalosti treninga na disajne volumene i difuzijski kapacitet. Dobijeni rezultati su
poređeni sa rezultatima za opštu populaciju.
Ispitanici i metode: Istraživanje je bazirano na dve studije: studija preseka i
anamnestičku studiju. Istraživanjem je obuhvaćeno ukupno 157 ispitanika muškog pola,
koji su prema obimu nedeljne fizičke aktivnosti podeljeni u dve grupe: fizički aktivne
(vrhunske sportiste) i fizički neaktivne (kontrolne) ispitanike bez prisustva
komorbiditeta. Grupu fizički aktivnih činilo je 115, a kontrolnu 42 ispitanika. Svi
ispitanici su uvršteni u istraživanje konsekutivno. Grupu vrhunskih sportista činili su
sportisti koji su se najmanje pet godina aktivno, takmičarski bavili različitom vrstom
sporta, trenirali najmanje 10 sati nedeljno, a koji su prema vrsti sportske aktivnosti
podeljeni u dve grupe: prva grupa- aerobna i druga- anaerobna grupa. Kontrolnu grupu
činili su studenti muškog pola izabrani metodom slučajnog izbora po frekvenciji godišta
kao u grupi sportista.
Nakon antropometrijskih merenja, svi ispitanici su bili podvrgnuti merenju
difuzijskog kapaciteta pluća za ugljen monoksid (DLCO) metodom jednog udaha i
spirometrijskom testiranju.
Istraživanjem su poređene srednje vrednosti antropometrijskih parametara
(telesna masa, telesna visina, indeks telesne mase), zatim srednje vrednosti disajnih
volumena i kapaciteta (vitalni kapacitet- VC, forsirani vitalni kapacitet – FVC, forsirani
ekspiratorni volumen u prvoj sekundi – FEV1, vršni ekspiratorni protok – PEF i odnos
FEV1/FVC), kao i srednje vrednosti parametara difuzijskog kapaciteta pluća za ugljen
monoksid (DLCO, transfer koeficijent (KCO), totalni plućni kapacitet (TLC) i
alveolarni volumen (VA)) između sve tri ispitivane grupe. U grupi sportista rađena je
korelaciona analiza uticaja vrste treninga, dužine treniranja (u godinama), učestalosti
(nedeljno) i sati treniranja nedeljno na parametre respiratorne funkcije.
U svim primenjenim statističkim metodama nivo statističke značajnosti bio je
na granici 0.05.
Rezultati. Vrednosti telesne mase bile su statistički značajno niže u grupi
aerobnih sportista u odnosu na kontrolnu grupu (p<0.05), dok je indeks telesne mase bio
statistički značajno niži u grupi sportista (p<0.05). Prosečna vrednost godina treniranja
statistički je značajno veća kod aerobista (p<0.01). Međutim, prosečna vrednost i
medijana učestalosti treninga i trajanja treninga u satima je bila statistički značajno veća
u grupi anaerobista. Vrednosti izmerenog vitalnog kapaciteta (VC (l) i VC (%)) bile su
statistički značajno više u grupi aerobnih sportista u odnosu na druge dve grupe
(p<0.01, p<0.05, redom). Statistički značajno veće vrednosti forsiranog vitalnog
kapaciteta u litrima (FVC (l)) imala je grupa aerobista u odnosu na druge dve (p<0.01),
dok u slučaju ostvarene procentualne vrednosti FVC, značajnost je bila blizu
konvencionalnog nivoa od 0.05, kada se porede aerobisti i kontrolna grupa, kao i
aerobisti i anaerobisti. Vrednosti izmerenog forsiranog ekspiratornog volumena u prvoj
sekundi u litrima (FEV1 (l)), bile su značajno više u grupi aerobista u odnosu na kontole
(p<0.01), dok je razlika između aerobistaa i anaerobista bila blizu konvencionalnog
nivoa značajnosti. Difuzijski kapacitet pluća za ugljen monoksid (DLCO) bio je
statistički značajno veći u grupi sportista. Nije utvrđena značajnost u vrednosti
koeficijenta difuzije (KCO) između ispitivanih grupa. Totalni plućni kapacitet (TLC (l),
%) (p<0.01, p<0.05, redom) i alveolarni volumen (VA (l), %) bio je statistički značajno
veći u grupi aerobnih sportista u odnosu na druge dve grupe (p<0.01). U grupi sportista
zajedno, utvrđena je pozitivna korelacija između godina treniranja i procentualno
ostvarenih vrednosti VC, FVC i FEV1. Učestalost treninga je u negativnoj korelaciji sa
FEV1/FVC odnosom, a sati treninga su negativno korelisali sa FEV1 (l) i FEV1 (%). U
aerobnoj grupi utvrđena je pozitivna korelacija između godina treniranja i FEV1 (%);
učestalost treninga je pozitivno korelisala sa VC (l), VC (%), FEV1 (%) i FEV1/FVC;
statistička značajnost nije utvrđena između sati treniranja i disajnih kapaciteta. U grupi
anaerobnih sportista nađena je pozitivna korelacija između godina treniranja i VC (%).
Sati treninga su negativno korelisali sa FEV1 (l). U grupi aerobista je utvrđena
negativna korelacija između godina treniranja i DLCO (l), DLCO % i KCO%. U
anaerobnoj grupi, godine treniranja su pozitivno korelisale sa sa TLC% i VA%
(konvencionalni nivo značajnosti).
Zaključak. Redovna, programirana i kontrolisana fizička aktivnost moduliše
respiratorni sistem u smislu adaptivnih promena specifičnih za vrstu fizičke aktivnosti.
Kontinuirana, intenzivna fizička aktivnost dovodi do brže razmene gasova na nivou
alveolo-kapilarne membrane. Rezultati ove doktorske disertacije pokazali su da postoje
značajne razlike u odgovoru respiratornog sistema na fizičku aktivnost između
vrhunskih aerobnih i anaerobnih sportista i ispitanika koji se aktivno ne bave sportom. | Introduction: The diffusion capacity of the lung for carbon monoxide (DLCO
or transfer factor) is defined as the amount of gas of carbon monoxide (CO) passing
through the alveolar-capillary membrane in the course of one minute at a pressure of 1
kPa. DLCO depends on the alveolar membrane diffusion capacity, the volume of blood
in alveolar capillaries and the speed of the oxyhemoglobin binding CO. The capacity of
the lung to exchange gas across the alveolarcapillary interface is determined by its
structural and functional properties. Earlier studies have shown that intense, prolonged
physical activity in athletes leads by increasing the DLCO.
Aims: The aims of this study were: to investigate the effect of regular,
programmed and controlled physical activity on a specific response alveolar-capillary
membrane in the rest in athletes and sedentary controls, differences in respiratory
volumes between physically active (athletes) and inactive, healthy people in peace and
the impact of anthropometric parameters on them and DLCO, and then to examine the
influence the intensity and frequency of training on lung volumes and diffusing
capacity.
Participants and methods: The research was based on two studies: cross-
sectional study and anamnestic study. The study included a total of 157 male
respondents, who, according to the volume of weekly physical activity divided into two
groups: physically active (top athletes) and physically inactive (control) examinees
without the presence of comorbidity. Physically active group consisted of 115, and 42
control subjects. All subjects were included in the study consecutively. A group of elite
athletes consisted of athletes who have at least five years of active competition practiced
different kinds of sports, train at least 10 hours a week, and who, according to the type
of sport activities are divided into two groups: aerobic and anaerobic. The control group
consisted of male students selected randomly by frequency as in the age group athletes.
After anthropometric measurements, all subjects underwent measurement of
lung diffusion capacity for carbon monoxide (DLCO) using single breath method and
spirometry testing.
The study compared the mean values of anthropometric parameters (body
weight, body height, body mass index), the mean values of respiratory volumes and
capacities (vital capacity- VC, forced vital capacity - FVC, forced expiratory volume in
one second - FEV1, peak expiratory flow - PEF and ratio of FEV1/ FVC), and the mean
value of parameters of diffusion capacity for carbon monoxide (DLCO, transfer
coefficient (KCO), total lung capacity (TLC) and alveolar volume (VA)) between the
three examined groups. In the group of athletes correlation analysis was done of the
impact types of training, length of training (in years), frequency (weekly) and hours of
training per week on parameters of respiratory function.
The level of statistical significance was less than 0.05.
Results. The values of body mass were significantly lower in the group of
aerobic athletes compared to the anaerobics and controls (p<0.05), while body mass
index were significantly lower in the group of athletes (p<0.05). The average value of
years of training was significantly higher in aerobic group (p <0.01). However, the
average value and the median frequency of training and training duration in hours were
significantly higher in the group of anaerobics. Values of measured vital capacity (VC
(l) i VC (%)) were significantly higher in the group of aerobic athletes compared to the
other two groups (p<0.01, p<0.05, randomly). Significantly higher values of forced vital
capacity in liters (FVC (l)) had aerobic group compared to the other two (p <0.01),
while in the case of realized percentages of FVC, significance was near the conventional
level of 0.05, when comparing aerobic and control groups, as well as aerobic and
anaerobic. Values of the measured forced expiratory volume in the first second (FEV1
(l)) were significantly higher in the group of aerobics compared to controls (p<0.01),
while the difference between aerobic and anaerobic group were near the conventional
level of significance. Lung diffusion capacity for carbon monoxide (DLCO) was
significantly higher in group of athletes. There was no significance in the value of
diffusion coefficient (KCO) between investigated groups. Total lung capacity (TLC (l),
%) (p<0.01, p<0.05, randomly) and alveolar volume (VA (l), %) was significantly
higher in the group aerobic athlete in relation to the other two groups (p <0.01).
Between the beginning of the training and the parameters of lung function and diffusion
capacity was not statistically significant correlation, as well as between the frequency
and hours of practice and the parameters of diffusion capacity of the lungs. In the group
of athletes together, a positive correlation was found between years of training and
percentage of realized value VC, FVC and FEV1. The frequency of training is
negatively correlated with FEV1 / FVC relations and hours of training were negatively
correlated with FEV1 (l) and FEV1 (%). The aerobic group had positive correlation
between years of training and FEV1 (%); training frequency was positively correlated to
the VC (l), VC (%), FEV1 (%) and FEV1/FVC; statistical significance was not found
between the hours of training and respiratory capacity. In the group of anaerobic athletes
a positive correlation was found between years of training and VC (%). Hours of
training were negatively correlated with FEV1 (l). Negative correlation was found
between years of training and DLCO (l), DLCO% and KCO% in aerobic group. In
anaerobic group, years of training were positively correlated with the TLC% and VA%
(conventional level of significance).
Conclusion. Regular, programmed and controlled physical activity modulates
the respiratory system in terms of adaptive changes specific to the type of physical
activity. Continuous, intensive physical activity leads to a faster gas exchange at the
alveolar-capillary membrane. The results of this doctoral thesis showed that there are
significant differences in the response of the respiratory system in physical activity
between the top aerobic and anaerobic athletes and those who are not actively involved
in sports. | true |
Značaj prevencije sekretornog otitisa kod dece sa urođenim rascepom nepca | Importance of prevention of otitis media with effusion in children with congenital cleft palate | Većina autora smatra da je sekretorni otitis kod dece sa rascepom nepca gotovo
uobičajena pojava i da se sekret u srednjem uvu stvara u prvim mesecima nakon rođenja.
Međutim, neslaganja u pristupu rešavanju ovog problema su brojna. Dok se jedni zalažu za
obaveznu ranu inserciju ventilacionih cevčica prilikom palatoplastike, drugi su zagovornici
konzervativnog pristupa, praćenja i insercije cevčica kasnije, od druge ili treće godine života
kada procene da je to neophodno. Jedna manja grupa autora ima pristup jednostrane insercije
prilikom palatoplastike uz kasnije praćenje pacijenata. Takođe postoji i različitost pristupa u
vezi kasnijih intervencija i lečenja vezanih za tok oboljenja i komplikacije.
U našoj zemlji gotovo da i nema radova na ovu temu, vezanih za specifični problem
sekretornog otitisa kod dece sa rascepom nepca, za razliku od mnogobrojnih radova
objavljenih na temu sekretornog otitisa kod dece bez rascepa nepca.
Na mnogo pitanja nisu dati odgovori u ovoj oblasti. Naime, malo je prospektivnih
studija koje su dovoljno dugo pratile pacijente da bi se došlo do pravih odgovora. Na osnovu
pregleda svetske literature nisu pronađeni odgovori na pitanja da li se tok i prognoza
sekretornog otitisa razlikuju u odnosu na tip rascepa nepca ili koliko rana insercija doprinosi
boljoj pneumatizaciji mastoida. Odgovori na ova pitanja mogli bi doprineti da se zauzme
konačni stav u vezi ove problematike i pronalaženju doktrinarnog pristupa koji bi dao
smernice kada i kako postupiti.
Postavljena je hipoteza da nema značajne razlike u otološkom nalazu, stanju sluha,
otološkim komplikacijama i pneumatizaciji mastoida između dece sa urođenim rascepom
primarnog i sekundarnog nepca i dece sa izolovanim rascepom sekundarnog nepca koja su od
rođenja konzervativno lečena (grupa K) u odnosu na istu grupu dece kod kojih je urađena rana
insercija ventilacionih cevčica (grupa R). U odnosu na prethodne dve grupe, deca sa urođenim
rascepom nepca kod kojih je ranije izvršena palatoplastika oba tipa urođenog rascepa nepca, a
koja su bila van redovne i sistematske ORL kontrole (grupa N), imaju značajno lošije sve
navedene nalaze. Iz ovih razloga prevencija hroničnog sekretornog otitisa kod dece sa
urođenim rascepom nepca u značajnoj meri smanjuje pojavu kasnih komplikacija.
Cilj rada je ispitati da li postoji razlika u otološkim nalazima, stanju sluha,
pneumatizaciji mastoida i učestalosti javljanja otoloških komplikacija (atrofija bubne opne,
recidivirajući otitisi, hronični otitis, holesteatom) između grupe dece sa urođenim rascepom
primarnog i sekundarnog nepca konzervativno lečenih od rođenja, grupe dece sa primarnim i
sekundarnim rascepom nepca kod kojih je planirana i izvršena rana insercija ventilacionih
cevčica prilikom palatoplastike i grupe dece kod kojih je ranije izvršena palatoplastika. ali su
bili van redovne i sistematske ORL kontrole.
U okviru istraživanja bila je sprovedena prospektivna kohortna studija kojom je, u
periodu od 2005. do 2014. godine bilo obuhvaćeno 184 dece sa urođenim rascepom nepca.
Istraživanje je sprovedeno u Službi za otorinolaringologiju Instituta za zdravstvenu zaštitu
majke i deteta »Dr Vukan Čupić«. U ispitivanju smo kao obeležja posmatranja koristili
otomikroskopiju, timpanometriju, play i objektivnu audiometriju, u planiranim terminima Rtg
snimak mastoida po Schulleru. Ustanovljen je obavezan period praćenja na 6 meseci za
svakog pojedinačnog ispitanika zbog kontrole i beleženja nalaza. Planirani period praćenja po
ispitaniku je bio 9 obaveznih kontrola sa beleženjem obeležja posmatranja
U rezultatima na kraju ispitivanja smo došli do sledećih nalaza: otomikroskopski nalaz
sa komplikacijama je značajno lošiji kod dece u grupi N (20.65%) u odnosu na grupu K
(8.7%) i grupi R (11%). Timpanometrijski nalaz tip B bio je najveći u grup N (82,61%)
naspram grupe K(69,57%) i grupe R(47,83%). Stanje sluha pokazalo je uredan nalaz u
grupama K+R u 70,1% ispitanika, dok je u grupi N kod 43,5%. Ustanovljena je značajna
razlika u normalnoj pneumatizaciji mastoida između grupa K+R (38,1%) i grupe N (10,1%).
U zaključku se može naglasiti da rana insercija ventilacionih cevčica kod dece sa
rascepom nepca ne dovodi do značajnog smanjenja dužine trajanja oboljenja, stanja sluha i
razvoja otoloških komplikacija. Deca kod kojih je ranije izvršena palatoplastika. ali su bili van
redovne i sistematske ORL kontrole imaju značajno lošije nalaze u odnosu na decu koja se
pod sistematskom ORL kontrolom, što ističe značaj prevencije hroničnog sekretornog otitisa
kod dece sa urođenim rascepom nepca. | Most authors agree that otitis media with effusion in children with cleft palate is
almost universal and that the middle ear effusion builds up in the first months after birth.
However, disagreements concerning the approach to treatment of this problem are numerous.
While some advocate mandatory early ventilation tubes insertion during palatoplasty, others
are more in favor of conservative approach coupled with careful monitoring and postponed
tube insertion, as of the age two or three, when deemed necessary. A smaller group of authors
promote lateral insertion during palatoplasty and monitoring further on. There are also
differences in the approach to further interventions and management of the course of the
disease as well as to treatment of possible complications.
Our hypothesis was that there is no significant difference in otological findings, hearing
status, otological complications and mastoid pneumatization between children with congenital
cleft of the primary and secondary palate and children with isolated cleft of the secondary
palate, which had conservative treatment since the birth (group K) with the same group of
children who had undergone early insertion of tympanostomy tubes during palatoplasty
(group R). Compared to the previous two groups, a third group consisted of children with
congenital cleft palate in which palatoplastica was previously done but they were without
regular ENT examination (Group N), and they have a significantly worse results in all the
above findings. For these reasons the prevention of chronic secretory otitis media in children
with congenital cleft palate significantly reduces the incidence of late complications.
The aim of this study was to examine whether there is a difference in otological findings,
hearing state, mastoid pneumatization and the incidence of otologic complications (eardrum
atrophy, recurrent otitis, chronic otitis, cholesteatoma) between the group of children with
congenital cleft of the primary and secondary palate which had conservative treatment since
the birth, group of children with primary and secondary cleft palate who had undergone early
insertion of tympanostomy tubes during palatoplasty and the group consisted of children with
congenital cleft palate in which palatoplastica was previously done but they were without
regular ENT examination.
In the prospective cohort study with predefined regular follow-up intervals and parameters
during the period from 2005 to 2014 were included 184 children with congenital cleft palate.
The survey was conducted in the Department of Otorhinolaryngology of the Mother and
Child Health Care "Dr Vukan Cupic". In this study we used parameters: otomicroscopy,
tympanometry, audiometry and fair play, in terms of the planned X-ray mastoid Schuller.
Established mandatory follow-up period to 6 months for each subjects for inspection and
recording of the findings. Planned follow-up period per participant was 9 mandatory controls
the recording characteristics of observation
At the end of the study we came to the following findings: otomicroscopical findings with
complications was significantly lower in children within group N (20.65%) compared to
group K (8.7%) and group R (11%). Tympanometry findings of type B was the highest in
Group N (82.61%) compared to the group K (69,57%) and Group R (47.83%). The hearing
state showed normal findings in groups K + R in 70.1% of respondents, while in group N at
43.5%. A significant difference in normal mastoid pneumatization between groups K + R
(38.1%) and Group N (10.1%).
In conclusion it can be emphasize that early insertion of tympanostomy tubes in children
with cleft palate does not lead to a significant reduction in the duration of diseases, conditions
and hearing development otologic complications. Children who had previously palatoplasty.
but they were out of regular and systematic control of ENT examination, are significantly
worse compared to children who are under the systematic control of ORL, which highlights
the importance of prevention of chronic secretory otitis media in children with congenital cleft
palate. | true |
Značaj rane koronarografije i revaskularizacije u bolesnika sa akutnim infarktom miokarda bez ST-elevacije | Importance of early angiography and revascularization in patients with acute myocardial infarction without ST-elevation | Uvod: Prethodne, kliničke, randomizovane studije su pokazale različite rezultate
uticaja primene rane invazivne terapije kod bolesnika sa akutnim koronarnim
sindromom bez elevacije ST-segmenta.
Cilj studije je bio da se ispita uticaj hitne u odnosu na odloženu invazivnu
terapiju kod bolesnika sa infarktom miokarda bez elevacije ST-segmenta (NSTEMI) na
pojavu novog infarkta miokarda ili smrtnog ishoda posmatranih zajedno − primarni cilj;
novog infarkta miokarda, smrtnog ishoda ili refraktarne ishemije posmatranih zajedno −
sekundarni cilj tokom 30-dnevnog perioda praćenja.
Metodologija: u odnosu na vreme primene invazivne terapije randomizovana su
323 NSTEMI bolesnika u grupe za hitnu (<2h nakon randomizacije, n=162) i odloženu
invazivnu terapiju (<72h nakon randomizacije, n=161).
Rezultati: mediana vremena od randomizacije do angiografije je u grupi za hitnu
invazivnu terapiju iznosila 1,4h, a u grupi za odloženu 61,0h (p< 0.001). Upoređivane
grupe su bile slične u pogledu osnovnih, kliničkih i angiografskih karakteristika. Nakon
30 dana, procenat smrtnog ishoda ili novog infarkta miokarda posmatranih zajedno je
bio značajno niži kod bolesnika u grupi za hitnu, u odnosu na odloženu invazivnu
terapiju (4,3% vs 13%, p=0.008). Postignuta razlika je rezultat značajno manjeg
procenta novog infarkta miokarda u prekateterizacionom periodu (0 smrt + 0 IM u grupi
za hitnu vs 1 smrt+10 IM u grupi za odloženu invazivnu terapiju). Takođe, hitna
invazivna terapija je bila povezana sa nižom incidencom refraktarne ishemije. U
pogledu pojave velikog krvarenja hitna invazivna terapija je bila sigurna kao i odložena
(0,6% vs 0,6%), ali je bila povezana sa značajno većim procentom minimalnog
krvarenja koje je uglavnom vezano za mesto punkcije (8,0% vs 3,7%, hitna vs
odložena).
Zaključak: hitna primena invazivne terapije kod bolesnika sa NSTEMI povezana
je sa nižim procentom smrtnog ishoda ili novog infarkta miokarda posmatranih zajedno,
u poređenju sa odloženom invazivnom terapijom, usled smanjena rizika od novog
novog infarkta u prekateterizacionom periodu. | Background: Previous, clinical, randomized studies provided heterogeneous
results on the effects of earlier invasive intervention in patients with acute coronary
syndrome without ST-segment elevation.
The aim of this study was to assess the impact of immediate versus delayed
invasive intervention in patients with non-ST-segment myocardial infarction (NSTEMI)
on composite of new myocardial infarction or death – primary endpoint, and composite
of new myocardial infarction, death or refractory ishaemia – secondary endpoint, during
30 day follow-up.
Methods: According to the time of performing invasive therapy were
randomized 323 NSTEMI patients into immediate (<2h after randomization, n=162) and
delayed-intervention group (<72h after randomization, n=161).
Results: Median time from randomization to angiography in the immediate
group was 1,4h and 61,0h in the delayed group (p < 0.001).The immediate and delyed
intervention group were well matched with respect to major baseline, clinical and
angiography characteristic. At 30 days, the rate of the primary endpoint was lower in
patients undergoing immediate versus delayed intervention (4,3% vs 13%, respectively;
p=0.008). The observed results were mainly attributable to the occurrence of new MI in
the pre-catheterization period (0 deaths + 0 MIs in the immediate-intervention vs 1
death + 10 MIs in the delayed-intervention group). Also, immediate invasive strategy
was associate with low incidence of recurrent ischaemia. Immediate invasive strategy
was safe as delayed in terms of major bleeding (0,6% vs 0,6%), but was associated with
significantly higher non-major bleeding which were mostly puncture-related (8,0 % vs
3,7%).
Conclusion: Immediate invasive strategy in NSTEMI patients is associated with
lower rates of death or new MI compared the delayed invasive strategy, mainly due to
minimization of the risk of new MI in the pre-catheterization time. | true |
Povezanost stepena razvijenosti kalcifikata arterija dojki i stepena razvijenosti koronarne arterijske bolesti kvantifikovane SYNTAX skorom (BASS studija) | Correlation between breast arterial calcification and severity of coronary artery disease quantified by SYNTAX score (BASS study) | Kako je koronarna bolest postala jedan od najznačajnijih problema kardiovaskularne
patologije čovečanstva (u visoko i srednje razvijenim zemljama u poslednjih 30-40 godina),
postoji interes za izučavanje njene etiologije, patogeneze, lečenja, a naročito prevencije i
dijagnostike. Koronarna bolest, karcinom dojke, cerebrovaskularni insult su vodeći uzrok
smrtnosti kod žena. Iako je napravaljen značajan progres na polju prevencije kardiovaskularnih
oboljenja, prvi znak koronarne bolesti kod asimptomatskih žena može biti akutni infarkt
miokarda ili naprasna srčana smrt. Neke studije ukazuju na lošiju prognozu za osobe ženskog
pola kada je ishemijska bolest miokarda potvrđena. Postoji konsenzus da skrinig pacijenktinja na
karcinom dojke mamografskim poregledima treba raditi na svake dve godine kod žena između
50-74 godine života, mada pojedini autori govore o potrebi skrining mamomgrafije svake
godine, dok skrinig metod za kardiovaskularne bolesti još uvek nije definisan. Arterijske
kalcifikacije dojke (BAC) koreliraju sa prisustvom fatalnih i nefatalnih neželjenih
kardiovaskularnih događaja prema rezultatima mnogih studija. Pojedini autori pokazali su
kvantitativnu korelaciju BAC i kalcifikacija na koronarnim krvnim sudovima. Još uvek nema
podataka koji potvrđuju korelaciju između ozbiljnosti koronarne bolesti kvantifikovane
SYNTAX skorom i BAC.
Cilj: Cilj ove studije bio je pokazati korelaciju prisustva i ekstenzivnosti arterijskih kalcifikacija
dojki i ozbiljnosti koronarne bolesti izražene SYNTAX skorom, kao i razvoj skora koji bi mogao
prepoznati pacijentkinje sa BAC i povišenim rizikom za neželjene kardiovaskularne događaje.
Materijal i metode: Studija predstavlja prospektivnu studiju preseka procene rizika pojave
neželjenih kardiovaskularnih događaja na osnovu različitih nivoa SYNTAX skora (nizak,
povišen ili visok nivo rizika) kod pacijentkinja kojima je urađena rutinska mamografija. Studija
je obuhvatitila populaciju od 102 bolesinice starije od 45 godina kojima je urađena koronarna
angiografija. Bolesnice su inicijalno stratifikovane u tri grupe prema vrednosti SYNTAX skora:
1) manji od 22, 2) 23-32, 3) 33 i više. U svaku grupu su uključene po 34 uzastopne bolesnice,
kako bi raspodela SYNTAX skora u populaciji bila ravnomernija. Sve bolesnice su u studiju
uključene nakon davanja informisanog pristanka. Kriterijumi za uključenje u studiju: bolesnice
starije od 45 godina; dat informisani pristanak za učešće u istraživanju. Kriterijumi za isključenje
iz studije: prethodna revaskularizacija miokarda (perkutana ili hirurška; napomena: moguće je u
studiju uključiti bolesnice kojima je perkutana revskularizacija urađena u istom aktu kada i
dijagnostička koronarografija, ali ne i bolesnice koje su u nekom ranijem aktu
revaskularizovane); bolesnice koje već imaju urađenu mamografiju unutar godinu dana od
predviđene studijske mamografije; bolesnice kod kojih je očekivani vremenski razmak između
koronarografije i mamorafije duži od tri meseca; bolesnice sa relativnim kontraindikacijama za
za mamografiju: trudnoća, simptomi i znaci karcinoma dojke, prisustvo implanta u dojkama. Sve
pacijentkinje biće analizirane u odnosu na njihove demografske parametre, laboratorijske analize
i prisustvo standradnih faktora rizika za kardiovaskularne bolesti. Opsežnost lezija koronarnih
krvnih sudova biće evaluirana SYNTAX skorom, a vaskularne kalcifikacije dojke pomoću 4-
stepene modifikovane Likertove skale. Za procenu značajnosti razlike posmatranih pojava i
stepena korelacije istih biće korišćene metode deskriptivne i analitičke statistike (X2 test,
Fisherov test tačne verovatnoće, univarijantna i multivarijantna logistička regresija, kanonička
diskriminaciona analiza). Primenom statističkih alata formirana je BACCADS (Breast Arterial
Calcification and Coronary Artery Disease Scale) skor za predikciju pacijenata sa Syntax skorom
>22.
Rezultati: Prosečna starost u ukupnoj populaciji od 102 pacijentkinje iznosila je 62.97 god ±
8.36 god. Pokazano je da je između odgovarajućih SYNTAX skor grupa postojala razlika u
učestalosti pušenja ili bivšeg pušenja, hiperlipoproteinemije, kao razlika u distribuciji po
učestalosti i ekstenzivnosti BAC. ANOVA testiranjem pokazano je da postoji razlika između
SYNTAX skor grupa u starosti, nivoima FBG, HbA1c, triglicerida, HDLc i fibrinogena u krvi. U
ostalim kontinuiranim varijablama, nije bilo značajne razlike. Multinominalnom logističkom
regresijom dobijena su tri značajna prediktora i konstanta za ishod 22< SYNTAX skor ≥32 i
ishod gde je SYNTAX skor >32 . Značajni prediktori bili su: (1) hiperlipoproteinemija, (2) nivo
fibrinogena i (3) BAC score. Pokazano je da se sa svakim povećanjem BAC skora za 1, oko 10
puta povećava verovatnoća da pacijentkinja pripadne grupi gde je 22< SYNTAX skor ≥32, a čak
13 puta povećava šansa da pripadne grupi gde je SYNTAX skor >32. Prisustvo
hiperlipoproteinemije povećava šansu nastanka pomenutih ishoda za oko 10 puta, dok se sa
svakim povećanjem fibrinogena za 1 g/L, rizik ishoda sa 22< SYNTAX skor ≥32 povećava 5
puta, a čak 8 puta se ovećava šansa da pacijentkinje imaju SYNTAX skor>32. Primena
kanoničke diskriminacione analize studijsku populaciju podelila je u dve grupe: grupu sa
SYNTAX skorom≤22 (34 bolesnice) i grupu sa SYNTAX skorom >22 (68 bolesnica). Grupa
pacijentkinja sa SYNTAX skorom> 22 u odnosu na grupu sa SYNTAX skorom ≤ 22 imala je
značajno češću pojavu hiperlipidemije, dijabetes melitusa, viših BAC skorova, a takođe je među
njima bilo više pušača ili bivših pušača. U odnosu na grupu sa SYNTAX skorom ≤ 22,
pacijentkinje sa SYNTAX skorom> 22, bile su značajno starije i imale su veće vrednosti za
FBG, HbA1c, trigliceride i fibrinogen, dok su imale značajno niže vrednosti za HDLc.
Multivarijatnom logističkom regresijom (binominalna) kao nezavisni prediktori pacijentkinja sa
SYNTAX skorom> 22 bili su BAC (OR 34.24, CI 8.05-145.70), holesterol >5mmol/l (OR
22.65, CI 4.18-122.81) i fibrinogen (OR 2.55, CI 1.28-5.07). Prvom kanoničkom
diskriminacionom analizom dobijena je diskriminaciona funkcija sa 6 varijabli (starost, pušenje,
HbA1C, trigliceridi, fibrinogen i BAC) čija je kanonička korelacija =0.660 (Wilks’ Lambda =
0.564; χ2 = 55.554; df = 5; p = 0.000). Snzitivnost i specifičnost Skora 1 dobijenog ovom
analizom je 92.65% odnosno 82.35%. Drugom kanoničkom diskriminacionom analizom
dobijena je diskriminaciona funkcija sa 3 varijable (starost, pušenje, BAC), čija je kanonička
korelacija = 0.581 (Wilks’ Lambda = .663; χ2 = 40.514; df = 3; p = 0.000). Snzitivnost i
specifičnost Skora 2 dobijenog ovom analizom je 79.41% odnosno 88.24%. Trećom kanoničkom
diskriminacionom analizom dobijena je diskriminaciona funkcija sa 5 varijabli (starost, pušenje,
HbA1C, fibrinogen, starost), čija je kanonička korelacija = 0.583 (Wilks’ Lambda = 0.660; χ2 =
40.563; df = 5; p = 0.000). Snzitivnost i specifičnost Skora 3 dobijenog ovom analizom je
89.71% odnosno 73.53%. ROC procedurom pokazano je da su skorovi 1 dobijeni na bazi
kanoničke diskriminacione funkcije u prvoj analizi imali najbolje test karakteristike u dtekciji
SYNTAX skora > 22, odnosno najveću senzitivnost, specifičnost, kao i pozitivnu i negativnu
prediktivnu vrednost u odnosu na skorove 2 dobijene iz druge i skorove 3 dobijene iz treće
diskriminacione analize. Analizom razlika u površini ispod krivih između pojedinih skorova,
pronađena je značajna razlika samo između skorova 1 u odnosu na skor 3 (difference between
areas =0.0489; z =0.064; p =0.039). Nije bilo razlike u površina ispod krivih između skorova 1 u
odnosu na skorove 2 (difference between areas = 0.0471; z = 1.692; p =0.090), jednako kao i u
površinama ispod krivih između skorova 2 u odnosu na skorove 3 (difference between
areas=0.000173; z =0.0425; p =0.966). Obzirom na ovakve karakteristike Skor 1 smo definisali
kao BASS skor (breast arterial-syntax score). Imajući u vidu ovakve rezultate diskriminacione
analize, formirana je BACCADS skala (cut off 1.25) koji sa senzitivnošću od 86.57% i
specifičnošću od 73.53% detektuje pacijentkinje sa SYNTAX skorom >22.
Zaključak: U ovoj studiji kod žena starijih od 45 godina, postoji visoko statistički značajne
korelacije između aretrijskih kalcifikacija dojki i koronarne arterijske bolesti. Opsežnost
arterijskih kalcifikacija dojki izražena semikvantitativnom skalom u korelaciji je sa stepenom
razvijenosti koronarne arterijske bolesti izražene SYNTAX skorom. BAC, fibrinogen,
hiperholesterolemija predstavljaju nezavisne prediktore ozbiljnosti koronarne arterijske bolesti
izražene SYNTAX skorom. | Since coronary artery disease became one of the most important problem of
cardiovascular pathology there is great interest for the study of its of its etiology, pathogenesis,
treatment, and in particular the diagnosis and prevention. Coronary artery disease (CAD), breast
cancer (BC) and stroke are the leading cause of mortality in women. Although there is significant
progress in field of prevention CAD, first sign CAD in the asymptomatic women can be acute
myocardial infarction and sudden cardiac death. Even more, some studies demonstrated that
women had worse outcome compare to men when CAD had been confirmed. There is some
consensus that women are screened for BC with mammography between 50 and 74 years old
every second year, but many advocate yearly screening. Bearing in mind this we can say that the
age range for screening mammography is the same age range as those who would benefit from
preventive cardiology. Screening method for CAD has not be still defined. Breast arterial
calcification (BAC) has been correlated with presence of fatal and non fatal cardiovascular
adverse event, also some studies quantitatively shown that BAC are in correlation with coronary
artery calcium (CAC). Severity of coronary artery disease was defined by SYNTAX score which
has prognostic value for short and long-time MACCE (major adverse cardiovascular events) in
this patients. There is no study which confirmed correlation between severity of coronary artery
disease quantifying by SYNTAX score and BAC after coronary angiography.
The Aim: The aim of this study was to demonstrate correlation between breast arterial
calcification and severity of coronary artery disease, regarding to SYNTAX score.
Material and methods: The study is prospective cross-sectional study of assessment of the risk
of adverse cardiovascular events based on different levels SYNTAX score (level of low, medium
and high risk) in patients who underwent screening mammography. The study was approved by
the local Ethics committee General Hospital Valjevo. This trial will include 102 consecutive
women older than 45 years old who already refer for coronary angiography. The patients will be
stratified in three groups according to values of SYNTAX score (SYNTAX score ≤22,
22<SYNTAX≤32 and SYNTAX>32). Inclusion criteria for this study were: patients older then
45 years, signed informed consent. Exclusion criteria were: previous myocardial
revascularisation (PCI-percutaneous coronary intervention or CABG-coronary artery bypass
surgery), but it is possible to include patients who have PCI procedure at the same time when
diagnostic coronary angiography is done; patients who already had diagnostic mammography
done within a year of anticipated study mammography; patients with relative contraindication for
mammography: pregnancy, ect.; symptoms and signs of BC; breast implants; patients with an
expected survival time less of than one year. For all included patients mammography was done
within 15 days after coronary angiography. All patients will be analyzed according to their
demographic parameters, standard risk factors and laboratory parameters. BAC was classified on
a 4-level Likert scale (0=no BAC, 1=few punctate BAC, 2=coarse BAC with tram track or ring
appearance in <3 vessels, 3= coarse BAC in ≥3 vessels). The severity of coronary artery disease
will be quantified on the basis of the SYNTAX score. To assess the significance of differences
observed phenomenon and the degree of correlation will be used the same methods of descriptive
and analytical statistics (X2 test, Fisher’s exact probability test, univariate and multivariate
logistic regression, canonical discriminant analysis). With specific statistic tools we developed
BACCADS (Breast Arterial Calcification and Coronary Artery Disease Scale) scale for
prediction patients with Syntax score >22.
Results: The average age of the total population of 102 patients was 62.97 ± 8.36. It is shown
that the SYNTAX score between the respective groups there is difference in the incidence of
smoking and ex-smoking, hyperlipidemia, as well as differences in the distribution of frequency
and extensiveness of BAC. Using ANOVA indicated that there was a difference between
SYNTAX score groups in age, the FBG levels, HbA1c, triglycerides, fibrinogen, and HDLc
levels. In the other continuous variables, without any significant effect. Multinomial logistic
regression were obtained three significant predictors for the outcome 22 <SYNTAX score ≥32
and outcome where the SYNTAX score> 32nd Significant predictors were: (1)
hyperlipoproteinemia, (2) the level of fibrinogen, and (3) BAC score. It is shown that with each
increase in BAC score of 1, 10 times increases the likelihood that patients belong to a group
where 22 <SYNTAX score ≥32, and as much as 13 times the chance to belong to a group where
the SYNTAX score> 32. The presence of hyperlipoproteinemia increases the chance of the
occurrence of the above mentioned outcomes for about 10 times, but with each increase of
fibrinogen to 1 g/L, the risk outcomes with 22 <SYNTAX score ≥32 increases 5 times and 8
times increases unnecessarily the chance that patients have a SYNTAX score> 32. Application of
canonical discriminant analysis study population was divided into two groups: a group with
SYNTAX skorom≤22 (34 patients) and the group with a SYNTAX score> 22 (68 patients).
Patients with SYNTAX score >22 have more often history of hiperlipoproteinemia, in this group
were more smokers and they were older. Group with SYNTAX score >22 has statistically higher
level of BFG, HbA1C, triglycerides, fibrinogen, but HDLc was lower the in group with
SYNTAX≤22. BAC was significantly higer in patients with SYNTAX score>22 (p<0.0001).
Multivariat logistic regresion, three independent variables were found to be significant predictors
of increased risk for intermediate-to-high SYNTAX score: BAC (OR 34.24, CI 8.05-145.70),
total cholesterol >5mmol/l (OR 22.65, CI 4.18 -122.81) i fibrinogen (OR 2.55, CI 1.28-5.07).
The first canonical discriminant analyses (CDA) contributed CDF (canonical discriminant
function) 1 with 6 variables (age, smoking, BAC, HbA1C, fibrinogen, triglycerides) with
canonical correlation (CC)=0.660 (Wilks’ Lambda=0.564; χ2=55.554; df=5; p=0.000).
Sensitivity and specificity of Scores 1 was 92.65% vs. 82.35% retrospectivly. The second CDA
gave us CDF 2 with 3 variables (age, smoking, BAC) with CC= 0.581 (Wilks’ Lambda=0.663;
χ2=40.514; df=3; p=0.000). Sensitivity and specificity of Scores 2 was 79.41% vs. 88.24%
retrospectivly. Third CDA gave us CDF with 5 variables (age, smoking, HbA1C, fibrinogen,
triglycerides) with CC=0.583 (Wilks’ Lambda=0.660; χ2=40.563; df=5; p=0.000). Sensitivity
and specificity of Scores 3 was 89.71% vs. 73.53% retrospectivly. Analyzing the difference in
the areas under ROC, significant difference was noted between Scores 1 and Scores 3 (difference
between areas=0.0489; z=0.064; p= 0.039). Scores 1 had the best characteristics and this score
can recognize patients with SYNTAX score >22 with sensitivity 92.65%, specificity 82.35%,
PPV 91.3%, NPV 84.8%, so we defined scores 1 as BASS score (breast arterial syntax score).
BACCADS scale (cut off 1.25) with sensitivity of 86.57% and specificity of 73.53% has
predictivepower in detection patients with SYNTAX score >22.
Conclusion: In this population of women >45 years, there is a significant correlation between
breast arterial calcification and coronary artery disease. Extensiveness of BAC expressed
semiquantitative scale is correlated with severity of coronary artery disease expressed by
SYNTAX score. BAC, fibrinogen, total cholesterol >5mmol/l were independent predictors of the
severity of CAD. | true |
Ispitivanje prognostičkih faktora za ishod lečenja bolesnika sa teškom traumom | Evaluation of prognostic factors in the treatment outcome of patients with severe trauma | Uvod: Cilj ove studije bio je određivanje nezavisnih prediktora i najboljeg trauma
skoring sistema (REMS, RTS, GSC, SOFA, APPACHE II) intrahospitalnog mortaliteta
kod pacijenata sa teškom traumom, lečenih u Urgentnom centru Kliničkog centra Srbije u
Beogradu.
Materijal i metode: Longitudinalna studija je uključila 208 konsekutivnih pacijenata sa
teškom traumom, primljenih u Urgentni centar Kliničkog centra Srbije u Beogradu. U
cilju određivanja nezavisnih prediktora preživljavanja, urađene su univarijantna i
multivarijantna Koksova regresiona analiza. Takođe, uticaj sistema skorovanja ranije
pomenutih skorova na prijemu u Urgentni centar (UC) u predikciji mortaliteta poređen je
korišćenjem AUC (Area under curve) testom.
Rezultati: Ispitivani uzorak činilo je 208 pacijenata (159 muškaraca, 49 žena), prosečnog
uzrasta 47,3±20,7 godina. Većina pacijenata bila je inicijalno intubirana (86,1%), na
prijemu u UC, a 59,6% pacijenata bilo je sedirano pre intubacije. Posle završetka
dijagnostičkih procedura, 17 pacijenata je dodatno intubirano, tako da je na mehaničkoj
ventilaciji bilo 94,2% pacijenata. Pacijenti su najčešći povređivani u saobraćajnim
nesrećama (33,2%), prilikom pada sa visine (26,4%) i kao pešaci (22,6%). Prosečna
dužina boravka u jedinici intenzivne nege iznosila je 24,7±21,2 dana. Letalitet je bio
17/208 (8,2%). Koksovom regresionom analizom pokazano je da su povišena srčana
frekvenca (HR=1,03, p=0,012) i snižena saturacija krvi kiseonikom (HR=0,91, p=0,033)
nezavisni prediktori smrtnog ishoda pacijenata sa teškom traumom. REMS (AUC
0,72±0,64) i SOFA (AUC 0,716±0,067) su pokazali sličnu prediktivnu vrednost, dok su
APACHE II (AUC 0,614±0,062) i RTS (0,396±0,068) bili loši prediktori
intrahospitalnog mortaliteta kod pacijenata sa teškom traumom.
Zaključak: Rezultati studije pokazali su važnu ulogu komponenti REMS u predikciji
ishoda pacijenata sa teškom traumom kao i da su srčana frekvenca i saturacija krvi
kiseonikom nezavisni prediktori intrahospitalnog mortaliteta. | Background: The aim of this study was to determine independent predictors and the best
trauma scoring system (REMS, RTS, GSC, SOFA, APPACHE II) of in-hospital mortality
in patients with severe trauma at the Department of Emergency, Emergency Center,
Clinical Center of Serbia, Belgrade.
Methods:Longitudinal study included 208 consecutive patients with severe trauma. In
order to determine independent contributors to survival, univariate and multivariate Cox
regression analyses were performed. The power of above mentioned scoring systems
(measured at admission in the Emergency center) to predict mortality was compared
using the area under the curve (AUC).
Results:There were 208 patients (159 male, 49 female), with average age of 47.3±20.7
years. Majority of patients were initially intubated (86.1%), at admission to ED, and
59.6% patients were sedated before intubation. After finishing of diagnostic procedures,
17 patients were additionally intubated, and, at that time, 94.2% patients were on
mechanic ventilation. The largest proportion of patients was traumatized in car crash
(33.2%), followed by falls from the height (26.4%) and as pedestrians (22.6%) Patients
had an average of 24.7±21.2 days spent in intensive care unit (ICU). The overall
case-fatality ratio was 17/208 (8.2%). In Cox regression analysis only elevated heart rate
(HR=1.03, p=0.012) and decreased arterial oxygen saturation (SpO2) (HR=0.91,
p=0.033) singled out as independent contributors to in-hospital mortality of patients with
severe trauma. REMS (AUC 0.72±0.64) and SOFA (AUC 0.716±0.067) scores were
found fair and similar predictor of in-hospital mortality, while APACHE II (AUC
0.614±0.062) and RTS (0.396±0.068) were poor predictors.
Conclusion: Results of this study showed important role of REMS, which appears to
provide balance between the predictive ability and the practical application, and
components of REMS in prediction of outcome in patients with severe trauma and that
heart rate and SpO2 are independent predictors of in-hospital mortality. | true |
Značaj polimorfizama u genima koji kodiraju enzime uključene u metabolizam metotreksata u dece sa akutnom limfoblastnom leukemijom | The significance of polymorphisms in the genes encoding enzymes involved in the metabolism of methotrexate in children with acute lymphoblastic leukemia | Uvod: Akutna limfoblastna leukemija (ALL) je najčešća maligna bolest u
pedijatrijskom uzrastu. Primenom savremenih protokola postignuto je preživljavanje u
skoro 90% obolele dece. Najnovija istraživanja su usmerena ka farmakogenetici, sa
ciljem da se smanji toksičnost primenjenih lekova, koji mogu biti uzrok smrtnog ishoda
ili dugoročnih komplikacija koje utiču na kvalitet života po završetku lečenja. Na osnovu
farmakogenetskih ispitivanja se može vršiti modulacija terapije, odnosno odrediti dozni
režim lekova koji je prilagođen svakom pacijentu. Metotreksat (engl. Methotrexate –
MTX) je antagonist folata i jedan je od ključnih lekova u terapijskim protokolima za
pedijatrijsku ALL. Delotvoran je u postizanju i održavanju remisije u dece sa ALL, ali su
odavno poznata neželjena dejstva koja njegova primena može da izazove.
Ciljevi: Sastoje se u ispitivanju uticaja gena koji kodiraju enzime uključene u
metabolizam MTX i njihovih varijanti na tok i ishod lečenja dece obolele od ALL. Na
prvom mestu cilj doktorske disertacije je bio da se utvrdi učestalost varijanti c.677C>T i
c.1289A>C u genu za MTHFR, -680 C>A, -675 A>G, -556 T>C, -464 A>T i -317 A>G u
genu za DFHR, c.80G>A u genu za SLC19A1, 28 bp tandemski ponovak i 6 bp delecija u
genu za TYMS. Učestalost polimorfizama je ispitana u dece obolele od ALL i kontrolnoj
grupi i učinjena je uporedna analiza incidence u bolesnih i zdravih osoba. Nezavisno od
farmakogenetičkih markera, cilj je bio da se ispita
farmakokinetika (engl.
Pharmacokinetics – PK) MTX i da se dobijeni rezultati koreliraju sa navedenim
polimorfizmima. Takođe, praćena je klinička i laboratorijska toksičnost terapije MTX i
istraženo je da li postoji povezanost pojedinačnih ili udruženih varijanti u ispitanim
genima sa povećanom toksičnošću MTX. Na osnovu ispitanih parametara ideja je bila da
se utvrdi da li postoji modulacija terapije i u kojoj meri kod prisustva pojedinačnih i/ili
udruženih genetičkih varijanti. Krajnji cilj je bio da se utvrdi uticaj navednih
polimorfizama u genima za DFHR, MTHFR, SLC19A1 i TYMS na ishod dece obolele od
ALL.
6
Materijal i metode: Dijagnostika i lečenje 161 deteta obolelog od ALL
sprovedeno je u Službi za hematologiju i onkologiju Univerzitetske dečje klinike (UDK)
po kriterijumima i smernicama savremenih internacionalnih protokola. U istoj ustanovi
su praćena PK MTX, kao i klinička i laboratorijska toksičnost, dok su farmakogenetičke
analize rađene na Institutu za medicinsku genetiku i genetički inžinjering u Laboratoriji
za molekularnu biomedicinu. Za uzorkovanje biološkog materijala su roditelji pacijenata
dali pismenu saglasnost. Kontrolna grupa je obuhvatila 104 zdrava ispitanika.
DNK je izolovana pomoću QIAamp DNA Blood Mini Kita prema uputstvu
proizvođača. Analiza DNK vršena je elektroforetskim razdvajanjem na horizontalnom
agaroznom gelu, dok je za analizu DNK fragmenata korišćena elektroforeza na
poliakrilamidnom gelu. Varijante u genu TYMS su određivane PCR metodom. PCR-
RFLP metoda je korišćena za određivanje varijante tipa SNV, konkretno MTHFR c.677
C>T. Alel-specifični PCR je bio metoda izbora za MTHFR c.1298 A>C i SLC19A1 c.80
G>A. Za detekciju varijanti u promotoru gena DHFR je rađeno sekvenciranje PCR
produkata. Statistička obrada podataka je vršena odgovarajućim testovima u zavisnosti od
prirode posmatrane varijable.
Rezultati: Istraživanje je ukazalo da ne postoji razlika u učestalosti ispitivanih
genetičkih varijanti u genima za MTHFR, DFHR, SLC19A1 i TYMS između dece obolele
od ALL i zdravih osoba. Dokazana je niska incidenca nepovoljnih genotipova u našoj
populaciji i prikazani su pojedinačni najčešći haplotipovi ispitivanih gena. Nije viđen
uticaj pola na učestalost detektovanih polimorfizama u navedenim genima, ali je
pokazano da deca kod kojih je detektovan TYMS 6 bp D/D polimorfizam kasnije
obolevaju od ALL u odnosu na druge genetičke varijante u istom genu.
U odnosu na imunofenotipske karakteristike, pokazana je statistički značajna razlika
među ispitivanim genima: MTHFR c.1298 A>C korelira sa manje povoljnim, T-ćelijskim
imunofenotipom, dok se DHFR varijante -675 A>G, -556 T>C, -464 A>T detektuju
isključivo u dece sa B-ćelijskom ALL. Nije viđena povezanost između ekstramedularne
propagacije, na prvom mestu u centralni nervni sistem (CNS infiltracija) i detektovanih
polimorfizama. Pokazana je korelacija genetičkih varijanti u TYMS genu sa kompleksnim
kariotipom u dece sa ALL.
7
Prikazana je brzina ulaska u remisiju bolesti u tačno određenim vremenskim
odrednicama i viđena je korelacija određenih genetičkih varijanti sa sporijom kinetikom
blasta 15. dana lečenja, procenjeno morfološkim pregledom koštane srži: TYMS 6bp i 28
bp i DHFR -680 C>A i -317 A>G. Polimorfizmi u ispitivanim genima nisu uticali na
stepen remisije 33. dana terapije.
Pokazano je da su veću ukupnu (kliničku i laboratorijsku) toksičnost ispoljila deca
koja su primala niže doze MTX (2g/m2 vs 5g/m2) i da se broj i stepen neželjenih efekata
statistički značajno češće javljao u starijem uzrastu, prosečno u desetoj godini života.
Viđeno je da parenteralna primena MTX u intenzivnoj fazi lečenja češće dovodi do
pojave kliničke toksičnosti u odnosu na peroralnu primenu u završnoj fazi terapijskog
protokola, kada se u većem procentu detektuje laboratorijska toksičnost, na prvom mestu
hepatotoksičnost. Deca kod kojih su se ispoljila neželjena dejstva terapije MTX su u
najvećem broju imala nizak stepen toksičnosti, prema jasno definisanom gradiranju u
internacionalnim vodičima. U odnosu na PK, dokazano je da je najčešće usporenje
eliminacije leka viđeno u 48. satu od početka primene MTX i da je u najvećem broju
dece trajalo manje od 24h, uz dodatne terapijske mere, predviđene protokolom lečenja.
Viđen je protektivni efekat varijante c.677 T/T u MTHFR genu u bolesnika koji su
primali niže doze MTX: deca sa tim polimorfizmom su najređe ispoljavala toksičnost
tokom primene leka u dozi od 2g/m2. Korelacijom PK i varijanti u ispitivanim genima
pokazano je da su deca sa TYMS 6bp D/D varijantom statistički značajno češće imala
povišene nivoe MTX. Takođe, deca sa varijantama MTHFR c.1298 C/C, DHFR -675
G/G, -556 C/C i -464 T/T i SLC19A1 c.80 A/A vremenom ispoljavaju veću toksičnost
MTX pri ponavljanim ekpozicijama većim dozama leka (5g/m2).
Ukupno preživljavanje ispitanika u studiji je iznosilo 87%. Jasno su definisani i
prikazani različiti faktori koji utiču na prognozu, među kojima se izdvojila varijanta -464
T/T u DHFR genu. Deca sa tim polimorfizmom su značajno češće razvila recidiv
osnovne bolesti što je uticalo na nepovoljan krajnji ishod lečenja.
Zaključak: Disertacija doprinosi razumevanju mehanizama koji učestvuju u
kliničkom i laboratorijskom ispoljavanju toksičnosti tokom primene MTX. Ovim
istraživanjem rasvetljeni su izvesni aspekti vezani za ulogu ispitivanih genetičkih
varijanti u leukemogenezi i njihova povezanost sa ishodom dece obolele od ALL.
8
Navedeni rezultati potkrepljuju pretpostavku da farmakogenetički markeri utiču na
pojavu i stepen toksičnosti tokom terapije MTX. Takođe, ukazuju na značaj prevencije
toksičnosti kroz modulaciju doznog režima prema genetskom profilu pacijenta.
Korelacija određenih genetičkih varijanti sa recidivom osnovne bolesti svrstava ispitane
polimorfizme u individualne prognostičke faktore kod pedijatrijskih pacijenata sa ALL. | Objective: Acute lymphoblastic leukemia (ALL) is the most common malignant
disease among children and adolescents. Contemporary protocols ensure survival rate in
almost
90% of affected children. The latest research is directed towards
pharmacogenetics, in order to reduce the toxicity of applied drugs, which may be the
cause of death or long-term complications that affect the quality of life after completion
of treatment. Pharmacogenetic studies are offering basis for therapy modulation, by
changing drugs dosage regimen in order to tailor the therapy according to needs of each
affected patient. Methotrexate (MTX) is a folate antagonist and is one of the key drugs in
therapeutic protocols for pediatric ALL. MTX is effective in achieving and maintaining
remission in children with ALL, but possible adverse side effects of its use are already
well known.
Aims: The most important goal was to test the influence of genes encoding
enzymes involved in the metabolism of MTX and their variants on the course and
outcome of children with ALL. First and foremost objective of the doctoral dissertation
was to determine the frequency of variants c.677C>T and c.1289A>C in MTHFR gene, -
680 C>A, -675 A>G, -556 T>C, -464 A>T and -317 A>G in DFHR gene, c.80G> A in
SLC19A1 gene, 6 bp deletion and 28 bp tandem repeats in TYMS gene. The incidence of
polymorphisms in children with ALL and a control group was explored and afterwards
compared in order to investigate eventual different pattern between pediatric ALL
patients and healthy individuals. The goal was to investigate the pharmacokinetics (PK)
and clinical and laboratory toxicity during MTX treatment and then to correlate with the
aforementioned polymorphisms with the idea to explore whether there is a relationship of
single or associated variants in the selected genes with already established MTX toxicity.
The aim was to investigate the extent of therapy modulation in presence of individual
and/or associated genetic variants by summarizing all results related to MTX toxicity.
The ultimate goal was to determine the effect of aforementioned polymorphisms in genes
MTHFR, DFHR, SLC19A1 and TYMS to the outcome of children with ALL.
10
Materials and Methods: Study enrolled 161 children with ALL in whom
diagnosis and treatment was conducted at the Department of Hematology and Oncology
at University Children's Hospital (UCH) according to the criteria and guidelines of
contemporary international protocols. In the same institution PK of MTX was performed,
as well as clinical and laboratory parameters of toxicity, while pharmacogenetics analysis
were done at the Institute of Medical Genetics and Genetic Engineering Laboratory for
Molecular Biomedicine. Written consent was obtained from parents for the biological
material sampling at diagnosis. The control group included 104 healthy subjects.
DNA was isolated using QIAamp DNA Blood Mini Kit according to the
manufacturer's instructions. DNA analysis was carried out by electrophoretic separation
on a horizontal agarose gel electrophoresis, and the DNA fragments used for
polyacrylamide gel electrophoresis. Variants in the TYMS gene were determined by PCR
method. PCR-RFLP method was used to determine the type SNV variants, namely
MTHFR c.677 C>T. Allele-specific PCR has been the method of choice for MTHFR
c.1298 A>C and SLC19A1 c.80 G>A. Sequencing the PCR products was done for the
detection of variants in the promoter of the DHFR gene. Statistical analysis was
performed by appropriate tests depending on the characteristics of the observed variables.
Results: Results did not indicate the differences in incidence of investigated
variants in MTHFR, DFHR, SLC19A1 and TYMS genes between children with ALL and
healthy individuals. Low incidence of adverse genotypes was proven in our population
and the most common single gene haplotypes were point out. There was no effect of
gender on the incidence of detected polymorphisms in investigated
genes, but it was
shown that children with TYMS 6 bp D/D polymorphism developed ALL in older age in
comparison with other variants in the same gene.
Considering the immunophenotypic characteristics, statistically significant difference
was demonstrated:
MTHFR
c.1298 A>C correlates with less favorable
T-cell
immunophenotype, while the DHFR variants -675 A>G, -556 T>C, -464 A>T were
detected only in children with B-cell ALL. Association between extramedullary disease,
primarily in the central nervous system (CNS infiltration), and detected polymorphisms
was not seen. Strong correlation of genetic variants in the TYMS gene with complex
karyotype in children with ALL was observed.
11
Remission evaluation at precise time points showed correlation with certain genes –
slower kinetics of leukemic blasts on day 15 of treatment, measured with flow citometry,
was detected in children with TYMS 6bp and 28 bp and DHFR -680 C>A and -317 A>G
variants. Polymorphisms in tested genes did not influence the remission on day 33.
It has been shown that overall (clinical and laboratory) toxicity was more frequently
manifested in children who received lower doses of MTX (2g/m2 vs 5g/m2). The rate of
toxic events was significantly more prevalent in the older children, with average age of
ten years. Parenteral administration of MTX signifficantly more often leads to
development of clinical
adverse
side effects in comparison to peroral
MTX
administration, where laboratory toxicity is more frequently observed, especially
hepatotoxicity. The majority of adverse effects of MTX therapy were classified as low
grade, according to precisely defined criteria. Considering PK monitoring, it has been
proven that the most common irregularity in drug elimination was at the 48th hour after
the MTX application and that in vast majority of children lasted less than 24 hours. In our
study group c.677 T/T variant in the MTHFR gene showed to be protective parameter in
patients who received lower doses of MTX: children with this polymorphism who
received MTX in dosage of 2g/m2 were less prone to toxic events. Correlation of PK and
variants in the examined genes showed that children with TYMS 6bp D/D variant
significantly often had increased MTX levels. Also, children with MTHFR c.1298 C/C,
DHFR -675 G/G, -556 C/C and -464 T/T and SLC19A1 c.80 A/A variants had greatly
numbered toxic events after repeated exposures to higher doses of the MTX (5g/m2).
Overall survival of pediatric patients in the study was 87%. Among different factors
that influenced the prognosis, variant -464 T/T in the DHFR gene stood out as the least
favorable. Children with this polymorphism are significantly more likely to develop a
relapse of the underlying disease, influencing their final outcome.
Conclusion: The dissertation contributes to the understanding of the mechanisms
involved in the clinical and laboratory manifestation of toxicity during the MTX therapy.
This research clarified certain aspects related to the role of the examined genetic variants
in leukemogenesis and their association with the outcome of children with ALL. These
results support the hypothesis that pharmacogenetic markers influence the occurrence and
degree of toxicity during treatment with MTX. It also highlights the importance of
12
prevention of toxicity through the dose regimen modulation according to the genetic
profile of the patient. The correlation of certain genetic variants with potential relapse of
the disease classified examined polymorphisms as individual prognostic factors in
pediatric patients with ALL. | true |
Ispitivanje poremećaja neurogeneze u subgranularnoj zoni hipokampusa na mišjem modelu Alchajmerove bolesti | Analysis of neurogenesis alterations in the subgranular zone of the hippocampus in a mouse model of Alzheimer's disease | Alchajmerova bolest je progresivno neurodegenerativno oboljenje i najčešći uzrok
demencije kod starijih osoba, sa prevalencom dva puta većom u ženskoj populaciji.
Jedna od struktura koje najranije bivaju zahvaćene patohistološkim promenama u AB je
hipokampus, deo limbičkog sistema koji ima važnu ulogu u procesima učenja i
formiranja memorije. Nova istraživanja potvrdila su da se i kod ljudi u subgranularnoj
zoni hipokampusa aktivno odvija proces neurogeneze u adultnom periodu. Imajući u
vidu činjenicu da novostvoreni neuroni imaju ulogu u procesima učenja i pamćenja,
odnosno da utiču na oblikovanje kognicije i ponašanje individue, smatra se da se
kognitivni deficit i gubitak pamćenja kod neurodegenerativnih oboljenja može delom
pripisati poremećenoj neurogenezi na nivou subgranularne zone hipokampusa.
Istraživanja procesa i dinamike adultne neurogeneze u hipokampusu životinja ili osoba
obolelih od Alchajmerove bolesti su dala kontradiktorne rezultate. U zavisnosti od
eksperimentalnih uslova, kao što su životinjski model Alchajmerove bolesti, starost i
pol životinje, kao i markeri kojima se analiziraju ćelijski procesi, rezultati su ukazali
kako na smanjenje, tako i na nepromenjen ili čak povećan obim neurogeneze kod
animalnih modela i kod pacijenata obolelih od Alchajmerove bolesti. Dosadašnja
istraživanja ukazuju na važnu ulogu članova SOXB grupe transkripcionih faktora u
brojnim ćelijskim procesima uključenim u neurogenezu tokom embrionalnog i adultnog
perioda razvoja, kao što su održavanje multipotentnosti, proliferacije i diferencijacije
neuralnih matičnih/prekursornih ćelija. Pored SOXB transkripcionih faktora određeni
neurotrofički faktori, kao što je neurotrofički faktor poreklom iz mozga (BDNF), utiču
na procese proliferacije i diferencijacije neuralnih matičnih/prekursornih ćelija.
Međutim, tačna uloga ovih faktora u nastanku različitih neurorazvojnih i
neurodegenerativnih poremećaja nije dovoljno razjašnjena. Imajući u vidu navedeno,
cilj ove studije bio je da se utvrdi obrazac uzrasno-zavisnih promena u ekspresiji SOXB
transkripcionih faktora u okviru procesa adultne neurogeneze kod jedinki muškog i
ženskog pola, kao i da se ispitaju promene u ekspresiji SOXB transkripcionih faktora
kod 5xFAD mišjeg modela Alchajmerove bolesti oba pola i različite starosti.
Za potrebe ovog istraživanja korišćeni su 5xFAD transgeni miševi i njihove
odgovarajuće kontrole, netransgeni miševi. 5xFAD miševi koeksprimiraju pet mutacija
koje su karateristične za familijarni oblik Alchajmerove bolesti. U istraživanje su bila
uključena 72 miša različitog genotipa, pola i starosti (6, 8 i 16 nedelja). Nakon
žrtvovanja životinja odgovarajućeg uzrasta, hipokampusi su izolovani za potrebe
histohemijskih, imunohistohemijskih, kao i analize nivoa proteina različitih markera
zrelih neurona, ćelijske proliferacije, neurogeneze, neuralnih matičnih ćelija i sinaptičke
plastičnosti (NeuN, Ki-67, PCNA, DCX, SOX1, SOX2, SOX21, BDNF).
Imunohistohemijske analize pokazale su da se ukupan broj granularnih neurona u
dentatnom girusu hipokampusa analiziranih životinja ne menja sa starenjem. Takođe,
rezultati su pokazali da je proliferativni kapacitet unutar subgranularne zone
hipokampusa ujednačen kod jedinki oba genotipa i pola starosti 6 i 8 nedelja dok se kod
životinja starosti 16 nedelja detektuje značajan pad. Pokazano je takođe da je kod
5xFAD transgenih mužjaka starih 8 nedelja broj mladih novostvorenih neurona manji
nego kod kontrolnih životinja. Promene u broju mladih novostvorenih neurona između
transgenih i netransgenih mužjaka, nisu detektovane kod miševa starih 6 i 16 nedelja.
Kod jedinki oba pola i genotipa detektovan je značajan pad u broju nezrelih neurona sa
starenjem. Polne razlike u morfologiji DCX pozitivnih ćelija, u korist klase I kod
mužjaka, a klase II kod ženki detektovane su kod životinja starih 8 nedelja. Ćelije u
stadijumu proliferacije bile su imunoreaktivne i na SOX1 i SOX2 transkripcione
faktore, dok je u malom broju novoformiranih neurona detektovana ekspresija SOX1
transkripcionog faktora. Broj ćelija koje eksprimiraju SOX1, SOX2 i SOX21 protein
značajno se smanjuje kod svih životinja tokom starenja i time prati pad u broju
novoformiranih DCX pozitivnih neurona. U okviru ispitivanih članova SOXB familije,
pad u broju SOX21 imunohistohemijski obeleženih ćelija subgranularne zone utvrđen je
kod transgenih mužjaka starosti 8 i 16 nedelja. Sa druge strane, imunoblot analiza
sugeriše da je ukupna količina BDNF proteina u hipokampusu bila niža kod transgenih
mužjaka starih 6 nedelja u odnosu na njihove netransgene kontrole, dok u ostalim
analiziranim grupama nisu uočene promene u nivou BDNF proteina.
Na osnovu rezultata ovih istraživanja izvedeno je nekoliko zaključaka. Proliferativni
kapacitet, broj novoformiranih, nezrelih neurona i broj SOX1, SOX2 i SOX21
imunoreaktivnih ćelija u subgranularnoj zoni hipokampusa smanjuje se tokom starenja
kako kod netransgenih, tako i kod transgenih jedinki oba pola. Uočene promene ne utiču
značajno na ukupan broj granularnih neurona u dentatnom girusu kod ovih životinja.
Broj novoformiranih neurona je značajno smanjen kod Tg mužjaka u odnosu na
kontrole, dok kod ženki ove promene nisu detektovane uprkos smanjenom broju ćelija
koje
eksprimiraju
SOXB
transkripcione
faktore.
Razlike
u
morfološkim
karakteristikama DCX pozitivnih ćelija uočavaju se između mužjaka i ženki, na osnovu
čega se može pretpostaviti da izvesni polno-specifični faktori imaju uticaj kako na sam
proces neurogeneze, tako i na kompenzatornu reakciju neurogene niše kojom se
sprečava propadanje ili produžava preživljavanje DCX pozitivnih ćelija u
subgranularnoj zoni ženki 5xFAD miševa.
Zaključci ovog istraživanja ukazuju na dinamičnost procesa adultne neurogeneze, čime
se otvara polje za veliki broj daljih istraživanja u kojima bi se ispitivala ekspresija SOX
transkripcionih faktora tokom različitih perioda bolesti, ali i u drugim životinjskim
modelima AB. Potrebna su i dodatna istraživanja koja bi ispitala molekularne
mehanizme koji utiču na kontrolu SOXB transkripcionih faktora, a samim tim i na ceo
proces adultne neurogeneze. | Alzheimer's disease is a progressive neurodegenerative disease and the most common
cause of dementia in the elderly, with a prevalence of two times higher in the female
population. One of the earliest affected structures by pathohistological changes in AB is
the hippocampus, a part of the limbic system that plays an important role in the
processes of learning and memory formation. New research has confirmed that even in
humans the neurogenesis process actively occurs through the adult period in the
subgranular zone of the hippocampus. Bearing in mind the fact that newly created
neurons play a role in the processes of learning and memory, affecting the cognition and
behavior of an individual, cognitive deficit and memory loss in neurodegenerative
diseases can be partly attributed to altered neurogenesis at the level of the hippocampal
subgranular zone. Analysis of the adult neurogenesis processes in the hippocampus of
animals or persons suffering from Alzheimer's disease have resulted in contradictory
data. Depending on experimental conditions, such as the Alzheimer's animal model, age
and sex, as well as the markers used to analyze the neurogenesis, the results indicated
both a decrease, unchanged or even increased levels of neurogenesis both in animal
models, and even in patients suffering from Alzheimer's disease in smaller number of
studies. Previous results indicate the important role of members of the SOXB group of
transcription factors in numerous cellular processes involved in neurogenesis during
embryonic and adult developmental periods, such as the maintenance of multipotency,
proliferation and differentiation of neural stem/precursor cells. In addition to SOXB
transcription factors, certain neurotrophic factors, such as the brain derived neurotrophic
factor (BDNF), affect the processes of proliferation and differentiation of neural
stem/precursor cells. However, the exact role of these factors in the patogenesis of
various neurodevelopmental and neurodegenerative disorders is not sufficiently
clarified. Bearing in mind the above, the aim of this study was to determine the pattern
of age-dependent changes in the expression of SOXB transcription factors within the
adult neurogenesis process in male and female individuals and to examine the changes
in the expression of SOXB transcription factors in the 5xFAD mouse model of
Alzheimer's disease of both sexes and different ages.
For the purpose of this study, 5xFAD transgenic mice and their corresponding controls,
non-transgenic mice were used. 5xFAD mice coexpress five mutations that are charac-
teristic for familial Alzheimer’s disease. 72 mice of different genotypes, sex and age (6,
8 and 16 weeks) were included in the study. After sacrificing the animals at the
appropriate
age,
their
hippocampuses
were
isolated
for
histochemical,
immunohistochemical and protein level analysis of different markers of mature neurons,
cell proliferation, neurogenesis, neural stem cells, and synaptic plasticity (NeuN, Ki-67,
PCNA, DCX , SOX1, SOX2, SOX21, BDNF).
Immunohistochemical analysis have shown that the total number of granule neurons in
the dentate gyrus of the hippocampus does not change with aging, and that the
proliferative capacity within the subgranular zone of the hippocampus is uniform in
animals of both genotypes, aged 6 and 8 weeks. A significant decline in the proliferative
capacity within the hippocampal subgranular zone was seen in animals aged 16 weeks
when compared to animals aged 6 and 8 weeks. Also, in 5xFAD transgenic males aged
8 weeks the number of newly created neurons is lower than in control animals of the
same age. Changes in the number of newly created neurons between transgenic and
non-transgenic males have not been detected in mice aged 6 and 16 weeks. In animals
of both genders and genotypes, a significant decrease in the number of immature
neurons with aging was detected. Gender differences in the morphology of DCX-
positive cells, such as the predominance of class I cells in males, and class II in females
were detected in animals aged 8 weeks. Proliferative cells were immunoreactive for
both SOX1 and SOX2 transcription factors, while a small number of newly formed
neurons were positive for the SOX1 transcription factor. The number of cells expressing
SOX1, SOX2, and SOX21 proteins significantly decreases in all animals during aging,
and thus follows the decline in the number of newly formed DCX-positive neurons.
Within the investigated members of the SOXB family, a decrease in the number of
SOX21 immunohistochemically labeled cells in the subgranular zone was detected in
transgenic males aged 8 and 16 weeks. On the other hand, the imunoblot analysis
suggested that the total amount of BDNF protein in the hippocampus was significantly
lower in transgenic males aged 6 weeks compared to their non-transgenic controls,
while in other analyzed groups no changes were observed in the levels of BDNF
protein.
Based on the above mentioned results, the following conclusions can be made. The first
is that the proliferative capacity, the number of newly formed, immature neurons, and
the number of SOX1, SOX2 and SOX21 immunoreactive cells in the hippocampal
subgranular zone decrease with aging, and that these changes are present both in non-
transgenic and transgenic animals of both genders. The observed changes do not
significantly affect the total number of granular neurons in the dentate gyrus. Bearing in
mind the fact that the early alteration of neurogenesis occurs only in males, it can also
be concluded that in female animals there are no changes in the number of newly
formed neurons despite the reduced expression of SOXB transcription factors. The
differences are, however, detected in the morphological characteristics of DCX-positive
cells between males and females, which suggests that certain gender-specific factors
have an impact both on the neurogenesis process itself and on the compensatory
reaction of the neurogenic niche which aims to prevent the deterioration or to prolong
the survival of DCX-positive cells in subgranular zone of female 5xFAD mice.
The conclusions of this study indicate that the adult neurogenesis process is extremely
dynamic and thus present a big unexplored area for a large number of further studies,
such as the analysis of the expression of SOX transcription factors in different time
periods, but also in other Alzheimer's disease models. Further research is needed to
investigate the molecular mechanisms that influence the control of SOXB transcription
factors and, consequently, the entire process of adult neurogenesis. | true |
Kvalitet života kod bolesnika sa sarkoidozom koji imaju promene na očima | The quality of life of sarcoidosis patients with ocular changes | Sarkoidoza je multisistemska bolest nepoznate etiologije koja se karakteriše
prisustvom nekazeifikujućih granuloma u tkivima i organima. Složena patogentska
osnova sarkoidoze i često nepredvidiv tok bolesti, uzrokuje značajan poremećaj
kvaliteta života obolelih. Posebnu grupu u tom smislu predstavljaju oboleli od
sarkoidoze sa promenama na očima, koje uzrokuju značajan pad opšteg i organ
specifičnog (vezanog za vid) kvaliteta života.
Materijal i metode: Opservacijsko (deskriptivno) kliničko istraživanje (studija preseka)
obavljeno je u Klinici za pulmologiju Kliničkog centra Srbije i Domu zdravlja
Voždovac. Prospektivnom analizom je obuhvaćen uzorak od 80 bolesnika sa
dokazanom sarkoidozom. Svim bolesnicima je uzeta detaljna anamneza sa procenom
kliničkih simptoma, kao i kompletan oftalmološki pregled. U odabranoj grupi od 20
bolesnika učinjena je paracenteza i analiza aktivnosti angiotenzin konvertujućeg enzima
(ACE) u očnoj vodici. Svi bolesnici su podeljeni u dve grupe (sa i bez očnih promena) i
popunjavali su upitnike za procenu kvaliteta života. Dobijeni rezultati su kodirani, uneti
u bazu podataka i analizirana je statistička veza podataka dobijenih ispitivanjem.
Ciljevi ispitivanja su bili: utvrditi razliku u kvalitetu života bolesnika sa sistemskom
sarkoidozom kod kojih postoje i promene na očima u odnosu na one bolesnike bez
očnih promena, ispitati korelaciju demografskih i kliničkih faktora na kvalitet života
bolesnika sa sistemskom sarkoidozom i sa očnim promenama, ispitati uticaj aktivnosti
ACE u očnoj vodici na očne manifestacije sarkoidoze.
Rezultati: Bilo je više muškaraca (56,25%) nego žena (43,75%) u obe grupe zajedno.
Odnos polova iznosio je 1,28 u korist muškaraca. Žene oboljevaju od očne sarkoidoze
češće od muškaraca i ta razlika je statistički značajna. U odnosu na sva pitanja iz
upitnika NEI 25 (National Eye Institute- Nacionalni institut za oči) statistički je visoko
značajna razlika između odgovora bolesnika sa i bez očnih promena u smislu lošijeg
kvaliteta života kod onih sa očnim promenama. U odnosu na sva pitanja iz upitnika
KSQ (King’s Sarcoidosis Questionairre- Upitnik Kraljevskog koledža za sarkoidozu)
uočena je visoko statistički značajna razlika u kvalitetu života vezanom za vid ali i u
opštem kvalitetu života po svim pitanjima između dve grupe ispitanika s tim što su
pacijenti s očnim promenama imali značajno niže skorove. Bolesnici sa očnom
sarkoidozom su imali povišene vrednosti ACE u očnoj vodici.
Zaključak: Žene oboljevaju od očne sarkoidoze češće od muškaraca i ta razlika je
statistički značajna. Kvalitet života pacijenata sa sarkoidozom a koji imaju i očne
manifestacije mnogo je lošiji kako po pitanjima vezanim za percepciju opšteg
zdravstvenog stanja, tako i vezanih za vidnu funkciju u odnosu na pacijente sa
sistemskom sarkoidozom ali bez očnih promena. KSQ upitnik se pokazao brži,
jednostavniji za popunjavanje, lakši i za pacijenta i za lekara. Analiza podataka zahteva
manje vremena, preglednije su tabele i brže može da se dođe do zaključka. Aktivnost
ACE u očnoj vodici je značajno viša kod bolesnika sa očnom sarkoidozom i parametar
je koji ukazuje na očnu sarkoidozu, bez potrebe za biopsijom | Sarcoidosis is a multisystemic disease of unknown aetiology
characterized by the presence of non-caseating granulomas in tissues and organs. The
complex pathogenic basis of sarcoidosis and the often unpredictable course of the
disease causes a significant disorder of the quality of life of thepatients. A particular
group are patients with sarcoidosis with changes in the eyes, which cause a significant
decrease in the general and organ specific (related to vision) quality of life.
Material and Methods: Observational (descriptive) clinical research (cross-section
study) was carried out at the Clinic for pulmonology of the Clinical Center of Serbia
and the Health Center Vozdovac. A prospective analysis included a sample of 80
patients with proven sarcoidosis. In all patients a detailed history was taken, with
assessment of clinical symptoms, as well as a complete ophthalmological examination.
In a specially selectedgroup of 20 patients, paracentesis and analysis of ACE activity in
aqueous humor was performed. All patients were divided into two groups (with and
without eye changes) and filled out questionnaires for the assessment of quality of life.
The obtained results are encoded, entered into the database, and the statistical analysis
performed.
The objectives of the study were: to determine the difference in the quality of life of
patients with systemic sarcoidosis in whom there are changes in eyes compared to those
patients without eye changes, to examine the correlation of demographic and clinical
factors to the quality of life of patients with systemic sarcoidosis and eye changes,
examine the effect angiotensin-converting enzyme activity (ACE) in the aqueous humor
on eye manifestations of sarcoidosis.
Results: There were more men (56.25%) than women (43.75%) in both groups
together. The gender ratio was 1.28 for men. Women suffer from ocular sarcoidosis
more often than men, and this difference is statistically significant. Regarding all the
questions from the NEI 25 questionnaire, a statistically significant difference was
observed between the patients with and without ocular changes in terms of poor quality
of life in those with eye changes. Regarding all the questions from the King's
Sarcoidosis Questionairre questionnaire (KSQ), a highly statistically significant
difference in the quality of life related to vision and overall quality of life was observed
on all issues between the two groups of patients and patients with ocular sarcoidosis had
significantly lower scores. Patients with eye sarcoidosis had elevated ACE levels in the
aquous humor.
Conclusion: Women had eye sarcoidosis more often than men, and this difference is
statistically significant. The quality of life of patients with eye sarcoidosis is much
worse both in terms of perception of general health status and visual quality of life
compared to patients with systemic sarcoidosis but without eye changes. The KSQ
questionnaire proved to be faster, easier to fill, easier for both the patient and the doctor.
Data analysis requires less time, more transparent tables, and more conclusions can be
reached faster. The ACE activity in the aqueous humor is significantly higher in patients
with eye sarcoidosis and this parameter is indicative of ocular sarcoidosis, without the
need for biopsy | true |
Povezanost akutnih uroloških i digestivnih komplikacija i doznih parametara konformalne i intenzitet-modulisane postoperativne radioterapije karcinoma grlića materice | Correlation between acute genitourinary and gastrointestinal toxicity and dosimetric parameters of conformal and intensity - modulated postoperative radiotherapy of cervical cancer | Postoperativna radioterapija smanjuje pojavu recidiva karcinoma grlića materice kod
pacijentkinja sa srednjim i visokim patološkim faktorima rizika, ali komplikacije lečenja
mogu uticati na kvalitet života. Obzirom na visoke stope preživljavanja kod ranih stadijuma
bolesti, kvalitet života je veoma važan kod ovih pacijentkinja. Tehnološki napredak
poslednjih decenija doveo je do razvoja modernih, veoma preciznih konformalnih
radioterapijskih tehnika. Baziraju se na imidžing tehnikama (CT, MRI i PET), uz upotrebu
kompjuterskih sistema za planiranje radioterapije i linearnih akceleratora sa sistemom
multileaf kolimatora (MLC). Intenzitetom-modulisana radioterapija (IMRT) je napredni
oblik standardne trodimenzionalne konformalne radioterapije (3DCRT), koja omogućava
precizno ozračivanje ciljnog volumena uz bolju poštedu okolnih organa od rizika. Ciljevi
ovog istraživanja su: evaluacija i poređenje dozimetrijskih parametara za ciljne volumene i
organe od rizika IMRT i trodimenzionalne konformalne radioterapije, evaluacija akutne
genitourinarne, gastrointestinalne i hematološke toksičnosti ovih pacijentkinja, i procena
uticaja dozimetrijskih parametara i konkomitantne hemoterapije na akutnu toksičnost.
Metode: U ovo istraživanje je uključeno ukupno 95 pacijentkinja. Kod 45 pacijentkinja sa
ranim operabilnim karcinomom grlića materice, UICC stadijuma I-III, sprovedena je
postoperativna eksterna IMRT sa dozom 40-45 Gy u 22-25 frakcija. U kontrolnoj grupi od
50 pacijentkinja sprovedena je 3DCRT. Brahiterapija je primenjena kod svih pacijentkinja,
jednom nedeljno ukupnom dozom od 18-24 Gy. Prema patohistološkim faktorima rizika,
pacijentkinje su imale i konkomitantnu hemoterapiju Cisplatinom (40 mg/m2), uniformno
po grupama.
Analizirani su dozimetrijski parametri pokrivenosti ciljnog volumena i organa od
rizika, i upoređeni između dve radioterapijske tehnike. Tokom terapije kod pacijentkinja je
praćena pojava akutne gastrointestinalne, urološke i hematološke toksičnosti, koja je
klasifikovana prema RTOG kriterijumima. Takođe je analiziran uticaj dozimetrijskih
parametara i konkomitantne hemoterapije na akutnu toksičnost.
Rezultati: Između pacijentkinja tretiranih IMRT i 3DCRT tehnikama zračenja, nije bilo
statistički značajne razlike u kliničkim i patološkim karakteristikama: starost, histologija,
tip operacije, UICC stadijum i prosečna maksimalna brahiterapijska doza na bešici i
rektumu. U obema grupama, najčešći tip tumora je bio skvamocelularni karcinom,
histološki gradus 2, a većina pacijentkinja je imala UICC stadijum Ib1 i IIb, i inicijalni
hirurški tretman radikalnu histerektomiju po Wertheim-Meigs-u.
U oba radioterapijska plana postiguta je adekvatna pokrivenost ciljnog volumena
preporučenim vrednostima za PTV95 (IMRT vs 3DCRT; 99.27% vs 99.90%). IMRT
planovi su pokazali veću konformalnost u odnosu na 3DCRT planove, sa statistički boljim
vrednostima za indekse homogenosti i konformalnosti, ali sa većom maksimalnom dozom
(predstavljenom parametrima PTV105 i D2). Utvrđena je statistički značajna razlika za
regije organa od rizika koji primaju visoke doze: V45 bešike (p = 0.000), rektuma V40 (p =
0.043) i V45 (p = 0.000), creva V45 (p = 0.000) i dozimetrijski parametri koštane srži V20-
V45, što potvrđuje bolju konformalnost IMRT planova. Nađena je i značajna razlika u
volumenu zdravih tkiva koji primaju dozu od 20 Gy, koja je bila veća kod IMRT, dok nije
bilo razlike za volumene koji primaju 10 Gy.
Sa aspekta akutne toksičnosti, između IMRT i 3DCRT grupa nađena je statistički
značajna razlika za ukupnu akutnu toksičnost (p=0.018), akutnu genitourinarnu toksičnost
(p=0.029), anemiju (p=0.043) i neutropeniju (p=0.027), bez razlika za akutnu
gastrointestinalnu
toksičnost.
Pacijentkinje
koje
su
primale
konkomitantnu
hemoradioterapiju bez obzira na tehniku zračenja, imale su statistički značajno višu ukupnu
akutnu toksičnost (CHRT vs RT; p=0.011) i hematološku toksičnost (p=0.001), u poređenju
sa pacijentkinjama kod kojih je sprovedena samo radioterapija. Pacijentkinje sa ≥3 ciklusa
hemoterapije imale su skoro duplo povećanje hematološke toksičnosti. U IMRT grupi
pacijentkinje sa konkomitantom hemoradioterapijom, u odnosu na pacijentkinje samo sa
radioterapijom, imale su statistički češće leukopeniju (p=0.009). Slično tome, u 3DCRT
grupi u vezi sa primenom hemoterapije, razlika je nađena za anemiju (p=0.021) i
neutropeniju (p = 0.029).
U IMRT grupi nađena je statistički značajna niža vrednost V45 bešike kod
pacijentkinja sa blažom genitourinarnom toksičnošću (4.11% prema 14.77%, p = 0.006).
Slično tome, u ovoj grupi pacijentkinje koje nisu imale hematološku toksičnost, imale su
niže vrednosti V10-V45 (V10-p = 0.047; V20-p = 0.008; V30-p = 0.022; V45-p = 0.019).
Zaključak: Intenzitetom- modulisana radioterapija je visoko konformalna tehnika,
povezana sa boljim dozimetrijskim parametrima za organe od rizika. Adekvatna
pokrivenost ciljnog volumena postignuta je sa obe radioterapijske tehnike. Kod
pacijentkinja tretiranih IMRT tehnikom zračenja nađena je manja ukupna, genitourinarna i
hematološka akutna toksičnost. Prisutna je viša hematološka toksičnost kod konkomitantne
hemoterapije, nezavisno od primenjene radioterapijske tehnike.
Na osnovu rezultata ovog istraživanja dokazane su prednosti intenzitet-modulisanog
zračenja u odnosu na 3D konformalnu radioterapiju, te bi ovaj modalitet lečenja trebalo
uvesti u svakodnevnu praksu i omogućiti dugoročno kvalitetniji život pacijentkinja. | Postoperative radiotherapy reduce recurrence of cervical cancer in patients
with intermediate and high-risk pathological factors, but might affects quality of life due to
toxicity. According to high overall survival rates, the quality of life is very important in this
patients. Technological advances of the last decades have led to the development of
modern, highly precise conformal radiotherapy techniques. They are based on imaging
techniques (CT, MRI and PET), computer systems for radiotherapy planning and linear
accelerators with multileaf collimator system (MLC). Intensity-modulated radiotherapy
(IMRT) is an advanced form of standard three-dimensional conformal radiotherapy
(3DCRT), which enables precise conformation of radiation dose to target volume with
better sparing surrounding organs at risk. Our goals in this research are: evaluate and
compared IMRT and three-dimensional conformal radiotherapy dosimetric parameters for
target volumes and organs at risk, evaluate acute genitourinary, gastrointestinal and
hematologic toxicity in this patients, and estimate influence of dosimetric parameters and
concomitant chemotherapy on acute toxicity.
Methods: This research included a total of 95 patients. A 45 patients with early, operable
cervical cancer UICC stage I-III, underwent postoperative external beam IMRT with 40-45
Gy in 22-25 fractions. The control group of 50 patients was treated with 3DCRT.
Brachytherapy was applied to all patients with dose of 18-24 Gy, once weekly. According
to patohistologic risk factors some of patients also had concomitant Cisplatin chemotherapy
(40 mg/m2). An analysis of dosimetric parameters for target volume coverage and organs at
risk was performed and compared between two external beam radiotherapy techniques.
During treatment patients were monitored for occurrence and grade of acute
gastrointestinal, urological and hematological toxicity which was classified by RTOG acute
radiation morbidity scoring criteria. We also analyzed the influence of dosimetric
parameters and concomitant chemotherapy on acute toxicity.
Results: There was no statistically significant difference for clinico-pathologic
characteristics of patients: age, histology, type of surgery, UICC stage and brachytherapy
bladder and rectum maximum dose between IMRT and 3DCRT treated patients. In both
groups the most frequent tumor type was squamos cell carcinoma, histologic grade 2 and
most patients had UICC stage Ib1 and IIb, with Wertheim-Meigs radical hysterectomy as
initially treatment.
Both radiotherapy plans achieved adequate planning target volume coverage
described with recommended constraints for PTV95 (IMRT vs 3DCRT; 99.27% vs 99.90%).
IMRT plans show better conformity compared to 3DCRT plans, with statistically better
values for homogenity index and conformity index, but with higher maximum dose
(represented with PTV105 and D2 parameters). Statistically significant difference between
plans was found for bladder, rectum and bowel high dose regions: bladder V45 (p=0.000),
rectum V40 (p=0.043) and V45 (p=0.000), bowel V45 (p=0.000), and bone marrow
dosimetric parameters V20-V45, and confirm better conformity of IMRT plans. Significant
difference was also found for volume of patient body normal tissue receiving dose of 20
Gy, which was higher in IMRT, with no diference for dose of 10 Gy.
From the aspect of acute toxicity, statistically significant difference for overall acute
toxicity (p=0.018), acute genitourinary toxicity (p=0.029), anemia (p=0.043) and
neutropenia (p=0.027) between IMRT and 3DCRT groups were found without difference
for acute gastrointestinal toxicity. Due to chemotherapy administration, regardless to
radiotherapy technique, significant difference was found between chemoradiotherapy and
radiotherapy group, in overall acute toxicity (CHRT vs RT; p=0.011) and hematological
toxicity (p=0.001), the both was higher in patients with combined treatment. Patients with
≥3 cycle of chemotherapy showed near doubling increase of hematologic toxicity. In IMRT
group according the administration of chemotherapy (chemoradiotherapy vs radiotherapy),
the statistically significant difference for leukopenia was found (p=0.009). Similar to that in
the 3DCRT group regarding to administration of chemotherapy, difference was found for
anemia (p=0.021) and neutropenia (p=0.029).
Statistically significant lower value of bladder V45 at patients with low genitourinary
toxicity (4.11% vs 14.77%, p=0.006) in the IMRT group was found. Similarly, in this
group patients without hematological toxicity had lower value of bone marrow V20-V45
(V10- p=0.047; V20- p=0.008; V30- p=0.022; V45- p=0.019).
Conclusion: Intensity-modulated radiotherapy is a highly conformal technique, asscociated
with better dosimetric parameters for organs at risk. Satisfied target volume coverage was
achieved with both techniques, IMRT and 3DCRT. In IMRT treated patients we found
lower overall, genitourinary and hematological acute toxicity. Higher hematological
toxicity at concomitant chemotherapy, was found despite the RT technique. Based on the
results of this research, the advantages of intensity-modulated radiation in relation to 3D
conformal radiotherapy have been demonstrated, and this treatment modality should be
introduced into everyday practice and allow a longer-term quality patient's life. | true |
Uticaj polimorfizama MDR1 gena na metabolizam kalcineurinskih inhibitora i funkciju presađenog bubrega | Influence of MDR1 gene polymorphisms on calcineurin inhibitors' metabolism and kidney graft function | Transplantacija bubrega je najbolji način lečenja bolesnika u terminalnoj fazi hronične
bolesti bubrega. Uvođenje kalcineurinskih inhibitora (KNI) u imunosupresivne protokole je jedan
od najznačajnijih koraka u razvoju transplantacione medicine koji je značajno poboljšao
preživljavanje kako alografta, tako i bolesnika sa presađenim bubregom. Ovi lekovi blokiraju
sintezu citokina potrebnih za aktivaciju T-limfocita (interleukina-2, interleukina-4, interferona-γ i
faktora nekroze tumora-α) i tako ostvaruju svoj imunosupresivni efekat. Imaju vrlo uzak terapijski
opseg, izraženu interidividaulnu i intraindividualnu varijabilnost, kao i veliki broj neželjenih
efekata koji utiču na funkciju alografta. Samo neki od neželjenih efekata mogu se objasniti
neadektavnom koncentracijom leka u krvi. Brojna istraživanja bavila su se ispitivanjem
povezanosti genskih polimorfizama i farmakokinetske i farmakodinamske varijabilnosti KNI.
Jedan od najznačajnijih gena za metabolizma KNI je MDR1 gen koji kodira sintezu P-
glikoproteina koji je proteinski nosač KNI iz intracelularnog u ekstracelularni prostor.
Ciljevi istraživanja: Osnovni cilj našeg istraživanja bio je da se ispita učestalost genotipova
pojedinačnih nukleotidnih polimorfizama (C1236T, G2677T/A i C3435T) MDR1 gena i njihovih
haplotipova. Pored toga, ispitivali smo i uticaj genotipova i haplotipova MDR1 gena na
farmakokinetiku KNI, učestalost akutnog odbacivanja (AO), učestalost odložene funkcije
alografta (OFA) i funkciju alografta. Imajući u vidu mnogobrojne neželjene efekte KNI, ispitivali
smo i uticaj genotipova i haplotipova MDR1 gena na koncentraciju glukoze, kalijuma, mokraćne
kiseline, holesterola, triglicerida i aminotransferaza u serumu.
Metode: Studija je dizajnirana kao neinterventno retrospektivno opservaciono ispitivanje,
sprovedeno u Klinici za nefrologiju Kliničkog centra Srbije i Institutu za mikrobiologiju i
imunologiju Medicinskog fakulteta Univerziteta u Beogradu. U ispitivanje su uključena 152
bolesnika sa presađenim bubregom koji su imali CYP3A5*3*3 genotip. Izolacija molekula DNK
vršena je iz uzoraka pune krvi standardnom metodom kolonica. Podaci o dozama i
koncentracijama KNI, funkciji alografta, AO i OFA, kao i vrednosti glikemije, hemoglobina,
hematokrita, mokraćne kiseline, kalijuma, aspartat- i alaninaminotransferaze, ukupnog holesterola
i triglicerida, dobijeni su iz ambulantnog kartona bolesnika sa presađenim bubregom. AO je
definisano kao pogoršanje funkcije algrafta koje se oporavilo nakon primene pulsnih doza
kortikosteroida, ili je dijagnostikovano na osnovu patohistološkog nalaza bioptiranog alografta.
OFA je definisana kao neuspostavljanje adekvatne funkcije alografta i potrebe za lečenjem
hemodijalizama tokom prvih 15 dana nakon transplantacije.
Rezultati: Analizom tri SNP-a MDR1 gena dobijeni su sledeći genotipovi: C1236T - CC (28,95%),
CT (70,39%), TT (0,66%); G2677T/A – GG (29,61%), TT (15,79%), GT (51,97%), TA (2,63%);
C3435T – CC (26,97%), CT (50,66%) i TT (22,37%). Na osnovu dobijenih genotipova
identifikovano je 10 haplotipova. Četiri najučestalija su CGC (45,38%), TTT (30,01%), CTT
(8,42%) i CGT (7,12%). Među bolesnicima koji su primali CsA nije bilo značajne razlike u dozama
potrebnim za dostizanje ciljne koncentracije leka u krvi. Najveća razlika u dozama leka kod
bolesnika koji su primali TAC bila je vezana sa polimorfizam na egzonu 21. Varijant
homozigotima su bile potrebne značajno veće doze leka da bi dostigli ciljni nivo u odnosu na divlje
homozigote i heterozigote u svakom trenutku praćenja nakon transplantacije (p < 0,05). Nije bilo
značajnog uticaja ni genotipova ni haplotipova na učestalost AO i OFA. Funkcija alografta nije
zavisila od polimorfizama MDR1 gena kod bolesnika koji su primali TAC. Najbolju funkciju,
mereno vrednošću serumskog kreatinina među bolesnicima koji su primali CsA, imali su divlji
homozigoti za sva tri polimorfizma MDR1 gena. AO je bilo jedini značajn prediktor nastanka
insuficijencije alografta (p=0,001).
Zaključci: Za sva tri SNPs MDR1 gena, heterozigoti su bili najučestaliji. Polimorfizmi MDR1
gena nisu uticali na doze CsA potrebne za dostizanje ciljnog nivoa leka u krvi. Bolesnicima koji
su bili „varijant homozigoti“ za polimorfizme G2677T/A i C3435T bile su potrebne najveće doze
TAC za dostizanje ciljnog nivoa leka u krvi. Polimorfizam G2677T/A bio je jedini nezavisan
prediktor doziranja TAC. Polimorfizmi MDR1 gena nisu uticali na učestalost AO i OFA, kao ni
na funkciju alografta kod bolesnika koji su primali TAC. Bolesnici koji su bili „varijant
homozigoti“ za sva tri polimorfizma imali su bolju funkcija alografta ukoliko su primali CsA.
Analizom faktora rizika za nastanak insuficijencije alografta AO je pokazano kao jedini prediktor
nastanka insuficijencije alografta. | Kidney transplantation is the best treatment option for patients with end stage chronic
kidney disease. The introduction of calcineurin inhibitors (CNI) in immunosuppressive protocols
have played an important role in improving the outcome of kidney transplantation. These drugs
block the cytokine synthesis needed to activate T-lymphocytes and thereby achieve their
immunosuppressive effect. They have a narrow therapeutic range, interindividual and
intraindividual variability, and a large number of side effects that affect the function of the
allograft. However, only some of the side effects can be explained by an inadequate drug
concentration in the blood. Numerous studies have investigated the relationship between gene
polymorphisms and pharmacokinetic and pharmacodynamic variability of CNI. One of the most
significant genes for CNI metabolism is the MDR1 gene that encodes the synthesis of the protein
carrier CNI.
Objective: The primary aim of our study was to examine the frequency of genotypes of SNPs
(C1236T, G2677T/A and C3435T) of the MDR1 gene and their haplotypes. In addition, we
examined the influence of genotypes and haplotypes of the MDR1 gene on the CNI
pharmacokinetics, the frequency of acute rejection (AR), the frequency of delayed function (DGF)
and the allograft function. Also, we examined the influence of SNPs and haplotypes of the MDR1
gene on the serum level of glucose, potassium, uric acid, cholesterol, triglyceride and
aminotransferase.
Methods: This study was designed as a retrospective observation study conducted at the Clinical
Center of Serbia, Clinic of Nephrology and the Institute of Microbiology and Immunology at the
University of Belgrade, Medical Faculty. This study included 152 patients who were kidney
transplant recipients with a CYP3A5 * 3 * 3 genotype. DNA molecules were extracted from whole
blood samples using a standard colonic method. The patient charts revealed data about the CNI
dosage and concentration, allograft function, frequency of AR and DGF, as well as the serum level
of glucose, hemoglobin, hematocrit, uric acid, potassium, aspartate and alanine aminotransferase,
total cholesterol and triglyceride. AR was diagnosed by allograft biopsy or on the basis of allograft
function deterioration that has improved after high-dose of corticosteroid therapy. DGF was
defined as a need for hemodialysis during the first two weeks after kidney transplantation.
Results: According to our results, genotype frequencies for the three SNPs of the MDR1 gene
were: C1236T-CC (28.95%), CT (70.39%), TT (0.66%); G2677T / A - GG (29.61%), TT
(15.79%), GT (51.97%), TA (2.63%); C3435T - CC (26.97%), CT (50.66%) and TT (22.37%).
On the basis of these isolated genotypes, 10 haplotypes were identified. According to the results,
the most frequent ones were: CGC (45.38%), TTT (30.01%), CTT (8.42%) and CGT (7.12%).
Among the patients receiving CsA there was no significant difference in dosage requirements for
achieving target drug concentration. The biggest difference in the drug dosage requirement in
patients receiving TAC was related to polymorphism on exon 21. The variant homozygotes had
significantly higher dose requirements than wild homozygotes and heterozygotes (p <0.05). There
was no significant difference observed between genotypes or haplotypes regarding the frequency
of AO and OFA. The function of the allograft did not depend on the polymorphisms of the MDR1
gene in patients receiving TAC. The best function, measured by the serum creatinine level among
patients receiving CsA, had wild homozygotes for all three polymorphisms of the MDR1 gene.
AR was shown as the only significant predictor of allograft insufficiency (p=0.001).
Conclusion: Heterozygotes were the most frequent genotypes out of all three SNPs of the MDR1
gene. Polymorphisms of the MDR1 gene did not affect the CsA doses needed to reach the target
level of the drug in the blood. The variant homozygotes for polymorphisms G2677T/A and
C3435T needed the highest TAC doses to reach the target level of the drug in the blood.
Polymorphism G2677T/A was shown as the only independent predictor of TAC dosing. MDR1
gene polymorphisms did not affect the incidence of AO, OFA, or the allograft function in patients
receiving TAC. The variant homozygote was associated with a better function of allograft in the
group of patients who received CsA. AO was shown to be the only predictor of allograft
insufficiency. | true |
Značaj određivanja nivoa ekspresije Vilmsovog tumorskog gena 1 kod pedijatrijskih pacijenata sa akutnom leukemijom | Significance of determination of Wilmsʼ tumor 1 gene expression levels in pediatric patients with acute leukemia | Akutne dečje leukemije su grupa oboljenja koja predstavlja najčešće
maligne bolesti dečjeg doba. Odlikuju se blokadom diferencijacije i
nekontrolisanom proliferacijom prekursorskih ćelija krvnih lozâ. Akutne
dečje leukemije su danas u velikoj meri izlečive. Akutna mijeloidna leukemija
(AML) i akutna limfoblastna leukemija (ALL) su suštinski različite bolesti.
Akutna mijeloidna leukemija se najčešće primarno klasifikuje po francusko-
američko-britanskom (FAB) sistemu morfološke klasifikacije na tipove M0-
M7,
uz
značajnu
dopunu
na
osnovu
savremenih
imunofenotipskih,
citogenetičkih i molekularno-genetičkih ispitivanja. Kod značajnog dela dece
sa AML, analizom kariotipa moguće je otkriti hromozomske aberacije. Mnoge od
njih su specifično povezane sa biološkim tipom leukemije i imaju
prognostički značaj. U tom smislu, naročito su važne tranlokacije povezane sa
genskim rearanžmanima, kao što su t(8;21) (fuzioni gen AML1/ETO),
inv(16)(p13;q22) (fuzioni gen CBFß/MYH11), translokacije/rearanžmani koji
zahvataju gen MLL na hromozomskom lokusu 11q23 i t(15;17) (fuzioni gen
PML/RARα). Na tok i prognozu AML utiču i mnogobrojne genske mutacije, kao
što je interna tandem duplikacija gena FLT3.
Akutna limfoblastna leukemija je u pedijatrijskom uzrastu znatno češća
od akutne mijeloidne leukemije (~ 9:1) i čini oko 30% svih malignih procesa
dečje dobi. Kao i AML, i ALL predstavlja heterogeno oboljenje, odnosno grupu
srodnih neoplastičnih procesa. Prema imunofenotipu, ALL se dele na
leukemije B i T ćelijske loze. Prema stepenu zrelosti, odnosno ekspresiji
molekula CD10 i citoplazmatskog μ lanca imunoglobulina, B prekursorske
leukemije se dele na pro-B, „common“ B i pre-B, dok zrela B-ćelijska leukemija,
koja se odlikuje ekspresijom imunoglobulina na površini ćelije, predstavlja
zaseban entitet i biološki je ekvivalentna Burkiovom limfomu. T-ćelijske
leukemije je takođe moguće podeliti prema stepenu zrelosti na ranu, srednju i
kasnu, ali ova podela ima relativno skroman klinički značaj. Standardnim
citogenetičkim ispitivanjem se hromozomske aberacije otkrivaju kod 60-85%
dece obolele od ALL. Hiperdiploidija se sreće kod 35-50% pacijenata i
udružena je sa povoljnom prognozom. Nasuprot tome, hipodiploidiju, koja je
zastupljena u 7-8% dece sa ALL, prati loša prognoza. Isto važi i za broj
hromozoma blizak haploidnom. Hromozomske translokacije/genski rearanžmani
koji se rutinski ispituju kod B-prekursorske ALL obuhvataju t(12;21)
(TEL/AML1), t(4;11) (MLL/AF4), t(1;19) (E2A/PBX) i t(9;22) (BCR/ABL). Fuzija
TEL/AML1 je najčešća (oko 25% ALL) i udružena je sa povoljnom prognozom.
Javlja se kod ALL sa pre-B fenotipom, pretežno kod dece uzrasta 1-10 godina.
Rearanžmani MLL/AF4 i BCR/ABL udruženi su sa nepovoljnom prognozom.
Učestalost fuzije BCR/ABL u dečjoj ALL iznosi 3-5%. Njeno prisustvo je
racionalna osnova za genski ciljanu terapiju specifičnim inhibitorima
tirozin-kinaze.
Brzina kojom maligne ćelije iščezavaju iz organizma deteta predstavlja
najvažniji prognostički parametar, budući da je ona zbirni ishod delovanja
velikog broja poznatih i nepoznatih bioloških činilaca. Budući da je prag
osetljivosti morfološkog praćenja broja blasta pri kontrolnim aspiracijama
koštane srži ograničen na oko 5%, razvijena su tri osetljivija i preciznija
načina da se proceni zastupljenost leukemijskih ćelija, što se naziva
minimalnom rezidualnom bolešću (MRB). To su imunofenotipizacija
multiparametarskom protočnom citometrijom, detekcija klonski rearanžiranog
gena za antigenske receptore (ukoliko postoji u leukemijskim ćelijama) i
detekcija fuzionog gena karakterističnog za leukemijske ćelije (ukoliko
postoji).
Vilmsov tumor (WT)1 je transkripcioni faktor koji igra značajnu ulogu
u regulaciji ćelijskog rasta i diferencijacije. Mada je prvobitno otkriven kod
Vilmsovog tumora, retke neoplazme embrionalnih ćelija koja prevashodno
zahvata bubreg, nađeno je da WT1 igra ulogu u patogenezi širokog spektra
malignih procesâ. Zanimljivo je da WT1, pod različitim okolnostima, može da
igra kako ulogu onkogena, tako i ulogu tumor-supresorskog gena. U koštanoj srži
pacijenata sa AML, često postoji povećana ekspresija WT1, što je pokazano kao
negativan prognostički činilac, kako kod odraslih, tako i kod dece. Međutim, u
pojedinim istraživanjima korelacija između ekspresije WT1 u koštanoj srži
pri dijagnozi i prognoze ishoda oboljenja nije nađena. Za razliku od AML,
ekspresija WT1 kod ALL je najčešće bliska onoj kod zdravih osobâ, premda
postoje i pacijenti sa relativno visokim nivoom ekspresije.
U naše istraživanje je uključeno 20 dece obolele od AML (12 dečaka i 8
devojčica), uzrasta od 3 do 16 godina (medijana 9½ godina) i 20 dece sa ALL (11
dečaka i 9 devojčica) uzrasta od 6 meseci do 17 godina (medijana 5 godina).
Kontrolna grupa je formirana od 15 dece usklađenog pola i uzrasta koja su
podvrgnuta aspiraciji koštane srži zbog imunske trombocitopenijske purpure
(ITP). Deca sa AML lečena su po protokolu BFM-AML-2004, a deca sa ALL po
protokolu BFM-ALL-IC-2009. Ekspresija gena WT1 analizirana je u uzorcima
koštane
srži
metodom
lančane
reakcije
polimeraze
sa
reverznom
transkripcijom, a protein WT1 je detektovan protočnom citometrijom.
Kod pacijenata sa AML zabeležena je značajno veća ekspresija gena WT1
(139,42 ± 244,03) nego kod pacijenata sa ALL (1,18 ± 54,37; U=82; p<0,01) ili u
kontrolnoj grupi pacijenata sa ITP (0,76 ± 1,01; U=32; p<0,01). Ekspresija gena
WT1 kod pacijenata sa ALL nije se statistički značajno razlikovala od one kod
pacijenata sa ITP (U=105,5; p>0,05)
Ekspresija gena WT1 pri dijagnozi kod 16 dece koja su ušla u punu
remisiju bolesti bila je 139,42 ± 186,51, dok je ekspresija gena WT1 pri
dijagnozi kod četvoro dece koja su preminula ne ušavši u remisiju iznosila
300,80 ± 407,01. U vreme analiziranja (medijana praćenja 1½ godina), 14 dece je i
dalje bilo u životu, a njihova ekspresija gena WT1 pri dijagnozi iznosila je
181,42 ± 192,52. Kod ukupno šestoro dece koja su do trenutka analiziranja
podlegla bolesti (četvoro bez ulaska u remisiju, jedno usled relapsa i jedno
usled fatalne infektivne komplikacije) ekspresija gena WT1 pri dijagnozi je
iznosila 104,29 ± 354,87. Razlika između gornje dve grupe nije bila statistički
značajna (U=41, p>0,05).
U
grupi
od
šestoro
pacijenata
sa
akutnom
promijelocitnom leukemijom (koja je kod svih potvrđena dokazanim prisustvom
genskog rearanžmana PML/RARα, ekspresija gena WT1 pri dijagnozi je bila
379,53 ± 183,52. Man-Vitnijevim U testom nije dobijena statistička značajnost
razlike između pacijenata sa promijelocitnom leukemijom i onih sa drugim
FAB tipovima (U=18, p>0,05; slika 2), što se može objasniti malobrojnošću
podgrupe. Ekspresija gena WT1 pri dijagnozi kod petoro dece sa FAB tipom M1
ili M2 iznosila je 5,20 ± 100,7 (U=22, p>0,05), a kod sedmoro dece sa FAB tipom
M5 51,02 ± 186,66 (U=24, p>0,05). Kod jednog od dva deteta sa leukemijom FAB
tipa M4 zabeležena je najveća vrednost ekspresije gena WT1 pri dijagnozi u
čitavoj seriji pacijenata (874,92), dok je kod drugog deteta sa ovim tipom
leukemije iznosila 305,91.
Mali broj dece sa T-ALL uključene u istraživanje onemogućio je
statističko poređenje ekspresija gena WT1 pri dijagnozi u odnosu na druge
tipove ili podtipove leukemije. Međutim, kod svih četvoro je ekspresija gena
WT1 pri dijagnozi premašila medijanu kod zdravih kontrola (ITP) za više od
3 standardne devijacije. Isto važi za četvoro od šesnaestoro pacijenata sa B-
ALL (25%). Podaci kontrolnog ispitivanja nakon mesec dana dobijeni su kod
15 dece. Svega dvoje od petoro dece kod koje se ekspresija gena WT1 mesec dana po
dijagnozi nalazila u četvrtom kvartilu bilo je živo u vreme analiziranja, dok su
sva deca (10 od 10) sa ekspresijom u prva tri kvartila bila živa. Ova razlika
ipak nije statistički značajna na osnovu Fišerovog testa tačne verovatnoće
(p=0,0952), što je verovatno prevashodno posledica malog broja ispitanikâ.
Primenjenom metodom indirektne fluorescence/protočne citometrije,
molekul WT1 je detektovan pri dijagnozi u leukemijskim ćelijama kod 16
pacijenata sa AML i svih četvoro pacijenata sa T-ALL. Kod pacijenata sa B-
ALL, WT1 na proteinskom nivou nije detektovan. Ni u jednom uzorku dobijenom
kontrolnim pregledima koštane srži tokom lečenja, ekspresija WT1 nije
detektovana na nivou proteina.
Sveukupno, rezultati ovog istraživanja potkrepljuju zaključak da bi
ispitivanje nivoa ekspresije gena WT1 moglo da bude korisna dopuna postojećim
protokolima za dijagnostiku dečje AML, T-ćelijske ALL, kao i određene
podgrupe pacijenata sa B-ćelijskom ALL. Naši rezultati takođe naglašavaju
značaj tumačenja podataka o ekspresiji WT1 u skladu sa složenim i
individualizovanim kontekstom. | Acute childhood leukemia is a group of disorders that represents the most
common malignancies in childhood. They are characterized by a block in differentiation
and uncontrolled proliferation of precursor cells of blood lineages. Childhood acute
leukemias are now highly curable. Acute myeloid leukemia (AML) and acute
lymphoblastic leukemia (ALL) are essentially different diseases. AML is usually
primarily classified by the morphological French-American-British (FAB) classification
system into types M0-M7, with important complementary information based on modern
methods of immunophenotyping, cytogenetic and molecular genetic investigations. In a
significant portion of children with AML, analysis of karyotype may reveal
chromosomal aberrations. Many of these are specifically associated with the biological
type of leukemia and have a prognostic significance. In this sense, translocations related
to gene rearrangements, such as t(8;21) (fusion gene AML1/ETO), inv(16)(p13;q22)
(fusion gene CBFß/MYH11), translocations/rearrangements involving MLL gene at the
11q23 locus, and t(15;17) (fusion gene PML/RARα) are of particular importance. The
clinical course and prognosis of AML are also influenced by many gene mutations, such
as internal tandem duplication of the FLT3 gene.
In the pediatric age group, ALL is much more common than AML (~ 9:1) and
constitutes about 30% of all childhood malignancies. ALL, as AML, is a heterogenous
disorder,
namely
a
group
of
related
neoplastic
processes.
According
to
immunophenotype, ALL is divided into B- and T-lineage leukemias. According to the
degree of maturation, displayed by the expression of CD10 and cytoplasmic
immunoglobulin μ chain, B-cell precursor leukemias are subdivided into pro-B,
common-B and pre-B subtypes, while mature B-cell leukemia, characterized by the
surface expression of immunoglobulin, is a separate entity, biologically equivalent to
Burkitt lymphoma. T-cell leukemias can also be subdivided according to the degree of
maturation, into early, middle, and late forms, but this distinction is of relatively modest
clinical value. Using stadard cytogenetic investigation methods, chromosomal
aberrations are found in 60-85% of children with ALL. Hyperdiploidy is encountered in
35-50% of patients and is associated with favorable prognosis. Conversly,
hypodiploidy, found in 7-8% of children with ALL, is a sign of poor prognosis. The
same
applies
to
a
near-haploid
number
of
chromosomes.
Chromosomal
translocations/gene rearrangements that are routinely investigated in B-cell precursor
ALL include t(12;21) (TEL/AML1), t(4;11) (MLL/AF4), t(1;19) (E2A/PBX), and t(9;22)
(BCR/ABL). TEL/AML1 fusion is the most common (about 25% of ALL) and associated
with favorable prognosis. It usually occurs with a pre-B phenotype in children aged 1-
10 years. MLL/AF4 and BCR/ABL rearrangements are associated with unfavorable
prognosis. The frequency of BCR/ABL fusion in childhood AML is 3-5%. Its presence
is a rationale for genetically targeted therapy by specific tyrosine-kinase inhibitors.
The rate of elimination of neoplastic cells during treatment is the most
significant prognostic parameter, because it is a compound result of action of a great
number of known and unknown biological factors. Since the sensitivity of
morphological enumeration of leukemic cells in the bone marrow is limited to about
5%, three sensitive and accurate methods to assess the quantity of leukemic cells have
been developed. This is called minimal residual disease (MRD). These methods are
immunophenotyping by multiparametric flow cytometry, detection of clonally
rearranged genes for antigen receptors (if present in leukemic cells), and detection of
fusion genes characteristic for leukemic cells (if they exist). Novel MRD methods are
being actively sought.
Wilms tumor (WT)1 is a transcription factor that plays a significant role in the
regulation of cell growth and differentiation. Although it was originally discovered in
Wilms tumor, WT1 is now known to be important in the pathogenesis of a wide range
of neoplastic processes. It is interesting to note that WT1, under different circumstances,
may play both the role of an oncogene and that of a tumor-suppressor gene. WT1 is
often hyperexpressed in the bone marrow of AML patients, and this has been
demonstrated as an unfavorable prognostic factor, both in adults and in children.
However, in some studies, no correlation between WT1 bone marrow expression at
diagnosis and disease outcome has been observed. In contrast to AML, WT1 expression
in ALL is mostly similar to that in healthy persons, although patients with a realtively
high expression have been encountered.
The subjects of our research were 20 children suffering from AML (12 boys and
8 girls), aged 3-16 years (median 9½ years) and 20 children with ALL (11 boys and 9
girls) aged 6 months to 17 years (median 5 years). The control group was formed by 15
sex- and age-matched children who underwent bone marrow aspiration because of
immune thrombocytopenic purpura (ITP). Children with AML were treated according
to the BFM-AML-2004 Protocol, while those with ALL were treated according to the
BFM-ALL-IC-2009 Protocol. WT1 gene expression was analysed in bone marrow
samples by reverse-transcription polymerase chain reaction, while WT1 protein
detection in leukemic cells was performed by flow cytometry.
A significantly higher WT1 gene expression was observed in AML patients
(139,42 ± 244,03) than in ALL patients (1,18 ± 54,37; Mann-Whitney U=82; p<0,01) or
in the control group with ITP (0,76 ± 1,01; U=32; p<0,01). WT1 gene expression in
ALL did not statistically significantly differ from that of ITP controls (U=105,5;
p>0,05). WT1 gene expression at diagnosis in 16 children who entered full remission
was 139,42 ± 186,51, while the four children who died without reaching remission had
WT1 expression at diagnosis of 300,80 ± 407,01. At the time of analysis (median
follow-up 1½ years), 14 chilren were still alive, and their WT1 expression was 181,42 ±
192,52. In a total of six children who succumbed to the disease by the time of analysis
(four without entering remission, one due to relapse and one as a consequence of a fatal
infectious complication), WT1 gene expression at diagnosis was 104,29 ± 354,87. The
difference between the above groups was not statistically significant (U=41, p>0,05).
In the group of six patients with acute promyelocytic leukemia (confirmed in all
cases by the presence of gene rearrangement PML/RARα, WT1 gene expression at
diagnosis was 379,53 ± 183,52. The difference between children with promyelocytic
leukemia and those with other FAB types was not shown to be statistically significant
(U=18, p>0,05), a fact that could be explained by insufficient subgroup size. WT1 gene
expression at diagnosis in five children with FAB type M1 or M2 was 5,20 ± 100,7
(U=22, p>0,05), and that in seven children with FAB type M5 was 51,02 ± 186,66
(U=24, p>0,05). One of the two patients with FAB type M4 had the highest value of
WT1 expression at diagnosis observed in our series (874,92), while the other child with
this type of leukemia displayed WT1 expression at diagnosis of 305,91.
A small number of children with T-ALL enrolled in this study prevented
statistical comparison of WT1 gene expression at diagnosis with other leukemia types or
subtypes. However, in all four T-ALL patients, WT1 expression at diagnosis was above
the median for healthy controls (ITP) by more than three times the standard deviation.
The same was true for four of 16 B-ALL patients (25%). Data on WT1 expression on
control examination one month after diagnosis were obtained for 15 children. Just two
of the five children who, a month after diagnosis, had WT1 expression in the fourth
quartile were alive at the time of writing, while all children (10 of 10) with WT1
expression below the fourth quartile survived. This rather conspicuous difference was
still not statistically significant on Fisher’s exact probability test (p=0,0952), which can
probably also be explained by the small number of subjects.
Using indirect fluorescence and flow cytometry, WT1 protein was detected at
diagnosis in leukemic cells in 16 patients with AML and four patients with T-ALL.
However, it was not detected in any B-ALL patients. None of the samples from control
bone marrow investigations during treatment had a detectable level of WT1 protein by
flow cytometry.
Taken as a whole, the results of this study support the conclusion that routine
WT1 expression testing could be a useful addition to the existing diagnostic protocols
for childhood AML, T-cell ALL and a subset of patients with B-ALL. Our results also
emphasize the importance of interpreting WT1 expression data in children with
leukemia within a complex and highly individualized context. | true |
Ispitivanje efekta akutne hiperglikemije na funkciju miokarda u pacijenata sa dijabetesom | Assessment of effect of acute hyperglycemia on myiocardial function in patients with diabetes | Akutna hiperglikemija se može javiti kod osoba sa ranije dijagnostikovanom
šećernom bolesti ili poremećenim metabolizmom glukoze. Prva klinička manifestacija
nedijagnostikovane šećerne bolesti može biti elevacija nivoa glukoze u krvi. Akutna
hiperglikemija se najčešće definiše kao koncentracija glukoze u krvi veća od 10.0
mmol/l ili 11.0 mmol/l pri prijemu. Poslednjih godina, razvijena je nova
dvodimenzionalna tehnika tzv. speckle tracking ehokardiografija (2D-STE) koja
omogućava procenu regionalne deformacije u tri pravca i to: longitudinalnom,
radijalnom i cirkumferentnom. Njenom primenom moguća je kvantifikacija globalne i
regionalne sistolne i dijastolne funkcije miokarda. Velika prednost ove tehnike u odnosu
na druge tehnike snimanja je u tome što ona omogućava praćenje i prikaz deformacije
miokarda kroz njegove različite slojeve (subendokardni, srednji i subepikardni sloj).
Cilj ovog istraživanja je bio da se ispita efekat akutne hiperglikemije na ultrazvučne
karakteristike miokardne funkcije i da se utvrdi stepen i reverzibilnosti uočenih
miokardnih promena u asimptomatskih bolesnika sa dijabetesom i očuvanom
ejekcionom frakcijom.
Metode: U istraživanje je uključeno ukupno 67 bolesnika sa dijabetesom tip 1 i tip 2
(grupa A) sa akutnom hiperglikemijom. Pacijenti koji su uključeni u ovu studiju
pažljivo su odabrani od pacijenata primljenih u jedinicu intenzivnog lečenja prema
sledećim kriterijumima uključivanja: 1) pacijenti sa poznatim i novootkrivenim DM sa
akutnom hiperglikemijom na prijemu (glukoza u krvi ≥11,1 mmol/l); 2) bez prethodno
poznatih ili novodijagnostikovanih kardiovaskularnih bolesti (KVB) (uključujući i
hipertenziju); 3) bez poznatih ili tek dijagnostikovanih mikro- i makrovaskularnih
komplikacija dijabetesa. Iz istraživanja su isključeni pacijenti mlađi od 18 godina ili
stariji od 65 godina, s nestabilnom anginom pektoris, AIM, srčanom insuficijencijom,
atrijalnom fibrilacijom ili nepravilnim ritmom na EKG-u, malignim bolestima,
obstruktivnom bolesti pluća, insuficijencijom jetre ili bubrega, sa akutnim/hroničnim
infekcijama, ketoacidozom, lečeni kortikosteroidima ili imunosupresivnim lekovima.
Određene su dve kontrolne grupe: 1) grupa B koja se sastojala od pažljivo odabranih
bolesnika sa dijabetesom koji su, u vreme uključivanja u studiju, imali zadovoljavajuću
metaboličku kontrolu (HbA1c≤7,0%, glukoza u plazmi <7 mmol/l) bez poznatih ili tek
dijagnostikovanih mikro- i makrovaskularnih komplikacija; 2) grupa C koja se sastojala
od zdravih dobrovoljaca. Svi bolesnici su bili podvrgnuti istim terapijskim merama do
uspostavljanja euglikemije (tretirani brzodelujućim insulinom u kontinuiranoj infuziji
pomoću pumpe). Svim ispitanicima su urađene biohemijske analize i ehokardiografski
pregled (aparat Vivid e9 (General Electric)). Snimci su analizirani naknadno (GE
EchoPAC, verzija 113), a korišćene su standardne ehokardiografske metode M-mode,
2D, kolor, pulsni, kontinuirani doppler, zatim tkivni dopler i 2D specle tracking. U
analizu su ušli parametri sistolne i dijastolne funkcije i miokardne mehanike. 2D-STE je
korišćen za procenu globalne i regionalne funkcije leve komore. U grupi A, posle 72 h
i.v. kontinuiranog lečenja insulinom (u vreme kada je postignuta euglikemija) (drugi
pregled) i nakon 3 meseca posle akutne hiperglikemije (treći pregled) sve analize su
ponovljene.
Rezultati: Globalni longitudinalni strain (GLS) u grupi A bio je značajno manji u
odnosu na obe kontrolne grupe na prijemu u bolnicu, dok nije bilo razlike između grupa
B i C. Peak sistolni longitudinalni strain u endokardu (Endo), srednjem sloju miokarda
(Mid) i epikardu (Epi) je bio značajno niži u grupi A u odnosu na obe grupe B i C.
Pogoršanje u peak sistolnom cirkumferentnom strain-u uočeno je na bazalnom nivou
leve komore u sva tri sloja (Endo, Mid i Epi) i na nivou papilarnog mišića u Epi sloju u
grupi A u poređenju sa grupom C. Uočen nepovoljan efekat akutne hiperglikemije na
sistolnu funkciju miokarda u asimptomatskih dijabetesnih bolesnika održava se i 3
meseca nakon uspostavljanja optimalne glikoregulacije.
Zaključak: Akutna hiperglikemija u asimptomatskih bolesnika sa dijabetesom i
očuvanom ejekcionom frakcijom ima značajne negativne učinke na sistolnu mehaniku
miokarda leve komore prvenstveno smanjenjem globalnog longitudinalnog strain-a,
peak sistolnog longitudinalnog strain-a (na Endo, Mid i Epi slojevima) i peak
cirkumferentnog strain-a (na sva tri sloja na bazi leve komore). Opažene promene u
sistolnoj funkciji leve komore nisu bile reverzibilne ni nakon kratkotrajnog (72h), ali ni
nakon dugotrajnog (3 meseca) uspostavljanja i održavanja dobre metaboličke kontrole
dijabetesa. | Acute hyperglycemia has also been documented to occur in people with
previously diagnosed diabetes or impaired glucose metabolism. The first clinical
manifestation of undiagnosed diabetes can be increased blood glucose levels. Acute
hyperglycemia is generally defined as blood glucose concentration greater than 10,0
mmol/l or >11,0 mmol/l upon admission in hospital. Over the past couple of years, a
new two-dimensional speckle tracking echocardiography (2D-STE), has been developed
that enables assessment of regional deformation in three directions: longitudinal; radial;
and circumferential. With the use of this technique it is possible to both measure
myocardial function parameters, and quantify global and regional systolic and diastolic
myocardial function. The great advantage of this technique compared to other imaging
techniques lies in the fact that it allows one to track and display myocardial deformation
through its’ different layers (subendocardial; middle; and subepicardial).
The aim of these study was to examine the effect of acute hyperglycemia on ultrasound
characteristics of myocardial function and to determine the degree and reversibility of
observed myocardial changes detected in asymptomatic patients with diabetes and
preserved ejection fraction
Methods: A total of 67 patients with diabetes type 1 and type 2 (Group A), and acute
hyperglycemia were included in this study. Patients included in this study were
carefully selected from patients admitted to Intensive Care Unit (ICU) according to the
following inclusion criteria: (1) patients with previously known diabetes or newly onset
diabetes with acute hyperglycemia upon admission (blood glucose ≥11mmol/l ); (2) free
of previously known or newly diagnosed cardiovascular diseases CVD (including
hypertension); (3) free of known or newly diagnosed micro and macrovascular diabetic
complications. Those patients younger than 18 or older than 65 years of age, with
unstable angina pectoris, AMI, heart failure, atrial fibrillation or irregular rhythm on
ECG, malignant diseases, obstructive pulmonary disease, hepatic or renal failure, acute
or chronic infections, ketoacidosis, treated with corticosteroids or immunosuppressive
agents were excluded from the study. Two control groups were identified: (1) Group B
consisting of carefully selected patients with diabetes who had optimal metabolic
control at the time of inclusion in the study (HbA1c≤7,0%, plasma glucose <7mmol/l)
without any known or newly diagnosed micro- and macrovascular diabetic
complications; (2) Group C consisting of healthy volunteers. All patients were
subjected to the same treatment measures untill euglycemia was established (treated
with fast-acting insulin in continuous insulin infusion pump). Biochemical analyses as
well as echocardiographic examination (Vivid E9, General Electric) was performed for
all patients. All patients were subjected to examined and 2D-STE (Vivid E9, General
Electric) as well as: M-mode, 2D, colour, pulsed, continuous Doppler; followed by
tissue Doppler and 2D speckle tracking, was performed and data analyzed
retrospectively (GE EchoPAC, version 113). Parameters of systolic and diastolic
function and myocardial mechanics were examined. 2D-STE was used to assess the
global and regional function of the left ventricle. In group A, after 72 h of i.v.
continuous insulin treatment (at the time euglycemia was achieved) (second
examination) and after 3 months following acute hyperglycemia (third examination) all
analyses was repeated.
Results: Global longitudinal strain (GLS) (− 19.6 ± 0.4%) in Group A was significantly
lower in comparison to both groups B (− 21.3 ± 0.4%; p < 0.05) and C (− 21.9 ± 0.4%;
p < 0.01) at baseline, while we could not detect the differences between groups B and C.
Peak systolic longitudinal endocardial (Endo), mid-myocardial (Mid) and epicardial
(Epi) layer strain were significantly lower in group A at baseline compared to both
groups B and C. Deterioration in peak systolic circumferential strain was observed at
basal LV level, in all three layers (Endo, Mid and Epi) and in mid-cavity LV level in
Epi layer in group A in comparison to group C. Moreover, in group A, after euglycemia
was achieved (at second and third examination) GLS, as well as peak longitudinal and
circumferential strain remain the same. observed changes in systolic LV functions was
not reversible after three months of good glycemic control.
Conclusion: Acute hyperglycemia in asymptomatic diabetic patients has significant
negative effects on systolic LV myocardial mechanics primarily by reducing GLS and
multilayer peak systolic longitudinal and circumferential strain which was not reversible
after three months of good glycemic control. | true |
Parametri radikalnosti kod laparoskopske i otvorene hirurgije karcinoma kolona i rektuma | Parameters of radical resection in laparoscopic and open colon and rectal cancer surgery | Veliki broj epidemioloških ispitivanja na svetskom nivou pokazala su da kolorektalni
karcinom predstavlja jedan od najčešćih oblika maligniteta ljudske populacije u svim
razvijenim zemljama sa zabrinjavajućim trendom porasta učestalosti koji podjednako zahvata
oba pola. Rezultati pokazuju da je kolorektalni karcinom u Srbiji drugi vodeći uzrok umiranja
(iza raka pluća) u muškoj, a treći (iza raka dojke i raka grlića materice) u ženskoj populaciji.
Hirurška resekcija i dalje predstavlja primarni vid lečenja obolelih od kolorektalnog
karcinoma. Resekcija kod karcinoma kolona i rektuma se smatra radikalnom kada su
proksimalna, distalna i radijalna linija resekcije bez prisustva tumorskih ćelija. Koncept
totalne mezorektalne ekscizije podrazumeva kompletno uklanjanje tumora unutar fascijalnog
omotača zajedno sa limfnim čvorovima, limfaticima i krvnim sudovima duž kojih tumor može
da se širi. Nekoliko randomizovanih multicentričnih studija pokazalo je da nema značajne
razlike između laparoskopske i otvorene hirurgije kolona kada se govori o parametrima
radikalnosti.
Cilj: Utvrditi da li se laparoskopskim pristupom obezbeđuju svi parametri onkološke
radikalnosti kao i u otvorenoj hirurgiji karcinoma kolona i rektuma.
Metod: U studiju su bila uključena 122 pacijenta sa karcinomom kolona i rektuma. Pacijenti
su podeljeni u dve jednake grupe, operisane laparoskopskim i otvorenim pristupom. U
hirurgiji kolona analizirali smo proksimalnu, distalnu resekcionu liniju i broj uklonjenih
limfnih žlezda. U hirurgiji rektuma: proksimalnu, distalnu i cirkumferentnu resekcionu liniju,
i broj uklonjenih limfnih žlezda. Takođe, u analizu su bili uključeni i sledeći parametri:
procenat konverzije u otvorenu proceduru, trajanje hospitalizacije, postoperativni morbiditet i
mortalitet.
Rezultati: Obe grupe su bile jednake u odnosu na uzrast, pol, ASA rezultat, lokalizaciju,
veličinu tumora, i vrstu operativnog zahvata. Prema lokalizaciji tumora, najčešće izvedena
operacija bila je prednja resekcija rektuma (60,7% u odnosu na 59%). Nije bilo slučajeva sa
pozitivnom distalnom linijom resekcije. U hirurgiji kolona, prosečna vrednost proksimalne
resekcione linije statistički je bila značajno veća kod otvorene u odnosu na laparoskopsku
hirurgiju (120 mm naprema 100 mm, p=0,047), što je identičan slučaj i u hirurgiji rektuma
(130 mm naprema 97,5 mm, p=0,004). Kada posmatramo distalnu resekcionu liniju, kod
pacijenata sa resekcijom kolona prosečna vrednost je bila takođe značajno veća kod otvorene
hirurgije u odnosu na laparoskopsku (120 mm naprema 60 mm, p=0,003), dok u grupi
pacijenata sa resekcijom rektuma nije bilo statistički značajne razlike u dužini distalne
resekcione linije (31 mm naprema 25 mm, p=0,110). Imali smo u dva slučaja pozitivnu
cirkumferentnu resekcionu liniju (CRM) u laparoskopskoj grupi (7,7%), a u tri slučaja u grupi
operisanih otvorenom metodom (8,8%). Prosečan broj uklonjenih limfnih čvorova bio je 15
naspram 16. Dužina boravka u bolnici kod pacijenata operisanih laparoskopskim pristupom
bila je kraća što je bilo veoma statistički značajno. U pogledu postoperativnih komplikacija,
nije utvrđena značajna razlika. Ukupni postoperativni morbiditet je bio 18% naspram 21,3%.
Zaključak: Laparoskopskim pristupom je moguće obezbediti sve parametre onkološke
radikalnosti kao i u otvorenoj hirurgiji karcinoma kolona i rektuma. | A large number of epidemiological studies on the world have shown that
colorectal cancer is one of the most common malignancies in the human population in all
developed countries with a worrying trend of increasing frequency that equally affects both
sexes. The results show that colorectal carcinoma in Serbia is the second leading cause of
death (behind lung cancer) in males, and the third (behind breast cancer and cervical cancer)
in the female population. Surgical resection is still primary treatment for patients with
colorectal cancer. In colon and rectal cancer surgery, resection is considered radical when
circumferential, proximal and distal resection margin is without the presence of tumor cells.
Concept of total mesorectal excision in rectal surgery involves complete removal of tumor
with mesorectal fascia which surrounds lymph nodes, lymphatics, and blood vessels. Several
randomized multicenter studies have shown that there is no significant difference between
laparoscopic and open colon surgery when discussing parameters of radicality.
Objective: To determine whether laparoscopic approach provides all parameters of
oncological radicality as open surgery of colorectal cancer.
Method: The study included 122 patients with carcinoma of colon and rectum, divided into
two equal groups, operated by laparoscopic and open approach. In colon surgery we analyzed
proximal, distal resection margin, and the number of removed lymph nodes. In rectal surgery:
proximal, distal and circumferential resection margins, and the number of removed lymph
nodes. In the analysis we also included the following parameters: conversion rate, length of
hospital stay, postoperative morbidity and mortality.
Results: Both groups were comparable in age, sex, ASA score, tumor localization, tumor size,
and type of surgical operation performed. According to localization of the tumor, the most
commonly performed operation was anterior resection of the rectum (60.7% versus 59%).
There was no case of tumor involvement of the distal margin. In colon surgery, the mean
value of the proximal resection line was statistically significantly higher in open versus
laparoscopic surgery (120 mm for 100 mm, p = 0.047), which is identical in the case of
rectum surgery (130 mm to 97.5 mm, p = 0.004). In patients with colon resection, the mean
value of distal resection line was also significantly higher in open surgery compared to
laparoscopic (120 mm for 60 mm, p = 0.003), while in the group of patients with rectal
resection there was no statistically significant difference in length of distal resection line (31
mm to 25 mm, p = 0.110). In two cases we had circumferential resection margin (CRM) of
1mm (7.7%) in laparoscopic group, and in three cases operated conventionally CRM was
1mm (8.8%). The average number of removed lymph nodes was 15 versus 16. Length of
hospital stay for patients assigned to the laparoscopic surgery was shorter with high statistical
significance. Concerning postoperative complications, no significant difference was found.
The overall postoperative morbidity was 18% vs 21.3%.
Conclusion: With laparoscopic approach it is possible to provide all parameters of oncological
radicality as well as in open surgery of colorectal cancer. | true |
Maternalni i perinatalni ishodi trudnoća nastalih vantelesnom oplodnjom kod žena starijeg životnog doba | Maternal and perinatal outcomes of pregnancies of patients with advanced maternal age resulted from IVF procedures | U životu modernih žena primećen je rastući trend ka odlaganju rađanja, tako da je evidentan sve
veći broj žena u odmakloj životnoj dobi koje pokušavaju da ostvare trudnoću (1). Usled
navedenog, metode vantelesne oplodnje (VTO), doživele su ekspanziju (8). koje nude priliku
velikom broju parova da se ostvare u ulozi roditelja. Mogućnosti koje nudi savremena medicina
povezane su i sa potencijalnim rizicima kako po majku, tako i po plod odnosno dete (10). Kada su
u pitanju majke, rizici proističu iz interakcije stresogenih činilaca koje trudnoća uopšteno nosi i
osobenosti pozne životne dobi majki po sebi. Iako je proučavanje povezanosti asistiranih
reproduktivnih tehnologija sa zdravljem majke i njenog potomstva predmet retrospektivnih studija
još od prve bebe nastale ovom metodom 1978. godine (34) dobijeni rezultati se odlikuju izvesnim
stepenom nekonzistentnosti, pa i protivurečnosti. Najveća razlikovanja su dobijena prilikom
poređenja različitih zajednica i etniciteta, što čini veoma značajnim pokretanje studije ovog tipa
na nacionalnom nivou.
Materijal i metode
Sprovedena je kohortna studija u koju su uključene sve trudnice starije od 40 godina koje su u toku
trudnoće bile hospitalizovane na Ginekološko-akušerskoj klinici „Narodni front“ u Beogradu, u
periodu od 01. januara 2007. godine do 31. decembra 2015. godine. Jednu kohortu činile su
trudnice kod kojih je uradjena IVF procedura, a drugu, kontrolnu kohortu one kod kojih je trudnoća
ostvarena prirodnim putem.
Rezultati
U studiju je uključeno ukupno 672 pacijentkinje, od čega su ispitivanu grupu činile 372
pacijentkinje, a kontrolnu 300 pacijentkinja koje su ostvarile trudnoću prirodnim putem. Pokazano
je da su hronična oboljenja pre trudnoće (hipitireoza, dijabetes mellitus tip II), kao poremećaji
zdravlja tokom trudnoće (gestacijska hipertenzija, GDM, placenta previa) značajno češći kod
pacijentkinja koje su trudnoću ostvarile vantelesnom oplodnjom. Takođe, višeplodne trudnoće
češće su u ispitivanoj grupi, kao i operativno završavanje trudnoće (94,4% pacijentkinja), za
razliku od kontrolne grupe gde je carskim rezom porođeno 52% pacijentkinja. Deca rođena iz
trudnoća koje su nastale vantelesnom oplodnjom imaju lošiji ishod na rođenju, odnosnu manju
APGAR ocenu težinu. Takođe, u ispitivanoj grupi zabeleženo je više slučajeva urođenih anomalija
novorđenčadi, kao i veći broj prevremeno rođenih beba.
Zaključak
Trudnoće ostvarene procesom vantelesne oplodnje kod žena uznapredovale životne dobi nose
znatno veću stopu rizika za maternalni i fetalni mortalitet i morbiditet. | In the life of modern women it is noticed a growing trend of postponing childbearing (1). Due to
the fact mentioned above, the In Vitro Fertilization (IVF), has experienced an expansion (8).
offering the opportunity to a large number of couples to acomplish the parental role. The
possibilities offered by modern medicine are associated with potential risks both for mother and
for the fetus or a child (10). As for the mothers, the risks arising from the interaction of stressful
factors that generally carries the pregnancy and characteristics of late maternal age itself. Although
the study of the relationship between assisted reproductive technology, health of the mother and
her offspring is the subject to retrospective studies since the first baby resulting from this method
in 1978 (34). The results obtained are characterized by a degree of inconsistency and even
contradictions. The biggest distinction are obtained when comparing different communities and
ethnicity, which makes it very important performing this type of study on a national level.
Method
We performed a cohort study in which we have included all pregnant women older than 40, who
were hospitalized in Gynecology and Obstetrics Clinic “Narodni front”, Belgrade since January
1st 2007 to December 31st 2015. Study cohort consisted of patients who underwent ART
procedure, and the control group was formed of patients who have accomplished ther pregnancy
naturally.
Results
The study included a total of 672 patients , of which study group consisted of 372 patients and
the control group of 300 patients who achieved pregnancy naturally. It has been shown that
chronic diseases before pregnancy ( hipitireoza , diabetes mellitus type II ) , as well as health
disorders during pregnancy (gestational hypertension, GDM , placenta previa ) were significantly
more common in patients who have achieved pregnancy by in vitro fertilization . Furthermore,
multiple pregnancies are more common in the study group , as well as the Cesarean Section (
94.4 % patients ) , in contrast to the control group where the rate of Caesarean section was 52 %.
Newborns which were born from pregnancies that were achived by in vitro fertilization have
worse outcomes at birth and lower APGAR score . Also , in the study group there were several
cases of congenital anomalies, and a large number of premature babies.
Conclusions
Pregnancies achieved by in vitro fertilization process in women with advanced maternal age are
at the higher risk of maternal and fetal mortality and morbidity | true |
Povezanost polimorfizama i ekspresije glutation transferaza klase omega sa nastankom i progresijom karcinoma prelaznog epitela mokraćne bešike | Polymorphisms and expression of glutathione transferase omega in development and progression of urinary bladder transitional cell carcinoma | Cilj: Cilj ove studije je bio da se razjasni uloga genskog polimorfizma GSTO1
(rs4925) i GSTO2 (rs156697) u individualnoj podložnosti za nastanak karcinoma
prelaznog epitela mokraćne bešike, zajedno sa njihovim modifikujućim efektom na
ukupno preživljavanje i/ili hemoterapiju kod ovih bolesnika. Takođe je ispitivana
i ekspresija GSTO1-1 u tumorskom i okolnom morfološki neizmenjenom epitelu
bolesnika sa karcinomom prelaznog epitela mokraćne bešike.
Materijal i metode: Polimorfizam GSTO1 i GSTO2 je određivan analizom
proizvoda restrikcione digestije DNK fragmenata nastalih reakcijom lančanog
umnožavanja (PCR-RFLP). Prediktivna vrednost različitih GSTO genotipova je
procenjivana Koksovim regresionim hazardnim modelima, dok su Kaplan-Majerove
krive korišćene za za prikazivanje verovatnoće ispitivanih događaja, a log-rank test
za utvrđivanje razlika u verovatnoći preživljavanja. GSTO1-1 ekspresija je
određivana metodom Vestern blota i reakcijom lančanog umnožavanja u realnom
vremenu (RT-PCR), dok je za ispitivanje ukupne S-glutationilacije izvedena
elektroforeza pod neredukujućim uslovima. Koncentracija ukupnog i oksidovanog
glutationa je određena spektrofotometrijski. Koncentracija interleukina-8 (IL-8)
u citosolu i urinarni 8-hidroksi-2′-deoksiguanozin (8-OHdG) su određeni metodom
enzimskog imunoeseja.
Rezultati: Nosioci varijantnog GSTO2*G/G genotipa su bili pod povećanim
rizikom za nastanak karcinoma prelaznog epitela mokraćne bešike (OR=2,6, 95%
CI=1,2-5,8, p=0,041), koji je bio još izraženiji kada je ovaj genotip bio udružen sa
pušenjem (OR-odds ratio =4,3, 95%CI-confidence interval =1,6-11,2, p=0,003). Dalje,
dobijeni rezultati ukazuju da su nosioci haplotipa GSTO1*C/GSTO2*G (GSTO1
referentni alel/GSTO2 varijantni alel) pod najvećim rizikom za nastanak
karcinoma mokraćne bešike (OR=2,8, 95%CI=1,5-5,2, p=0,002). Mada je koncentracija
urinarnog 8-OHdG kod pacijenata sa karcinomom prelaznog epitela bila znatno viša
u odnosu na kontrole, nije uočen efekat udruženog GSTO1/GSTO2 genotipa na stepen
oksidativnog oštećenja DNK. Pokazano je da su varijantni, GSTO1*A/A ili
GSTO2*G/G genotipovi bili nezavisni prediktori ukupnog rizika za smrtni ishod
kod bolesnika sa karcinomom mokraćne bešike (HR-hazard ratio =2,9, p=0,022;
HR=3,9, p=0,001) i značajno su uticali na ukupno preživljavanje ovih bolesnika. S
druge strane, značajan uticaj na preživljavanje pacijenta koji su primali
hemoterapiju je pokazan jedino za GSTO2 polimorfizam (p=0,006). Sadržaj
redukovanog glutationa, zajedno sa GSTO1-1 aktivnošću i ekspresijom je bio
statistički značajno viši u tumorskom tkivu u odnosu na okolni neizmenjeni
uroepitelijum. Posmatrajući GSTO1-1 tioltransferaznu aktivnost, kao i
koncentraciju citosolnog IL-8, uočena je jasna korelacija sa gradusom i stadijumom
tumora. Nasuprot tome, ukupna proteinska glutationilacija je bila intenzivnija u
netumorskom u odnosu na tumorsko tkivo.
Zaključci: Rezultati ukazuju da je GSTO1*C/GSTO2*G haplotip povezan sa
povećanim rizikom za nastanak karcinoma mokraćne bešike, a najizraženiji je kod
pušača, nosilaca varijantnog GSTO2*G/G genotipa. Pored toga, funkcionalni
GSTO1 i GSTO2 polimorfizmi mogu imati prognostičku i/ili farmakogenomsku
ulogu kod bolesnika sa invazivnim karcinomom prelaznog epitela mokraćne bešike.
Novootkrivena deglutationilišuća aktivnost GSTO1-1 ukazuje da povećana
aktivnost ovog enzima može imati važnu ulogu u poremećaju redoks ravnoteže u
karcinomu prelaznog epitela, kao i u progresiji bolesti. | Purpose: The aim of the study was to clarify the role of GSTO1 (rs4925) and GSTO2
(rs156697) genetic polymorphisms in individual susceptibility to transitional cell carcinoma
(TCC) of urinary bladder, together with their modifying effect on the overall survival and/or
chemotherapy treatment in these patients. We also examined the GSTO1 expression pattern
in tumor and non-tumor tissue of TCC patients.
Methods: GSTO1 and GSTO2 genotyping was performed by polymerase chain reaction–
restriction fragment length polymorphism (PCR-RFLP). The effect of GSTOs
polymorphisms on predicting mortality was analyzed by the Cox proportional hazard models,
while Kaplan-Meier curves with log-rank tests were used to assess differences in survival
probability. GSTO1-1 expression was determined by Western blot and real time-PCR, while
for the total S-glutathionylation electrophoresis under non-reducing conditions was
performed. The total and oxidized glutathione content was measured by an enzymatic
recycling method. Tumor cytosolic interleukin-8 (IL-8) and urine 8-hydroxy-2′-
deoxyguanosine (8-OHdG) concentrations were estimated by enzyme-linked immunosorbent
assay (ELISA).
Results: Carriers of the variant GSTO2*G/G genotype were at increased risk of TCC
development (OR-odds ratio =2.6, 95% CI-confidence interval =1.2-5.8, p=0.041), which
was more pronounced, when associated with smoking (OR=4.3, 95%CI=1.6-11.2, p=0.003).
Furthermore, these results indicate that GSTO1*C/GSTO2*G (GSTO1 wild type/GSTO2
variant) haplotype carriers were at the highest risk for the TCC development (OR=2.8,
95%CI=1.5-5.2, p=0.002). Although urinary 8-OHdG in TCC patients was significantly
higher than in controls, the effect of combined GSTO1/GSTO2 genotype on the extent of
oxidative damage was not found. GSTO1*A/A or GSTO2*G/G variant genotypes were
independent predictors of the higher risk of death among TCC patients (HR-hazard ratio =2.9,
p=0.022; HR=3.9, p=0.001; respectively) and significantly influenced the overall survival.
Only GSTO2 polymorphism showed a significant effect on the survival in the subgroup of
patients who received chemotherapy (p=0.006). The content of reduced glutathione, together
with GSTO1-1 activity and expression were significantly higher in tumor compared to
surrounding non-tumor TCC tissue. Moreover, GSTO1 thioltransferase activity, as well as
cytosolic IL-8 showed clear correlation with tumor grade and stage. In contrast, total protein
glutathionylation was more intense in non-tumor in comparison with the corresponding
tumor samples.
Conclusions: These results indicate that GSTO1*C/GSTO2*G haplotype is associated with
increased TCC risk, which is more pronounced in smokers carriers of variant GSTO2*G/G.
Furthermore,
GSTO1*A/A
and
GSTO2*G/G
genotypes
may
have
a
prognostic/pharmacogenomic role in patients with muscle invasive TCC. Newly discovered
deglutathionylase activity of GSTO1-1 suggests its potential important role in redox
perturbations present in TCC, which might contribute to progression of TCC. | true |
Komparativni efekti muzičkih festivala na lokalnu zajednicu i turizam EXIT versus SZIGET | Komparativni efekti muzičkih festivala na lokalnu zajednicu i turizam EXIT versus SZIGET | Po istraživanju Turističke organizacije Srbije (TOS) događaji su prvi na listi
turističkih motiva za dolazak stranih turista u našu zemlju. Manifestacioni
turizam je zbog toga istaknut u „Strategiji razvoja turizma Srbije“ kao veoma
značajan segment razvoja turizma u Srbiji, ali i kao komparativna prednost domaćeg
turizma. Prema podacima Turističke organizacije Vojvodine, u Vojvodini se
godišnje održi 1382 manifestacije. Jedna od najvažnijih manifestacija je EXIT
festival koji se već 15 godina održava u Novom Sadu. Ovaj festival je uvršten u 10
najboljih evropskih festivala. Marketing strategija Vojvodine predlaže da se u
razvoju turizma sledi primer Mađarske. U Mađarskoj se u toku godine održi više
od 3000 festivala koji privlače 18-20 miliona posetilaca iz Mađarske i
inostranstva, što govori o značaju koji turizam događaja ima na turizam Mađarske.
Budimpešta je glavni grad Republike Mađarske. Nalazi se na 300 km od Novog Sada
i izuzetno je posećena turistička destinacija. Jedan od značajnijih turističkih
događaja u Budimpešti je muzički festival SZIGET, koji okuplja veliki broj
izvođača i posetioce iz preko 70 različitih zemalja, čime doprinosi pozitivnom
imidžu Budimpešte na turističkoj mapi Evrope.
Lokalno stanovništvo je bitan stejkholder u razvoju turističe destinacije. U vezi
sa određenim područjem i životnom sredinom, ima mnogo bolji osećaj za to šta su
realne potrebe tog područja, kao i jasniju viziju budućeg razvoja, nego centralna
uprava. Zbog navedenog je potrebno uključiti vizije, želje i potrebe, potencijale i
entuzijazam lokalne zajednice u planove za budući razvoj.
S obzirom da je vrlo malo istraživanja o efektima muzičkih festivala na lokalnu
zajednicu naših prostora, anketirani su stanovnici Novog Sada i Budimpešte, o
efektima koje EXIT i SZIGET festivali ostvaruju, primenom modifikovane FSIAS
skale. Sakupljeno je ukupno 505 validnih upitnika koji su dalje korišćeni u
statističkim analizama. Primenom eksplorativne faktorske analize utvrđena je
dvofaktorska struktura modifikovane FSIAS skale, a faktori su imenovani na
sledeći način: F1 pozitivni efekti - društvene koristi i F2 negativni efekti -
društveni troškovi festivala.
Istraživanjem se došlo do saznanja da lokalno stanovništvo Novog Sada i
Budimpešte više percipira pozitivne nego negativne efekte festivala na lokalnu
zajednicu, pri čemu ispitanici iz Novog Sada obe grupe efekata ocenjuju višim
prosečnim ocenama u odnosu na ispitanike iz Budimpešte. Takođe, istraživanjem je
potvrđeno da festivali doprinose razvoju turizma, promociji i imidžu destinacije.
Utvrđeno je koje su i jake tačke oba festivala, a na koje stavke bi menadžmet trebao
više uticati kako bi se pozitivni efekti multiplikovali, kao i koji efekti mogu
biti zanemareni po mišljenju lokalnog stanovništva, a da festival ne gubi na
kvalitetu.
Socijalni uticaji na lokalnu zajednicu nisu univerzalni, ono što ima važan uticaj
u jednoj zajednici može imati zanemarljiv uticaj u drugoj zajednici. | According to Tourist Organization of Serbia (TOS) research events are the first motive for
arrival of foreign tourists in our country. Event tourism is therefore one of the pillars in
„Tourism Development Strategy of Serbia" as a very important segment, as a comparative
advantage of domestic tourism. According to Tourist Organization of Vojvodina, 1382
Александра Продановић Стаменовић Докторска дисертација
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Компаративни ефекти музичких фестивала на локалне заједнице и туризам - EXIT versus SZIGET
248
events are annually held in Vojvodina. One of the most important manifestations is the
EXIT festival, held in Novi Sad for 15 years. This festival has been listed as one of the top
10 European festivals. In development of tourism Marketing Strategy of Vojvodina suggests
following the example of Hungary. In period of one year more than 3000 festivals are held
in Hungary which are attracting 18-20 million of visitors from Hungary and abroad, that fact
indicates importance of events in Hungarian tourism. Budapest is the capital of Republic of
Hungary. It is 300 km away from Novi Sad and it is highly visited tourist destination. One
of the most important tourism events in Budapest is Sziget music festival, which gathers a
large number of performers and visitors from more than 70 different countries. Therefore
Sziget festival is contributing to the positive image of Budapest on European tourist map.
Local population is an important stakeholder in development of tourist destinations. In
relation to specific area and environment local population can have better sense of what are
real needs, what is more sustainable and can gain more benefit in future development, than
the central government. As result it is necessary to include vision, desires and needs,
potentials and enthusiasm of local community in plans for future development.
As there are no studies on effects of music festivals on local community in our area, this
scientific research investigated local population perception on effects of music festivals. The
survey about effects of Exit and Sziget festival sampled residents from Novi Sad and
Budapest. Appropriate sampling collected total of 505 valid surveys that are used in
statistical analysis. Modified FSIAS scale showed positive and negative effects of festival
and what significance these effects have on local community.
The results of the study show that local population from Novi Sad and Budapest perceives
more positive effects from festivals than negative effects. Respondents from Novi Sad gave
higher average grades for both groups of effects. Also, the results confirmed that festivals
contibute to tourism development, promotion and image of destination.
Strong points or strengths of both festivals were determined as well as areas that should be
more influenced by management so positive effects could be multiplied. Also low priority
or possible overkill points are defined and can be ignored, as they are not influencing
quality of festival.
Social impacts on local community are not universal, those that have important impact on
one community may have a negligible effect on the other. | true |
Kliničke, genetske i morfološke karakteristike bolesnika sa demencijom ranog početka | Clinical, genetic and morphological features of early onset dementia | Alzheimerova bolest (AB) i frontotemporalna demencija (FTD) predstavljaju dve najčešće forme degenerativnih demencija ranog početka (DRP). DRP se definiše kao demencija čiji kognitivni i/ili bihejvioralni simptomi počinju pre 65. godine života. Uprkos značajnom napretku na polju neuropsihologije, neuroimidžinga, genetike, biomarkera iz cerebrospinalne tečnosti, DRP je još uvek nedovoljno prepoznat entitet čija se konačna dijagnoza često pogrešno ili prekasno postavlja predstavljajući izazov kliničarima čak i u tercijarnim centrima. Novija istraživanja ukazuju na veliku kliničku heterogenost, značajan procenat atipičnih prezentacija na početku bolesti (bihejvioralni simptomi, depresija, psihotični simptomi ili neamnestički kognitivni deficiti), ali i preklapanje simptoma u okviru pojedinih entiteta spektra AB i FTD ranog početka čime se problem dijagnoze i diferencijalne dijagnoze degenerativnih DRP značajno komplikuje. Stoga, pored dobrog poznavanja kliničkih, neuropsiholoških i psihijatrijskih razlika koje proizilaze iz prirodnog toka AB i FTD, savremeni dijagnostički algoritmi teže ka uvođenju sofisticiranih, novih dijagnostičkih procedura kojima će se ubrzati postavljanje adekvatne dijagnoze, definisati subtipovi bolesti, pratiti progresija bolesti i efikasnost terapijskih tretmana. Ciljevi. Osnovni ciljevi studije su: a) ispitivanje heterogenosti kliničkog, kognitivnog i neuropsihijatrijskog ispoljavanja spektra AB i FTD ranog početka (ABrp) i (FTDrp); b) ispitivanje učestalosti različitih izoformi apolipoproteina E (APOE) u spektru ABrp i FTDrp; c) ispitivanje obrasca nasleđivanja i mutacija u genima za amiloidni prekusorski protein (APP), presenilin 1 (PSEN1), progranulin (GRN), tau protein (MAPT), chromosome 9 open reading frame 72 (C9ORF72) u spektru ABrp; d) ispitivanje obrasca nasleđivanja i mutacija u genima za GRN, MAPT, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG) u spektru FTDrp; e) ispitivanje učestalosti heksanukleotidne ekspanzije u C9ORF72 genu u grupi konsekutivnih bolesnika sa degenerativnom DRP (ABrp, FTDrp, DLT); f) ispitivanje morfoloških specifičnosti mozga multimodalnim metodama magnetne rezonance (MR) u bolesnika sa amnestičkom ABrp i bihejvioralnom varijantom FTD Metode. U studiju je uključeno 207 bolesnika kojima je u periodu od 01.04.2012. do 01.04.2017. godine na Klinici za neurologiju KCS postavljena dijagnoza na osnovu važećih kriterijuma za spektar AB i FTD kao i 3 bolesnika sa DLT (za potrebe genetske pilot studije). Istraživanje jednim delom predstavlja studiju slučajeva i kontrola, a drugim delom studiju preseka. U okviru spektra ABrp i FTDrp bolesnici su podeljeni prema kliničkoj prezentaciji na početku bolesti. Za prikupljanje podataka o sociodemografskim i kliničkim karakteristikama bolesnika sa DRP, korišćen je unapred dizajniran semistrukturisani upitnik. U istraživanju je korišćena opsežna baterija testova i upitnika za procenu kognitivnog i bihejvioralnog statusa bolesnika. Bolesnicima je posle pismenog pristanka uziman uzorak krvi za molekularno-genetske analize: ispitivanje profila APOE kao i postojanje mutacija u genima za APP, PSEN1, GRN, TAU, C9ORF72, a u određenim slučajevima i za VCP i ANG. Kod 62 bolesnika sa amnestičkom formom ABrp, 28 bolesnika sa FTDbv i 48 zdravih kontrolnih ispitanika pregled mozga je obavljen na MR aparatu jačine 1,5 T. Na snimcima je analizirana debljina korteksa, mikrostrukture promene bele mase i aksonalnih puteva mozga pomoću difuzionog tenzorskog imidžinga (DTI) kao i promene u fukcionalnoj povezanosti delova mozga na „sekvencama bazičnog stanja mirovanja“ (resting) sekvencama. Rezultati: Demografske i kliničke karakteristike:Bolesnici iz spektra ABrp i FTDrp nisu se međusobno razlikovali po godinama starosti, godinama starosti na početku bolesti, trajanju bolesti, polu kao ni u obrazovanju. Bolesnici iz spektra ABrp imali su značajno manja dostignuća na testovima verbalnog i vizuelnog epizodičkog pamćenja, vizuoprostornih i egzekutivnih funkcija, dok su ispitanici spektra FTDrp značajno češće ispoljavali agitaciju, euforiju, apatiju, dezinhibiciju, iritabilnost, aberantno motorno ponašanje i izmene na planu ishrane. Parkinsonizam, motorne stereotipije, ataksija i disfagija su bili značajno češći u spektru FTDrp, dok je jedino u ovih ispitanika verifikovana BMN, klinička slika PSP-a i distonija. Iako je amnestička prezentacija bila najčešća forma našeg spektra ABrp, čak trećina ovih bolesnika prezentovala se atipično- posteriornom kortikalnom atrofijom, potom frontalnom varijantom i jezičkom formom AB. Bolesnici sa FTDrp očekivano su najčešće ispunjavali kriterijume za FTDbv, posle čega je sledila nfvPPA, FTD sindromi preklapanja (FTD-BMN, FTD-PSP, FTD-KBS) i PPAsv. Genetske karakteristike: Familijarnu formu bolesti imala je trećina bolesnika sa ABrp (najveći broj ispitanika je ispunio kriterijume za amnestičku, potom frontalnu varijantu ABrp) i FTDrp (najveći broj bolesnika ispunio je kriterijume za FTDbv, potom PNFA), dok je autozomno dominantan (AD) obrazac nasleđivanja postojao u 4.7% i 7.7% probanada sa ABrp i FTDrp redom. Genske mutacije su dokazane u 4 bolesnika sa ABrp (3.1% svih ABrp): 2 bolesnika su imala mutacije u PSEN1 genu (mutacija Tyr159Cys u egzonu 5 do sada nije objavljena), a 2 bolesnika u APP genu. Nijedan bolesnik sa ABrp nije bio nosilac mutacija u MAPT, GRN i C9ORF72 genima. Navedene mutacije su identifikovane u 7.3% ABrp ispitanika sa familijarnom ABrp (trećina ABrp bolesnika sa AD obrascem nasleđivanja) i 1.2% ispitanika bez obolelih srodnika... | and/or behavioral symptoms before the age of 65. Despite significant advances in neuropsychology, neuroimaging, genetics and biomarkers from cerebrospinal fluid, uncertainties regarding the early and correct diagnosis of EOD even at the level of tertiary referral centres still exist. Recent studies indicate a high clinical heterogeneity, a significant percentage of atypical presentations at disease onset (behavioral symptoms, depression, psychotic symptoms or non-cognitive cognitive deficits), as well as overlap of symptoms within individual entities of the AD and FTD which further complicate early diagnosis and differential diagnosis of degenerative EOD. Therefore, in addition to a good knowledge of clinical, neuropsychological and psychiatric differences arising from the natural course of AD and FTD, new diagnostic algorithms tend to introduce sophisticated diagnostic procedures that will speed up making the adequate diagnosis, define dementia subtypes, monitor progression of the disease and the effectiveness of therapeutic treatments. Objectives. The main objectives of the study are: a) investigating the heterogeneity of clinical, cognitive and neuropsychiatric manifestations of the early onset AD (EOAD) and FTD (EOFTD) spectrum; b) testing the frequency of the different isoforms of apolipoprotein E (APOE) in the EOAD and EOFTD spectrum c) examination of the inheritance pattern and mutations in the genes for the amyloid precursor protein (APP), presenilin 1 (PSEN1), progranulin (GRN), tau protein (MAPT), chromosome 9 open reading frame 72 (C9ORF72) in the EOAD spectrum; d) examining the inheritance pattern and mutations in the genes for GRN, MAPT, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG) in the EOFTD spectrum; e) testing the frequency of hexanucleotide repeat expansion in the C9ORF72 gene in a group of consecutive patients with degenerative DRP (EOAD, EOFTD, Dementia with Lewy bodies (DLT)); f) examining the morphological specificity of the brain with multimodal magnetic resonance imaging (MR) in amnestic EOAD and the behavioral variant of FTD patients (FTDbv). Methods. Two hundred and seven consecutive patients diagnosed according to the current clinical criteria for AD and FTD spectrum were recruited from the Neurology Clinic, Clinical Centre of Serbia from 01.04.2012. until 01.04.2017. We also included 3 patients with DLB (for the needs of the genetic pilot study). The research partly had characteristics of case-control study and partly was cross-section study. Within the spectrum of EOAD and EOFTD, patients were divided according to the clinical presentation at the disease onset. In order to collect data on sociodemographic and clinical characteristics of patients with EOD, a pre-designed semi-structured questionnaire was used. We used an extensive battery of tests and questionnaires to evaluate the cognitive and behavioral status of patients. The blood sample for molecular-genetic analysis was taken: (after the written consent) for testing of the APOE profile as well as mutations in the genes for APP, PSEN1, GRN, TAU, C9ORF72, and in certain cases for VCP and ANG. In 62 patients with amnestic EOAD, 28 patients with FTDbv and 48 healthy control subjects brain scan was performed on a 1.5 T MRI. The topographic distribution of gray matter and white matter (WM) atrophy were assessed by unconventional MRI methods: cortical thickness and diffusion tensor (DT) MRI analysis. We also investigated functional connectivity of different brain networks by resting state functional MRI (RS fMRI). Results: Demographic and clinical features: EOAD and EOFTD patients did not differ in age, age at the disease onset, duration of the disease, gender and education. Patients in the EOAD spectrum had significantly lower achievements in verbal and visual episodic memory tests, visuospatial and executive functions, while patients in the EOFTD spectrum more frequently expressed agitation, euphoria, apathy, disinhibition, irritability, aberrant motor behavior and dietary changes. Parkinsonism, motor stereotyping, ataxia, and dysphagia were significantly more common in the EOFTD spectrum, while MND, clinical picture of PSP and dystonia were only seen in EOFTD patients. Although the amnesic presentation was the most common form in our EOAD spectrum, a third of these patients presented atypicaly- posterior cortical atrophy, following frontal variant and language form of AD. As expected, the majority of FTD patients met criteria for FTDbv, followed by non-fluent progressive aphasia (nfvPPA), FTD-overlap syndroms (FTD-BMN, FTD-PSP, FTD-CBS) and semnatic variant of primary progressive aphasia (svPPA). Genetic analysis: In our cohort, one third of EOAD (majority of patients with amnestic and frontal variant) and EOFTD (majority of patients with FTDbv then nfvPPA) patients had familial form of dementia, while the autosomal dominant (AD) inheritance pattern existed in 4.7% and 7.7% of probands with EOAD and EOFTD, respectively. There were 4 gene mutations carriers within our EOAD cohort (3.1% of all EOAD patients): 2 patients had mutations in the PSEN1 gene (the mutation Tyr159Cys in exon 5was reported for the first time) and 2 patients in the APP gene... | false |
Fatigue life assessment of damaged integral skin-stringer panels | Procena zamornog veka oštećenih integralnih oplata-uzdužnici panela | Zamorni vek integralnih oplata-uzdužnici panela dobijenih metodom laserskog zavarivanja
jeste osnovna tema ove teze. Integralni paneli se obično koriste u vazduhoplovnim strukturama
kod kojih su zamor i tolerancija oštećenja od velike važnosti, pošto letelice moraju biti
projektovane tako da izdrže i pojavu rekativno velikih zamornih prslina. U ovom radu su razvijeni
numerički modeli oplata-uzdužnici panela, sprovedene su kompjuterske simulacije na njima i
dobijeni rezultati su upoređeni sa eksperimentalnim vrednostima iz testova na zamor panela
debljine 2.8 mm od aluminijuma Al6156-T6. Cilj sprovedenih numeričkih simulacija i poređenja
sa eksperimentom bio je verifikacija numeričkih modela za predviđanje veka pod zamorom
oštećenih oplata-uzdužnici panela. U tu svrhu su koriščeni parametri mehanike loma, a modeli su
analizirani pomoću proširene metode konačnih elemenata (PMKE) integrisane u kompjuteski kod
ABAQUS. Pored ove metode korišćene su i druge: analitička, za procenu statičke i zamorne
čvrstoće zavarenih spojeva (a na osnovu smernica definisanih u FKM standardima) i klasična
metoda konačnih elemenata za simulaciju procesa laserskog zavarivanja i identifikaciju zone
uticaja toplote. Numerička simulacija laserskog zavarivanja je pokazala da nakon samog procesa
postoje zaostali naponi u materijalu koji se moraju tretirati pre nego što se oplata-uzdužnici paneli
izlože spoljašnjem promenljivom opterećenju.
U svrhu procene zamornog veka oštećenih integralnih panela (tj. veka panela sa prslinom
iniciranom na sredine osnove) i potom poboljšanja njihovog ponašanja sa aspekta zamora, korišćen
je softverski kod Morfeo/Crack for Abaqus. Ovaj kod izračunava coordinate 2D i 3D fronta prsline
kako se prslina širi kroz strukturu, a potom i raspodelu faktora intenziteta napona KI, KII i KIII duž
fronta prsline (vrednosti efektivnog faktora intenziteta napona Keff se takođe određuju). Potom se
koristi Parisov zakon za procenu broja ciklusa spoljnjeg opterećenja koji će prslinu proširiti do
kritičnih dimenzija. Vrednosti zamornog veka oplata-uzdužnici panela dobijene na ovaj način,
korišćenjem PMKE, bile su bliske eksperimentalnim, ali je u nekim slučajevima razlika bila oko
30%. Utvrđeno je da je tolika razlika bila plod nedovoljno dobro definisane mreže konačnih
elemenata; iz tog razloga je uticaj broja čvorova i elemenata mreže (tj. njene gustine) takođe
analiziran u ovoj tezi. Mora se, međutim, istaći da numerički modeli ovih dimenzija (razmere 1:1)
ranije nisu bili korišćeni i da su svi zamorni vekovi dobijeni u simulacijama bili kraći nego oni u
VI
eksperimentima. To znači da su sva predviđanja dobijena numerikom bila konzervativna, odn. na
strani sigurnosti.
Da bi se produžio zamorni vek oštećenih oplata-uzdužnici panela koriste se ojačanja u vidu
tzv. klipova. Numerički modeli panela sa klipovima su takođe napravljeni, sprovedeni su proračuni
i vrednosti broja ciklusa su upoređene sa vrednostima iz eksperimenata sa panelima bez klipova.
Dobijen je veći broj ciklusa nego u eksperimentu, što opravdava korišćenje ovakvih elemenata za
produženje zamornog veka oštećenih panela. Međutim, potrebna su dalja eksperimentalna
istraživanja da bi se potvrdili numerički rezultati, ali ova teza daje dobru osnovu za sledeće korake
u tom pravcu. | Fatigue life of integral skin-stringer panels produced by laser beam welding (LBW) is
analysed in this thesis. This type of panel is usually used in airframe structure where fatigue and
damage tolerance are of paramount importance, since aircraft must be designed to tolerate
relatively large fatigue cracks. In this work numerical models of skin-stringer panel were
developed, computer simulation were carried out and results were compared to experimental
values from fatigue tests of panels made of Al6156-T6/2.8 mm (LB welded). The main aim was
to validate a numerical method for fatigue life prediction of damaged skin-stringer panels. This is
why a fracture mechanics approach was used in the first place and why models were analyzed
using the Extended Finite Element Method (XFEM) through code ABAQUS. Another methods
were also used: analytical for static and fatigue strength assessment of welded joints (based on
FKM guidelines) and Finite Element Method (FEM) for laser beam welding process simulation
and identification of heat affected zone. Numerical simulation of LBW showed significant amount
of residual stresses which must be treated before exposing skin-stringer panels to variable external
load.
In order to evaluate fatigue life of damaged panels (i.e. the life of panels with crack initiated
in the middle of the base metal) and consequently improve the damage tolerance performance of
integral structures, Morfeo/Crack for Abaqus code was used. This code calculates coordinates of
the 2D or 3D crack fronts (as cracks grow through the structure) and distribution of stress intensity
factors KI, KII and KIII along the crack front (effective stress intensity factor Keff is also calculated).
Then, Paris law is used for estimation of number of cycles that will grow crack to critical length.
Values of fatigue life of skin-stringer panels obtained by XFEM method were close to those
obtained in the experiment, but in some cases differences were about 30%. It was discovered that
difference was caused by not adequately defined mesh; this is why the influence of the element
size on the fatigue life estimation was also analyzed in thesis. But, it must be emphasized that
numerical models of this size (scale 1:1) were never used before, and that all fatigue life values
obtained in numerical simulations were less than experimental values. This means that all
predictions were conservative, i.e. on the safe side.
In order to increase life of damaged skin-stringer panels so-called clips are used. Numerical
models with clips were also made, calculations carried out and results compared with experimental
IV
values for panels without clips. Longer fatigue life was obtained in simulations with clips,
justifying the use of these elements for fatigue life extension. However, experimental
investigations must be carried to confirm these numerical findings, but this thesis gives basis for
next steps. | true |
Epidemiološko-klinička studija kongenitalnog hipotirodizma zasnovana na rezultatima 30 godina skrininga novorođenčadi u Srbiji | Epidemiology-clinical study of congenital hypothyroidism detected during 30 years of a screening programe in Serbia | Uvod: Kongenitalni hipotiroidizam (KH) je najčešće kongenitalno endokrinološko oboljenje, koje je u eri pre skrininga bilo vodeći uzrok mentalne retardacije. Program skrininga na KH, omogućio je pravovremeno postavljanje dijagnoze i rani početak supstitucione terapije, što je dovelo do skoro potpunog iščezavanja mentalne retardacije pouzrokovane ovim oboljenjem. U Srbiji, skrining na KH započet je 1983. godine jednogodišnjom pilot studijom u porodilištima grada Beograda, a potom se proširio na ostale regione Srbije. Ciljevi ovog istraživanja su bili određivanje kumulativne incidencije i prevalencije KH na teritoriji Srbije bez pokrajina u periodu od 1983. do 2013. godine, analiza kliničkih i laboratorijskih karakteristika dece sa KH, kao i definisanje glavnih kliničkih i laboratorijskih karakteristika dece sa trajnim i tranzitornim oblikom bolesti. Metodologija: U Srbiji, skrining na KH se bazira na određivanju koncentracije tireostimulišućeg hormona (TSH) iz uzorka kapilarne krvi. Tokom perioda 1983-1987. granična vrednost TSH je bila 30 mIJ/l (P1), 1988-1997. granična vrednost TSH je iznosila 15 mIJ/l (P2), 1998-2006. 10 mIJ/l (P3), a 2007- 2013. iznosila je 9 mIJ/l (P4). Koncentracija TSH između granične i 40 mIJ/l zahtevaju ponavljanje uzoraka, dok koncentracija TSH ≥40 mIJ/l ukazuje na verovatno postojanje primarnog KH i novorođenče se odmah hospitalizuje Na osnovu scintigrafskog nalaza, svi ispitanici su podeljeni u dve grupe, sa trajnim i tranzitornim oblikom KH. Trajni KH su imala novorođenčad s atireozom, ektopijom, hemiagenezijom i hipoplazijom tiroideje. Novorođenčad čija je tiroideja bila na mestu, normalne veličine ili uvećana, sa normalnom funkcijom posle reevaluacije u uzrastu od tri godine, svrstana su u grupu sa tranzitonim KH. Rezultati: U periodu 1983-2013. godine programom skrininga na KH na teritoriji Srbije bez pokrajina obuhvaćeno je 1.547.122 novorođenčeta. Primarni KH je dijagnostikovan kod 434, 59,7% (n=259) devojčica i 40,3% (n=175) dečaka. Kumulativna incidencija KH je iznosila 28,6 na 100 000 (1:3495), dok je prevalencije sa 1:5084 u P1 porasla na 1:1807 u P4... | Introduction: Congenital hypothyroidism (CH) is the most frequent congenital endocrine disorder and the main cause of preventable mental retardation. Newborn screening (NBS) programs for CH have been established in most countries in order to enable early diagnosis and treatment of CH, thus preventing related neurodevelopmental complications. In Serbia, the CH screening program was initiated as a pilot study in Belgrade maternity hospitals in 1983 and then integrated into all maternity hospitals in Central Serbia. The purpose of the present study was to determine the incidence of CH from 1983 to 2013, and to assess changes in prevalence and etiology of CH during the study period. The secondary goal was to analyze clinical and laboratory characteristics of children with CH. Metodology: Newborn screening program for CH was based on measuring neonatal thyroid-stimulating hormone (TSH) levels using a 30 mU/l cutoff until 12/1987 (P1), 15 mU/l until 12/1997 (P2), 10 mU/l until 12/2006 (P3) and 9 mU/l thereafter (P4). When the TSH value was between cutoff and 40 mU/l, a positive was suspected and a new blood sample was extracted, while TSH result ≥ 40 mU/l was considered positive for CH and the newborn was immediately referred to the hospital. In regards to etiology, according to the scintigraphy result, all of the patients were classified as having permanent or transient CH. The patients with athyreosis, ectopy, hemiagenesis and hypoplasia in situ were considered to have permanent CH. The patients with eutopic normally sized gland and eutopic goiter whose thyroid function was within the normal range after a reevaluation at the age of 3, were considered to have transient CH. Results: During the study period from 1983 to 2013, there were 1,547,122 live births screened for CH. Primary CH was detected in 434 newborns, 59.7% (n=259) female and 40.3% (n=175) male, resulting in an overall incidence of 28.6 per 100 000 (1:3495). Among children with CH, 325 had permanent and 65 transient CH. The incidences standardized in regard to the number of screened newborns during each period showed significant increase (p<0.001) from 1:5084 in P1 to 1:1807 in P4... | false |
Sekrecija insulina i insulinska senzitivnost perifernih tkiva pre i nakon radikalnog lečenja primarnog hiperparatireoidizma | Insulin secretion and insulin sensitivity of peripheral tissues before and after radical treatment of primary hyperparathyroidism | Uvod i cilj: Prethodno je uočeno postojanje insulinske rezistencije i povećana prevalenca
oštećene tolerancije na glikozu i tipa 2 dijabetesa kod pacijenata sa primarnim
hiperparatireoidizmom. Efekat paratireoidektomije na insulinsku senzitivnost je praćen
kontraverznim nalazima u zavisnosti od metode koja je korištena za procenu insulinske
senzitivnosti: nije bilo promene kada su korišteni HOMA i QUICKI dok je Minimalnim
modelom pokazano značajno poboljšanje insulinske senzitivnosti.Cilj ovog rada je bio da se
proceni insulinska senzitivnost pre i nakon paratireoidektomije kod pacijenata sa PHPT
putem euglikemijskog hiperinsulinemijskog klampa. Materijal i metode: Kod 44 pacijenta
sa PHPT i 11 zdravih kontrola komparabilne starosti i indeksa telesne mase procenjivali smo
insulinsku senzitivnost (pomoću tehnike klampa, HOMA IR i ISI indeksa), insulinsku
sekreciju (putem površine pod krivom za glikemije i insulinemije tokom OGTTa i
izračunavajući akutni insulinski odgovor iz podataka dobijenih IVGTTom), lipidni profil i
nivo hsCRP kao marker hronične inflamacije. Rezultati: Pre operacije vrednosti M indeksa i
HOMA IR su ukazivale na postojanje insulinske rezistencije kod pacijenata sa PHPT. Nije
bilo razlike u M indeksu (3.74±1.89 vs 4.62±2.27, p >0.05), HOMA IR (2.94±1.39 vs.
3.29±0.81, p > 0.05), AUC glikoze (863.0±261.3 vs 842.3±165.5, p>0.05), AUC insulina
(7068.7±4159.0 vs 7229.6±2581.7, p>0.05), ISI (4.73±2.77 vs 4.25±2.94, p>0.05) i AIR
(47.89±32.05 vs. 38.96±21.20, p>0.05) izmeĎu pacijenata sa PHPT i zdravih kontrola. Došlo
je do značajnog poboljšanja insulinske senzitivnosti nakon operacije al ii preoperativna i
postoperativna vrednost M indeksa se nisu razlikovale od zdravih kontrola. Nije uočena
promena u HOMA IR, AUC za glikozu i insulin ISI i AIR, lipidima i hsCRP nakon operacije.
Zaključak:
Dobili
smo
značajno
poboljšanje
insulinske
senzitivnosti
nakon
paratireoidektomije kod pacijenata sa PHPT koristeći klamp tehniku. Postoperativno nije do
došlo do značajne promene u drugim pokazateljima insulinske senzitivnosti, paramtrima
insulinske sekrecije, lipidima i hsCRP. | Background and Aims: Previous studies demonstrated insulin resistance and increased
prevalence of impaired glucose tolerance and type 2 diabetes mellitus in patients with
primary hyperparathyroidism (PHPT). The effect of curative parathyroidectomy on insulin
sensitivity was associated with conflicting results depending on which method for measuring
the insulin sensitivity has been used. There was no improvement using HOMA and QUICKI
while minimal model demonstrated significant improvement in insulin sensitivity. The aim
of our study was to evaluate the insulin sensitivity before and after parathyroidectomy in
patients with PHPT using a euglycemic clamp. Material i methods: Forty-four patients with
PHPT and eleven age and body mass index matched healthy controls participated in study
protocol. We measured insulin sensitivity using euglycemic clamp technique, HOMA IR and
ISI. Insulin secretion was evaluated using area under the curve for glucose and insulin during
OGTT and calculating the acute insulin response durin IVGTT. Also, lipid profile and hsCRP
were evaluated Results: Before surgery M values and HOMA IR suggest insulin resistance in
patients with PHPT. There was no difference in M index (3.74±1.89 vs 4.62±2.27, p >0.05),
HOMA IR (2.94±1.39 vs. 3.29±0.81, p > 0.05), AUC glucose (863.0±261.3 vs 842.3±165.5,
p>0.05), AUC insulin (7068.7±4159.0 vs 7229.6±2581.7, p>0.05), ISI (4.73±2.77 vs
4.25±2.94, p>0.05) and AIR (47.89±32.05 vs. 38.96±21.20, p>0.05) between patients with
PHPT and HC. There was significant improvement in insulin sensitivity after
parathyroidectomy but both preoperative and postoperative M values were not significantly
different in comparison to HC. There were no significant changes in HOMA IR, AUC
glucose, AUC insulin, ISI and AIR before and after therapy, as well in lipid and hsCRP
levels. Conclusion: we observed significant improvement in insulin sensitivity after
parathyroidectomy in patients with PHPT. There was no difference in parameters of insulin
secretion before and after parathyroidectomy in patients with PHPT. | true |
The role of Cytomegalovirus and Epstein-Barr virus in the development and progression of Salivary Gland Cancer | Uloga citomegalovirusa i Epštajn-Bar virusa u nastanku i progresiji karcinoma pljuvačnih žletda | Uvod: Karcinomi pljuvačnih žlezda su retki tumori koji u različitim histološkim
tipovima pokazuju spektar različitih morfoloških promena koje odgovaraju različitom
kliničkom ispoljavanju i toku. Etiologija karcinoma pljuvačnih žlezda je još uvek nepoznata.
Brojna istraživanja su pokazala značajan uticaj faktora sredine na njihov nastanak i
progresiju, ali je samo za mali procenat jasno pokazano da je tumor nastao upravo direktnim
uticajem nekog od faktora sredine. Sve je više istraživanja koja ukazuju na čestu i tesnu
povezanost infektivnih agenasa sa pojavim maligniteta. Novija istraživanja pokazala su
direktnu povezanost infekcija Citomegalovirusom (CMV) i Epštajn-Barr virusom (EBV) sa
nastankom različitih oblika karcinoma. U različitim tkivima pokazano je da CMV i EBV
mogu uzrokovati povećanje ekspresije IL-6, NFκB, MMP-2 i MMP-9, proteina koji su
direktno povezani sa određenim tipovima karcinoma. Naša hipoteza je bila da CMV i EBV
mogu dovest do zapaljenja i do deregulacije gena ćelijske proliferacije, te uticati na nastanak
i razvoj karcinoma pljucačnih žlezda.
Ciljevi: Ciljevi ove studije bili su da se utvrdi prisustvo CMV i EBV u tkivu
karcinoma pljuvačne žlezde, da se uporedi immunohistohemijska i nested PCR detekcija
CMV i EBV u karcinomu pljuvačne žlezde, da se ispita ekspresija virusnih proteina u
različitim
histološkim
tipovima
karcinoma
pljuvačnih
žlezda,
da
se
ispita
imunohistohemijska ekspresija prognostičkih markera IL6, MMP2, MMP9 i NFκB, da se
ispita povezanost prisustva CMV i EBV sa imunohistohemijskom ekspresijom pomenutih
prognostičkih markera i da se uradi analiza polimorfizma IL6, MMP2 i MMP9 gena i ispita
asocijacija polimorfizama i odgovarajuće ekspresije proteina.
Materijal i metode: Ova studija preseka obuhvatila je 93 pacijenta kod kojih je
dijagnostikovan karcinom pljuvačne žlezde, koji su operisani na Klinici za
otorinolaringologiju i maksilofacialnu hirurgiju, Kliničkog centra Serbije u periodu od 2004.
do 2013. Detekcija CMV i EBV analizirana je imunohistohemijskom i nested PCR metodom.
Imunohistohemijska metoda korišćena je da se utvrdi ekspresija IL-6, MMP2, MMP9 i
NFκB. Jačina ekspresije određivana je prema intenzitetu bojenja sa jedne strane, i utvrđivanju
broja pozitivno obojenih karcinomskih ćelija u odnosu na ukupan broj ćelija. Slučajevi su
ocenjeni kao pozitivni ako je nađeno više od 10% pozitivno obojenih tumorskih ćelija.
Shodno jačini imunoreaktivnosti pozitivnost je ocenjena kao slaba, umerena i izražena.
Rezultati: Imunohistohemijski CMV antigeni su detektovani u 66 od 92 slučaja
karcinoma pljuvačne žlezde (71.7%), dok su svi kontrolni slučajevi bili negativni. CMV je
češće bio prisutan u adenoidno cističnom karcinomu nego u drugim histološkim tipovima
(p<0.05). EBV je detektovan u 32 (34,8%) od 92 slučaja i u 1 kontrolnim slučaju. Rezultati
nested PCR ispitivanja se nisu značajno razlikovali od imunohistohemijskih. U 16 od 92
(17.4%) slučajeva tumora pljuvačnih žlezda nije nađena ekspresija ni CMV ni EBV virusnih
antigena, dok je u 76 slučajeva (82.6%) detektovana ekspresija antigena bar jednog od
ispitivanih virusa. U 22 slučaja nađena je ekspresija i CMV i EBV antigena.
Imunohistohemijska pozitivnost i intenzitet ekspresije IL-6 i NFκB bili si značajno viši u
karcinomima pljuvaćnih žlezda nego u kontrolnim slčajevma (p<0.01), dok se ekspresija
MMP-2 i MMP-9 nije razlikovala u tumorima i kontrolnoj grupi. U slučajevima tumora
pljuvačnih žlezda u kojima je nađena CMV pozitivnost zapažena je značajno veća ekspresija
IL-6, NFκB i MMP-2 (p<0.01), dok razlika u ekspresiji MMP-9 u kontrolnoj grupi i
slučajevima karcinoma nije primećena. Nije utvrđena razlika ekspresije ni jednog
prognostičkog markera između EBV pozitivnih i EBV negativnih slučajeva karcinoma
pljuvačnih žlezda. Međutim, u slučajevima u kojima je nađena ekspresija i CMV i EBV
antigena, ekspresija IL-6, NFκB i MMP-2 je bila veća nego u slučajevima u kojima je nađena
samo ekspresija CMV antigena.
C alel IL-6 -174G>C polimorfizma povećava rizik oboljevanja od carcinoma
pljuvačne žlezde i u formi homozigota CC i heterozigota GC. Povećan rizik je potvrđen i u
dominantnom modelu (OR 3.77, 95% CI 1.91-7.44, p<0.001 za CT+TT genotip). T alel
MMP-2 -1306 C>T polimorfizma pokazuje efekat u heterozigotnim nosiocima, povećevajući
rizik za dobijanje carcinoma pljuvačne žlezde (OR 1.98, 95% CI 1.07-3.65, p=0.03). Prema
dominantnom modelu, CT+TT genotipovi imaju 2 puta veći rizik od razvijanja carcinoma
pljuvačne žlezde (p=0.02). Prema dominantnom modelu MMP2 -1575 G>A polimorfizma,
osobe koje poseduju GA+AA genotipove pokazuju 1.77 puta veći rizik od razvitka kancera,
ali je statistička značajnost granična (P=0.049). Heterozigotni nosioci T alela MMP-9 -1562
C>T polymorfizmaimaju oko 2 puta veći rizik od oboljevanja od carcinoma pljuvačne žlezde
u poređenju sa nosiocima homozigota CC (p=0.02). Međutim, ni jedan od ispitivanih
genotipova IL-6 i MMP-2 gena nije povezan sa većom ekspresijom svog proteinskog
produkta, dok je CC genotip MMP-9 -1562 C>T polimorfizma povezan sa jačom ekspresijom
MMP-9, ali je statistička značajnost granična gymorphism was associated with a higher
expression of MMP, but only with border line significance (p=0.049).
Zaključci: Prisustvo CMV i EBV nađeno je češće u karcinoma pljuvačnih žlezda
nego u normalnom tkivu pljuvačnih žlezda. Kako se rezultati IHH i PCR poklapaju u velikom
procentu, za detekciju virusa u tkivu iz parafinskog bloka mogu se koristiti obe metode
podjednako uspešno. IL-6 i NFκB mogu se smatrati dobrim pozitivnim prognostičkim
markerima u slučajevima karcinoma pljuvačnih žlezda, dok se ekspresija MMP-2 i MMP-
9 ne razlikuje u slučajevima karcinoma i u tkivu normalne pljuvačne žlezde. Dok EBV
izgleda da nema neki značajniji uticaj na ekspresiju bilo kog ispitivanog prognostičkog
markera, u slučajevima CMV pozitivnih karcinoma plljuvačnih žlezda nađena je povećana
ekspresija IL-6, NFκB i MMP-2.
IL-6 -174 G>C, MMP-2 -1306 C>T i MMP-9 -1562 C>T polimorfizmi izgleda da utiču na
razvoj karcinoma pljuvačnih žlezda, dok MMP-2 -1575 G>A da ima manji značaj. Nijedan
od ispitivanih polimorfizama nije uticao na povišenu proteinsku produkciju. | Introduction: Salivary gland carcinomas (SGC) are rare tumors characterized by an
enormous morphological diversity between different subtypes going along with diverse
clinical courses. The etiology of SGC is still unknown, although a correlation has been shown
between the occurrence of SGC and some environmental factors, however, only a very small
percentage of malignancies develop as a direct result of these factors. There is growing
evidence that infectious agents are frequently associated with human cancer. Recent studies
show that Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) CMV infections are
associated with various epithelial malignancies. It has been shown that in various tissues
CMV and EBV could increase the expression of IL-6, NFκB, MMP-2 and MMP-9. These
proteins are associated with certain types of cancer. We hypothesized that CMV and EBV
could cause inflammation and deregulation of genes involved in cell proliferation and could
induce the development of salivary gland cancer.
Aims: The aims of this study were to determine the prevalence of CMV and EBV in
SGC tissues, to compare the immunohistochemical and nested PCR detection of CMV and
EBV in SGC, to investigate the viral protein expression in different histological types of
salivary gland cancer, to investigate the immunohistochemical expression of prognostic
markers IL6, MMP2, MMP9 and NFκB, to investigate the association of the presence of
CMV and EBV and the immunohistochemical expression of these prognostic markers and to
analyze the polymorphisms of IL6, MMP2 and MMP9 genes and investigate the association
of the polymorphisms and the corresponding protein expression.
Material and Methods: This cross-section study included 93 patients diagnosed with
salivary gland cancer (SGC), surgically treated at the Clinic of Otorhinolaryngology and
Maxillofacial Surgery, Clinical Center of Serbia from 2004 to 2013. For the
immunohistochemical analysis, the control consisted of healthy salivary gland tissue from
20 autopsy cases with no malignancies and salivary gland pathology. For the analysis
concerning DNA polymorphisms, the control group consisted of buccal swabs from 100
healthy volunteers, matching the study group in sex and age. CMV and EBV detection was
performed by immunohistochemistry and by nested PCR. Immunohistochemistry (IHC) was
performed to demonstrate the expression of IL6, MMP2, MMP9 and NFκB. The level of
expression was scored according to both the intensity of staining and the proportion of
positive staining of carcinoma cells within the entire slide. Cases were considered positive if
more than 10 % of tumor cells immunoreacted. Positive reactivity was graded as weak,
moderate, and strong according to the relative strength of the immunoreactivity.
Results: Using IHC staining, CMV antigens were detected in 66 out of 92 SGC cases
(71.7%), while all control cases were negative. EBV was detected in 32 (34,8%) from our 92
cases and in 1 case of control. The nested PCR results did not differ significantly from IHC.
In 16 of the 92 (17.4%) SGC cases there was no expression of viral antigens, neither CMV
nor EBV, while 76 cases (82.6%) expressed antigens of at least one virus. However, there
were 22 cases that expressed both CMV and EBV antigens. The prevalence and intensity of
expression of IL-6 and NFκB were significantly higher in SGC than in control cases (p<0.01),
while the expressions of MMP-2 and MMP-9 did not show a difference between SGC and
control cases. SGC cases that were CMV positive showed a significantly higher expression
of IL-6, NFκB and MMP-2 (p<0.01), while MMP-9 expression did not differ between SGC
and control cases. There was no difference in the expression of any prognostic marker in
SGC and control cases. However, in cases that expressed both CMV and EBV antigens, the
expressions of IL-6, NFκB and MMP-2 were higher than in cases that expressed only CMV
antigens.
The C allele for the IL-6 -174G>C polymorphism increases the risk for SGC both in
homozygote CC and heterozygote GC. This increase in susceptibility was also confirmed
using the dominant model (OR 3.77, 95% CI 1.91-7.44, p<0.001for the CT+TT genotypes).
The T allele for the MMP-2 -1306 C>T polymorphism exhibits its effect in heterozygous
carriers, increasing the risk for SGC (OR 1.98, 95% CI 1.07-3.65, P=0.03). According to the
dominant model, CT+TT genotypes had a 2-fold increased risk of developing SGC
(p=0.02).When the dominant model is applied for the MMP2 -1575 G>A, individuals with
GA+AA genotypes exhibited a 1.77-fold increase in cancer risk, but with borderline
significance (P=0.049). Heterozygous carriers of the variant T allele for the MMP-9 -1562
C>T polymorphism had roughly a two-fold increase in susceptibility for SGC compared to
wild type homozygotes (CC). (p=0.02). However, the polymorphisms of IL-6 and MMP-2
were not associated with a higher expression of their protein products, while the CC genotype
of the MMP-9 -1562 C>T polymorphism was associated with a higher expression of MMP,
but only with border line significance (p=0.049).
Conclusions: Both CMV and EBV are found more often in SGC than in normal
salivary gland tissue. Since the results of IHC and nested PCR coincide in a high percentage,
both methods can be used in the detection of viruses from formalin-fixed, paraffin embedded
tissues. IL-6 and NFκB could be considered as good positive prognostic factors for SGC,
while MMP-2 and MMP-9 expression does not differ between SGC and normal tissue. While
EBV does not seem to influence the expression of any of the tested markers, CMV positive
SGC cases showed a higher expression of IL-6, NFκB and MMP-2.
IL-6 -174 G>C, MMP-2 -1306 C>T and MMP-9 -1562 C>T polymorphisms
genotypes seem to influence the development of SGC, whereas MMP-2 -1575 G>A seems
to be of a minor importance. None of the analyzed polymorphisms led to a higher protein
production. | true |
Dugotrajni efekti maternalne deprivacije na holinergički sistem i redoks regulaciju u mozgu pacova | Long-term effects of maternal deprivation on cholinergic system and redox regulation in rat brains. | Uvod: Animalni model maternalne deprivacije zasnovan je na izlaganju stresu u
ranom postnatalnom periodu. Pokazano je da rani perinatalni stres može
izazvati različite kratkotrajne i dugotrajne poremećaje u kognitivnim,
emocionalnim i bihejvioralnim odlikama (Koehl i sar., 2001; Viveros i sar., 2010),
kao i da rani postnatalni stres može povećati rizik za oboljevanje od
shizofrenije (Ellenbroek i Cools, 1998; Bramon i sar., 2001). Poremećaj u
holinergičkoj neurotransmisiji često je opisivan kod shizofrenije (Terry i
Mahadik, 2007; Sarter i sar., 2005), a holinergički sistem se smatra potencijalnom
metom za razvoj novih lekova (Freedman i sar., 2008; Scarr, 2012) koji bi
poboljšali kognitivne poremećaje i negativne simptome kod obolelih.
Oksidativni stres se smatra jednim od etiopatogenetskih faktora shizofrenije.
U ovom radu je ispitivan uticaj maternalne deprivacije na strukturne i
biohemijske karakteristike pojedinih moždanih regiona Wistar pacova.
Ciljevi: (1) Ispitati uticaj maternalne deprivacije na holinergički sistem
(aktivnost acetilholinesteraze kao i određivanje gustine holinergičkih
vlakana u retrosplenijalnom korteksu i hipokampalnoj formaciji), (2) ispitati
pokazatelje oksidativnog stresa (sadržaj redukovanog glutationa, aktivnosti γ-
glutamil cistein ligaze, glutation peroksidaze i glutation reduktaze,
superoksid dizmutaze, zatim ekspresije SOD1 i SOD2 kao i sadržaja lipidnih
peroksida izražen preko koncentracije malondialdehida (MDA)), (3) ispitati
uticaj na mitohondrijalni metabolizam određivanjem aktivnosti enzima
respiratornog lanca (kompleksa I i citohrom c oksidaze), i ekspresiju
membranskih (gp91phox, p22phox) i citosolnih (p47phox , p67phox ,p40phox) subjedinica
NADPH oksidaze u korteksu, hipokampusu, talamusu i nc.caudatus-u mozga
pacova.
Materijal i metode: Trudne ženke Wistar pacova su pojedinačno čuvane u
kavezima sa 12-časovnim ciklusom svetlo-mrak. Hrana i voda bili su dostupni
ad libitum. Dan porođaja smo označili kao nulti postnatalni dan (PN0). Devetog
postnatalnog dana (PN9) legla smo podvrgnuli maternalnoj deprivaciji
(Ellenbroek i Cools, 1995b; Roceri i sar., 2002). Desetog postnatalnog dana (PN 10)
mladunci su vraćeni u kavez sa majkom (eksperimentalna grupa). U kontrolnoj
grupi mladunci ostaju sa svojom majkom sve vreme. Nakon toga mladunce nismo
uznemiravali, osim zbog rutinskog čišćenja kaveza, do PN 21 kada smo izvršili
klasifikaciju prema polu. Životinje su žrtvovane cervikalnom dislokacijom
šezdesetog postnatalnog dana (PN60). Za morfometrijske i biohemijske studije
koristili smo mužjake, kako bi izbegli seksualni dimorfizam (Vivinetto i sar.,
2013; Own i Patel, 2013).
Aktivnost enzima acetilholinesteraze, kao i pokazatelje oksidativnog stresa
(sadržaj redukovanog glutationa, aktivnosti γ-glutamil cistein ligaze,
glutation peroksidaze i glutation reduktaze, superoksid dizmutaze, sadržaja
lipidnih peroksida) i aktivnosti enzima respiratornog lanca (kompleksa I i
citohrom c oksidaze) određivani su odgovarajućim spektrofotometrijskim
metodama. Tehnikama imunohistohemije određivana je gustina holinergičkih
vlakana u retrosplenijalnom korteksu i hipokampalnoj formaciji. Tehnikom
Western blota ispitivana je ekspresija SOD1 i SOD2, i ekspresija subjedinica
NADPH oksidaze (gp91phox, p22phox, p47phox , p67phox , p40phox) u korteksu,
hipokampusu, talamusu i nc.caudatus-u mozga pacova.
Rezultati: Istraživanje je pokazalo da rani stres izazvan maternalnom
deprivacijom prouzrokuje dugotrajne promene u holinergičkom sistemu i redoks
regulaciji. Prvenstveno stres prouzrokovan ranim odvajanjem mladunaca od
majke dovodi do smanjenja aktivnosti AChE u korteksu kao i do povećanja
aktivnosti AChE u hipokampusu. Takođe, dovodi do smanjenja gustine
holinergičkih vlakana u retrosplenijalnom korteksu mozga pacova kao i do
povećanja gustine holinergičkih vlakana u CA1 području hipokampusa.
Maternalna deprivacija dovodi do sniženja redukovanog glutationa u svim
ispitivanim strukturama, dovodi do povećanja aktivnosti enzima GPx u
korteksu, i smanjenja aktivnosti ovog enzima u talamusu, ali ne dovodi do
promena u aktivnosti enzima γ-GCL i GR. Takođe, u istraživanju smo pokazali
da maternalna deprivacija uzrokuje povećanje aktivnosti enzima SOD u korteksu
i hipokampusu kao i povećanu ekspresiju SOD1 i SOD2 u korteksu, kao i da
dovodi do lipidne peroksidacije u korteksu i talamusu.
Maternalna deprivacija uzrokuje poremećaj mitohondrijalnog metabolizma koja
se ogleda u povećanoj aktivnost kompleksa I u hipokampusu, talamusu i
nc.caudatus-u, ali ne dovodi do promena u aktivnosti COX.
Maternalna deprivacija dovodi do povećane ekspresije subjedinice gp91phox
NADPH oksidaze u korteksu i hipokampusu, kao i do sniženja ekspresije u
talamusu i nc.caudatus–u. Takođe uzrokuje povećanu ekspresiju p22phox
subjedinice NADPH oksidaze u hipokampusu i sniženje ekspresije u
nc.caudatus–u, kao i sniženje ekspresije p47phox subjedinice u hipokampusu i
nc.caudatus-u. Maternalna deprivacija uzrokuje povećanje ekspresije subjedinice
p40phox u hipokampusu, ali ne uzrokuje promene u ekspresiji p67phox subjedinice
NADPH oksidaze ni u jednoj od ispitivanih struktura mozga pacova.
Zaključak: Navedeni rezultati ove doktorske disertacije potkrepljuju
pretpostavku da se redoks disregulacija i poremećaj funkcija holinergičkog
sistema javljaju kao dugoročne posledice izlaganja ranom postnatalnom stresu.
Navedeni podaci mogu biti od značaja u smislu sagledavanja i razumevanja
etiopatogenetskih
mehanizama
shizofrenije,
kao
i
u
razvoju
novih
eksperimentalnih modela i strategija u lečenju ove bolesti. | Objective: Animal model of maternal deprivation is based on exposure to stress in early
postnatal life. It has repeatedly been shown that early perinatal stress can cause various
short and long-term disturbances in cognitive, emotional and other behavioral
performances (Koehl et al. 2001; Viveros et al. 2010). Nonetheless, there is evidence
that early stressful life events can increase the risk of developing schizophrenia
(Ellenbroek and Cools, 1998; Bramon et al. 2001). Alterations in holinergic
neurotransmission have been commonly reported in schizophrenia (Terry and Mahadik,
2007; Sarter et al. 2005), cholinergic system is a target for drug development (Freedman
et al. 2008; Scarr, 2012) against the negative symptoms and cognitive disorder.
Growing body of evidence indicates that oxidative damage is connected to
schizophrenia. Animal model of Wistar rats we used in order to investigate the
influence of maternal deprivation to the structural and biochemical characteristics of
certain brain regions.
Aim: The aims of present dissertation were elucidate the effects of maternal deprivation
on: (1) holinergic system (measure AChE activity and morphometric analysis density of
cholinergic fibers in hippocampus and retrosplenial cortex) ,(2) to analyse oxidative
stress parameters using appropriate spectrophotometric techniques (GSH content,
activity of γ-glutamyl-cysteine-glycine, glutathione peroxidase, glutathione reductasa,
superoxide dismutase, expression of SOD1 and SOD2 and levels of lipid peroxides
(malondialdehyde-MDA)), (3) to analyse mitochondrial respiratory chain enzyme
activity using appropriate spectrophotometric techniques (activity of Complex I and
COX) and the expression of different NADPH oxidase subunits (gp91phox, p22phox,
p67phox, p47phox, and p40phox ) in cortex , hippocampus, thalamus and caudate nucleus.
Methodology: Pregnant female Wistar rats was in single cages on a standard 12 h
light/dark cycle, with water and food available ad libitum. The day of delivery was
denoted as postnatal day P0. On P9, eight litters were subjected to the maternal
deprivation procedure according to the previously published protocol (Roceri et al.,
2002; Ellenbroek et al. 2005). On P10 pups was returned in their home cage with dam
(experimental group). In control group pups left undisturbed with their mother. All
litters were later left undisturbed except for the routine cleaning of the cages, until P21.
On P21 the litters were were weaned and classified according to sex .Animals were
sacrificed by cervical dislocation at 2 months of age (P60). For morphometric and
biochemical studies only male rats were used in order to avoid sexual dimorphism
Results: The result of our survey was shown that early perinatal stress, maternal
deprivation, can cause long term effects in holinergic system and redox regulation.
Obtained results showed that AChE activity in the cortex is significantly decreased
while in hippocampus AChE activity is significantly increased. Morphometric analysis
density of cholinergic fibers in cortex is decreased while in hippocampus is significantly
increased density only in CA1 region. Results of our study have confirmed the presence
of oxidative stress in MD rats. We observed a decrease of GSH content in all
investigated structures, the activity of was not changed, GPx activity was increased in
the cortex, and decreased in thalamus. No changes observed in activity of γ-GCL and
GR. Also, maternal deprivation leads to increased activity of SOD in cortex and
hippocampus, as well as increased expression of SOD1 and SOD2 in cortex. Levels of
lipid peroxides was increased in cortex and thalamus. Long term effects of maternal
deprivation in our study include increased activity of Complex I in all structures except
cortex, without changes of COX activity. In our study, in cortex, the single observed
change in NOX2 was increased expression of membrane subunit gp91phox. On the other
hand, in hippocampus, increased expression of gp91phox was accompanied by increased
expression of p22phox and p40phox, as well as decreased expression of p47phox. In
thalamus only gp91phox is decreased, while in the nucleus caudatus decreased expression
of gp91phox, p22phox and p47phox was observed.
Conclusion: The results of this doctoral dissertation support the assumption that early
maternal deprivation produces long-term redox alterations and holinergic disturbance in
the brain of rats. Understanding of the etiological role of oxidative stress and holinergic
disturbance in the pathogenesis of schizophrenia could offer new experimental models
as well as therapeutic strategies. | true |
Efekat barijatrijske hirurgije na kardiopulmonalni funkcionalni kapacitet kod bolesno gojaznih osoba | Effects of bariatric surgery on cardiopulmonary functional capacity in morbidly obese patients | Uvod: Gojaznost je vodeći javno zdravstveni problem u 21. veku. Ona predstavlja
hroničnu bolest, uzrokovanu prekomernim nakupljanjem masti u telu i povećanjem
telesne mase, koja dovodi do zdravstvenih poremećaja
, lošeg kvaliteta života i
morbiditeta. Takođe, gojaznost i prekomerna telesna masa povezani su sa poremećajima
kardiopulmonalne funkcije i sa povećan
im ukupnim mortalitetom, pre svega od
kardiovaskularnih bolesti. Barijatrijska hirurgija, posebno Roux-en-Y želudačni bajpas
(RYGB), postala je jedna od najefikasnijih hirurških metoda koja dovodi do značajnog i
dugoročnog gubitka telesne mase kod ekstremne gojaznosti, sa veoma niskom stopom
smrtnosti.
Cilj: Ispitivanje efekata barijatrijske hirurgije na kardiopulmonalni funkcionalni
kapacitet kod morbidno gojaznih pacijenata posle šest meseci od zahvata, kao i efekat
takve intervencije na poznate faktore rizika za kardiovaskularne bolesti. Takođe,
praćena je stopa preživljavanja bolesnika kao i stepen održavanja stabilnog gubitka
telesne mase posle pet godina od hirurške intervencije uz analizu uticaja na poznate
kardiovaskularne faktore rizika.
Metodologija: Rađena je retrospektivna studija preseka koja je obuhvatila 66 morbidno
gojaznih pacijenata (BMI ≥ 40kg/m2 ili BMI ≥ 35kg/m2 sa prisutnim komorbiditetima),
starosti od 20 do 61 godine, uglavnom ženskog pola (77.3%) koji su podvrgnuti
barijatrijskoj operaciji u periodu od 1.06.2011-31.12.2012. godine. Oni su u sklopu
pripreme za operaciju pregledani od strane endokrinologa, dijetologa, pulmologa,
kardiologa, psihijatra, anesteziologa i hirurga. Za pravljenje baze korišćeni su podaci iz
istorije bolesti. Kardiopulmonalni test fizičkim opterećenjem (CPET) rađen je na
pokretnoj traci prema Bruce protokolu uz istovremenu analizu gasova u izdahnutom
vazduhu preko maske na licu i sistema za ergospirometriju. Kardiopulmonalni
funkcionalni kapacitet procenjivan je pre i šest meseci posle RYGB u Laboratoriji za
CPET. Kompletna statistička analiza podataka izvršena je pomoću statističkog
softverskog paketa PASV Statistics 18® [SPSS (Hong Kong) Ltd., Hong Kong].
Rezultati: Značajan gubitak telesne mase (29.80 ± 13.27kg) nakon RYGB operacije bio
je povezan sa značajnim smanjenjem komorbiditeta, posebno dijabetesa i sedentarnog
načina života. (p = 0.005, p = 0.002, redom). Što se tiče funkcionalnog kapaciteta, došlo
je do značajnog povećanja maksimalne potrošnje kiseonika (VO2 peak, p = 0,003),
dužine trajanja testa fizičkim opterećenjem, metaboličkih ekvivalenata (vreme vežbanja
i MET, p < 0,001) i maksimalnog kiseoničnog pulsa (peak O2 pulse). Poboljšanje
pomenutih parametara funkcionalnog kapaciteta posebno je izraženo u grupi pacijenata
koji su izgubili više od 18% početne telesne mase. Takođe, plućni parametri kao što su
ventilatorna efikasnost i rezerva disanja bili su značajno bolji nakon operacije kod
pacijenata sa većim s
manjenjem telesne mase. Petogodišnja stopa preživljavanja
morbidno gojaznih bolesnika nakon operacije bila je 97% i predstavljena je Kaplan-
Majerovom analizom. Znatan gubitak telesne mase (33,73±18,34kg) nakon RYGB
operacije zabeležen je kod 94% pacijenata, dok je samo 6% imalo poveća nje telesne
težine (5,50±2,12kg) nakon petogodišnjeg perioda praćenja. Gubitak u kilaži bio je
povezan i sa značajnim smanjenjem komorbiditeta, najviše dijabetesa i sedentarnog
načina života. (p = 0.005, p < 0.001, redom). Takođe treba napomenuti da je broj lekova
za hipertenziju smanjen, ali se broj pušača povećao.
Zaključci: Smanjenje telesne mase nakon RYGB operacije morbidne gojaznosti
povezano je sa značajnim poboljšanjem kardiopulmonalnog funkcionalnog kapaciteta
šest meseci posle operacije, posebno kod pacijenata koji su izgubili više od 18% svoje
početne telesne mase. Pored toga, značajno smanjenje telesne mase povezano je sa
smanjenjem kardiovaskularnih faktora rizika kao što su dijabetes, pušenje,
hipertrigliceridemija i sedentarni način života posle šest meseci. Dugoročno
petogodišnje praćenje nakon operacije, pokazalo je da je RYGB siguran i efikasan
tretman za morbidnu gojaznost. Značajno smanjenje telesne mase i BMI posle operacije
bilo je povezano sa smanjenjem faktora rizika za kardiovaskularne bolesti kao što su
dijabetes melitus i sedentarni način života. | Background: Obesity is a leading public health problem in the 21st century. It is a
chronic disease caused by excessive body fat accumulation and weight gain leading to
health disorders, poor quality of life and morbidity. Also, obesity and being overweight
are associated with cardiopulmonary function disorders and with increased total
mortality, especially due to cardiovascular disease. Bariatric surgery, especially Roux-
en-Y gastric bypass (RYGB), has become the most effective surgical method for
significant and sustained weight loss in extreme obesity, with very low mortality rate.
Objectives: The aim of this study was to examine the effects of surgically induced
weight loss on cardiopulmonary function six months after the procedure, as well as the
effect of such an intervention on well known risk-factors for cardiovascular diseases.
Also, how surgically induced weight loss is maintained after five years of follow up has
been examined and how it effects on cardiovascular risk factors.
Method: This is cross-sectional study with 66 morbidly obese patients (BMI ≥ 40kg/m2
or BMI ≥ 35kg/m2 with present co-morbidities), age 20 to 61 years, mostly women
(77.3%) who underwent bariatric surgery in the period 1.06.2011-31.12.2012. During
the preparations for the operation, they were examined by endocrinologists, dieticians,
pulmologists, cardiologists, psychiatrists, anesthesiologists and surgeons. Data from the
history of the disease were used to create the database. The cardiopulmonary exercise
test was done on treadmill using Bruce protocol, while simultaneously analyzing gases
in the exhaled air through the facial mask and the ergospirometry system.
Cardiopulmonary functional evaluation was performed prior and 6 months after RYGB.
Also a follow up of those patients comparing their body mass and co-morbidities prior
to and five years after Roux-en-Y bypass, as well as the global outcome has been done.
All patients were examined at the Clinical Center of Serbia, in the Laboratory for CPET.
Complete statistical analysis of data was done using the statistical software package,
PASW Statistics 18® [SPSS (Hong Kong) Ltd., Hong Kong].
Results: The substantial amount of weight loss (29.80 ± 13.27kg) after RYGB surgery
was associated with significant reduction of co-morbidities, especially diabetes and
sedentary life-style. (p=0.005, p=0.002 respectively). Regarding functional capacity
there was significant increase in peak oxygen uptake (VO2 peak, p=0.003), duration of
exercise testing, metabolic equivalents (exercise time and METs, p < 0.001) and in peak
O2 pulse. These findings were particularly pronounced in a group of patients who had
lost more than 18% of initial weight. Also, ventilatory efficiency and breathing reserve
were significantly better after surgery in patients with greater body mass reduction.
Five year survival rate of morbid obese patients after surgery was 97% as presented by
Kaplan-Meier analysis. The substantial amount of weight loss (33,73 ± 18,34kg) after
RYGB surgery was seen in 94% patients, while 6% have increased body mass (5,50 ±
2,12kg) after that period. Reduction of body mass weight was associated with
significant reduction of co-morbidities, especially diabetes and sedentary life style (p =
0.005, p < 0.001, respectively). The number of drugs taken for hypertension treatment
was reduced, but number of smokers was increased.
Conclusions: Reduction of body weight after RYGB surgery is associated with
significantly improved cardiorespiratory function 6 months after surgery, especially in
patients who lost more than 18% of their initial body weight. In addition, substantial
decreases in body weight were also associated with a reduction of cardiovascular risk-
factors such as diabetes, smoking, hypertrygliceridemia and sedentary life-style after six
months. Also, long term analysis after surgery showed that RYGB is a safe and an
effective treatment for morbid obesity. Significant decreases in body weight and BMI
after surgery were associated with a reduction of cardiovascular risk factors such as
diabetes mellitus as well as sedentary life-style. | true |
Uloga Interleukina-23 u prevremenom razvoju emfizema pluća među HIV-1 + pušačima | The Role of Interleukin-23 in the Early Development of Emphysema in HIV1+ Smokers | Genska ekspresija matriks metaloproteinaze-9 (MMP-9) je pojačana u alveolarnim
makrofagima (AM) HIV-1 pozitivnih pušača obolelih od emfizema pluća. Na osnovu
podataka koji ukazuju da supernatant bronhoalveolarnog lavata u plućima HIV-1
pozitivnih pušača sadrži povišene koncentracije inflamatornih citokina u odnosu na
ovu tečnost u plućima HIV-1 negativnih pušača, postavili smo hipotezu da povišene
koncentracije inflamatornih citokina u populaciji HIV-1 pozitivnih pušača utiču na
povišenje koncentracije metaloproteinaza, na taj način dovodeći do ranog razvoja
emfizema pluća.
Putem multicitokinske analize, analizirali smo supernatante bronhoalveolarnog
lavata 5 različitih fenotipskih grupa: HIV-1 negativnih nepušača, HIV-1 negativnih
pušača bez poremećaja disajnih puteva, HIV-1 negativnih pušača sa ranim
emfizemom pluća, HIV-1 pozitivnih nepušača i HIV-1 pozitivnih pušača sa ranim
emfizemom pluća. Pored pojačane ekspresije inflamatornih citokina u plućima
pušača zaraženih virusom HIV-1, povišene vrednosti citokina koji indukuju Th-17,
pre svega interleukina IL-23, predstavljaju zajedničku karakteristiku HIV-1
pozitivnih nepušača, HIV-1 pozitivnih pušača sa ranim emfizemom pluća i HIV-1
negativnih pušača sa ranim emfizemom pluća. Relativna ekspresija IL-23 gena u AM
HIV-1 pozitivnih osoba je povišena u odnosu na AM HIV-1 negativnih ispitanika, i
značajno je povišena u odnosu na AM HIV-1 pozitivnih pušača sa ranim emfizemom
pluća. Akutna infekcija HIV-1 virusom in vitro dovodi do pojačane ekspresije IL-23 u
HIV-1 negativnim AM. Stimulacija kultura AM IL-23 dovodi do pojačane ekspresije
MMP-9 gena i pojačane koncentracije MMP-9. S obzirom na to da AM zdravih osoba
ne eksprimiraju IL-23 receptor (IL-23R), činjenice da kulture makrofaga prečišćenih
adherencijom sadrže izvestan procenat T limfocita i činjenice da dodavanje T
7
limfocita ovim kulturama pojačava produkciju MMP-9, efekat IL-23 na pojačano
lučenje MMP-9 može biti indirektan i zahteva učešće T limfocita u ovom procesu.
Uticaj IL-23 na MMP-9 je jedan od mogućih mehanizama koji dovode do ranog
razvoja emfizema pluća i ukazuje na mogući uticaj Th-17 indukovanog imunskog
odgovora u razvoju ovog fenomena. | Matrix metalloproteinase-9 (MMP-9) is up-regulated in alveolar macrophages (AM)
of HIV1+ smokers, who develop emphysema in an accelerated time frame compared
to HIV1- smokers. The epithelial lining fluid (ELF) of HIV1+ smokers has increased
levels of inflammatory cytokines compared to their HIV1- counterparts. To assess
the hypothesis that up-regulation of lung cytokines may be functionally related to
the increased concentrations of MMP-9, arrays were used to evaluate relative
cytokine protein levels in the ELF obtained from 5 groups of individuals: HIV1‾
healthy nonsmokers, HIV1‾ healthy smokers, HIV1‾ smokers with early emphysema,
HIV1 + nonsmokers, and HIV1 + smokers with early emphysema. While several pro-
inflammatory cytokines were increased in smoking and HIV1+ phenotypes,
increased levels of Th17-related cytokines such as IL-23 and IL-17 represented a
common finding in HIV1- smokers with early emphysema as well as in HIV1+
individuals independently of their smoking history. We further hypothesized that
IL-23 is up-regulated in the setting of HIV1 infection and that this pro-inflammatory
cytokine may be directly correlated to increased concentrations of MMP-9 in the
ELF of HIV1+ smokers with early emphysema. Relative gene expression of AM IL-23
is significantly increased in HIV1+ individuals, with a trend toward even greater
expression in HIV1+ smokers with early emphysema. Infection with HIV1 laboratory
strain JRFL in vitro induced IL-23 expression in normal AM. With the knowledge that
AM cultured by the adherence method contain a small number of other cells,
including lymphocytes, we hypothesized that in an AM/lymphocyte co-culture
system IL-23 would up-regulate MMP-9. Stimulation of AM/lymphocyte co-cultures
with IL-23 in vitro induced increased MMP-9 gene expression and protein. While AM
obtained from healthy individuals do not express IL-23 receptors, T lymphocytes
express IL-23R and act as an intermediary to up-regulate AM MMP-9. This
9
mechanism may contribute to the increased tissue destruction in the lungs of HIV1+
smokers and suggests that Th-17 related inflammation may play a role. | true |
Značaj Power Doppler ultrazvučnog pregleda za dijagnozu perifernih entezitisa kod bolesnika sa spondiloartritisima | Value of the Power Doppler ultrasound findings for diagnosis of the peripheral enthesitis in patients with spondyloarthritis | Uvod. Ultrazvuk ima vaţnu ulogu za dijagnozu perifernog entezitisa kod bolesnika sa spondiloartritisima (SpA) jer je dokazano da je senzitivniji i specifičniji dijagnostički metod od kliničkog nalaza entezitisa. Cilj: Utvrditi razlike u ultrazvučnim karakteristikama entezitisa kod bolesnika sa SpA u odnosu na bolesnike sa reumatoidnim artritisom (RA) i bolesnike sa mehanički uslovljenim entezitisom (MRE). Metodologija: Istraţivanje je sprovedeno kao prospektivna, duplo slepa studija. Istraţivanje je obuhvatilo 127 bolesnika sa postavljenom dijagnozom entezitisa od strane ordinirajućeg reumatologa. MeĎu ispitivanim bolesnicima bilo je 75 bolesnika sa SpA, 26 bolesnika sa RA i 26 bolesnika sa MRE. Bolesnici su dolazili na 4 predviĎene vizite u toku 6 meseci. Pored demografskih podataka, istraţivanje je obuhvatilo analiziranje kliničkih, laboratorijskih i radiografskih nalaza, pokazatelja aktivnosti bolesti i funkcionalne sposobnosti bolesnika. Na svakoj viziti klinički pregled obavljao je jedan reumatolog, a ultrazvučno ispitivanje enteza dvoje ultrasonografista. Reumatolog i ultrasonografisti nisu znali osnovnu dijagnozu bolesti, mesto entezitisa, laboratorijske, radiografske, kliničke i ultrazvučne nalaze. Klinički i ultrasonografski su ispitivane obostrano sledeće enteze: plantarne fascije (PF), Ahilove tetive (AT), gornjeg pripoja ligamenta patele (GLP), donjeg pripoja ligamenta patele (DLP), tetive kvadricepsa (TK), tetive gluteusnih mišića (TGM), zajedničke tetive ekstenzora podlaktice (ZTEP), zajedničke tetive fleksora podlaktice (ZTFP) i tetive tricepsa (TT). Na svakoj viziti, u toku istraţivanja, oboje ultrasonografista su kod svakog od 127 bolesnika pregledali svaku od navedenih 18 enteza u longitudinalnoj i transverzalnoj ravni. Ultrazvučne znake entezitisa predstavljali su: (1) povećana debljina enteze, (2) hipoehogenost sa istovremeno prisutnim gubitkom normalne fibrilarne strukture enteze, (3) entezofit, (4) PD signal u nivou enteze (< 2mm od korteksa kosti) i (5) erozija... | Introduction. Ultrasound (US) has an important role for diagnosis of the enthesitis in spondyloarthritis (SpA) because it is proved to be a more sensitive and more specific diagnostic tool than clinical examination. Objectives. To identify the differences in ultrasound characteristics of enthesitis in patients (pts) with SpA compared to patients with rheumatoid arthritis (RA) and patients with mechanically related enthesitis (MRE). To determine the relationship between ultasound and Power Doppler (PD) findings of the peripheral enthesitis with clinical and radiographic findings of the peripheral enthesitis. Methods. This prospective, blinded study included 127 pts with enthesitis (76 pts with SpA, 26 pts with rheumatoid arthritis, 25 pts with mechanically-related enthesitis). Demographic, clinical, laboratory anad radiographic findings, as well as values of the diseases activity and functional indexes were summarized. Data were summarized by descriptive statistics (frequencies, mean and standard deviation). The entheses of the plantar fascia (PF), the Achilles tendon (AT), the patellar tendon distal (PTD) and the patellar tendon proximal (PTP) insertion, the quadriceps tendon (QT), the gluteus tendons (GT) on the greater trochanter, the common extensor tendon (CET) on the lateral epicondyle, the common flexor tendon (CFT) on the medial epicondyle, and the triceps tendon (TT) were examined bilaterally by clinical and US examination. Clinical rheumatologist and two US operators were blind to clinical diagnosis, sites of the enthesitis, laboratory, radiographic and US findings. The operators assessed enthesis thickness, echogenicity, enthesophytes, PD signal and erosions. Logistic regression and receiver operating characteristic (ROC) curve analysis were used to determine the predictive value of each enthesitis lesion for diagnosis of SpA. The best predictive value for SpA was accomplished when absence and presence of increased thickness, hypoechogenicity and enthesophytes were scored as 0 and 1; absence and presence of PD and erosions were scored as 0 and 4... | false |
Prognostički značaj GDF-15 kod bolesnika sa manifestnim pogoršanjem hronične srčane slabosti | Prognostic significance of gdf-15 in patients with manifest deterioration of chronic heart failure. | Akutno manifestno pogoršanje kod pacijenata sa hroničnom srčanom insuficijencijom (HSI) je klinički sindrom od posebnog značaja kao životno ugrožavajuće stanje koje zahteva hitnu medicinsku pomoć i obično se završava hitnim prijemom u bolnicu... | Acute manifest decompensation of patients with chronic heart failure (CHF) is a clinical syndrome of particular interest as a life threatening condition that requires immediate medical attention and usually leads to urgent hospital admission... | false |
Stanje i ponašanje dinamički napregnutih struktura u ekstremnim uslovima rada | The state and behavior of dynamicaly loaded structures in extreme operating conditions | Osnovna ideja na kojoj se zasnivaju bazni ciljevi disertacije je identifikacija
ekstremno teških uslova eksploatacije mašinskih struktura i njihovih
opterećenja koji predstavljaju kompleksnu interakciju izuzetno visokih
toplotnih i nehomogenih uticaja, intenzivnih uticaja strujanja fluida, uticaja
visokih brzina rotacije, sopstvenih i prinudnih vibracija i dr. Ovi su uticaji
prisutni kod gasogeneratora turbomlaznih i turbovratilnih motora za koji je
bilo potrebno razviti inovativno konstrukcijsko rešenje multifunkcionalne
pregrade između rotora kompresora i turbine. Za realizaciju postavljenog cilja
razvijena je odgovarajuća metodologija inženjerskog dizajna zasnovana na
iterativnom razvoju, ispitivanju i analizi stanja i razaranja delova pregrade, pod
nazivom Failure-based Design – FBD. Razvijen je skup od pet konstrukcijskih
rešenja ove pregrade. Četvrto rešenje je postalo prihvatljivo za eksploataciju u
ovim uslovima, a peto rešenje je ostvarilo sve funkcije i zadovoljilo sve zahteve.
Za ovu svrhu sprovedena su mnoga eksperimentalna ispitivanja, brojne numeričke
analize strujanja fluida (CFD), analiza toplotnog stanja (raspodele temperature),
proračuna napona i deformacija delova pregrade, razvoj konstrukcijskih rešenja
i dr. Radi realizacije osnovnog cilja, rad je obuhvatio širok spektar
eksperimentalnih sadržaja, značajan broj numeričkih analiza i proračuna,
analiza
brojnih
specifičnih
havarijskih
oštećenja
i
predloženih
konstrukcijskih rešenja da bi se ova razaranja izbegla. | The general idea on which the basic goals of the dissertation are founded on is the
identification of extremely hard conditions of mechanical structures and their loads which
represent a complex interaction of several influences, i.e. extremely high heat,
nonhomogeneous influences, intensive influences of fluid flow, high rotation speeds, its
natural and forced vibrations etc. These influences are present at the gas generator of
turbojet and turboshaft engines for which there was a need to develop an innovative
construction solution for the multifunctional bulkhead between the compressor rotor and
the turbine. In order to accomplish the set goal, an appropriate methodology of
engineering design was developed which is based on iterative development, testing and
analysis of the state and damage of the parts of the bulkhead, which is called Failure-
based Design – FBD. A set of five construction solutions for the bulkhead was developed.
The fourth solution became acceptable for exploitation in these conditions, while the fifth
solution accomplished all functions and met all the requirements. In order to achieve this,
numerous experimental testings were performed, along with many numerical analyses of
the fluid flow (CFD), heat state (temperature distribution), stress and deformations
calculations of the bulkhead parts, the development of construction solutions etc. In order
to achieve basic goal, the paper encompassed a wide range of experiments, a significant
number of numerical analyses and calculations, analyses of many specific damages and
suggested construction solutions so as to avoid these damages. | true |
Procena efektivnosti odložene rekonstrukcije dojke posle mastektomije modifikovanom suspenzornom tehnikom | Assessment of efficiency of delayed breast reconstruction after mastectomy by modified suspension technique | UVOD: Odložene, sekundarne, rekonstrukcije su operativni zahvati u periodu posle
mastektomije. Tehnike su razne, ali se najčešće se izvode korišćenjem ekspander proteza, a
potom zamenom trajnim u drugom aktu ili korišćenjem mišićno-kožnih režnjeva. Rekonstrukcija
ekspander protezama je retko korišćena u našoj zemlji jer je značajno skuplja procedura, a
tehnike sopstvenim tkivom zahtevaju dobru kondiciju pacijenata i duži oporavak posle operacije
kao i moguće komplikacije donorne regije.
Tehnika suspenzorne metode u kojoj se koristi lokalni klizajući režanj omogućava sekundarnu
rekonstrukciju dojke u kombinaciji sa trajnom protezom. Ova tehnika prvi put bila je opisana
1979. godine (Lewis i sar.), a kasnije i modifikovana korišćenjem neresorptivne mrežice
(Riejtens i sar., 2005.) koji su koristili istu tehniku u kombinaciji sa trajnom protezom da bi
obezbedili najoptimalniji estetski rezultat.
CILJ: Ispitati prednosti modifikovane suspenzorne tehnike za odloženu rekonstrukciju kroz
analizu postoperativnog oporavka pacijenata i procenta postoperativnih komplikacija.
Istovremeno prikazati mogućnosti modifikovane suspenzorne tehnike u odloženoj rekonstrukciji
u odnosu na veličinu i oblik endoproteze i istovremenu simetralizaciju suprotne dojke. Cilj je bio
i procena kozmetskog efekta nakon modifikovane suspenzorne tehnike rekonstruktivnog hirurga
i pacijentkinja neposredno posle operacije i 2 godine kasnije.
MATERIJAL I METODE: Ova klinička kohortna studija uključila je 139 pacijentkinja sa
primarnim karcinomom dojke koje su imali unilateralnu odloženu rekonstrukciju dojke
modifikovanom suspenzornom tehnikom nakon mastektomije. Sve pacijentkinje su operisane u
Institutu za onkologiju i radiologiju Srbije, u periodu od 1996. do 2010. godine. Pacijentkinje su
inicijalno imale operabilni karcinom dojke, bez udaljenih metastaza. Hirurško lečenje je
podrazumevalo modifikovanu radikalnu mastektomiju i adjuvantnu terapiju (hemioterapija,
hormonoterapija) koja je bila primenjena shodno indikacijama. U ovom istraživanju ispitan je
uticaj 4 grupe parametara: karakteristike pacijenata, karakteristike bolesti, karakteristike
adjuvantne terapije i karakteristike rekonstrukcije na pojavu neželjenih ishoda rekonstrukcije
(ranih, kasnih komplikacija i lokalnih recidiva) i kozmetski ishod rekonstrukcije neposredno
nakon zahvata i dve godine posle, a shodno subjektivnim procenama pacijentkinja i ocenama
rekonstruktivnog hirurga Nakon rekonstrukcije, u dve vremenske odrednice: neposredno posle
operacije i 2 godine kasnije, pacijentkinje i rekonstruktivni hirurg su ocenili izgled
rekonstruisane dojke i postignutu simetriju ocenama od 1 do 5.
REZULTATI: Ukupna učestalost komplikacija bila je 19% u čijoj strukturi su najčešće bile
komplikacije kontrakture kapsule (37% od svih komplikacija i 7.25 % od ukupnog broja
pacijenata). Efikasnost metode se pokazala i u malom broju ranih komplikacija koje su se javile
u svega 5 pacijentkinja ili 3.6% u vidu infekcije koja je tretirana konzervativno. Ispitivanjem
povezanosti komplikacija sa karakteristikama pacijentkinja (starosna dob, indeks telesne mase i
navike pušenja), kao i uticaja stadijuma bolesti i onkološkog lečenja na pojavu komplikacija
posle rekonstruktivnog zahvata, zaključeno je da ispitivani parametri nisu uticali na veći
procenat pojave komplikacija. Prosečna ocena koju su pacijenti davali za kozmetski rezultat
posle operacije bio je 4.57, odnosno 61.15% onih čija je ocena bila odličan kozmetski efekat.
Nešto nižu ocenu davali su hirurzi - 4.53, odnosno 57.55% odličnih. Zabeležene ocene koje
prikazuju konačni utisak u periodu praćenja bile su niže i kod pacijenata (4.28) i kod hirurga
(4.17). Tokom godina, kozmetski rezultat postajao je lošiji a najčešće uslovljen pojavom
komplikacija, kontrakture kapsule, kao i opuštanjem zdrave dojke. Vrednosti ocena estetskog
rezultata statistički značajno su veće posle dve godine kod pacijentkinja kod kojih je urađena
korekcija zdrave dojke, kao i kod onih kod kojih je korišćena proteza u kontralateralnoj zdravoj
dojci.
ZAKLJUČAK: Modifikovana suspenzorna tehnika klizajućeg režnja sa gornjeg prednjeg
trbušnog zida za odloženu rekonstrukciju dojke uz korišćenje trajnog implanta ima mnoge
prednosti u odnosu na druge tehnike, od kojih su najvažnije dobar kozmetski efekat i izostanak
komplikacija vezanih za donorsku regiju, kao i smanjenje broja hirurških procedura, što je
posebno važno za zemlje u razvoju jer redukuje troškove lečenja. | INTRODUCTION: Delayed breast reconstruction after mastectomy is mainly performed using
expander prostheses that are later replaced by permanent ones, or using pedicle or free
musculocutaneous flaps. Insufficient amount of skin in this area represents the main problem.
Expander technique is rarely available in our country due to financial implications of this
method. Flap procedures are performed in several instances which increase treatment costs and
prolong the patient’s recovery due to many expected complications.
Besides these two techniques, it is possible to use AAF technique to increase the skin
envelope for permanent prosthesis. This surgical technique was first described by Lewis in 1979.
Later, in 2005 it was modified by Riejtens combined AAF with non-absorbable mesh. This
technique reduces the number of operational stages, as well as donor-site complications, whilst
providing more optimal aesthetical results.
PURPOSE: To evaluate the adverse outcomes after delayed breast reconstruction (DBR) by
abdominal advancement flap (AAF) and permanent prosthesis in patients treated with
mastectomy due to unilateral breast carcinoma, as well as to determine which factors are
predictive for their occurrence. In the same time, purpose was to evaluate cosmetic results after
surgery and two years later.
MATERIALS AND METHODS: This clinical cohort study included 139 patients with primary
breast carcinoma who were subjected to unilateral delayed breast reconstruction using modified
suspension technique upon mastectomy. All patients were operated at the Institute for Oncology
and Radiology of Serbia from 1996 to 2010. Patients initially had operable breast carcinoma with
no distant metastases. Surgical treatment consisted of modified radical mastectoimy followed by
adjuvant treatment (chemotherapy, radiotherapy, hormonotherapy) applied accordingly.
This research examines four groups of parameters: characteristics of the patients, of the disease,
of adjuvant therapy and of the reconstructions, and their influence on appearance of adverse
outcomes of reconstruction (early and late complications and local relapses) and on cosmetic
outcome of reconstruction immediately after the procedure as well as two years later, taking into
account subjective assessment of patients and evaluations of reconstructive surgeons. Both the
patients and the surgeons rated appearance of the reconstructed breast and achieved symmetry in
two time intervals - immediately upon reconstruction and two years later – using grades from 1
to 5.
RESULTS: Total frequency of complications was 19%, most frequent being capsule contracture
(37% of all complications appearing in 7, 25% of patients). Effectiveness of the method is
evident from the small number of early complications which appeared in only 5 patients (3.6%)
in the form of infections treated conservatively.
Examining correlation of complications with characteristics of patients, their age, ITM and
smoking habits as well as influence of stage of disease and oncological treatment on occurrence
of complications after reconstruction, we concluded that examined parameters did not contribute
to a significant increase in complication rate. Average mark given by patients for cosmetic result
after procedure was 4.57 meaning that 61.15% patients considered cosmetic result to be
excellent. Surgeons rated the results slightly lower – 4.53 (57.55% respectively).
Second, reflecting the final assessment during observance period, were lower both in the case of
patients (4.28) and in the case of surgeons (4.17). In the following years, cosmetic result
deteriorated mostly due to the appearance of complications, capsule contractures and sagging of
the healthy breast. Grade given after two years is significantly higher in the patients where
correction of the healthy breast was also performed and in the patients with placed implants in
contralateral healthy breast.
CONCLUSION: Delayed breast reconstruction by modified suspension technique using
abdominal advancement flap and permanent implant has many advantages over other techniques,
most important being good cosmetic result and lack of complications related to the donor region
followed by decreased number of necessary surgical procedures which is particularly important
in developing countries since it reduced the costs of the treatment. | true |
Klinički značaj prediktivnih faktora u nastanku i lečenju karotidne restenoze kod pacijenata nakon everzione endarterektomije | Clinical significance of predictive factors in development and treatment of carotid restenosis in patients after eversion endarterectomy. | Uvod: Karotidna endarterektomija je vrlo pouzdana metoda za lečenje simptomatske i
asimptomatske visoko-stepene karotidne stenoze. Karotidna restenoza predstavlja
ponovno suženje karotidne arterije koje nastaje kao rezultat neointimalne hiperplazije u
ranom postoperativnom periodu (unutar 36 meseci) ili rekurentnih aterosklerotskih
lezija u kasnijem toku. Nekoliko studija je pokazalo da je povišena koncentracija C-
reaktivnog proteina (CRP) nezavistan prognostički faktor budućih kardioloških
ishemičnih događaja, ali je malo raspoloživih podataka koji govore o povezanosti
karotidne ateroskleroze i serumske koncentracije hs-CRP i drugih proteina akutne faze
inflamacije.
Ciljevi: Cilj naše studije bio je da ispitamo uticaj preoperativno i neposredno post
operativno (48h) povišenih vrednosti sistemskih markera inflamacije („high sensitive“
C-reaktivni protein (hs-CRP), C3 komplement i fibrinogen), njihovih oscilacia i uticaj
na nastanak karotidne restenoze nakon everzione endarterektomije tokom praćenja.
Takođe smo analizarali uticaj infamatorne komponente i strukture karotidnog plaka na
nastanak karotidne restenoze kao i uticaj svih faktora rizika i drugih udruženih
oboljenja. Poslednji cilj bio je da uporedimo rezultate perkutane angioplastike i
ponovnog hirurškog lečenja pacijenata sa karotidnom restenozom uz evaluaciju
prediktivnih faktora koji mogu imati uticaja na konačni ishod oba modaliteta lečenja.
Materijal i metode: Ispitivanjem obuhvaćeno je 300 pacijenata kojima je na Klinici
za Vaskularnu hirurgiju Instituta za kardiovaskularne bolesti „Dedinje“ učinjena
everziona karotidna endarterektomija od 1.marta do 1. avgusta 2010. godine.
Analizirana je serumska koncentracija „high-sensitive“ C-reaktivnog proteina (hs-
CRP), fibrinogena i C3 komplementa na dan operacije neposredno pre
enadarterektomije, 48 časova nakon endarterektomije, kao i na redovnim kontrolnim
pregledima nakon 1 meseca, 6 meseci, godinu dana i dve godine.
Drugi deo studije podrazumeva retrospektivnu analizu i komparaciju endovaskularnih
i ponovnih hirurških procedura učinjenih kod pacijenata sa karotidnom restenozom u
periodu od 2002-2012. godine. U tom periodu ukupno je učinjeno 319 perkutanih
angioplastika i 52 ponovne hirurške procedure kod pacijenata sa karotidnom
restenozom. Analizirano je prisustvo postproceduralnog morbiditeta kao i neurološki i
ukupni mortalitet. Kod svih pacijenata analizirana je prediktvna vrednost svih faktora
rizika u odnosu na ishod nakon angioplastike i ponovnog hirurškog lečenja.
Rezultati: Pacijenti koji su imali povišene vrednosti hs-CRP-a na dan operacije su
imali povišeni rizik za nastanak rane karotidne restenoze unutar godinu dana kao i
pacijenti koji su imali povišene vrednosti fibrinogena 48h nakon operacije. Pacijenti
koji posle operacije nisu uzimali aspirin su imali povišeni rizik za nastanak karotidne
restenoze. Pokazalo se da je pol značajan, nezavisan prediktor nastanka restenoze pri
čemu žene imaju veći rizik za nastanak restenoze nego muškarci (odds ratio = 0.351;
p=0.030). Muškarci koji su uzimali aspirin i imali inflamacijski skor >2 (povišena 2
od 6 faktora inflamacije) imali su i veći rizik za nastanak restenoze tokom praćenja u
poređenju sa pacijentima koji su imali inflamacijski skor <2. Jednostavnom primenom
vrednosti uzimanja/ne uzimanja aspirina nakon operacije i vrednosti fibrinogena 48h
nakon operacije u Fišerovoj jednačini, moguće je izračunati da li će pacijent imati
značajan rizik za nastanak rane karotidne restenoze unutar godinu dana ili neće imati
rizik za nastanak karotidne restenoze. Takođe, pacijenti koji imaju hipotireozu imali
su i veći rizik za nastanak karotidne restenoze. Što se tiče modaliteta lečenja, nema
značajnih razlika u ishodu angioplastike i „redo“ operativnog lečenja u svim
posmatranim ishodima, osim u odnosu na pojavu post-proceduralnog moždanog udara
i rekurentne restenoze sa boljim rezultatima karotidnog stentinga. Pacijenti koji su
imali prethodni tranzitorni ishemični atak imaju veći rizik od nastanaka
postoperativnog moždanog udara nakon «redo» operativnog lečenja karotidne
restenoze. Sa druge strane, ženski pol, pušenje, koronarna bolest, lokalizacija
restenoze i kalcifikacije plaka, tip stenta i cerebralne protekcije imaju značajan uticaj
na lošiji ishod karotidne angioplastike.
Zaključak: Rezultati naše studije pokazuju da inflamacija ima važnu ulogu u
nastanku karotidne restenoze nakon everzione endarterektomije. Kliničkom primenom
dobijenih rezultata moguće je identifikovati pacijente koji umaju povišeni rizik za
nastanak karotidne restenoze i kod istih agresivnijom terapijom uticati na smanjenje
stope restenoze. Posebno je važno otkiće jednačine kojom se izračunava rizik od
nastanka restenoze što može biti od velikog medicinskog i naučnog značaja. Što se
tiče lečenja karotidne restenoze pokazano je da su obe procedure bezbedne, sa ipak
malo boljim rezultatima karotidnog stentinga, a takođe su dobijeni i važni prediktori
ishoda obe procedure koji mogu imati uticaj na odabir odgovarajuće procedure kog
svakog pacijenta. | Objective: Carotid endarterectomy is known as very reliable procedure for
symptomatic and asymptomatic carotid stenosis treatment. Carotid restenosis
represents recurrent stenosis that occurs as a result of neointimal hyperplasia in the
early postoperative period (within 36 months) or recurrent atherosclerotic lesions in
the following period. Several studies have shown that increased C-reactive protein
(CRP) values is independent prognostic factor of future cardiological ischemic events,
but there is a few studies that describe connection between CRP serum concentration,
carotid atherosclerosis and other acute inflammatory phasec proteins.
Aims: The aim of our study was to examine influence of increased values of markers
of systemic inflammation (high sensitivity C-reactive protein (hs-CRP), C3
complement and fibrinogen) taken just before and after the surgery, its oscillations
and its mutual impact on carotid restenosis development after eversion
endarterectomy. We have also analyzed the impact of inflammatory component and
structure of the carotid plaque on carotid restenosis development as well as influence
of all risk factors and other comorbidities. The last aim was to compare the outcome
of percutaneous angioplasty and “redo” surgical treatment in patients with carotid
restenosis with evaluation of predictive factors influencing the final outcome in both
treatment modalities.
Methodology: In the presented study, 300 patients were included in whom eversion
carotid endarterectomy was performed from 1st march till 1st august 2010. on the
Vascular surgery Clinic, “Dedinje” cardiovascular Institute. We have analyzed serum
concentration of hs-CRP, fibrinogen and C3 complement taken just before the surgery
(06h), 48h after the surgery and on the regular check-ups after 1 month, 6 months, one
year and two years. In then second part of the presented study we have retrospectively
compared the outcomes of endovascular and “redo” surgical treatment of patients
with carotid restenosis in the period from 2002. till 2012.
During this period a total of 319 percutaneous angioplasty procedures were performed
and 52 “redo” surgical procedures. We have analyzed post procedural morbidity as
well as neurological and overall mortality. In all patients we have evaluated predictive
value of all risk factors and other comorbidities influencing outcome of both
procedures.
Results: Patients with increased values of hs-CRP just before the surgery (06h) had
increased risk of carotid restenosis occurrence during the follow up as well as patients
with increased fibrinogen values 48h after the surgery. Patients who were not taking
aspirin had increased risk of carotid restenosis occurrence as well. Gender showed to
be independent predictor of restenosis occurrence with females having higher risk for
restenosis during the follow up, (odds ratio = 0.351; p=0.030). Males taking aspirin
and inflammation score >2 (increased 2 out of 6 inflammation markers) had increased
risk for restenosis when compared to males with inflammation score <2. With simple
implementation in the Fishers’ equation of the data referring to aspirin use (taking/not
taking) and fibrinogen values 48h after the surgery (normal/elevated) we can calculate
wheatear a patient will have high risk of early restenosis occurrence with the first year
or will not have an increased risk. Likewise, patients with hypothyreosis had
increased risk of restenosis occurrence as well. As for treatment modalities, there is
no significant difference between carotid angioplasty and “redo” surgical treatment in
all evaluated outcomes except for post procedural stroke and recurrent restenosis rate
with better results of carotid stenting. Previous transient ischemic attack was
independent predictor for postoperative stroke in patients with “redo” surgical
treatment. On the opposite, female gender, smoking, coronary artery disease,
restenosis localization, plaque calcifications, type of the stent and cerebral embolic
device have influence on adverse outcome of carotid stenting.
Conclusion: The results of the presented study clearly indicate that inflammation has
significant role in carotid restenosis growth after eversion endarterectomy. With
clinical implementation of obtained results it is possible to identify high-risk patients
for carotid restenosis resulting in more aggressive medical therapy in such patients
finally leading to decrease of restenosis rate. Particularly important is the discovery of
the equation calculating the risk of restenosis that could be of great medical and
scientific importance.
As for carotid restenosis treatment, our results showed that both procedures are safe
with a little bit better results of carotid angioplasty while on the other hand we have
obtained important predictors of outcome of both procedures that could influence
appropriate selection of the procedure in each specific patient. | true |
Značaj odnosa indeksa slobodnog i ukupnog prostata specifičnog antigena prema gustini prostata specifičnog antigena u dijagnostici karcinoma prostate u "sivoj zoni" | Significance of free to total prostate specific antigen ratio and prostate specific antigen density in gray zone prostate cancer diagnostic | Ispitivali smo znaĉajnost, odnos slobodnog i ukupnog PSA (F/T) prema PSA gustini (F/T)/PSAD u sivoj zoni, PSA 4-10 ng/ml za rano otkrivanje karcinoma prostate. Materijal i metode: Istraţivanje je rađeno na Urološkoj klinici Kliniĉkog centra Srbije i Medicinskog fakulteta Univerziteta u Beogradu u periodu od 2007. godine do 2015. godine. Kriterijum za odabir 150 bolesnika bio je serumski PSA između 4,0-10,0 ng/ml. Svim bolesnicima određivan je serumski PSA, slobodni PSA (F PSA), odnos slobodnog i ukupnog PSA (F/T PSA) i PSA gustina (PSAD), korišćen je Abbott test. Volumen prostate meren je transrektalnim ultrazvukom (TRUS), svima je rađena TRUS sextant biopsija prostate. Rezultati rada: Od 150 ispitivanih bolesnika, kod 91 (60,7%) bolesnika je patohistološki verifikovana benigna prostatiĉna hiperplazija (BPH), a 59 (39,3%) bolesnika imalo je patohistološki verifikovan kracinom prostate (CaP). (F/T)/PSAD je pokazao statistiĉki znaĉajno niţe vrednosti kod bolesnika sa CaP (0,75), nego kod BPH (1,42) (p<0,01). F/T statistiĉki niţi kod CaP (0,15) nego kod BPH (0,21) (p<0,01) i PSAD statistiĉki znaĉajno viši kod CaP (0,21) nego kod BPH (0,17) (p<0,01). Cutoff za (F/T)/PSAD 0,85, daje senzitivnost 68,6% i specifiĉnost 66 %, a površina ispod krive (AUC) 0,725, cutoff za F/T 0,145 daje senzitivnost 70,3%, specifiĉnost: 60,3% i AUC: 0,671 i cutoff za PSAD: 0,185 daje senzitivnost: 65,0%, specifiĉnost: 65,1% i AUC: 0,683. Poređenjem površina ispod krive (AUC) vidi se da najbolje vrednosti pokazuje odnos (F/T)/PSAD. Zakljuĉak: Bolesnicima sa PSA od 4-10 ng/ml moţe se predloţiti cutoff za (F/T)/PSAD 1,40, koji će smanjiti broj nepotrebnih biopsija za 25% Bolesnicima koji imaju niske vrednosti (F/T)/PSAD, F/T i visoke vrednosti PSAD, predlaţe se biopsija prostate zbog visokog rizika za karcinom prostate. | We have examined usefulness of the free to total PSA (F/T) against PSA density (F/T)/PSAD) in the gray zone, PSA 4-10 ng/ml for the early cancer detection. Material and methods : The examination took place at the Urology Clinics of Clinical Centre of Serbia and University of Belegrade School of Medicine in the period from 2007. to 2015. The criteria for the selection of 150 patients was the serum PSA between 4.0 – 10.0 ng/ml. All the patients were determined with serum PSA, free PSA (F PSA), free to total PSA ratio (F/T PSA) and PSA density (PSAD) by the Abbott test. Prostate volume was measured by transrectal ultrasound (TRUS) procedure and all of them had undergone TRUS sextant prostate biopsy. Results : Of 150 examined patients, 91 (60,7%) were histopathologically verified with the benign prostatic hyperplasia (BPH), and another 59 (39,3%) were with histopathologically verified prostate cancer (CaP). (F/T)/PSAD showed statistically significant lower values at the patients with CaP (0,75) then those with BPH (1,42) (p<0,01). F/T is statistically lower with CaP (0,15) than with BPH (0,21) (p<0,01) and the PSAD is significantly higher with CaP(0,21) than with BPH(0,17) (p<0,01). Cutoff for (F/T)/PSAD of 0,85 gives 68,6% sensitivity and 66,0% specificity and area under the curve (AUC) is 0,725, cutoff for F/T of 0,145 gives 70,3% sensitivity and 60,3% specificity and AUC 0,671 and PSAD 0,185 cutoff gives 65,0% sensitivity and 65,1% specificity and AUC 0,683. By area under the curve (AUC) comparison it can be seen that the best values are with (F/T)/PSAD ratio. Conclusion Patients with PSA 4-10 ng/ml can be recommended cutoff for (F/T)/PSAD 1,40, which and reduces number of unnecessary biopsies for 25%. Patients with low (F/T)/PSAD, F/T values, and high PSAD are prostate biopsy recommended because of prostate cancer high risk. | false |
Minimalno invazivni hirurški tretman urođenog krivog stopala | Minimally invasive surgical treatment of the congenital clubfoot | Urođeno krivo stopalo i dalje predstavlja ozbiljan problem u patologiji koštano-zglobnog sistema kod djece Mnoga pitanja iz oblasti urođenog krivog stopala i danas su predmet istraživanja i dilema. Najčešća pitanja koja su predmet rasprave odnose se na:etiologiju, kliničku klasifikaciju i načine liječenja. Pes equinovarus congenitus (PEVC) je deformitet stopala koji se liječi neoperativnim procedurama i operativno. U literaturi postoje različiti pristupi problemu liječenja PEVC , što zavisi od specijalnosti, ustanove koja se bavi ovim problemom i regije. Minimalno invazivni hirurški tretman (MIHT) je novi, savremeni, način liječenja urođenog krivog stopala. Cilj rada bio je da se upoređivanjem rezultata liječenja ispitati i dokaže da je minimalno invazivan hirurški tretman urođenog krivog stropala bolji način liječenja, sa kojim se dobijaju bolji rezultati, u odnosu na radikalni hirurški tretman. Metod. Klinička studija sprovedna u Klinici za dečiju hirurgija Banjaluka i UDK Beograd. Ispitivanje je provedno kod dve grupe ispitanika, grupa A (kontrolna grupa) -deca lečena radikalnom hirurkom korekcijom i grupa B (eksperimentalna grupa)- deca lečena sa MIHT-om. Ukupan broj ispitanika u grupi A bio je 50, muškog pola 35 (70%) i ženskog pola 15 (30%). Obostranih deformiteta bilo je kod 38 (76%), jednostranih kod 12 (24%) ispitanika. Uzrast dece bio je od 5 do 15 godina. Ukupan broj ispitivanih stopala je 88. Ukupan broj ispitanika u grupi B bio je 48, muškog pola 35 (73%) i ženskog pola 13 (27%). Obostranih deformiteta bilo je kod 38 (79%), jednostranih kod 10 (21%) ispitanika. Uzrast djece bio je od 3 do 7 godina. Ukupan broj ispitivanih stopala je 84. Za analizu rezultata korišten je upitnik. Za svako ispitivano stopalo praćeno 15 parametara i to po pet kliničkih, radiografskih i funkcionalnih parametara. Za praćenje kliničkih parametara korišten je McKay protokal, za radiografsku evaluaciju korišten je G.W.Simons protokol i za funkionalone paremetre Laaveg-Ponseti protokol. Indikacija za tenotomiju Ahilove tetive kod ispitanika lečenih MIHT-om postavljena je na osnovu Piranijevog skora... | Congenial clubfoot continues to represent a serious problem in pathology of the bone-joint system of children. Many questions from the field of congenial clubfoot are a subject of research and dilemmas even today. The most frequent questions which are the subject of discussion are related to: aetiology, clinical classification and manners of treatment. Pes equinovarus congenitus (PEVC) is a deformity of feet treated by non operative procedures and operationally. In literature, there are different approaches to the problem of the treatment of PEVC, what depends from the speciality, the institution that deals with this problem and the region. Minimally invasive surgical treatment (MIST) is a new, modern, manner of treatment of the congenial clubfoot. The aim of this paper was that by comparison of the results of treatment is to question and proven that the minimally invasive surgical treatment of the congenial clubfoot is a better manner of treatment, by which are obtained a better results, in comparison with the radical surgical treatment. Method. Clinical study was conducted at the Clinic for Pediatric Surgery of Banja Luka and University Children's Hospital Belgrade. The testing was conducted in two groups of subjects, group A (control group) - children treated with the radical surgical correction and group B (experimental group) -children treated with MIST. The total number of subjects in group A was 50, males 35 (70%) and females 15 (30%). Bilateral deformities was at 38 (76%) and unilateral at 12 (24%) subjects. The age of the children was from 3 to 7 years. The total number of the tested feet is 84. For the analysis of the results a questionnaire was used. For each tested foot were monitored 15 parameters and that means five clinical, radiographic and functional parameters. For monitoring of the clinical parameters, it was used a McKay protocol, for the radiographic evaluation was used G.W.Simons protocol and for the functional parameters Laaveg-Ponseti protocol. Indication for tenotomy of the Achilles tendon at the subjects treated with MIST was set on the basis of Pirani score... | false |
Studije praćenja kliničkih karakteristika, toka, onesposobljenosti, kvaliteta života i psiholoških poteškoća kod dece i adolescenata sa migrenom | A follow-up study of clinical characteristics, course of disease, disability, quality of life and pshychological difficulties in children and adolescents with migraine | Migrena je hronično neurološko oboljenje koje se karakteriše ponavljanim, epizodičnim glavoboljama, često udruženim sa mučninom, povraćanjem, foto i/ili fonofobijom. Pokazano je da migrena može značajno uticati na fizičke, emocionalne i socijalne aspekte svakodnevnog funkcionisanja. Procena težine bolesti samo na osnovu učestalosti i intenziteta glavobolja ne pruža dovoljan uvid o uticaju migrene na kvalitet života. Korišćenje specifičnih upitnika daje mogućnost praćenja onesposobljenosti, efekata terapije i kvaliteta života obolelih kako u toku tako i između migrenskih ataka. Cilj: Cilj rada je utvrđivanje povezanosti relevantnih varijabli bolesti (učestalost glavobolja, težina napada i toka) sa onesposobljenošću i kvalitetom života, kao i utvrđivanje nivoa anksioznih i depresivnih simptoma i poteškoća u ponašanju kod dece sa migrenom. Metodologija: Multicentričnom studijom praćenja su obuhvaćeni deca i adolescenati sa migrenom koji su dijagnostikovani i lečeni u tri tercijarna centra, koji se bave neurologijom dečjeg i adolescentnog doba na teritoriji Beograda. U studiju je uključeno 52 ispitanika uzrasta 7-17,5 godina, dva ispitanika su izgubljena tokom praćenja. Ispitivanje onesposobljenosti dece sa migrenom je procenjeno PedMIDAS testom (engl. „Pediatric Migraine Disability Assessment“). Kvalitet života bolesnika sa migrenom je procenjen Upitnikom o Zdravlju za decu i mlade ljude KIDSCREEN-27 (engl.“Kidscreen-27 Health Questionnaire for Children and Young People“). Revidirana skala za anksioznost i depresiju dece - (RCADS) je korišćena za procenu nivoa anksioznih i depresivnih simptoma, Nisonger upitnik za procenu ponašanja dece urednog razvoja (engl. NCBRF) je korišćen da bi se procenile poteškoće u ponašanju. Rezultati: U ovoj studiji je kod oko trećine ispitanika utvrđen umeren do težak stepen onesposobljenosti usled migrene. Uočeno je da PedMIDAS skor visoko korelira sa brojem glavobolja u poslednjih mesec dana pre procene (p < 0,01)... | Migraine is a chronic neurological condition characterized by recurrent, episodic headaches often associated with nausea, vomiting, photophobia and/or phonophobia. Evidence suggests that migraine attacks significantly limit daily activities and adversely affect quality of life (QOL). The evaluation of the severity of the disease based solely on the frequency and intensity of the headache does not provide sufficient insight into the impacts of migraine on QOL. The use of specific questionnaires provides the ability to monitor the effects of therapy, disability, and QOL of patients during the course and between migraine attacks. Objective: The aim of the study was to determine the association between the relevant variables of the disease (headache frequency and severity and the course of disease) with disability and QOL, as well as determining levels of anxiety, depressive symptoms and behavioral disorders in children with migraine. Methods: This was a follow-up study of children and adolescents with migraine, diagnosed and treated at three pediatric/child neurology clinics in Belgrade. Fifty two patients age 7-17,5 years were enrolled and two patients were lost to follow-up. Disability due to migraine was assessed by the Pediatric Migraine Disability Assessment tool – PedMIDAS (Pediatric Migraine Disability Assessment). The KIDSCREEN-27 was used to assess QOL. Depressive and anxiety symptoms were assessed by the Revised Child Anxiety and Depression Scale (RCADS), while the Nisonger questionnaire for assessing the behavior of children with normal development (NCBRF) was used to assess symptoms of behavioral disorders. Results: In this study, about one-third of respondents identified a moderate to severe disability due to migraine. It was noticed that the PedMIDAS score was highly correlated with the number of headaches in the month before the assessment (p <0.01). In the six-month follow-up period, PedMIDAS scores statistically significant decrease (x;ˉ (SD)početak = 22,72 (23,39), x;ˉ (SD)3 meseci = 14,60 (17,63), x;ˉ (SD)6 meseci = 9,58 (12,48); F (df) = 11,81 (1,6), p < 0,01)... | false |
Ispitivanje kvaliteta života dece sa atopijskim dermatitisom: procena ukupnog ishoda bolesti | Investigating the quality of life of children with atopic dermatitis: evaluation of the total disease outcome | Atopijski dermatitis (AD) je hronična, recidivirajuća, inflamatorna, pruriginozna
bolest kože, koja se javlja prvenstveno kod dece i koju karakterišu faze remisije i
egzacerbacije. Podaci iz literature jasno ukazuju na veliki uticaj AD na kvalitet života dece.
Vrlo često fizički izgled deteta sa AD nailazi na komentare vršnjaka, što može da dovede
do osećaja stida. Mnoga deca se osećaju socijalno izolovano, a vršnjaci ih neretko odbacuju
ili zlostavljaju, što vodi gubitku samopouzdanja, promenama raspoloženja i depresivnosti.
Umor, kao posledica nespavanja zbog svraba kože, utiče na uspeh u školi i smanjenje
koncentracije. AD ne samo da menja život obolelom detetu, nego utiče i na fizičko,
socijalno i emocionalno funkcionisanje njihovih roditelja. Zbog stalne potrebe za negom
obolele dece i brige o njima kod roditelja često dolazi do problema sa spavanjem,
iscrpljenosti, ali i finansijskih poteškoća zbog troškova oko topikalnih i sistemskih lekova.
Uspešna kontrola AD kod dece zavisi od roditelja, njihovog znanja o bolesti, stava i
ponašanja prema obolelom detetu.
Ciljevi. 1) Ispitivanje kvaliteta života dece sa AD na inicijalnom pregledu, nakon 6 i nakon
12 meseci. 2) Ispitivanje uticaja AD deteta na kvalitet života njegovih roditelja/negovatelja
na inicijalnom pregledu deteta, i nakon 6 i 12 meseci. 3) Ispitivanje prediktora promene
kvaliteta života deteta tokom vremenskog perioda od jedne godine. 4) Procena validnosti i
pouzdanosti primenjenih upitnika, prethodno lingvistički i kulturološki adaptiranih na
srpski jezik, za merenje kvaliteta života dece sa AD i njihovih roditelja/negovatelja. 5)
Ispitivanje znanja roditelja o AD, kao i njihovih stavova i ponašanja prema oboleloj deci.
Metod. Kvalitet života dece ispitivan je prospektivnom studijom koja je obuhvatila kohortu
98-oro dece sa dijagnozom AD, uzrasta 1-16 godina, koja su lečena na Klinici za
dermatovenerologiju Kliničkog centra Srbije, u periodu od januara do juna 2014. godine. U
istraživanju je korišćen opšti standardni upitnik koji je sadržao podatke o oboleloj deci i
njihovim roditeljima. Za procenu težine i proširenosti promena kod dece obolele od AD
korišćen je SCOring Atopic Dermatitis indeks – SCORAD. Kvalitet života deteta uzrasta 5
– 16 godina procenjen je uz pomoć Dermatološkog indeksa kvaliteta života kod dece (engl.
Children Dermatology Life Quality Index – CDLQI), dok je za procenu kvaliteta života
deteta uzrasta do 4 godine korišćen Dermatološki indeks kvaliteta života kod malog deteta
(engl. Infants Dermatitis Quality of Life Index - IDQOL). Uticaj AD deteta na kvalitet
života roditelja procenjen je upitnikom Indeks uticaja dermatitisa na porodicu (engl.
Dermatitis Family Impact Questionnaire – DFI). Kvalitet života dece i roditelja procenjen
je na inicijalnom pregledu, nakon 6 i nakon 12 meseci. Sva tri upitnika su prethodno
prevedena sa engleskog na srpski jezik i kulturološki adaptirana za korišćenje u našoj
sredini. Studija preseka kojom su ispitivani znanje, stavovi i ponašanje roditelja prema
detetu sa AD sprovedena je od februara 2015. do marta 2016. godine na Klinici za
dermatovenerologiju KCS. U istraživanju je korišćen upitnik koji je dizajniran za potrebe
ove studije i sadržao je pitanja o znanju roditelja o AD, stavovima i ponašanju prema
obolelom detetu. U statističkoj analizi korišćene su mere deskriptivne statistiike, testovi za
procenu značajnosti razlike (analiza varijanse − ANOVA, χ2 test), metode univarijantne i
multivarijantne analize i metode korelacije. Nivo statističke značajnosti u svim testovima
iznosio je p < 0,05. Statistička analiza podataka sprovedena je u statističkom programu
SPSS verzija 20 (SPSS Inc, Chicago, IL, U.S.A.).
Rezultati. Kvalitet života starijeg deteta sa AD bio je narušen na sva tri merenja (CDLQI
skorovi − 13,1; 8,5 i 7,3), s tim da je uočeno značajno poboljšanje na drugom merenju
(posle 6 meseci). Deca sa lakšom kliničkom slikom pri inicijalnom merenju (niže vrednosti
SCORAD-a), imala su značajnije poboljšanje kvaliteta života tokom perioda praćenja od 12
meseci. Težina bolesti, kvalitet života roditelja i kvalitet života starije dece sa AD značajno
su pozitivno korelirali tokom sva tri merenja. Starija deca, čija je klinička slika AD bila
lakša na inicijalnom merenju, imala su značajnije poboljšanje kvaliteta života. Kvalitet
života malog deteta bio je narušen na sva tri merenja (IDQOL skorovi − 10,6; 6,7 i 8,7), sa
značajnim poboljšanjem na drugom merenju (posle 6 meseci). Roditelji su procenili da se
težina bolesti dece smanjila tokom posmatranog perioda. Težina AD, kvalitet života
roditelja i kvalitet života mlađe dece značajno su pozitivno korelirali na sva tri merenja.
Takođe, postojala je i jaka pozitivna korelacija između procene težine AD od strane
roditelja i vrednosti SCORAD indeksa. Mlađa deca sa lakšom kliničkom slikom na
inicijalnom merenju, imala su značajnije poboljšanje kvaliteta života. Kvalitet života
roditelja pod uticajem AD deteta bio je narušen na sva tri merenja (DFI skorovi − 12,6; 8,1
i 10,7), sa značajnim poboljšanjem i na drugom i na trećem merenju (posle 6 i 12 meseci),
dok je u 12. mesecu došlo do značajnog pogoršanja kvaliteta života u odnosu na 6. mesec.
Težina AD, kvalitet života dece (CDLQI i IDQOL skorovi) i kvalitet života roditelja
značajno su pozitivno korelirali na sva tri merenja. Roditelji čija su deca imala lakšu
kliničku sliku na inicijalnom merenju, kao i roditelji sa višim stepenom školske spreme,
imali su značajnije poboljšanje kvaliteta života. Upitnici CDLQI, IDQOL i DFI pokazali su
dobru internu konzistentnost. Stariji roditelji i roditelji koji su bili u braku/imali partnera,
kao i oni koji su bolovali od AD pokazali su veće znanje o bolesti deteta. Stariji i zaposleni
roditelji imali su pozitivniji stav prema bolesnom detetu, dok su stariji i manje obrazovani
roditelji pružali veću podršku detetu sa AD.
Zaključak. Ovo istraživanje je pokazalo da AD značajno utiče na smanjenje kvaliteta života
obolele dece, kao i da ima negativni uticaj na kvalitet života njihovih roditelja. Studija je
pokazala da postoji jaka pozitivna korelacija između kvaliteta života dece i kvaliteta života
njihovih roditelja, kao i između težine bolesti deteta i kvaliteta života i deteta i roditelja.
Roditelji su bili u velikoj meri upoznati sa AD, imali su pozitivne stavove prema bolesti
svog deteta i pružali su veliku podršku detetu obolelom od AD. Procena kvaliteta života
obolele dece, kao i procena uticaja bolesti na kvalitet života njihovih roditelja i čitave
porodice trebalo bi da se koriste u svakodnevnoj, rutinskoj praksi lekara pri određivanju
terapije, kao i za evaluaciju uspešnosti lečenja. Znanje roditelja može da utiče na stavove i
ponašanje prema oboljenju deteta, što dalje može da bude ključ uspešnog držanja AD pod
kontrolom. | Atopic dermatitis (AD) is chronic, recurrent, inflammatory, pruriginous skin
disease that occurs mostly in children. It is characterized by periodical remission and
exacerbation. According to the literature data, AD has great impact on the quality of life
(QoL) of children. It is not uncommon that peers comment on physical appearance of ill
child which can lead to the feeling of shame. Many children feel socially isolated, rejected
or abused by their peers and that can result with loss of self-confidence, mood changes and
depression. Tiredness, as a consequence of sleep deprivation due to skin itching, influences
the success in school and leads to concentration impairment. AD changes life not only of ill
child, but also affects physical, social and emotional functioning of its parents/guardians.
Because of constant need of caring for ill children, parents often report troubles with
sleeping and exhaustion, as well as financial difficulties due to local and systemic therapy.
Successful management of AD depends on parents, their knowledge, attitudes and behavior
toward ill child.
Aims. 1) Investigation of QoL of children with AD, initially, after 6 and 12 months. 2)
Investigation of the impact of child AD on the QoL of parents/guardians, initially, after 6
and 12 months. 3) Investigation of potential predictors of QoL changes during the period of
1 year. 4) Assessment of validity and reliability of applied QoL questionnaires those are
previously linguistically and culturally adapted to Serbian language. 5) Investigating of
parents’ knowledge, attitudes and behavior toward children with AD.
Methods. QoL was assessed in prospective study that had included the cohort of 98
children with AD, age 1 – 16, who were treated at the Clinic of Dermatovenereology of
Clinical Center of Serbia (CCS) in the period of January to June, 2014. General
standardized questionnaire which contained the information on children and their parents
was applied. The severity of AD was assessed using SCOring Atopic Dermatitis Index –
SCORAD. QoL of children age 5 – 16 was measured by Children Dermatology Life
Quality Index – CDLQI, while Infants Dermatitis Quality of Life Index – IDQOL was used
for children up to 4 years. The impact of AD on parents’ QoL was assessed with Dermatitis
Family Impact Questionnaire – DFI. QoL of children and their parents was measured
initially, after 6 and after 12 months. All QoL questionnaires were previously translated and
culturally adapted for using in our environment. Cross-sectional study investigating
parents’ knowledge, attitudes and behavior toward children with AD was conducted in the
period of February 2015 to March 2016, at the Clinic of Dermatovenerology of CCS. The
questionnaire designed particularly for the purpose of this research which contained
questions about knowledge, attitudes and behavior toward ill child was applied. Statistical
analysis included descriptive statistic, tests for difference significance assessment (analysis
of variance – ANOVA, chi square test), uni and multivariate regression analysis methods,
as well as correlation method. The level of statistical significance was 0.05 in each
statistical test. Statistical analysis was performed using SPSS, version 20 (SPSS Inc,
Chicago, IL, U.S.A.).
Results. QoL of older child with AD was impaired at all measuring (CDLQI scores were as
following: 13.1; 8.5 and 7.3), therewith the significant improvement was observed at the
second measurement (after 6 months). Children with less severe form of disease initially
(lower SCORAD scores), had greater improvement of QoL during the period of 12 months.
Severity of disease, parental QoL and QoL of older children with AD significantly
correlated at all measurements. Older children with less severe disease initially, had greater
improvement of QoL. QoL of younger children was also impaired at all three
measurements (IDQOL scores were as observed: 10.6; 6.7 and 8.7), with significant
increase of QoL at the second measurement (after 6 months). Parents assessed that severity
of AD of their children had decreased during the period of follow-up. Statistically
significant correlation was observed between AD severity, parental QoL and QoL of
younger children, at all measuring. Also, there was significant correlation between parental
assessment of AD and SCORAD scores. Younger children with less severe disease had
more significant improvement of QoL. QoL of parents was impairment at all
measurements, as a consequence of children AD (DFI scores were as following: 12.6; 8.1
and 10.7), with significant improvement at the second and third measurement (after 6 and
12 months), while significant impairment was observed in 12th compared to 6th month.
Severity of AD, children QoL (CDLQI and IDQOL scores) and parental QoL positively
correlated at all three measurements. Parents whose children had less severe AD initially,
as well as those with higher level of education had greater improvement of QoL. CDLQI,
IDQOL and DFI questionnaires showed good internal consistency. Older parents, as well as
those who were married/partnered and had personal history of AD, showed higher level of
knowledge on children’s disease. Older and employed parents had more positive attitudes
toward ill child, while older and less educated parents were more supportive.
Conclusion. This study showed that AD had significant impact on QoL impairment not
only of children with AD, but also of their parents. The study showed that there was strong
positive correlation between children and parental QoL, as well as between disease severity
and children and parental QoL. Parents were familiar with their child disease to a large
degree, had positive attitudes and supportive behaviour toward the child with AD. The
assessment of QoL of children with AD and their parents and whole family, should be used
in regular, routine physician practice when determining therapy and treatment success
evaluation. Parental knowledge can influence the attitudes and behaviour toward the ill
child and that can be the key of the successful AD management. | true |
Ispitivanje terapijskog dejstva arilpiperazinskih dopaminergičkih liganada u modelu multiple skleroze kod pacova | Investigation of therapeutic effect of arylpiperazine dopaminergic ligands in the model of multiple sclerosis in rats | U ovom radu je ispitivano dejstvo dva novosintetisana arilpiperazinska D2/5-HT1A dopaminergička/serotoninergička liganda, koji ispoljavaju neuroprotektivna svojstva in vitro, u eksperimentalnom autoimunskom encefalomijelitisu (EAE) kao modelu multiple skleroze kod pacova. Oba jedinjenja, N-{4-[2-(4-phenyl-piperazin-1-yl)- ethyl}-phenyl]-picolinamide (6a) i N-{3-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}- picolinamide (6b), su u dozi od 10 mg/kg i.p. ispoljila pozitivan efekat na klinički tok EAE-a kod Dark Agouti pacova imunizovanih homogenatom kičmene moždine (KM), pri čemu je derivat 6b ispoljavao nešto izraženiji efekat u odlaganju početka bolesti i snižavanju maksimalne kliničke težine, što je u skladu sa njegovim višim afinitetom za D2 i 5-HT1A receptore. Povoljan efekat na klinički tok EAE-a se zadržavao ukoliko je tretman vršen tokom efektorske faze bolesti (od 8. dana pa na dalje), ali ne i tokom induktivne faze (od 0. do 7. dana) EAE-a. Arilpiperazini su smanjivali infiltraciju CNSa inflamatornim ćelijama, kao i ekspresiju iRNK za proinflamatorne citokine TNF, IL-6, IL-1, i GM-CSF, TH1 citokin IFN-γ, TH17 citokin IL-17, kao i za glavne transkripcione faktore TH1 (T-bet) i TH17 (RORγt) ćelija u tkivu CNS-a ali nisu uticali na ekspresiju proinflamatornih medijatora u infiltratu mononuklearnih ćelija, niti su menjali njegov ćelijski sastav. Tretman arilpiperazinima je smanjio apoptotsku ćelijsku smrt i povećao aktivnost kinaze Akt (engl. v-Akt Murine Thymoma Viral Oncogene), važne u preživljavanju ćelija, i supstrata glavnog inhibitora autofagije mTOR-a (engl. mammalian target of rapamycin), p70S6K kinaze (engl. ribosomal protein S6 kinase) u CNS-u životinja obolelih od EAE-a. Konačno, u in vitro kokultivaciji oligodendrocita i neurona sa stimulisanim T limfocitima, arilpiperazini su ispoljili neuroprotektivan efekat prema oligodendrocitnoj (OLN-93) i neuronskoj (PC12) ćelijskoj liniji, spasavajući ih od normalnih T ćelija aktiviranih mitogenom i encefalitogenih T ćelija stimulisanih mijelin-baznim proteinom, ali nisu uticali na imunomodulatornu aktivnost T limfocita... | In the present study we investigated the effect of the two newly synthesized arylpiperazine D2/5-HT1A dopaminergic/serotoninergic ligands, which display neuroprotective properties in vitro, in experimental autoimmune encephalomyelitis (EAE), as an animal model of multiple sclerosis. Both compounds, N-{4-[2-(4-phenylpiperazin- 1-yl)-ethyl}-phenyl]-picolinamide (6a) and N-{3-[2-(4-phenyl-piperazin-1- yl)-ethyl]-phenyl}-picolinamide (6b), at 10 mg/kg i.p, reduced clinical signs of EAE in the spinal cord homogenate-immunized Dark Agouti rats. Compound 6b had somewhat pronounced effect in delaying the disease onset and reducing the maximal clinical score, which correlated with its higher affinity for D2 and 5-HT1A receptors. The protection was retained if the treatment was limited to the effector (from day 8 onwards), but not the inductive (day 0-7) phase of EAE. Arylpiperazines reduced CNS immune cell infiltration and expression of mRNA encoding proinflammatory cytokines TNF, IL-6, IL-1, and GM-CSF, TH1 cytokine IFN-γ, TH17 cytokine IL-17, as well as the signature transcription factors of TH1 (T-bet) and TH17 (RORγt) cells in the CNS tissue, arylpiperazines did not affect the expression of mRNA for proinflammatory mediators in mononuclear cell infiltrate, neither they changed its cellular composition. Arylpiperazine treatment reduced apoptotic cell death and increased activation of the prosurvival kinase Akt (v-Akt Murine Thymoma Viral Oncogene) and p70S6K kinase (ribosomal protein S6 kinase), the substrate of the major autophagy inhibitor mTOR (mammalian target of rapamycin), in the CNS of EAE animals. Finally, the in vitro treatment with arylpiperazines protected oligodendrocyte cell line OLN-93 and neuronal cell line PC12 from mitogen-activated normal T cells or myelin basic protein-activated encephalitogenic T cells, without exerting immunomodulatory activity... | false |
Uticaj insulinske rezistencije, dislipidemije, oksidativnog stresa i adipokina na krvni pritisak i kardiovaskularne bolesti kod gojazne dece i adolescenata | Impact of insulin resistance, dyslipidemia, oxidative stress and adipokines on blood pressure and cardiovascular diseases in obese children and adolescents. | Uvod: Gojaznost je postala jedan od najvažnijih globalnih zdravstvenih problema. Globalna epidemija gojaznosti je udružena sa porastom prevalencije arterijske hipertenzije. Sa porastom broja dece sa hipertenzijom, očekuje se porast broja komplikacija hipertenzije u detinjstvu. Najvažnija komplikacija arterijske hipertenzije je hipertrofija miokarda leve komore koja se nalazi u oko 30% dece sa hipertenzijom. Hipertrofija leve komore je poznat faktor rizika za kardiovaskularnu bolest odraslih. Metabolički činioci udruženi sa gojaznošću kao što su insulinska rezistencija, inflamacija i oksidativni stres mogu uticati na kardiovaskularna oštećenja kod dece i adolescenata. Cilj: Cilj rada je ispitati faktore rizika kardiovaskularnih obolenja kod gojazne dece i adolescenata sa i bez hipertenzije. Radi ostvarenja cilja ispitivanja postavljeni su sledeći zadaci istraživanja: ispitivati povezanost parametara oksidativnog stresa i adipokina sa debljinom intime i medije karotidne arterije i sa insulinskom rezistencijom; odrediti prevalenciju hipertrofije miokarda leve komore i poremećene geometrije leve komore; otkriti faktore koji utiču na povećanje indeksa mase leve komore i na poremećenu geometriju leve komore. Metodologija: Studija presek izvedena na Univerzitetskoj dečjoj klinici, uključila je 103 gojazna pacijenta i 30 zdrave normalno uhranjene dece. Gojazni pacijenti su na osnovu rezultata ambulatornog monitoringa krvnog pritiska podeljeni u 2 grupe: gojazne sa i bez hipertenzije. Učinjena su sledeća ispitivanja: odreĎivanje debljine intime i medije karotidnih arterija, ehokardiografija, test opterećenja fizičim naporom, i laboratorijske analize krvi i urina. Laboratorijske analize su uključivale oralni glukoza tolerans test sa insulinom, glikozilirani hemoglobin (HbA1c), serumske elektrolite, ureju, kreatinin, mokraćnu kiselinu, C reaktivni protein, holesterol, trigliceride, lipoproteine velike gustine (HDL-holesterol), lipoproteine male gustine (LDL-holesterol), markere oksidativnog stresa, leptin i adiponektin. Parametri oksidativnog stresa koji su odreĎeni su prooksidativno-antioksidativni balans, uznapredovali produkti oksidacije proteina, malondialdehid, i superoksidni anjon... | Introduction: Obesity has become one of the most important global health problems. The global epidemic of obesity is associated with an increase in the prevalence of hypertension. Increase of the number of children with hypertension is expected to increase the number of complications of hypertension in childhood. The most important complication of hypertension is left ventricular hypertrophy which is found in about 30% of children with hypertension. Left ventricular hypertrophy is a known risk factor for cardiovascular disease of adults. Metabolic factors associated with obesity such as insulin resistance, inflammation and oxidative stress may affect the cardiovascular damage in children and adolescents. Aim: to investigate the risk factors of cardiovascular disease in obese children and adolescents with and without hypertension. In order to realize the aim the following tasks were assigned: analyze the relationship of oxidative stress parameters and adipokines with intima-media thickness of the carotid artery (cIMT), and with insulin resistance; determine the prevalence of left ventricular mass and impaired left ventricular geometry; discover the factors affecting the increase in left ventricular mass index, and abnormal left ventricular geometry. Methodology: The cross-sectional study performed at the University Children’s Hospital, included 103 obese patients and 30 healthy nonobese children. Obese patients were divided into 2 groups based on the results of ambulatory monitoring of blood pressure: obese with and without hypertension. We performed the following tests: the determination of the intima and media thickness of the carotid artery, echocardiography, exercize stress test, and laboratory analysis of blood and urine. Laboratory analysis included oral glucose tolerance test with insulin, glycosylated hemoglobin (HbA1c), serum electrolytes, urea, creatinine, uric acid, C-reactive protein, cholesterol, triglycerides, high-density lipoproteins (HDL-cholesterol), low density lipoprotein (LDL-cholesterol), markers of oxidative stress, leptin and adiponectin. Parameters of oxidative stress, which are determined included prooxidant-antioxidant balance, advanced oxidation protein products, malondialdehyde, and superoxide anion... | false |
Predviđanje ishoda asistirane fertilizacije na osnovu testova ovarijalne rezerve | Assisted fertilization outcome assesment using ovarian reserve tests | Uvod: Optimizacija i individualizacija kontrolisane ovarijalne hiperstimulacije
postaje sve značajnija, pa se brojna ispitivanja bave identifikacijom kliničkih
parametara koji mogu da utiču na ovarijalni odgovor, kao i da povećaju efikasnost i
bezbednost primenjene stimulacije. Cilj ovog istraživanja je ispitivanje mogućnosti
predviđanja ovarijalnog odgovora i ishoda asistirane fertilizacije na osnovu
biomarkera funkcionalne ovarijalne rezerve, kao i identifikacija onog koji bi imao
preciznost nezavisnu od primenjenog protokola stimulacije.
Metodologija:Prospektivna kohortna studija je obuhvatila 363 pacijentkinje u
postupku asistirane fertilizacije u okviru Nacionalnog programa na Klinici za
ginekologiju i akušerstvo Kliničkog centra Srbije. Svima su određeni starost, indeks
telesne mase, uzrok i vrsta infertiliteta. Broj antralnih folikula i vrednosti AMH,
Inhibina B, FSH, LH, estradiola, progesterona i testosterona u serumu su mereni
drugog dana ciklusa pre započinjanja stimulacije. Broj i kvalitet dobijenih oocita i
embriona i stope biohemijskih i kliničkih trudnoća su korišćeni za evaluaciju
prediktivne mogućnosti ovih biomarkera.
Rezultati: Pokazano je da su starost ispitanica, broj antralnih folikula, vrednost AMH
i odnos FSH/LH prediktori broja dobijenih oocita kao i stope trudnoća. Dodatno, broj
antralnih folikula je bio najvažniji paramtar koji je uticao na broj dobijenih oocita i
stopu trudnoća, nezavisno od primenjenog protokola stimulacije.
Zaključak: Individualizacija protokola stimulacija bi mogla biti poboljšana
pristupom zasnovanim na broju antralnih folikula i vrednosti AMH, s obzirom da je
pokazano da su veoma pouzdani prediktori kako adekvatnog tako i prekomernog
ovarijalnog odgovora i značajni prediktori stope trudnoća, nezavisno od izabranog
protokola stimulacije. | Background The optimization and individualization of controlled ovarian stimulation
have become increasingly important and significant efforts have been made to
identify clinical parameters that can imply on the ovarian response and also improve
efficacy and safety outcomes. The aim of this study was whether biomarkers of the
functional ovarian reserve, as well as which one, are able to predict ovarian response
and assisted fertilization outcome, with accuracy independent of selected treatment.
Methods A prospective cohort study included 363 patients who underwent assisted
fertilization within National program at the Clinic of Gynecology and Obstetrics,
Clinical Center of Serbia. Age, BMI, cause of infertility and the infertility type were
determined for all patients. Antral follicle number, serum AMH, Inhibin B, FSH, LH,
estradiol, progesterone and testosterone levels were measured on the 2nd cycle day
prior to stimulation commencement. The number and quality of obtained oocytes and
embryos and biochemical and clinical pregnancy rates were used in order to evaluate
possible predictive function of these biomarkers.
Results Patients’ age, number of antral follicles, AMH level and FSH/LH ratio were
confirmed as predictors of the number of obtained oocytes and also pregnancy rates.
Additionally, the number of antral follicles was the main parameter that influenced
the number of obtained oocytes and pregnancy rates regardless of stimulation
protocol.
ConclusionThe individualization of stimulation protocols may be further improved
by using both AFC- and AMH- tailored approach since they are very reliable
predictors of both adequate and excessive ovarian response, and significant predictors
of pregnancy rates, regardless of selected stimulation protocol. | true |
Prevalencija i faktori rizika produženog QT intervala i QT disperzije kod pacijenata obolelih od dijabetesa tip 2 | Prevalence and risk factors for prolonged QT interval and QT dispersion in patients with type 2 diabetes | Produženi QT interval je udružen sa malignim srčanim aritmijama i naprasnom smrti... | Prolonged QT interval is associated with malignant cardiac arrhythmias and sudden death... | false |
Poređenje subkliničke nefrotoksičnosti izazvane gadolinijumom i jodnim kontrastnim sredstvom kod dece sa normalnom bubrežnom funkcijom | Comparison between subclinical nephrotoxicity after gadolinium and iodinatedbased contrast media exposure in children with normal renal function | Da se utvrdi razliku između gadolinijumskog i jodnog kontrasta u nastanku subkliničkog
oštećenja bubrega iskazanog novim biomarkerima (NGAL i KIM). Da se ispita pojava
eventualnog kliničkog oštećenja bubrega u populaciji dece sa normalnom bubrežnom funkcijom
posle primene gadolinijumskog i jodnog kontrasta kao i mogućnost njenog što ranijeg otkrivanja
upotrebom novih biomarkera, serumskog i urinarnog NGAL-a i urinarnog KIM-1. Da se evaluira
eventualni uticaj intravenske hidracije pre i posle primene kontrasta na nastanak bubrežnog
oštećenja kod dece sa normalnom bubrežnom funkcijom. Da se razmotri uticaj doze primenjenog
kontrasta kao i istovremene primene antihipertenzivne terapije na nastanak bubrežnog oštećenja
Metodologija: Naše prospektivno istraživanje je obavljeno kod 123 dece i adolescenata kod
kojih su primenjene dve vrste kontrastnih snimanja u periodu od 1. januara 2013 godine do 31
decembra 2015 godine. Prva grupa (n=58) pacijenata sa acijanogenim urođenim srčanim
manama je tokom angiografije primala nisko osmolarni, ne-jonski kontrast na bazi joda
(iopromide, Ultravist® 370). Drugu grupu (n=65) su sačinjavali pacijenti sa suspektnim
anomalijama urotrakta, bilo izvodnog sistema, bilo krvnih sudova bubrega kojima je rađena MR
angiografija/urografija sa primenom gadolinijumskog kontrasta (gadopentetate dimeglumine,
Magnevist®). Svakom pacijentu su uzimani uzorci urina pre snimanja (unutar 24h od snimanja,
0h), zatim posle 4, 24 i 48 sati od primenjenog kontrasta. Uzorci seruma su uzimani tri puta: pre
snimanja, posle 24 i 48 sati od primenjene kontrastne procedure. Pored standardnih
laboratorijskih parametara, u navedenim uzorcima su metodom ELISA određivani i serumski
cistatin C, serumski i urinarni NGAL i urinarni KIM-1.
Rezultati: Pacijenti koji su primili iopromide (n=58) su imali izraženiji pad eGFR posle 24 h
(ΔGFR 10,77 (21,24) ml/min/1,73m2) u poređenju sa pacijentima koji su kao kontrasno sredstvo
primili Gd-DTPA (n=65), (ΔGFR 5,93 (21,23) ml/min/1,73m2). Za razliku od cistatina C koji se
nije menjao kroz vreme u obe grupe kontrasta, u grupi pacijenata koja je primala iopromide,
posle 24h od ekspozicije kontrastu, serumski kreatinin je značajnije porastao u odnosu na grupu
koja je primila Gd-DTPA (Δcreatinine 6,0 (10,0) µmol/l, P= 0,03; Δcreatinine 4,0 (12,0) µmol/l,
P=0,027). Slični nalazi su bili i posle 48h, ali bez statistički značajne razlike među grupama
kontrasta. Vrednosti FENa i FEK su posle 24 časa od primene jodnog kontrasta bile statistički
značajno niže u odnosu na bazalne, a vrednosti TRP i glikozurije su istovremeno u obe kontrasne
grupe beležile tranzitorni porast. Posle 24 sata od primene kontrasta, serumski NGAL je imao
veći porast u grupi koja je primala jodni kontrast i ovaj porast je i dostigao statističku značajnost.
(iopromide: ΔsNGAL 4,3 (16,55) ng/ml, P=0,032; Gd-DTPA: ΔsNGAL 0,7(16,6) ng/ml,
P=0,783). U isto vreme, porast serumskog NGAL za ≥25% u odnosu na bazalne vrednosti je
zabeležen kod 32,6% ispitanika koji su primili iopromide i kod 25.5% ispitanika koji su primili
Gd-DTPA. Srednji porast serumskog NGAL-a u ove dve subgrupe ispitanika je bio 62,23% u
grupi koja je dobila jodni kontrast i 36,44% u grupi koja je primila Gd-DTPA (p= 0,002). Posle
48 sati od primene kontrasta, urinarni KIM-1 je porastao značajnije u grupi koja je primila Gd-
DTPA (Gd-DTPA: ΔuKIM-1 50,9 (200,7) pg/ml, P=0,015; iopromide: ΔuKIM-1 34,5 (210,45)
pg/ml, P=0,23). Međugrupna razlika u procentu porasta uKIM-1 je takođe bila statistički
značajna (P=0,012). U grupi ispitanika koji su dobili jodni kontrast, dva (3,9%) su
dijagnostikovani kao CI-AKI, a u grupi koja su primila Gd-DTPA bilo je šest ispitanika sa CI-
AKI ili 9,7% (p=0,29). Samo je porast urinarnog KIM-1 posle 24 sata od ekspozicije kontrastu
bio značajno veći u grupi ispitanika sa dijagnostikovanom CI-AKI (CI-AKI: 367,3 (221,5)
pg/ml; ne CI-AKI: 308,2 (192,1) pg/ml, p=0,009). Rezultati ROC analize za normalizovane
vrednosti uKIM-1 su pokazale da je AUC uKIM-1/uCr posle 24 sata od ekspozicije kontrastu
0,757 (95% interval pouzdanosti [CI]:0,629-0,885: P=0,035). Posle 24 sata od ekspozicije
kontrastu, vrednosti KIM-1/uCr za ranu detekciju CI-AKI veće od 214 pg/mg su pokazale
senzitivnost od 83,3 % i specifičnost od 54,2%.
Zaključak: Primena gadolinijuma u grupi dece sa normalnom bubrežnom funkcijom može
dovesti do slicne nefrotoksičnosti kao i primena jodnih kontrastnih sredstava. CI-AKI prema
najnovijim i do sada naojoštrijim kriterijumima je bio zastupljen čak i kod većeg broja pacijenata
posle primene gadolinijumskog helata, ali bez statističke značajnosti. Primena jodnog i
gadolinijumskog kontranog sredstva kod dece sa normalnom bubrežnom funkcijom nije dovela
do izrazitog (najmanje dvostrukog) porasta novih biomarkera, ali je porast uKIM-1 bio statistički
značajan posle primene gadolinijumskog helata. Normalizovana vrednost urinarnog KIM-1 može
da bude rani prediktivni faktor za nastanak oštećenja bubrega posle intravenske primene
kontrasta kod dece sa normlno bubrežnom funkcijom. | To determine the difference between gadolinium and iodine contrast media in the
development of subclinical kidney damage expressed with new biomarkers (NGAL and KIM).
To investigate the possible occurrence of acute kidney injury in children with normal renal
function after administration of iodinated and gadolinium based contrast and investigation the
possibility of its early detection by using new biomarkers, such serum and urinary NGAL and
urinary KIM-1. Also, to evaluate the possible effect of intravenous hydration before and after
contrast on kidney function in children with normal renal function. And, to assess the impact of
the dose of administered contrast media, as well as, evaluation of concomitant antihypertensive
therapy on the possible renal impairment in children with normal kidney function.
Material and Methods: We performed a prospective study of 123 children and adolescents
undergoing contrast media exposure in a single center from January 1st, 2013 to December 31st,
2015. The first group (n=58) of patients with acyanotic congenital heart disease were
undergoing angiography with low osmolar non-ionic, iodine based contrast administration
(iopromide, Ultravist® 370). The second one (n=65) consisted of patients with suspected urinary
tract anomalies who were undergoing MR angiography/urography with gadolinium based
contrast administration (gadopentetate dimeglumine, Magnevist®). For each patient, four urine
samples were obtained that corresponded to time 0 h (within 1-day pre contrast exposure), 4, 24
and 48 hours after procedure. The serum samples were obtained three times: within 1-day pre
contrast exposure, 24 and 48 hours after procedure. In addition to standard laboratory
parameters, serum cystatin C, serum and urinary NGAL and urinary KIM-1 were determined by
ELISA.
Results: Patients who have received iopromide (n = 58) had a more pronounced decrease eGFR
after 24 h (ΔGFR 10.77 (21.24) ml / min / 1.73m2) as compared to patients who received a Gd-
DTPA ( n = 65), (ΔGFR 5.93 (21.23) ml / min / 1.73m2). In contrast to the cystatin C, which did
not change over time in both groups of contrast, in the group of patients who received iopromide,
after 24 hours of exposure contrast, serum creatinine, is significantly increased in comparison
with the group which received Gd-DTPA (Δcreatinine 6.0 (10.0) mcmol/l, P = 0.03; Δcreatinine
4.0 (12.0) mcmol/l, P = 0.027). Similar findings were after 48 hours, but without statistically
significant differences between groups. Values of FEK and FENa after 24 hours from the
administration of iodinated contrast were significantly lower in comparison to baseline, and at
the same time point, values of glycosuria and TRP had a transient increase in the both contrast
group. In the iopromide group, 24h after, the serum NGAL rose higher than in the Gd-DTPA
group but without statistical significance between the two groups (ΔsNGAL 4.3 ng/ml (IQR
16.55), ΔsNGAL 0.7 ng/ml (IQR 16.6), p=0.992). At the same time point, serum NGAL
increased ≥25% from baseline in 32.6% of patients who received iopromide and in 25.5% of
patients who received Gd-DTPA. The median increase in this subgroup of patients was 62.23%
in iopromide group and 36.44% in Gd-DTPA group (p= 0.002). In the Gd-DTPA group, 48h
after, the urinary KIM-1 rose higher than in the iopromide group (Gd-DTPA: ΔuKIM-1 50,9
(IQR 200.7) pg/ml, P=0,015; iopromide: ΔuKIM-1 34.5 (IQR 210.45) pg/ml,p=0.23. The
difference between groups were also statistically significant(p=0,012). In the iopramide group, 2
patients (3.9%) were diagnosed with CI-AKI as did 6 patients (9.7%) in the Gd-DTPA group.
Urinary KIM-1 levels 24 hours after contrast exsposure were significantnly higher in the group
of patients with CI-AKI (CI-AKI:367.3 (221.5) pg/ml; ne CI-AKI:308.2 (192.1) pg/ml,
p=0,009). The results of the ROC analyses for the normalized urinary KIM-1 show the AUC of
the uKIM-1/uCr at 24 hours post CM exposure was 0.757 (95% confidence interval [CI]:0.629-
0.885, P=0.035). At 24 hours after CM exposure, values in normalized urinary KIM-1 with
concentrations > 214 pg/mg had a sensitivity of 83.3 %, and a specificity of 54.2% for the early
detection of CI-AKI.
Conclusions: In children with normal renal function exposures to iodinated and gadolinium
based media might lead to subclinical nephrotoxicity and could be detected using serum NGAL
and urinary KIM-1. Iodine and gadolinium contrast media aplications did not lead to pronounced
(at least double) increase in new biomarkers, but u KIM-1 increase was significant after
gadolinium exposures. Acording new criteria, CI-AKI incidence was higher in gadolinium
contrast group, but without statistically significant difference. Normalized urinary KIM-1 could
be one of the most useful non-invasive markers in detecting CI-AKI after iodine and
gadolinium-based media exposure. | true |
Validnost različitih laboratorijskih metoda za dijagnozu onihomikoza i identifikacija faktora rizika | Validity of different laboratory methods in diagnosis of onychomycosis and identification of risk factors. | Uvod: Onihomikoza predstavlja gljivičnu infekciju jednog ili više noktiju koja je
izazvana bilo kojom vrstom gljiva: dermatofitima, kvasnicama ili nedermatofitnim plesnima.
Oboljenje može da zahvati bilo koji deo nokta, uključujući matriks, nokatno ležište i/ili
nokatnu ploču. Procene su da oko 5% svetske populacije ima neki oblik onihomikoze i zbog
toga ova bolest predstavlja značajan zdravstveni problem. Novije studije ukazuju da je u
zemljama zapadne i centralne Evrope prevalencija onihomikoza 3 – 22%. Kada je u pitanju
Srbija, ne postoje podaci o učestalosti onihomikoza niti o najčešćim uzročnicima ovog
oboljenja kod naših pacijenata.
Ciljevi: Određivanje učestalosti javljanja onihomikoza, kao i najčešćih uzročnika
onihomikoza kod pacijenata sa kliničkom sumnjom na onihomikozu, analiziranje validnosti
različitih laboratorijskih metoda za dijagnozu onihomikoza, ispitivanje uticaja primene
tripsina na bolju identifikaciju uzročnika onihomikoza, identifikovanje faktora koji doprinose
nastajanju onihomikoza.
Materijal i metode: Studija slučajeva obuhvatila je 374 pacijenata sa kliničkom
sumnjom na onihomikozu iz šest ustanova: Institut za Mikrobiologiju i imunologiju,
Medicinski fakultet Univerziteta u Beogradu; Zavod za javno zdravlje, Pančevo; Opšta
bolnica „Dr Đorđe Joanović“, Zrenjanin; Opšta bolnica, Užice; Zavod za javno zdravlje
„Timok“, Zaječar; Zavod za javno zdravlje, Kraljevo. Podaci od pacijenata su prikupljeni
odgovarajućim anketnim upitnikom. Od svakog pacijenta uzet je uzorak nokta u zavisnosti od
kliničkog tipa onihomikoze i poslat u Institut za mikrobiologiju i imunologiju, Medicinskog
fakulteta Univerziteta u Beogradu gde je vršena dalja obrada materijala. U cilju
identifikovanja uzročnog faktora onihomikoze za svaki uzorak nokta urađeni su sledeći
laboratorijski testovi, sa i bez prethodnog tretiranja tripsinom: direktan mikroskopski preparat
sa KOH, direktan mikroskopski preparat sa Blankophor-om, kultivisanje na neselektivnim
mikološkim podlogama SDA i RSDA, kao i selektivnoj podlozi za dermatofite DTM. Svaki
uzorak nokta je testiran i pomoću Dermatophyte PCR kita kojim je moguće identifikovati
dermatofite uopšteno (panderm marker), kao i specifično Trichophyton rubrum. Kriterijum za
postavljanje dijagnoze onihomikoze podrazumevao je postojanje jasne kliničke sumnje na
onihomikozu uz pozitivnost bilo kog laboratorijskog testa. Na osnovu laboratorijske
dijagnoze ispitanici su podeljeni u dve grupe: osobe sa laboratorijski potvrđenom dijagnozom
onihomikoze i pacijenti bez ovog oboljenja, u cilju identifikacije faktora rizika za nastajanje
onihomikoze. Kod svakog pacijenta određivan je klinički SCIO indeks. U statističkoj obradi
podataka primenjene su univarijantna i multivarijantna logistička regresiona analiza.
Statistička analiza značajnosti uočenih razlika vršena je primenom χ2 testa. Za svaki ispitivani
test, odnosno njihove kombinacije, određivana je osetljivost, specifičnost, pozitivna i
negativna prediktivna vrednost, pozitivni i negativni faktori verovatnoće kao i dijagnostički
unakrsni odnos. Odnos između osetljivosti i specifičnosti ispitivanih metoda predstavljena je
pomoću ROC krive.
Rezultati: Najčešći klinički tip onihomikoze je bio distalna i lateralna subungvalna
onihomikoza (92,51%). Na osnovu vrednosti SCIO indeksa 178 (47,59%) pacijenata je bilo
indikovano za sistemsku antimikotičnu terapiju. Od ukupno 374 pacijenata sa sumnjom na
onihomikozu, oboljenje je potvrđeno laboratorijskim testovima kod 190 (50,8%), dok je kod
čak 20% pozitivnih pacijenata bio pozitivan samo PCR. Najčešći izazivači onihomikoze su
bili dermatofiti (88,95%), od kojih su najčešći bili Trichophyton rubrum (89,35%) i
Trichophyton interdigitale (8,28%). U manjem procentu identifikovane su i kvasnice
(6,84%), kao i nedermatofitne plesni (4,21%). Onihomikoza je bila 6 puta češće lokalizovana
na noktima na nogama u odnosu na nokte na rukama (163:27). Izazivači onihomikoze na
noktima na nogama su bili dermatofiti kod 95,1% pacijenata, od kojih je najzastupljeniji bio
Trichophyton rubrum (86,6%). Na noktima na rukama najčešći izazivači onihomikoze su bili
dermatofiti (52%) i kvasnice (44%). Najveći stepen pozitivnosti na noktima na nogama
(48,29%) detektovan je pomoću PCR metode koja je i uzeta za zlatni standard za određivanje
validnosti ispitivanih laboratorijskih testova. Kod onihomikoze lokalizovane na noktima na
rukama, najviše pozitivnih pacijenata je detektovano Blankophor-om u kombinaciji sa RSDA
(43,40%) koja je i uzeta za zlatni standard za određivanje validnosti primenjenih
laboratorijskih metoda. Tripsinizacijom metodom po Xess-u značajno je povećan stepen
pozitivnosti kako direktnog mikroskopskog preparata (p<0,001), tako i kultivisanja na svim
ispitivanim mikološkim podlogama (SDA, RSDA, DTM) (p<0,001).
U konačni model multivarijantne logističke regresione analize bilo je uključeno
šesnaest varijabli: uzrast, zanimanje, kompromitovana periferna cirkulacija, ranije prisustvo
onihomikoze, pozitivna porodična anamneza za onihomikozu, putovanje u poslednjih godinu
dana, bavljenje sportom, kontakt sa zemljom, pojačano znojenje nogu, stepen zahvaćenosti
nokta, stepen zadebljanja nokta, broj zahvaćenih noktiju, lokalizacija onihomikoze, SCIO
indeks, paronihija i deformacija nokta. Na osnovu rezultata multivarijantne logističke
regresione analize nezavisni faktori rizika, koji su bili značajno povezani sa nastankom
onihomikoze su: stariji uzrast (UO=2,33; p<0,001), pozitivna porodična anamneza za
onihomikozu (UO=2,71; p=0,001), pojačano znojenje nogu (UO=2,28; p=0,001) i veći stepen
zadebljanja nokta (UO=2,04; p<0,001).
Zaključci: Identifikacijom najčešćih uzročnih faktora onihomikoze primećena je
predominacija dermatofita što je u skladu sa rezultatima drugih studija i može biti od koristi u
cilju sagledavanja epidemiološke situacije i planiranja strategija za prevenciju onihomikoza u
Srbiji. Značajan doprinos predstavlja i uvid o značaju primene pojedinih konvencionalnih,
kao i metoda molekularne biologije u dijagnozi onihomikoza s obzirom da je u ovoj studiji po
prvi put u Srbiji korišćena molekularna metodologija u cilju laboratorijske potvrde dijagnoze
onihomikoza. Rezultati ove doktorske disertacije bi mogli da pomognu u određivanju
najpovoljnijeg laboratorijskog protokola za pouzdanu identifikaciju uzročnika onihomikoza
prilagođenog našoj lokalnoj epidemiološkoj situaciji kao i ekonomskim prilikama. | Background: Onychomycosis represents fungal infection of one or more nails caused by
any type of fungi: dermatophytes, yeasts or nondermatophyte molds. The disease can affect
any part of the nail, including matrix, nail bed and/or nail plate. It is estimated that about 5%
of the world's population has some form of onychomycosis which makes it a significant
health problem. Recent studies indicate that in the countries of Western and Central Europe,
the prevalence of onychomycosis is 3-22%. Regarding Serbia, there are no data on frequency
of onychomycosis nor about the most common causes of this disease in our patients.
Aims: Determination of frequency of onychomycosis, as well as the most common causes
of onychomycosis in patients with clinical suspicion of onychomycosis, analyzing the
validity of the different laboratory methods in the diagnosis of onychomycosis, investigation
of the impact of application of trypsin in better identification of causativ agents of
onychomycosis, identification of risk factors associated with onychomycosis.
Material and methods: The case study included 374 patients with clinical suspicion of
onychomycosis from six institutions: Institute of Microbiology and Immunology, Faculty of
Medicine, University of Belgrade; Department of Public Health, Pančevo; General Hospital
'Dr Đorđe Joanović", Zrenjanin; General Hospital Užice; Public Health Institute "Timok",
Zaječar; Department of Public Health, Kraljevo. Data from patients was collected by
appropriate questionnaire. From each patient a nail sample was taken according to clinical
type of onychomycosis and was sent to the Institute of Microbiology and Immunology,
Faculty of Medicine, University of Belgrade, where further processing of the material was
done. In order to identify the causative agent of onychomycosis each nail sample underwent
the following laboratory tests, with and without previous treatment with trypsin: direct
microscopic examination with KOH, direct microscopic examination with Blankophor,
culturing on non-selective mycologic media SDA and RSDA, and on selective medium for
dermatophytes DTM. Each nail sample was also tested by Dermatophyte PCR Kit which can
identify dermatophytes in general (panderm marker), as well as the specific identification of
Trichophyton rubrum. The criteria for the diagnosis of onychomycosis implied the existence
of clear clinical suspicion of onychomycosis with positivity of any laboratory test. Based on
laboratory diagnosis, subjects were divided into two groups: patients with a laboratory
confirmed diagnosis of onychomycosis and subjects without the disease, in order to identify
risk factors for onychomycosis. Clinical SCIO index was calculated for each patient. In
statistical analysis were used univariate and multivariate logistic regression anlyses.
Statistical analysis of the significance of the observed difference was performed by using chi-
square test. For each test as well as any combination thereof, the sensitivity and specificity,
positive and negative predictive value, positive and negative likely hood ratio and diagnostic
odds ratio were calculated. The relationship between sensitivity and specificity of laboratory
test methods was presented by ROC curve.
Results: The most common clinical type of onychomycosis was distal and lateral
subungual onychomycosis (92.51%). Based on the SCIO index value 178 (47.59%) patients
were indicated for systemic antimycotic therapy. From 374 patients with suspected
onychomycosis, the disease is confirmed by laboratory tests in 190 (50.8%), while up to 20%
of positive patients tested positive only by PCR. The most frequent causative agent of
onychomycosis were dermatophytes (88.95%), of which the most common were
Trichophyton rubrum (89.35%) and Trichophyton interdigitale (8.28%). In lower percentage
were identified yeasts (6.84%), and nondermatophyte molds (4.21%). Onychomycosis was 6
times more often localized on toenails compared to fingernails (163:27). Aetiologic agents of
onychomycosis in toenails were dermatophytes detected in 95.1% patients, of which the most
common was Trichophyton rubrum (86.6%). On fingernails the most common causes of
onychomycosis were dermatophytes (52%) and yeasts (44%). The highest degree of
positivity on toenails (48.29%) was detected by PCR method which is choosed as gold
standard for determination of validity of applied tests. In fingernails, the most positive
patients were detected by Blankophor in combination with RSDA (43.40%), which is taken
as gold standard for determination of validitz of applied test methods. Significant increase in
positivity level of direct microscopic preparation (p<0.001), as well as cultivation on all
tested mycological media (SDA, RSDA, DTM) (p<0.001) was observed using trypsinization
method by Xess.
In the final model of multivariate logistic regression analysis were included sixteen
variables: age, occupation, compromised peripheral circulation, a positive personal history
for onychomycosis, a positive family history for onychomycosis, travel in past year, sports,
contact with the soil, excessive feet sweating, degree of nail involvement, degree of nail
thickening, the number of affected nails, localization of onychomycosis, SCIO index,
paronychia and nail deformity. Based on the results of multivariate logistic regression
analysis, independent risk factors that were significantly associated with the occurrence of
onychomycosis are: older age (OR=2.33; p<0.001), a positive family history for
onychomycosis (OR=2.71; p =0.001), excessive feet sweating (OR=2.28; p=0.001) and a
higher degree of nail thickening (OR=2.04; p<0.001).
Conclusions: Identification of the most common causative agents of onychomycosis
revealded the predominance of dermatophytes which is consistent with other studies and may
be useful in discerning the epidemiological situation and planning strategies in prevention of
onychomycosis in Serbia. A significant contribution is insight in the importance of certain
conventional and methods of molecular biology in the diagnosis of onychomycosis since that
in this study for the first time in Serbia molecular methodology was used in laboratory
confirmation of the diagnosis of onychomycosis. The results of this doctoral thesis could help
in determining the optimal laboratory protocols for reliably identification of causative agents
of onychomycosis suitable to our local epidemiology and the economic situation. | true |
Transkutani parcijalni pritisak kiseonika u proceni efikasnosti hiperbarične oksigene terapije za ishod lečenja dijabetičnog stopala | Transcutaneous oxygen partial pressure in evaluation of the efficacy of hyperbaric oxygene therapy for the diabetic foot treatment outcome | Dijabetičnim stopalom nazivamo patološke promene na stopalu kod pacijenata koji
boluju od šećerne bolesti, a uzrokovane su angiopatijom, polineuropatijom i
osteoartropatijom. Savremenu terapiju dijabetičnog stopala pored medikamentoznog i
hirurškog lečenja čini i hiperbarična oksigenacija.
Cilj. UtvrĎivanje efikasnosti hiperbarične oksigene terapije primenjene kod bolesnika sa
dijabetičnim stopalom, odreĎivanje visine parcijalnog pritiska kiseonika na ishod lečenja i
odreĎivanje PtcO2 u pektoralnom predelu i okoline dijabetične rane (torako-pedalni indeks)
za ranu procenu sanacije rane.
Materijal i metode. U Specijalnoj bolnici za hiperbarčnu medicinu u Beogradu i u
Hirurškoj klinici KBC Zvezdara, 2016. i 1017. godine uraĎena je prospektivna klinička
studija ambulantno lečenih bolesnika sa dijabetičnim stopalom, kod kojih je kliničkim
pregledom pedalno brahijalnog indeksa (ABI) <0,6, kolor dopler ultrazvukom,
arteriografijom i MSCT angiografijom utvrĎeno da ne postoji mogućnost hirurške ili
endovaskularne revaskularizacije. Ispitanici su podeljeni u dve grupe, eksperimentalnu sa
62 pacijenta koji su pored konvencionalne terapije tretirani i hiperbaričnom oksigenom
terapijom i kontrolnu grupu od 36 pacijenata lečenih samo konvencionalnom terapijom.
Hiperbarična oksigena terapija sprovedena je u 20 seansi u trajanju od 70 minuta, pod
povišenim pritiskom od 2,2 ATA udisanjem 100% kiseonika preko maske. Posmatrani su u
obe grupe demografski podaci, trajanje dijabetesa i komplikacije dijabetesa, stanje
koronarne bolesti, laboratorijski nalazi i lipidni status, opis dijabetične rane i merenje
dimenzije i dubine rane. Preduslov za ulazak u studiju bila je rana u stadijumu II i većem
prema Wagnerovoj klasifikaciji i stanje periferne ishemijske bolesti prema Fontenu u II
stadijumu ili većem. Za statističku obradu podataka korišćena je SPSS metodologija.
Rezultati. Svi navedeni parametri u obe grupe pre početka terapije, statističkom obradom
pokazali su da meĎu grupama nema značajne razlike.
Dimenzije rane (dužina, širina i dubina) posle terapije su statistički značajno smanjene u
eksperimentalnoj grupi.
PoreĎenjem statusa po Fontenovoj klasifikaciji i statusa rane po Wagner klasifikaciji,
pokazano je, da je statistički visoko značajna razlika, posle terapije, u korist
eksperimentalne grupe.
Bolesnicima eksperimentalne grupe je u višemesnoj komori meren transkutani parcijalni
pritisak kiseonika (PtcO2) u pedalnoj regiji i u torakalnoj regiji i izračunavan regionalni
perfuzioni index (RPI). Merenje je vršeno, u 12.minutu, 35. i u 60. minutu hiperbarične
oksigene terapije. Rezultati lečenja hiperbaričnom oksigenom terapijom praćeni su u
odnosu na krajnji ishod lečenja dijabetičnog stopala, koji je podeljen u tri stepena
(pogoršanje, nepromenjeno stanje rane i poboljšanje) i uporeĎivani izmeĎu grupa.
Zaključak. Izračunavanjem regionalnog perfuzionog indeksa RPI (odnos pedalnog
PtcO2/toraklani PtcO2), utvrĎeno je da su indeksi u korelaciji sa krajnjim rezultatom lečenja
pokazali visoku statističku značajnost i mogu da se koriste kao prognostički pokazatelj
uspeha HBO terapije. | Diabetic foot is the term for the pathological changes on foot in patients with
diabetes and is caused by diabetic angiopathy, polyneuropathy and osteoarthopathy. Besides the
medical and surgical treatment, the contemporary treatment of the diabetic foot is also the
hyperbaric oxygenation.
Aim. The determination of efficacy of hyperbaric oxygen therapy applied to the patients with
diabetic foot, the determination of the altitude of oxygen partial pressure on the treatment
outcome and the determination of PtcO2 in pectoral region and the surroundings of the diabetic
wound (ankle-brachial index) for an early assessment of the wound healing.
Materials and methods. During 2016 and 2017 at Special Hospital for Hyperbaric Medicine in
Belgrade and at Clinic for Surgery, Zvezdara University Medical Center, Belgrade a prospective
clinical study was conducted in patients with diabetic foot that were ambulatory treated. Among
those patients by clinical examination of ankle-brachial index ABI<0,6, color doppler
sonography, arteriography and MSCT angiography it was determined that there was no
possibility of surgical or endovascular revascularization.The respondents were randomized into
two groups, the experimental one consisting of 62 patients who were treated by the hyperbaric
oxygen therapy besides the conventional therapy and the control group of 36 patients treated only
by the conventional therapy. Hyperbaric oxygen therapy was carried out in 20 sessions of 70-
minutes duration, under higher pressure of 2,2 ATA breathing 100% oxygen through the mask. In
both groups there were observed the demographic data, the duration and the complications of
diabetes, the status of coronary disease, the laboratory results and the lipid panel, the description
of the diabetic wound and the measurement of the dimensions and the depth of the ulcer.
Precondition for entering the study was the Wagner grade II ulcer or higher and the stage II or
higher of peripheral ischemic disease according to the Fontaine classification. SPSS methodology
was used for the statistical data analysis.
Results. Before the beginning of the therapy all the above-mentioned parameters in both groups
have shown that there was no significant difference between the groups by the statistical analysis.
The dimensions of the wound (length, width, depth) after the therapy have statistically significant
reduction in the experimental group.
By the comparison of the stages, according to the Fontaine classification and according to the
Wagner ulcer grade classification, it was demonstrated that the statistically highly significant
difference after the therapy is in favor of the experimental group.
In a multiplace hyperbaric chamber the patients from the experimental group were measured the
transcutaneous oxygen partial pressure (PtcO2) in pedal region and in the thoracic region and the
regional perfusion index (RPI) was calculated. The measurement was performed in 12. minute, in
35. and in 60. minute during hyperbaric oxygen therapy. The results of the hyperbaric oxygen
therapy were surveyed for the final outcome of the diabetic foot treatment which was divided into
three stages (the deterioration, the unaltered stage of the ulcer and the improvement) and they
were compared between the groups.
Conclusion. By calculating the regional perfusion index RPI (the ratio of pedal PtcO2/thoracic
PtcO2), it was determined that the indexes in correlation with the final outcome of the treatment
demonstrated high statistical significance and that they may be used as the prognostic indicators
of success of HBO therapy. | true |
Faktori rizika za pojavu intraoperativnih hemodinamskih poremećaja tokom operacija primarnog hiperparatireoidizma | Risk factors for intraoperative hemodynamic instability during surgery for primary hyperparathyroidism | Uvod: Cilj rada je da odredi uĉestalost i faktore rizika za pojavu intraoperativnih hemodianmskih
poremećaja kod bolesnika sa komorbiditetima pobrgnutih hirurškom leĉenju oboljenja
paraštitaste ţlezde.
Metodologija: ovo je kohortna studija, u kojoj su ukljuĉena 269 bolesnika ASA 1,2,3 statusa.
Ispitivani su sledeći faktori rizika: pol, godine ţivota, indeks telesne mase, ASA status, prijemna
dijagnoza, vrsta hirurške intervencije, duţina trajanja operacije, vreme provedeno pod
anestezijom,forma primarnog hiterparatireoidizma,vrednosti kalcijuma i fosfata,kao i sledeći
komorbiditeti: hipertenzija, kardiomiopatija, poremećaji srĉanog ritma, angina pektoris-
ishemijska bolest srca, dijebetes melitus, bubreţne bolesti. Registrovani su sledeći intraoperativni
poremećaji: hipertenzija, hipertenzivna kriza, hipotenzija i poremećaji srĉanog ritma (tahikrdija,
bradikardija, novonastala intraoperativna atrijalna fibrilacija i ekstrasistole). Za statistiĉku obradu
korišćen je Pirsonov Hi kvadrat test, univarijantna i multivarijantna logistiĉka regresiona analizu.
Rezultati: većinu bolesnika su ĉinile ţene 195 (87.3%). Intraoperativni hemodinamski poremećaji
su registrovani kod 220 bolesnika (81.8%) bolesnika. Najĉesšći intraoperativni poremećaj je bila
hipertenzija, registrovana kod 153(56.9%) bolesnika, kao i poremećaji srĉanog ritma kod bolesnika
129(48.0%) . Univarijanta analiza je registrovala sledeće faktore rizika: starije ţivotno doba, ASA
3 status, BMI >25kg/m², trajanje operacije, vreme provedeno pod anestezijom, hipertenzija,
kadriomiopatija, vrsta kardiomiopatije. Multivarijantna regiresiona analiza je pokazala da su
nezavisni prediktori pojave IOHP: godine starosti, hipertenzija i kardiomiopatija.
Zakljuĉak: Intraoperativni hemodinamski poremećaji su ĉesti tokom paratireoidne hirurgije, pre
svega intraoperativna hipertenzija. Starije ţivotno doba, hipertenzija i kardiomiopatija kao
koegzistirajuće bolesti su nezavisni faktori rizika za pojavu IOHP. | Introduction: The aim of this study is to determine the incidence and risk factors for
intraoperative hemodianmskih disorder in patients with comorbid pobrgnutih surgical treatment
of the parathyroid gland.
Methodology: This is a cohort study, which included 269 patients ASA 1,2,3 status. We studied
the following risk factors: gender, age, body mass index, ASA status, receiving a diagnosis, type
of surgery, duration of surgery, time spent under anesthesia, form the primary
hiterparatireoidizma, values of calcium and phosphate, as well as the following comorbidities:
hypertension, cardiomyopathy, heart rhythm disorders, angina pectoris-ischemic heart disease,
diabetes mellitus, renal disease. Registered the following intraoperative disorders: hypertension,
hypertensive crisis, hypotension, and heart rhythm disorders (tahikrdija, bradycardia, the new
intraoperative atrial fibrillation and extrasystoles). For statistical analysis we used the Pearson
Chi-square test, univariate and multivariate logistic regression analysis.
Results: The majority of patients were women 195 (87.3%). Intraoperative hemodynamic
disturbances were registered in 220 patients (81.8%) patients. Najĉesšći intraoperative disorder
was hypertension, deposited with the 153 (56.9%) patients, as well as cardiac rhythm disorders in
patients 129 (48.0%). Univariate analysis has registered the following risk factors: older age,
ASA 3 status, BMI> 25kg / m², duration of operation, time spent under anesthesia, hypertension,
kadriomiopatija, type of cardiomyopathy. Regiresiona Multivariate analysis showed that
independent predictors of occurrence IOHP: age, hypertension and cardiomyopathy.
Conclusion: Intraoperative hemodynamic disturbances are common during parathyroid surgery,
primarily intraoperative hypertension. Older age, hypertension and cardiomyopathy as a
coexisting disease are independent risk factors for the occurrence of IOHP. | true |
Kliničke i laboratorijske osobenosti infekcije izazvane Herpes simpleks virusom kod novorođene dece | Clinical and laboratory characteristics of herpes simplex virus infection in newborn infants | Cilj rada: analiza kliničkih i laboratorijskih karakteristika novorođenčadi sa
infekcijom izazvanom Herpes simpleks virusom (HSV). Procena učestalosti
neonatalnog herpesa (NH) u našoj sredini. Ispitivanje korelacije seroloških i
molekularnih metoda dijagnostike. Definisanje kriterijuma za dijagnostičke i
terapijske postupke.
Materijal i metode: Analizirani su podaci o novorođenčadi i odojčadi uzrasta ≤45
dana sa sumnjom na infekciju HSV u periodu od januara 2003. do maja 2015.
godine. Dokazana HSV infekcija je podrazumevala ispoljenu kliničku sliku NH i
pozitivan PCR i/ili serologiju na HSV. Za ispitivanje incidencije NH korišćeni su
podaci Republičkog zavoda za statistiku Srbije. Analizirane su kliničke
manifestacije, laboratorijske analize, ishod lečenja, kao i kvatnifikovanje težine
bolesti korišćenjem skorova SNAP II i SNAPPE II. Za statističku analizu korišćene
su deskriptivne i analitičke metode.
Rezultati: Studija ima 168 ispitanika, 29 sa dokazanom, 133 sa suspektnom i 6 sa
asimptomskom HSV infekcijom. Incidencija NH tokom ispitivanog perioda je 3,01
na 100.000 živorođenih. U periodu 2010-2015. godine, sa uvođenjem rutinske PCR
dijagnostike zabeležen je porast incidencije na 4,78 na 100 000 živorođenih.
Najveći broj novorođenčadi sa dokazanom infekcijom, 72,45%, imao je herpesni
encephalitis, 24,1% je imalo diseminovani oblik i 3,5% lokalizovani oblik bolesti.
Većina infekcija uzrokovana je HSV-2 tipom (55,2%). Teži oblik bolesti imala su
novorođenčad sa HSV-1 infekcijom. Ukupna smrtnost iznosila je 13,8%.
Zaključak: Učestalost neonatalnog herpes u našoj populaciji odgovara učestalosti u
ostalim evropskim zemljama. Sa unapređenjem dijagnostičkih metoda očekujemo
dalji porast incidencije. Osobenosti NH u našoj sredini su veći broj HSV-2 infekcija i
češća pojava herpes encefalitisa. Smrtni ishod je češći kod HSV-1 infekcije. | Aim of study: Analysis of clinical and laboratory characteristics of newborns with
Herpes simplex virus infection (HSV). Estimation of neonatal herpes incidence
(NH) in our population. Correlation of serologycal and PCR tests. Comparison
between suspected and confirmed cases of NH in order to define diagnostic and
therapeutic protocol.
Material and methods: Medical records of infants age ≤ 45 days with suspected NH,
from January 2003 to May 2015. A confirmed case of NH was defined in an infant
with clinical signs compatible with HSV disease and positive serology or PCR for
HSV. Incidence was calculated by using Statistical Office of Republic of Serbia’s
data of live births. We analyzed clinical manifestations, laboratory analysis,
treatment outcome and predicting scores (SNAP II and SNAPPE II). Descriptive and
analytic statistical methods were used for analysis of study results.
Results: There were 168 infants, 133 with suspected, 29 with confirmed and 6 with
asymptomatic HSV infection. Incidence of NH during the study period was 3.01 per
100.000 live births. Rise of incidence to 4.78 per live births 100.000 was noted
after 2010. Majority of infants, 72.45%, presented with encephalitis, 24.1% had
disseminated and 3,5% localized disease. Majority of infections were caused by
HSV-2 (55.2%). Mortality was 13.8%, mostly accompanied with HSV-1 disease.
Conclusion: Incidence of NH in our population is similar to other European
countries. The rise of incidence was observed with improvement of HSV
diagnostics. Characteristics of NH in our population are predominance of HSV-2
infections and herpes encephalitis. Mortality in our group is in accordance with
other reports of NH. | true |
Indeks malignosti u diferencijalnoj dijagnozi ovarijalnih neoplazmi kod žena u premenopauzi i postmenopauzi | Risk of malignancy index in the differential diagnosis of ovarian cancer in premenopausal and postmenopausal women | Naslov doktorske disertacije: „Indeks malignosti u diferencijalnoj dijagnozi
ovarijalnih neoplazmi kod žena u premenopauzi i postmenopauzi“
Uvod
Karcinomi jajnika su vodeći uzrok smrtnosti u grupi ginekoloških maligniteta, stoga je
karcinom jajnika najizučavanije polje u ginekološkoj onkologiji. Uzrok visoke stope
smrtnosti od karcinom jajnika jeste njegova asimptomatičnost i nedovoljna efikasnost
dijagnostičkih metoda, usled čega se u više od 70% slučajeva dijagnostikuje u
uznapredovalom stadijumu bolesti. Rano dijagnostikovanje ovarijalnih neoplazmi je od
izuzetnog značaja, kako bi se optimizovali načini lečenja, smanjili troškovi a
pacijentkinje uputile u odgovarajuće onkološke centre. Napredak u cilju bolje
diferencijacije benignih od malignih tumora jajnika, napravljen je razvijanjem indeksa
malignosti (RMI) koji kombinuje kliničke, ultrazvučne nalaze i koncentracije tumor
markera CA 125 u serumu. Drugi značajan predikcioni test predstavlja ROMA indeks
koji uzima u obzir koncentracije CA 125 i HE4 u serumu, zajedno sa menopauzalnim
statusom. Iako su RMI i ROMA pouzdane metode koje mogu da pomognu u
preoperativnom razlikovanju pacijentkinja sa adneksalnim masama, neophodna je dalja
validacija ovih metoda.
Cilj istraživanja
Utvrditi validnost RMI u diferencijalnoj dijagnozi benignih od malignih tumora jajnika
kod pacijentkinja u premenopauzi i postmenopauzi, kao i validnost pojedinačnih
komponenti predikcionih testova (RMI i ROMA) u zavisnosti od menopauzalnog
statusa pacijentkinja.
Metodologija
Itraživanja u okviru ove doktorske disertacije obavljena su po tipu studije preseka u
Ginekološko akušerskoj klinici „Narodni front“ u periodu jul – decembar 2015. godine.
U studiju su uključene 153 pacijentkinje koje su bile podvrgnute operativnom lečenju
(laparotomija, laparoskopija) tumora adneksalnih masa. Svim pacijentkinjama
preoperativno je urađen transvaginalni ultrasonografski pregled i određene su
koncentracije CA 125 i HE 4 u serumu i izračunavani su RMI i ROMA. U cilju
postavljanja konačne dijagnoze i određivanja stadijuma bolesti odstranjeni adneksalni
tumori su analizirani histopatološki.
Rezultati
Na osnovu histoloških analiza 116 (75,8 %) pacijentkinja su imale benigne tumore, a 37
( 24,2 % ) pacijentkinja su imale maligne tumour jajnika. Pacijentkinje sa malignim
tumorima jajnika su bile statistički značajno starije (p <0,001), a takođe su imale
značajno veće koncentracije CA 125 (p <0,001) i HE4 (p <0,001) serumu i značajno
veće vrednosti RMI (p <0,001) i ROMA (p <0,001) u poređenju sa pacijentkinjama koje
su imale benigne tumour jajnika. Najbolju prediktivnu vrednost u razlikovanju benignih
od malignih tumora jajnika imala je granična vrednost RMI od 200. RMI je pokazao
dobru prediktivnu vrednost i pravilno klasifikovao 85,0% pacijentkinja u celokupnom
uzorku,
90,1%
premenopauzalnih
i
77,4%
postmenopauzalnih
pacijentkinja.
Senzitivnost RMI, CA 125, HE4, i ROMA kod premenopauzalnih pacijentkinja je
iznosila 73,7/ 66,4/ 63,3/ 71,7, dok je kod postmenopauzalnih pacijentkinja iznosila
77,6/ 62,5/ 66,7/ 78,1. Specifičnost RMI, CA 125, HE4, i ROMA kod
premenopauzalnih pacijentkinja je iznosila 86,5/ 61,0/ 72,3/ 63,0, dok je kod
postmenopauzalnih pacijentkinja iznosila 88,9/ 73,3/ 85,0/ 90,9.
Zaključak
Rezultati prikazani u ovoj doktorskoj disertaciji ukazuju da je RMI najbolji metod za
preoperativnu identifikaciju benignih i malignih adneksalnih masa u celokupnom
uzorku i kod premenopauzalnih pacijentkinja, dok kod postmenopauzalnih pacijetkinja
bolju prediktivnu vrednost pokazuje ROMA. Optimalna granična vrednost RMI od 200
za preoperativnu trijažu adneksalnih masa obezbeđuje visoku osetljivost i specifičnost. | Title of doctoral dissertation: “Risk of malignancy index in the differential
diagnosis of ovarian cancer in premenopausal and postmenopausal women”
Background
Ovarian cancers are the leading cause of mortality in the group of gynecological
cancers, and because of that ovarian cancer is the most widely studied field in
gynecological oncology. The lack of sympthoms and low efficiency of diagnostic
methods, are main reasons for high rate of morthality, because more than 70% of
women with ovarian cancer are diagnosed at advanced stages of disease. Early
diagnosis of ovarian cancer is extremely important in order to optimize treatments,
reduce the cost of treatment, and to refere the patient to appropriate oncology centers.
Progress in finding better approach in differentiation between benign and malignant
ovarian tumors, resulted in developing the risk of malignancy index (RMI), which
combines clinical, ultrasound findings and the value of the tumor marker CA 125. Other
significant predictive test represents ROMA index that takes into account the
concentrations of CA 125 and HE4 in serum, together with the menopausal status.
Although the RMI and ROMA are reliable methods helping in preoperative
discrimination of patients with adnexal masses, further validation of these methods still
need to be assessed.
The aim of the research
To determine the validity of the RMI in the differential diagnosis of benign and
malignant ovarian tumors in premenopausal and postmenopausal patients, and validite
each of the individual components of predictive tests (RMI and ROMA) depending on
menopausal status of the patients.
Methods
The study for this doctoral thesis was conducted in the Clinic for Gynecology and
Obstetrics “Narodni front”, Belgrade, Serbia, during the last six months of 2015. The
study group included 153 adult patients who had undergone surgery (laparatomy,
laparascopy) for adnexal tumours. All patients included in this study were
preoperatively underwent detailed ultrasonographic examination and have determined
concentration of serum CA 125 and HE4, and RMI and ROMA were calculated.
Histopathological findings of excised adnexal masses were analyzed in order to make
the final diagnosis and to determine the stage of the disease, after standard operative
procedures appropriate for the staging of the tumour.
Results
According to the histological examination of the specimens 116 (75.8%) women had
benign gynaecologic conditions, whereas 37 (24.2%) women had malignant masses.
Patients with malignant ovarian tumors were significantly older (p <0.001), and also
had significantly higher concentrations of serum CA 125 (p <0.001) and HE4 (p
<0.001), and levels of RMI (p <0.001) and ROMA (p <0.001) compared with patients
with benign ovarian tumor. The best predictive value of RMI in preoperative
dicrimination between benign and malignant tumors had a catoff value of 200. RMI
shows good predictive value and correctly classified 85.0% of patients in the total
population, 90.1% of premenopausal and 77.4% of postmenopausal patients. Sensitivity
for RMI, CA 125, HE4, i ROMA in premenopausal patients were 73.7/ 66.4/ 63.3/ 71.7,
while in postmenopausal patient were 77.6/ 62.5/ 66.7/ 78.1. Specificity for RMI, CA
125, HE4, i ROMA in premenopausal patients were 86.5/ 61.0/ 72.3/ 63.0 while in
postmenopausal patient were 88.9/ 73.3/ 85.0/ 90.9.
Conclusion
The results presented in this study indicate that the RMI is the best method for
preoperative identification of benign and malignant adnexal masses in total population
and premenopausal patients, while in postmenopausal patients ROMA show a better
predictive value. The optimal cut-off value of 200 provides the high sensitivity and
specificity of the RMI. | true |
Uticaj primene kortikosteroida kadaveričnom donoru na ishod transplantacije bubrega | Influence of deceased donor corticosteroid treatment on kidney transplant outcome | Uvod: Nedovoljan broj raspoloživih organa za transplantaciju je posledica nedovoljne
identifikacije potencijalnih moždano mrtvih davaoca u jedinicama intenzivnog lečenja i
nedovoljne konverzije potencijalnih u aktuelne davaoce iz medicinskih i organizacionih
razloga. Moždana smrt ima brojne posledice kao što su hemodinamski poremećaji,
hormonski disbalans i inflamacija, što sveukupno utiče na kvalitet organa i ishod
transplantacije. Hipoperfuzija organa donora ima za posledicu ishemijsko oštećenje i
oksidativni stres, što povećava učestalost odložene funkcije alografta (OFA). Zbog
povećane
ekspresije
citokina,
adhezivnih
molekula
i
antigena
tkivne
histokompatibilnosti, nastale inflamatorne promene organa donora utiču na povećanje
učestalosti akutnih odbacivanja (AO) posle transplantacije. Zbog prevazilaženja ovih
poremećaja, primenjuju se različite terapijske opcije kod donora, koje su važan deo
strategije za popravljanje kvaliteta organa i ishoda transplantacije.
Ciljevi
istraživanja: Sa
ciljem održavanja aktivnosti programa kadaverične
transplantacije bubrega u Kliničkom centru Srbije ispitivali smo uticaj primene
indikatora efikasnosti programa kadaverične transplantacije bubrega u periodu 2010-
2012. Pored toga, ispitivali smo efikasnost primene metil-prednizolona (MP) na
hemodinamiku i bubrežnu funkciju davaoca, kao i učestalost OFA, AO i funkciju
presađenog bubrega do kraja prve godine od transplantacije. Uzimajući u obzir
povezanost moždane smrti, oksidativnog stresa i inflamacije, određivali smo serumsku
koncentraciju 8-hidroksi 2-deoksi guanozina (8-OH-dG), trombospondina-1 (TSP-1) i
nuklearnog faktora kapa B (NF-κB) kod donora organa posle dijagnoze moždane smrti i
njihove kasnije implikacije kod primaoca.
Metode: Studija je prospektivna interventna i opservaciona sprovedena je u Centralnoj
aseptičnoj jedinici intenzivne nege Urgentnog Centra Kliničkog centra Srbije i Centru
za transplantaciju bubrega Kliničkog Centra Srbije u periodu 2010-2013. godine. U
periodu istraživanja smo analizirali tri grupe indikatora efikasnosti programa
kadaverične transplantacije koji se odnose na potencijal za donaciju organa,
organizacione nedostatke i ukupnu efikasnost programa. U program kadaverične
transplantacije je uključeno 172 potencijalna davaoca bubrega identifikovanih u periodu
2010-2012. godine. Moždana smrt je potvrđena kod 163 bolesnika. Kod svih
potencijalnih donora u vreme moždane smrti smo primenili jedan od dva terapijska
pristupa: standardnu terapiju koja je podrazumevala nadoknadu volumena, održavanje
elektrolitnog statusa i inotropnu potporu (73 potencijalna donora) ili stanadardnu
terapiju uz dodatak 500 mg MP u intravenskoj infuziji (90 potencijalnih donora). Uzorci
krvi ovih 163 potencijalnih donora za određivanje 8-OH-dG, TSP-1 i NF-κB su uzeti
odmah nakon dijagnoze moždane smrti i 3 sata kasnije. Od 163 potencijalna davaoca, u
aktuelne davaoce je konvertovan 61, od kojih je 37 primilo standardnu terapiju, a 24 je
primilo i 500 mg MP. Nastavili smo da pratimo 37 aktuelnih donora bubrega mlađih od
70 godina, kod kojih nije registrovan privremeni srčani zastoj, koji nemaju dijabetes
melitus, koji su održavani manje od 24 sata do eksplantacije, imali očuvanu bubrežnu
funkciju u vreme prijema i čiji organi su transplantirani u Kliničkom centru Srbije. Prvu
grupu je sačinjavalo 21 aktuelnih donora organa koji su održavani standardnim
protokolom, a drugu grupu 16 aktuelnih donora koji su osim standardne terapije primili
i pojedinačnu dozu od 500 mg MP. Prikupljeni su podaci o starosti donora, polu,
indeksu telesne mase, uzroku smrti, istoriji hipertenzije, vremenu moždane smrti,
krvnom pritisku i trajanju inotropne terapije. Bubrežna funkcija donora je praćena
merenjem koncentracije serumskog kreatinina na prijemu, zatim najmanje jednom
dnevno do terminalnog kreatinina, što podrazumeva njegovu vrednost u vreme
eksplantacije. Uzorci krvi za određivanje koncentracije 8-OH-dG, TSP-1 i NF- κB ovih
37 donora su obrađeni i zamrznuti na -80˚ C, dok su uzorci ostalih potencijalnih
davaoca odbačeni. Ispitivana je učestalost OFA, AO i funkcija presađenog bubrega u
periodu od godinu dana posle transplantacije kod 60 primaoca bubrega koji su
transplantirani u Centru za transplantaciju bubrega Kliničkog Centra Srbije. Prva grupa
od 30 primaoca dobila je bubreg od donora lečenih standardnim protokolom (grupa 1), a
druga grupa primaoca je dobila bubreg od donora koji su primili MP (grupa 2). Podaci o
primaocu su podrazumevali starost, pol, osnovnu bubrežnu bolest, učestalost OFA i AO,
epizode infekcije, vreme hladne ishemije, HLA podudarnost i funkciju presađenog
bubrega godinu dana od transplantacije. Brzina oporavka funkcije presađenog bubrega
je definisana vremenom od transplantacije kada je prvi put registrovan serumski
kreatinin manji od 150 μmol/l pod uslovom da do kraja perioda praćenja nije bilo
pogoršanja funkcije. Serumska koncentracija 8-OH-dG, TSP-1 i NF- κB primaoca je
određena pre transplantacije, jedan, deset i dvadeset dana posle transplantacije.
Rezultati: Tokom 2010., 2011. i 2012. godine, broj identifikovanih potencijalnih
davaoca bubrega je bio 8,9%, 6,5% i 7,1% od ukupnog broja primljenih bolesnika, što
nije predstavljalo statistički značajnu razliku (p>0,05). Potencijalni donori druge grupe
su imali viši srednji arterijski pritisak (p<0,01) u odnosu na prvu grupu. Primaoci
presađenog bubrega druge grupe su imali signifikantno manju učestalost AO (p<0,05) i
viši klirens kreatinina na kraju prve godine posle transplantacije (p<0,05). Primaoci
druge grupe su oporavili funkciju presađenog bubrega značajno brže u odnosu na
primaoce prve grupe (p<0,05). Primena MP kod donora je značajno doprinela manjoj
učestalosti AO (p<0,05). Cox-ova regresiona analiza je pokazala da je primena MP kod
donora značajan pozitivan prediktor oporavka funkcije presađenog bubrega (p<0,05).
Linearna regresiona analiza je pokazala da primena MP donoru značajno utiče na
serumsku koncentraciju 8OH-dG (p<0,01), TSP-1 (p<0,05) i NF-κB (p<0,01) donora.
Primena MP donoru je imala statistički značajan uticaj na koncentraciju TSP-1 (p<0,01)
i 8OH-dG prvog dana (p<0,01) posle transplantacije.
Zaključak: Najznačajniji efekti primene MP potencijalnim donorima su manja
učestalost AO, brži oporavak funkcije presađenog bubrega i bolja funkcija na kraju prve
godine od transplantacije. Primena MP smanjuje koncentraciju 8OH-dG, TSP-1 i NF-
κB kod kadaveričnog donora i sveukupno doprinosi boljem kliničkom toku posle
transplantacije bubrega. | Introduction: Shortage of organs available from brain dead donors is attributed to the
insufficient reporting of potential donors as well as to low conversion rates of potential
donors into actual donors due to medical and organisational issues. Brain death has
numerous consequences, including hemodynamic disorders, hormonal imbalance and
inflammation, which together influence organ quality and consequently transplantation
outcome. Hypoperfusion of donor organs leads to ischemic lesions and also increases
oxidative stress, which raises the frequency of delayed graft function (DGF). Due to
enhanced expression of cytokines, adhesion molecules and tissue histocompatibility
antigens, subsequent inflammatory changes in donor organs increase the rate of acute
rejection (AR) after transplantation. With the aim of overcoming these disorders donors
are subject to various therapy options that are an important part of the strategy for
improvement of organ quality and transplantation outcome.
Objective: With aim to maintain deceased donor kidney transplant program, we
assessed the impact of indicators of program effectiveness application in Clinical center
of Serbia, between 2010–2012. In adition, we examined the efficiency of methyl-
prednisolone (MP) applied to potential donors on donor hemodinamics and kidney
function, as well as frequency of DGF, AR and kidney allograft function during the first
posttransplant year. Considering the link between brain death, oxidative stress and
inflammation, we measured the serum concentration of 8-hydroxy 2-deoxy guanosine
(8-OH-dG), thrombospondin-1 (TSP-1) and nuclear factor kappa B (NF-κB) in organ
donors after diagnosed brain death, as well as their further implications in recipients.
Method: Prospective interventional and observational study was conducted in Central
aseptic intensive care unit, Emergency center, Clinical center of Serbia and Kidney
transplant center, Clinical center of Serbia. Deceased donor kidney transplant program
involved 172 potential kidney donors that were identified between 2010-2012. Brain
death was confirmed in 163 patients. We conducted an analysis of an effectiveness
indicators of deceased donor kidney transplant program. Three groups of indexes
presenting potential for donation, areas of improvement and global effectiveness
indicators were used. One of the two treatment protocols was applied in all potential
donors with confirmed brain death,: standard therapy including volume compensation,
maintanance electrolytes and inotropic support (73 potential donors) or standard therapy
with 500 mg MP intravenously after brain death diagnosis (90 potential donors). Donor
blood samples for 8-OH-dG, TSP-1 i NF-κB serum concentration were taken
immediately after brain death confirmation, and again 3 hours later. Among 61 actual
donors, standard protocol was applied in 37, while 24 actual donors received 500 mg
MP in addition. Among them, 37 actual donors younger than 70 years, without history
of temporary cardiac arrest, without history of diabetes, maintained for less than 24
hours until organ recovery, with preserved renal function at admission and whose
organs are transplanted in the Clinical Center of Serbia, continued with follow up. The
group consisted of 21 actual kidney donors who were maintained with standard protocol
(Group 1) and 16 actual donors, who besides the standard therapy received a single 500
mg dose of MP immediately after diagnosed brain death (Group 2). We collected data
on donors’ age, sex, body mass index, cause of death, history of hypertension, time of
brain death and duration of inotropic therapy. Donor renal function was monitored by
measuring the concentration of serum creatinine on admission and then at least once a
day until organ recovery. Blood samples from 37 actual donors for determination of 8-
OH-dG, TSP-1 and NF-κB were frozen at -80̍˚ C. We examined frequency of DGF, AO
and kidney allograft function during the first posttransplant year in sixty recipients that
were transplanted in Kidney transplant center, Clinical center of Serbia. The first group
of thirty recipients were allocated organs from donors treated by the standard protocol
(group 1), and the other group received kidney transplants from donors who had been
given MP (group 2). Data on the recipients included age, sex, basic kidney disease,
frequency of DGF and AR, infection episodes and allograft function monitored for a
year after transplantation, cold ischemia time and HLA matching. The allograft function
recovery was defined by the time from transplantation to the reduction of creatinine
concentration to 150 μmol/l and less. Recipient serum concentration of 8-OH-dG, TSP-
1 and NF-κB were measured before transplantation, then at 1, 10 and 20 days after
transplantation.
Results: During 2010., 2011. and 2012. year, the percentage of admitted patients that
were identified as potential kidney donors was 8,9%, 6,5% i 7,1% (p>0,05). Potential
donors that received MP had higher mean arterial pressure (p<0,01) comparing to
potential donors treted with standard therapy ( p<0,01). Kidney allograft recipientsa in
Group 2 had significantly lower AR frequency (p<0.05) and higher creatinine clearance
at the end of the firs posttransplant year (p<0.05). The recipients of Group 2 recovered
allograft function considerably faster than those of the first group (p<0.05). Treatment
of the donors with MP was identified as a statistically significant variable contributing
to lower AR frequency (p<0.05). Cox regression analysis showed that MP treatment of
the donor is a significant positive predictor of graft function recovery (p<0.05). Linear
regression analysis identified donor MP treatment as a significant for donor 8OH-dG
(p<0.01), TSP-1 (p<0.05) and NF-κB (p<0.01) serum level. MP treatment was a
significant for TSP-1 (p<0.01) and 8OH-dG on day 1 (p<0.01) in kidney allograft
recipients.
Conclusion: The most important effects of MP treatment of donors are lower frequency
of AR, faster recovery of kidney allograft function and better functioning at the end of
the first posttransplant year. MP reduces 8OH-dG, TSP-1 and NF-κB in deceased
donors, and altogether it contributes to better organ quality with a consequently more
favorable clinical course after transplantation. | true |
Statini pospešuju zarastanje rana blokirajući aktivaciju glukokortikoidnog receptora farnezil pirofosfatom, međuprozvodom u sintezi holesterola | Statins improve wound healing through inhibition of activation of the glucocorticoid receptor by farnesyl pirophosphate | Uvod: Glukokortikoidni hormoni (GH) su mimo svog anti-inflamatornog
dejstva i jedni od najpoznatijih inhibitora zarastanja rana. Nedavno je pokazano da
farnezil pirofosfat (FPP), ključni međuprodukt mevalonatskog puta sinteze
holesterola i farnezilacije proteina može delovati i kao agonista za nekoliko
nuklearnih hormonskih receptora uključujući glukokortikodni receptor (GR).
Interesantno je da statini, lekovi koji se koriste u terapiji ateroskleroze, svoje
dejstvo ostvaruju upravo inhibirajući ovaj sintetski put. Međutim, statini imaju i
dodatne plejotropne efekte, koji se ostvaruju nezavisno od sniženja koncentracije
holesterola u plazmi i značajno doprinose njihovom korisnom dejstvu u različitim
bolestima. Jedan od dobro dokumentovanih plejotropnih efekata je poboljšana
reparacija tkiva uključujući i zarastanje rana. Zanimljivo je da se upravo inhibicija
farnezilacije signalnih molekula, usled sniženja nivo ćelijskog FPP-a, smatrala do
sada ključnim mehanizmom kojim statini ostvaruju ove svoje dodatne efekte.
Međutim otkriće da FPP može delovati kao ligand za GR otvara vrata za drugačiju
interpretaciju mehanizma dejstva plejotropnih efekata statina i novu primenu ovih
lekova.
Ciljevi: U ovoj disertaciji dokazivano je postojanje novog mehanizma
dejstva statina, kojim oni mogu pospešiti zarastanje rana. Ovaj efekat se zasniva na
sniženju koncentracije endogenog FPP-a u ćelijama kože, putem inhibicije HMG-
CoA reduktaze Osnovna hipoteza je da, s obzirom da statini svoje dejstvo ostvaruju
upravo inhibirajući ovaj sintetski put, modifikuju FPP-GR signalizaciju i tako
učestvuju u stimulaciji zarastanje rana. Prvi cilj istraživanja je bio
aktivacije glukokortikoidnog signalnog puta i stimulacije transkripcije gena. Potom
je ispitatano da li povećanje nivoa endogenog FPP-a putem inhibicije enzima
skvalen sintetaze i farnezil transferaze ima isti efekat na aktivaciju
glukokortikoidnog receptora kao i dodavanje egzogenog FPP-a. U cilju testiranja
funkcionalnog značaja ovog rezultata ispitano je dejstvo FPP-a na procese u
zarastanju rana in vitro i ex vivo. Finalni korak u dokazivanju postavljene hipoteze
je bilo ispitivanje efekata statina, na aktivaciju GR i dinamiku zarastanja akutne
rane.
Materijal i metode: U cilju ispitivanja efekata FPP-a na različite faze
aktivacije
glukokortikoidnog
signalnog
puta
korišćene
su
tehnike
imunofluorescencije, imunoblota, esej imunoprecipitacije hromatina i tranzijentne
transfekcije. U cilju testiranja funkcionalnog značaja ovih rezultata korišćene su
tehnike mikronizova kojima su upoređivani transcripcioni profili u keratinocitima
in vitro nakon tretmana sa GH i FPP. U daljem istraživanju korišćene su
funkcionalne studije poput testa migracije keratinocita i ex vivo model epitelizacije
rane, za procenu učinka FPP-a i statina na zarastanje akutnih rana.
Rezultati: Pokazano je da egzogeno dodati FPP može da aktivira
glukokortikoidni signalni put delujući kao agonista GR, nezavisno od prisustva GH
in vitro i ex vivo. Identičan rezultat dobili smo povišenjem nivoa endogenog FPP-a
u ćelijama, inhibicijom enzima skvalen sintetaze zaragozinskom kiselinom (ZGA).
U cilju testiranja funkcionalnog značaja ovog rezultata, korišćene su tehnike
mikronizova kojima su upoređivani transcripcioni profili u keratinocitima in vitro
nakon tretmana sa GH i FPP. Analiza genskih čipova pokazala je značajno, ali ne i
potpuno, preklapanje između gena regulisanih glukokortikoidima i FPP-om. Ovaj
rezultat pokazuje da FPP nije samo putativni ligand, već i agonista GR. U daljem
istraživanju korišćeni su funkcionalni testovi za procenu učinka FPP na zarastanje
rana. I FPP i ZGA su inhibirali migraciju keratinocita i epitelizaciju in vitro i ex vivo.
Ovi efekti su proizilazili iz aktivacije GR i bili su nezavisni od procesa farnezilacije
proteina. Pokazano je da je inhibicija zarastanja rana uzrokovana FPP, delom
posledica represije keratina 6. Nadalje, pokazano je da mevastatin delujući kao
inhibitor enzima 3-hidroksi-3-metilglutaril-CoA-reduktaze, ne samo da neutrališe
efekat ZGA na aktivaciju GR i inhibiciju epitelizacije, već i sam stimuliše
epitelizaciju akutnih rana snižavajući nivo endogenog FPP.
Zaključci: U ovoj studiji pokazano je da FPP, međuproizvod u biosintezi
holesterola, može da inhibira epitelizaciju i zarastanje rana delujući kao agonista
glukokortikoidnog receptora. Dalje, pokazano je da statini promovišu zarastanje
rana novootkrivenim mehanizmom dejstva, koje se upravo zasniva na inhibiciji
mevalonatskog sintetskog puta i sledstvenom smanjenju koncentracije endogenog
FPP i njegovog dejstva na GR. Otkriće mehanizma dejstva kojim FPP može da
inhibira migraciju keratinocita i epitelizaciju, predstavlja novi pomak u
razumevanju biološke uloge steroidnih hormona i njihovih receptora, jer u ovom
slučaju funkcionalna aktivacija glukokortikoidnog signalnog puta ne zavisi od
prisustva GH i posledica je dejstva endogeno prisutnog metabolita koji ne pripada
s
, kako akutnih tako i hroničnih
rana. | Introduction: Glucocorticoid hormones, in addition to their anti-
immflamatory effect, are well known inhibitors of wound healing. Recent studies
have shown that farnesyl pyrophosphate (FPP), a key intermediate in the
mevalonate pathway of the cholesterol synthesis and protein farnesylation, can act
as an agonist for several nuclear hormone receptors including glucocorticoid
receptor (GR). Interestingly, mechanism of action of statins, drugs used in therapy
of atherosclerosis, is based on inhibition of mevalonath pathway. However, statins
might exert also additional pleiotropic, noncholesterol lowering effects which
significantly contribute to their therapeutic action. One of the well known
pleiotropic effects of the statins is stimulation of tissue repair, including wound
healing. Interestingly, mechanism of pleiotropic effects is traditionally explained
by statin mediated inhibition of the farensylation of signaling molecules. By
inhibiting the enzime HMG-CoA reductase, statins prevent the synthesis of
substrate for reaction, farnesylpyrophosphate. Given that is recently shown that
FPP can act as a ligand for GR, it is not surprising that statins might have additional
mechanisms of action beyond inhibition of the farnesylation. Better understanding
of this mechanism may contribute to novel therapeutic roles for this drugs.
Objectives: In this study we are exploring new mechanism of action of
statins that can contribute to improvement of wound healing. This effect is based
on decreasing the levels of endogenus FPP in keratinocytes by inhibition of the
HMG-CoA reductase. We postulate that statins, acting as an inhibitors of
mevalonate pathway, stimulate wound healing through modulation of FPP-GR
signal. The first step in in our study is to prove that the exogenous FPP, acting as an
agonist for GR, can activate the glucocorticoid signaling pathway and regulate the
transcription of the target genes. Second, will explore the effects of ZGA and B581,
which both can increase the level of endogenous FPP, on activation of
glucocorticoid receptors. ZGA and B581 acomplish their effects through inhibition
of squalene synthetase and farnesyl transferase respectively. To test the functional
significance of this findings, we will explore effects of FPP on processes crucial for
wound healing such as inflammation, migration and epithelization. Finally, to
prove our hypothesis will test effects of statins on GR activation and acute wound
healing.
Materials and methods: To detect the effect of FPP on various stages of
glucocorticoid signaling pathway activation, we have used molecular biology
techniques
such
as:
immunofluorescence,
Western
blot,
chromatin
immunoprecipitation assay and transient transfection. To test the functional
significance of this finding we utilized a large scale microarray to compare the
specific transcriptional effects of DEX and FPP in keratinocytes in vivo. Finally, we
used functional studies: scratch test and humans skin organ culture wound model
to evaluate the effects of FPP and statins on the acute wound healing.
Results: In this study we show that elevation of levels of endogenous FPP
by the squalene synthetase inhibitor zaragozic acid A (ZGA) or addition of FPP to
the cell culture medium results in activation and nuclear translocation of the GR, a
known wound healing inhibitor. To test the functional significance of this finding
we utilized a large scale microarray to compare the specific transcriptional effects
of DEX and FPP on keratinocytes in vitro. Microarray analyses showed significant,
but not complete, overlapping between genes regulated by glucocorticoids and
FPP. This result indicated that FPP is not just a putative ligand, but also an agonist
for GR. Both GC and FPP regulate genes important for inflammation, cytoskeletal
rearrangements and extracellular matrix remodeling in the same fashion. We used
functional studies to evaluate the effects of FPP on wound healing. Both FPP and
ZGA inhibited keratinocyte migration and epithelialization in vitro and ex vivo.
These effects were independent of farnesylation and indicate that modulation of
FPP levels in skin may be beneficial for wound healing. We conclude that FPP
inhibits wound healing by acting as a GR agonist. FPP inhibition of keratinocyte
migration and wound healing proceeds, in part, by repression of the keratin 6
gene. Furthermore, we show that the HMG-CoAreductase inhibitor mevastatin,
which blocks FPP formation, not only promotes epithelialization in acute wounds
but also reverses the effect of ZGA on activation of the GR and inhibition of
epithelialization.
Conclusion: In the current study we show that farnesyl pyrophosphate, a
key intermediate in the mevalonate pathway and cholesterol synthesis can inhibit
epithelization and wound healing, acting as an agonist for a glucocorticoid
receptor. Conversely, we show that statins promote wound healing through novel
mechanism of action, based upon the inhibition of the FPP synthesis and its effect
on GR. The finding that FPP inhibits keratinocyte migration and epithelialization
introduces a new paradigm shift, because the activation of GR does not depend on
the presence of glucocorticoids. These results provide insight in novel mechanisms
of inhibition of wound healing and open new therapeutic approaches in utilizing
statins as drugs in therapy of acute and chronic wounds. | true |
Ispitivanje faktora koji doprinose formiranju stavova o estetskoj hirurgiji | Examination of the factors that contribute to establishing the attitudes toward cosmetic surgery | Porast broja estetskih intervencija u svetu, doprinep je velikom interesovanju autora za stavove ljudi o estetskoj hirurgiji... | The increase in the number of cosmetic procedures around the world contributed to a greater interest of researchers about attitudes toward cosmetic surgery... | false |
Savremeni pristup u hirurškom lečenju stenoze uretre | Contemporary approach in surgical treatment of urethral strictures | Uvod: Stenoza uretre predstavlja suženje lumena uretre različitog stepena. Kliničke
karakteristike stenoze uslovljavaju izbor odgovarajuće hirurške procedure za njeno rešavanje. Na
raspolaganju su nam sledeće terapijske opcije: dilatacija (bužiranje) uretre, endoskopska
resekcija (uretrotomija interna), ugradnja uretralnih stentova i otvorene hirurške procedure
(„end-to-end“anastomoza i augmentaciona uretroplastika). Pretpostavka je da su česti recidivi
ove bolesti, koje srećemo u kliničkoj praksi, rezultat neadekvatnog terapijskog pristupa.
Ciljevi: Cilj ove studije je definisanje optimalne metode u lečenju stenoze uretre
poreĎenjem ishoda tri različita načina lečenja: uretrotomija interna (UI), augmentacija uretre uz
korišćenje vaskularizovanog kožnog režnja i augmentacija uretre korišćenjem transplantata
bukalne mukoze (BMG). Osim procene efikasnosti lečenja, cilj rada bio je i utvrĎivanje vrste i
učestalosti komplikacija koje prate svaku od navedena tri modaliteta lečenja, kao i analiza
kliničkih karakteristika stenoza uretre i njihovog uticaja na ishod lečenja.
Matrijal i metode: Tokom ove studije praćeno je 84 pacijenata koji su lečeni zbog stenoze
uretre u periodu od februara 2007. do januara 2015. Posmatrani paciijenti su bili podvrgnuti
sledećim operativnim zahvatima: kod dvadeset i šest (26) pacijenata uraĎena je uretrotomija
interna (grupa 1), kod 17 pacijenata uraĎena je augmentacija uretre primenom režnja penilne
kože (grupa 2), a kod 41 pacijenta uraĎena je operacija augmentacije uretre primenom grafta
bukalne mukoze (grupa 3). Svi pacijenti su redovno praćeni tokom ranog postoperativnog
perioda, a zatim 1, 6 i 12 meseci od operativnog zahvata, i kasnije po potrebi. Pacijenti su davali
usmeni izveštaj o kvalitetu mokrenja i navodili subjektivni osećaj ispražnjenosti bešike i podatak
o postojanju urinarnih infekcija. Tokom perioda praćenja pacijentima je raĎena urofloumetrija i
ultrazvučno im je merena količina rezidualnog urina. Ukoliko su postojale jasne subjektivne
smetnje, ili nalazi urofloumetrije ili ultrazvuka nisu bili zadovoljavajući, raĎene su dodatne
procedure u vidu uretrografije ili uretroskopije. Uspeh operativne procedure definisan je kao
mogućnost spontanog mokrenja, brzina mokrenja merena urofloumetrijom od najmanje 15 ml/s i
odsustvo potrebe za nekom od dodatnih intervencija uključujući i bužiranje uretre.
Rezultati: Na osnovu anamnestičkih i kliničkih podataka utvrdili smo da je kod najvećeg
broja pacijenata uzrok stenoze bila je hipospadija (21), zatim kateterizacija mokraćne bešike ili
endoskopska intervencija (19), nepoznat uzrok (19), trauma (10), lichen sclerosus (8), infekcija
(7). Prema lokalizaciji stenoze uretre su se nalazile u glandijalnom delu kod 20 pacijenta, u
penilnom kod 23, u bulbarnom tj. bulbomembranoznom kod 25 pacijenata, a panuretralne i
multiple strikture postojale su kod 16 pacijenta. Period postoperativnog praćenja iznosio je 14 do
109 meseci (prosečna vrednost 41 mesec). Procenat uspešnosti lečenja u grupi 1, kod pacijenata
kod kojih je raĎena UI, bila je 26,9% (7/26). U navedenoj grupi, kod 19 pacijenta (73,1%) bila je
potrebna neka od dodatnih hirurških procedura. Pacijenti iz grupe 2 su operisani korišćenjem
kožnog režnja, što je bilo uspešno u 76,5% (13/17). Kod preostalih 23,5% pacijenata primenjen
metod lečenja nije bio efikasan. Treća grupa pacijenata sa stenozom uretre lečena je primenom
BMG, što je dalo dobre rezultate u 35 od 41 slučaja (85,4%), a kod 6 pacijenata (14,6%) lečenje
nije bilo uspešno. Komplikacije su se češće dešavale kod pacijenata lečenih UI (73%) ili kožnim
režnjem (76%), u odnosu na grupu pacijenata lečenih BMG (41%).
Zaključci: U ovoj studiji utvrdili smo da vrsta operativnog zahvata predstavlja jedini
nezavisni prediktor za pojavu recidiva stenoze uretre. Uretrotomija interna, i pored svoje
jednostavnosti i popularnosti, predstavlja neadekvatan način lečenja stenoze uretre zbog velikog
stepena neuspeha. Najveći broj pacijenata kojima je uraĎena UI moraju kasnije da se podvrgnu
otvorenoj hirurškoj intervenciji u cilju definitivnog izlečenja stenoze uretre. Korišćenje
fasciokutanih režnjeva u rekonstrukciji uretre daje dobre rezultate, sa zadovoljavajućom
stepenom uspeha. Nedostatak ovog modaliteta lečenja bio je veći broj pratećih komplikacija.
OdreĎen broj pacijenata sa stenozom uretre nisu kandidati za ovu vrstu intervencije zbog
nedostatka zdrave kože penisa potrebne za formiranje upotrebljivog i kvalitetnog režnja.
Operacija stenoze uretre korišćenjem grafta bukalne mukoze ima najviše šanse za definitivni
uspeh, uz prihvatljivu stopu komplikacija i minimalan morbiditet donorske regije, pa, shodno
tome, predstavlja „zlatni standard“ u lečenju stenoze uretre. Našim ispitivanjem smo utvrdili da
raniji koncept lečenja stenoza uretre, tzv. »postepenim pristupom«, koji je baziran na principu da
uvek treba pokušati jednostavnije procedure pre pomaka ka kompleksnijim zahvatima, treba u
potpunosti odbaciti. Savremeni stav u lečenju stenoza uretre podrazumeva primenu adekvatne i
efikasne, a ne najjednostavnije metode. | Introduction: Urethral stenosis presents narrowing of the urethral channel. Clinical
characteristics of every urethral stricture determine the choice of surgical treatment for its repair.
Following surgical options are available: dilation, direct vision internal urethrotomy, urethral
stents and open surgical repair (“end-to-end” anastomosis and augmentation urethroplasty). We
suppose that recidivant urethral strictures, which can be noted frequently, are result of inadequate
treatment.
Objective: Goal of this study is to define optimal method in the treatment of urethral
strictures, by comparison of three different treatment options: internal urethrotomy,
augmentation urethroplasty using fasciocutaneous skin flap and augmentation urethroplasty
using buccal mucosa graft. Furthermore, we evaluated the types and rate of postoperative
complications, as well as impact of clinical characteristics on outcome of the treatment.
Materials and methods: In the period from February 2007 to January 2015, 84 patients
were treated because of urethral stricture disease. First group of patients (26) underwent internal
urethrotomy, second group (17) underwent urethroplasty using faciocutaneous flap, and third
group (41) underwent urethroplasty using buccal mucosa graft. All patients were followed during
early postoperative period and 1, 6 and 12 months thereafter, and longer if needed. Patients
reported voiding habits, feeling of emptying of the bladder and history of urinary tract infections.
All patients underwent uroflowmetry and measurement of postvoiding residual urine. Additional
evaluation, as urethrography or urethroscopy were conducted if patient reported symptoms of
obstruction or unsatisfactory uroflow measurements were found. Success was defined as
possibility for normal and complete voiding without need for additional procedures (including
dilations) and Qmax at least 15ml/sec.
Results: According to history and clinical features we found that 21 patients had stricture
due to failed hypospadias, 19 patients develop urethral stricture after catheterization or
transurethral procedures, 19 had stricture of unknown origin, 10 had trauma, 8 had lichen
sclerosus and 7 had an infection. Twenty patients had their stricture in glandial urethra, 23 in
penile urethra, 25 in bulbar, and 16 had panurethral or multiple strictures. Follow up period was
14 to 109 months (mean 41 months). Success rate in first group (internal urethrotomy) was
26,9% (7/26), while in 19 patients (73,1%) additional procedures were necessary for definitive
treatment of urethral stricture. Success rate in second group (fasciocutaenous flap) was 76,5%
(13/17). Treatment failed in 23,5% patients. Patients with buccal mucosa graft urethroplasty
(group 3) were successfully treated in 85,4% of cases (35/41), while the treatment was
unsuccessful in 14,6% cases (6/41). Postoperative complications were more often in group 1
(73%) and group 2 (76%), than in group 3 (41%).
Conclusion: Our study revealed that type of the operative procedure presents independent
predictor for recurrence of the urethral stricture. Internal urethrotomy is mostly unsuccessful
treatment option, with high failure rate. The majority of these patients were referred to open
urethroplasty procedure as final solution of their condition. Fasciocutaneous flap urethroplasty
had acceptable success rate, but there were significant numbers of minor complications. Patients
with scarred and deformed skin were not good candidate for this procedure. The most successful
procedure in our study was urethroplasty using buccal mucosa graft with low overall
complication rate, minimal donor site morbidity; and therefore presents a “gold standard” in the
treatment of urethral strictures. Our study confirmed that “ladder approach”, that includes “less”
invasive treatment as first option, should be completely abandoned. Contemporary management
of urethral strictures is based on adequate and effective approach, not the simplest one. | true |
Procena kognitivnog statusa kod bolesnika sa različitim kliničkim fenotipovima multiple skleroze | Assessment of cognitive status in patients with different multiple sclerosis phenotypes | Uvod: Kognitivni poremećaji kod bolesnika sa multiplom sklerozom (MS) se javljaju u 43 -72%. Cilj našeg istraţivanja bio je da se proceni kognitivni status kod bolesnika sa razliĉitim kliniĉkim fenotipovima MS u srpskoj populaciji. Metode: Raova Kratka Ponovljiva Baterija neuropsiholoških testova (BRB-N) je primenjena kod 168 MS bolesnika [(43 bolesnika sa kliniĉki izolovanim sindromom (KIS), 59 sa relapsno remitentnom MS (RRMS), 31 sa sekundarno progresivnom MS (SPMS) i 35 pacijenata sa primarnom progresivnom MS (PPMS)]. Rezultati: Procenat kognitivno oštećenih bolesnika u našoj ukupnoj MS kohorti bio je 58,9%. Prevalencija kognitivne disfunkcije bio 41,9% u KIS grupi, 35,6% u RRMS, 96,8% u SPMS, a 85,7% u PPMS grupi. Bolesnici u KIS i RRMS grupi imali su bolja postignuća u svim testovima BRB-N baterije u odnosu na bolesnike u SPMS i PPMS kohorti. Razlika u postugnućima na testovima BRB-N nije pokazana izmeĊu bolesnika sa KIS i RRMS. MeĊutim, postoji znaĉajna razlika u postignućima BRB-N baterije izmeĊu SPMS i PPMS bolesnika u pet testova. Zakljuĉak: Naša studija pokazuje da su kognitivni poremećaji ĉesti 0u svim MS fenotipovima. Pokazali smo da je kognitivni deficit najteţi i najĉešći kod SPMS bolesnika, a zatim PPMS i konaĉno kod KIS i RRMS bolesnika. | Background: Cognitive impairment is prevalent in multiple sclerosis (MS) occurring in 43-72% of patients. The aim of our study was to assess cognitive performance in different MS subtypes in Serbian population. Methods: Rao’s Brief Repeatable Battery of neuropsychological tests (BRB-N) was administered to 168 MS patients [43 patients with clinically isolated syndrome (CIS) , 59 with relapsing-remitting MS (RRMS), 31 with secondary progressive MS (SPMS) and 35 patients with primary progressive MS (PPMS)]. Results: The percentage of cognitively impaired patients in our total MS cohort was 58.9%. Prevalence of cognitive dysfunction was 41.9% in CIS group, 35.6% in RRMS, 96.8% in SPMS, and 85.7% in PPMS group. Patients in CIS and RRMS groups performed consistently better all tests of the Rao’s battery than patients in SPMS and PPMS cohort. Difference in the performance of any of the BRB-N tests was not found between CIS and RRMS. However, there was a significant difference between SPMS and PPMS patients in the performance on five tests of Rao’s battery. Conclusion: Our study demonstrates that cognitive impairment is frequent in all MS phenotypes. We have found that cognitive deficit is most severe and most frequent in SPMS patients, followed by PPMS subjects and then CIS and RRMS patients. | false |
Uticaj karakteristika aterosklerotskog plaka procenjenih višeslojnom kompjuterizovanom tomografijom na ishod perkutane koronarne intervencije na račvama koronarnih arterija | The influence of atherosclerotic plaque characteristics estimated using multislice computerized tomography coronary angiography on the outcome of percutaneous coronary interventions in bifurcations | Aterosklerotske lezije su izražene na mestima sniženog stresa istezanja
zida koronarnih krvnih sudova – račvama. Prisustvo značajnih suženja na glavnoj
(MB) i bočnoj grani (SB) dodatno otežava uspešno interventno lečenje. Uz pomoć
višeslojne CT koronarne angiografije (CTCA) se pouzdano može isključiti prisustvo
koronarne bolesti. Istraživanja koja su analizirala “prave” bifurkacije nativnih
koronarnih arterija pomoću CTCA nisu do sada predstavljena.
Cilj: Cilj istraživanja je pokazati da li se primenom CTCA može predvideti nastanak
kompromitacije SB nakon “provizorne“ implantacije stenta u MB kod „pravih“
bifurkacija.
Materijal i metode: Studija je prospektivna, opservaciona i izvedena na Službi
kardiologije, Klinike za internu medicinu, Kliničko-bolničkog centra Zemun i
uključila je pacijente sa stabilnom koronarnom bolešću i „pravom“ bifurkacijom,
koja ne uključuje glavno stablo leve koronarne arterije, koji su podvrgnuti CTCA
pre PCI, a potom intravaskularnom ultrazvuku (IVUS) MB tokom intervencije.
Studija nije uključila pacijente sa atrijalnom fibrilacijom, akutnim koronarnim
sindromom, sniženom ejekcionom frakcijom manjom od 30%, bubrežnom
insuficijencijom,
prethodno
hirurški
revaskularizovane,
kao
i
one
sa
kontraindikacijom za CTCA i/ili PCI. Analiza je uključila kvantitativne i kvalitativne
parametre plaka na longitudinalnim i poprečnim presecima bifurkacije na tri nivoa
(karina, 5mm proksimalno i distalno) i na mestu minimalnog dijametra lumena
(MLD).
Rezultati:Uključeno je 70 ispitanika sa 72 „prave“ bifurkacije. Većina bifurkacija se
nalazila na teritoriji prednja silazna grana (LAD) – dijagonalna grana (D).
Kompromitacija SB nastala je kod 17/72 bifurkacija (23.6%). Intervencija je u tom
slučaju nastavljena balon angioplastikom (9/17, 52.9%) ili implantacijom stenta u
SB (8/17, 47.1%). Na longitudinalnom preseku lezije na strani karine bifurkacije u
MB i SB su značajno ređe prisutne i imaju manji denzitet u poređenju sa plakovima
na lateralnoj strani MB i SB (p<0,001). U multivarijabilnoj regresionoj analizi koja je
uključila poznate prediktore kompromitacije bočne grane na CTCA samo je
cirkumferentni plak u proksimalnom segmentu MB nezavisni prediktor pogoršanja
protoka u SB < TIMI 3. U multivarijabilnoj regresionoj analizi gde su uključeni
prethodno poznati prediktori kompromitacije SB u QCA analizi samo je količnik MB
RVD i dijametra stenta nakon PCI ostao nezavisni prediktor kompromitacije SB.
Pokazana je značajna korelacija između CTCA i IVUS-a u proceni površine krvnog
suda na svim analiziranim nivoima, kao i između prosečnog denziteta plaka na
CTCA i procenta kalcifikovanog aterosklerotskog plaka primenom IVUS-a na svim
nivoima.
Zaključak:
Kompromitacija
ostijuma
SB
povezana
je
sa
prisustvom
cirkumferentnog plaka u proksimalnom segmentu bifurkacije. CTCA i IVUS
saglasni su u proceni površine krvnog suda i kalcifikovanog plaka, ali ne i lumena i
nekalcifikovanog plaka kod kompleksnih bifurkacija. Kompromitacija ostijuma SB
povezana je sa uvećanjem dijametra MB nakon implantacije stenta u QCA analizi. | Atherosclerosis develops in the areas of low endothelial shear
stress, especially at the branching points of the coronary arteries. Presence of
significant stenoses in both main (MB) and side branch (SB) – true bifurcation,
adds significant complexity to intervention. Due to its high sensitivity and moderate
specificity with high negative predictive value, CT coronary angiography (CTCA)
can reliably exclude presence of coronary artery disease. CTCA hasn’t been
extensively used in evaluating bifurcation lesions.
Aim: The aim of the study was to determine whether qualitative and quantitative
analysis of true bifurcations using CTCA can predict the compromise of the SB
ostium, defined as decrease in flow below TIMI III, after provisional stenting of the
MB.
Materials and methods: The study was prospective, observational and was
conducted at Cardiology department, Internal medicine clinic, Clinical Hospital
Centre Zemun. The study included patients with stable coronary artery disease
having “true“bifurcations, not located in left main left coronary artery, and
scheduled for PCI. Prior to PCI they underwent CTCA using 128-row scanner with
contrast optimized protocol. During PCI they underwent intravascular ultrasound
(IVUS) of MB using automated, motorized pullback. The patients having acute
coronary
syndrome,
atrial
fibrillation,
renal
failure,
previous
surgical
revascularization and contraindications for CTCA and/or PCI were not included in
the study. The analysis included qualitative and quantitative parameters of
atherosclerotic plaques in longitudinal and cross-section of bifurcation using CTCA
and IVUS.
Results: The study included 70 patients with 72 “true“bifurcations. The most of the
bifurcations were located in left anterior descending (LAD) – diagonal (D) territory.
SB compromise occurred in 17/72 bifurcations (23.6%). The PCI was continued
with balloon angioplasty of the SB (9/17, 52.9%) or stent implantation in SB (8/17,
47.1%). In longitudinal cross-section plaques on carina side of MB and SB
occurred less frequently and had lower density compared to plaques on lateral side
of both branches (p<0.001). In multivariable regression analysis that included
known predictors of SB compromise on CTCA analysis, only circumferential plaque
in MB proximal segment was an independent predictor of SB compromise. In
multivariable regression analysis that included known predictors of SB compromise
on QCA measurements only ratio MB RVD/stent diameter remained an
independent predictor of SB compromise. There was a fair correlation between
CTCA and IVUS regarding vessel area at all levels of MB, but not regarding lumen
of the MB. Also, there was a significant correlation regarding average plaque
density on CTCA and percentage of calcified plaque on IVUS tissue analysis and
between plaque classification on CTCA and percentage of non-calcified plaque on
IVUS.
Conclusions: Compromise of SB ostium was associated with circumferential
plaque in bifurcation’s MB proximal segment. CTCA showed fair correlation with
IVUS regarding vessel area and calcified plaques in true bifurcations with
advanced
atherosclerosis.
SB
compromise
was
associated
with
vessel
enlargement after stent implantation on QCA analysis. | true |
Ispitivanje homocisteina kao markera ateroskleroze kod pacijenata sa metaboličkim sindromom | Homocysteine research as an atherosclerosis marker in patients with metabolic syndrome | Gojaznost je povezana sa promenama funkcije adipoznog tkiva, što vodi u
insulinsku rezistenciju (IR) i hroničnu upalu niskog stepena. Hiperhomocisteinemija je
nađena kod pacijenata sa metaboličkim sindromom (MS) i vaskularnim komplikacijama.
Hiperhomocisteinemija korelira sa IR, povećava oksidativni stres, koji uzrokuje
endotelne
lezije
i
disfunkciju,
doprinoseći
hipertenziji
i
aterosklerozi.
Ciljevi: Ciljevi ove studije bili su ispitivanje faktora MS kod osoba sa MS, u odnosu na
osobe bez MS, kao i stepen korelacije homocisteina sa faktorima MS. Ispitivanje
korelacije siMS skora, siMS skora rizika sa osnovnim i pridruženim faktorima MS.
Metode: Studija obuhvata 148 ispitanika (>30 godina, ITM>25kg/m2) koji su podeljeni
u dve grupe: I - sa MS (68 pacijenata); II – bez MS (80 pacijenta). Merenja su uključivala:
antropometriju, lipide, poremećaj glikoregulacije i faktore inflamacije. IR je određena
putem
HOMA-IR.
ATP-III
klasifikacija
je
korišćena
za
dijagnozu
MS.
Rezultati: Statistička značajnost između grupa nađena je za faktore MS (obim struka,
glikemiju, trigliceride, sistolni i dijastolni pritisak, HDL-holesterol) i pridružene faktore
MS (CRP, HOMA-IR, mokraćna kiselina, ALT (alanin aminotransferaza) i GGT (gama
glutamil transferaza)). SiMS skor je korelirao sa homocisteinom, logCRP, mokraćnom
kiselinom, logHOMA-IR, logALT, logGGT, trombocitima, fibrinogenom, proteinima i
kreatininom. SiMS skor rizika statistički značajno korelirao je sa homocisteinom,
trombocitima, mokraćnom kiselinom, ureom, albuminima i proteinima.
Zaključak: Pacijenti sa MS imali su povećanu stomačnu gojaznost, hipertenziju,
hipertrigliceridemiju, faktore inflamacije, IR, mokraćnu kiselinu i parametre funkcije
jetre. Korelacija siMS skora sa homocisteinom, CRP i mokraćnom kiselinom,
fibrinogenom, HOMA-IR, logALT, logGGT, ukazuje da su oni pridruženi faktori MS.
Korelacija siMS skora rizika sa homocisteinom ukazuje da se hiperhomocisteinemija
povećava sa godinama. Hiperhomocisteinemija je povezana sa genetskim faktorima i
porodičnim navikama vezanim za ishranu i povećava rizik za aterosklerozu. | Patients with metabolic syndrome (MS) and vascular complications have
higher values of homocysteine. Hyperhomocysteinemia correlates with IR, increasing
oxidative stress. Oxidative stress causes lesions of vascular endothelium leading to
endothelial dysfunction, hypertension and atherosclerosis.
Objective: The objectives of the study were: to examine MS factors in patients with and
without MS, as a correlation between homocysteine and MS factors; to examine
correlation of siMS score and siMS risc score with MS factors and MS co-founding
factors.
Methods: The study included 148 obese individuals (age over 30, body mass index (BMI)
>25 kg/m2), classified into two groups: I - with MS (68 patients); II - without MS (80
patients). Measurements included: anthropometry, lipids, glucose regulation parameters
and inflammation parameters. IR was determined by HOMA IR. ATP-III classification
was applied for diagnosing MS.
Results: A significant difference between groups was found for MS factors (waist
cicumference, glycaemia, blood pressure, triglycerides, HDL-cholesterol) and MS co-
founding factors (CRP, HOMA-IR, uric acid, ALT (alanine aminotransferase) and GGT
(gama glutamil transferase)). The siMS score confirmed significant correlation with
homocysteine, logCRP, uric acid, logHOMA-IR, logALT, logGGT, thrombocytes,
fibrinogen, proteins and creatinine. siMS risk score showed a statistically significant
correlation with homocysteine, uric acid, thrombocytes, urea, albumin and total proteins.
Conclusion: Patients with MS had increased abdominal obesity, hypertension,
hypertriglyceridemia, inflammation factors, IR, uric acid and liver function parameters.
Correlation of siMS score with homocysteine, fibrinogen, CRP and acidum uricum
indicates that they are co-founding factors of MS. siMS risk score correlation with
homocysteine
indicates
that
hyperhomocysteinemia
increases
with
age.
Hyperhomocysteinemia is linked with genetic factors and family nutritional scheme,
increasing the risk for atherosclerosis. | true |
Procena efektivnosti psihijatrijskog lečenja na glikoregulaciju i komplikacije kod obolelih od šećerne bolesti | Assessing the effectiveness of psychiatric treatment onto glycoregulation and diabetic complications in patients with diabetes mellitus | Uvod: Još uvek nije sigurno da li se posledice depresije kod dijabetičara mogu ublažiti
lečenjem depresije. Primarni cilj bio je da se utvrdi da li dodatak antidepresiva postojećoj
insulinskjoj terapiji u pacijenata obolelih od šećerne bolesti i depresije može poboljšati
glikoregulaciju. Sekundarni cilj bio je da se utvrdi da li lečenje antidepresivima dovodi do
pogoršanja lipidnog i inflamatornog statusa kod ovih pacijenata, koji predstavljaju faktore
rizika za nastanak komplikacija šećerne bolesti.
Materijal/Metode: Ukupno 192 pacijenta sa loše regulisanim dijabetesom tip 2 (HbA1c viši
od 8%) u odsustvu bilo kojeg drugog zdravstvenog stanja, bilo je uključeno u 6-mesečno
ispitivanje, stabilizacionu fazu koja je podrazumevala optimizaciju antidijabetične terapije.
Depresivni status je skrinovan na kraju ove faze uz pomoć BDI-II (Bekove skale depresije).
Pacijenti koji su imali skor preko 14 i od strane psihijatra potvrdjenu depresiju (58 pacijenata)
ukljućeno je u 6-mesečnu interventnu fazu studije sa SSRI klasom antidepresiva.
Rezultati: 50 pacijenata je završilo studijsko praćenje. Tokom stabilizacione faze, hbA1c je
opao od vrednosti 10.0±1.8% do 8.5±1.2% (p<0.001), a tokom interventne faze opao je od
vrednosti 8.5±1.2% do 7.7±0.7% (p<0.001). Skor na Bekovoj skali depresije se značajno
popravio od 30.4±13.2 to 23.5±11.0 (p=0.02) tokom interventne faze. Zapažena je pozitivna
linearna korelacija izmedju pobljšanja u skoru depresije i poboljšanja glikoregulacije
(R2=0.139, p=0.008). Lipidni i inflamatorni status nisu se promenili značajno kod ovih
pacijenata tokom interventne faze ispitivanja.
Zaključak: Pacijenti sa loše kontrolisanim dijabetesom i prisutnom komorbidnom depresijom
mogu imati značajne koristi od skrininga i lečenja depresije SSRI antidepresivima, u smislu
poboljšanja glikoregualcije. Ova terapija nije dala neželjene efekte na lipidni niti inflamatorni
status ovih pacijenata. | Background: It is still disputable whether negative effects of comorbid depression in diabetics
can be diminished by successful treatment of depression. The primary aim of this study was
to assess whether addition of antidepressants to existing insulin treatment would further
improve glycemic control in these patients. A secondary objective was to assess whether such
treatment impairs their lipid and inflammatory status.
Material/Methods: Total of 192 patients with poorly controlled diabetes (defined as HbA1c
≥ 8%) in the absence of any uncontrolled medical condition entered the 6-month run-in phase
with optimization of diabetic therapy. Depression status was screened at the end of this phase
by BDI-II depression testing. Patients with BDI-II ≥ 14 and psychiatric confirmation of
depression (58 patients) entered the 6-month interventional phase with SSRI class
antidepressants.
Results: Fifty patients completed the study. During the run-in phase, HbA1c dropped from
10.0% ± 1.8% to 8.5% ± 1.2% (p<0.001), and during the interventional phase it dropped from
8.5% ± 1.2% to 7.7% ± 0.7% (p<0.001). BDI-II scores improved significantly from 30.4 ± 13.2 to
23.5 ± 11.0 (p=0.02) during the interventional phase. A positive linear correlation between
improvement in depression scale and improvement in glycemic control was observed
(R2=0.139, p=0.008). Lipid profile and inflammatory status did not change significantly during
the interventional phase.
Conclusions: Patients with poorly controlled diabetes and comorbid depression might benefit
from screening and treatment of depression with SSRI antidepressants by achieving an
incremental effect on glycoregulation. This therapy did not have any adverse effects on lipid
profile or inflammatory status.
MeSH | true |
Ispitivanje povezanosti metaboličkog sindroma sa kolorektalnim karcinomom | Examination of conection between metabolic syndrom and colorectal cancer | Uvod: Metabolički sindrom (MS) i slični metabolički poremećaji prikazani su kao
faktor rizika za nastanak kolorektalnog karcinoma (KRK). Cilj ove studije bio je da se
istraži potencijalna uloga MS u patogenezi KRK. Takođe, upoređivani su i nivoi
serumskih inflamatornih i tumorskih markera, kao i vrednosti biohemijskih parametara
sa prisustvom MS kod pacijenata sa KRK.
Metode:
Retrospektivna
kohortna
studija
obuhvatila
je
194
bolesnika
sa
dijagnostikovanim KRK, koji su podeljeni u dve grupa na osnovu prisustva MS. Podaci
su prikupljani iz istorija bolesti kao i na osnovu merenja bolesnika (telesna težina,
visina, obim struka), na odeljenju Opšte hirurgije Kliničko bolničkog centra „Bežanijska
kosa“ u Beogradu. Ispitivani su biohemijski parametri, kao i nivoi CEA, CA 19-9, AFP
i CRP koji su upoređivani sa prisustvom MS.
Rezultati: Vrednosti indeksa telesne mase, obima struka, sistolnog pritiska, glukoze i
triglicerida bili su statistički značajno povišeni kod pacijenata sa KRK kog kojih je
dijagnostikovan MS, dok su vrednosti HDL-holesterola bili značajno sniženi. Broj
komponenti metaboličkog sindroma bio je značajno manji 3 meseca nakon hirurške
intervencije. Vrednosti alaninin aminotransferaze, aspartat aminotransferaze, alkalne
fosfataze, direktnog i ukupnog bilirubina, ukupnih proteina, uree i kreatinina nisu se
značajno razlikovale među ispitivanim grupama. Uočeno je značajno smanjenje
vrednosti CRP među ispitivanim grupama tri meseca nakon hirurške intervencije.
Vrednosti AFP i CEA bile su povišene i znad graničnih vrednosti među pacijentima sa
metaboličkim sindromom, ali uočene razlike nisu bile statistički značajne. Vrednost CA
19-9 bile su statistički značajno veće u grupi sa metaboličkim sindromom i pre i 3
meseca postopeativno, ali vrednosti ispitivanog markera nisu prelazile granične
vrednosti.
Zaključak: Rezultati ove studije ukazuju na moguću povezanost između prisustva MS i
povećanog rizika za nastanak KRK. Potrebno je sprovesti velike prospektivne studije da
bi se ispitala potecijalna uloga serumskih markera u skriningu KRK kod pacijenata kod
kojih je dijagnostikovan MS. | Background: Metabolic syndrome (MS) and related metabolic alteration have been
represented as a risks for colorectal carcinoma (KRK) development. This study aimed to
evaluate potential role of MS in the pathogenesis of colorectal cancer. Additionally, the
levels of serum - inflammatory and tumor markers, as well as biochemical parameters
were correlated with the presence of MS in patients with diagnosed KRK.
Methods: The retrospective cohort study consisted of 194 patients diagnosed with
KRK, divided into a two groups based on the presence of MS. Medical data were
collected from the patients medical records as well as meserment of patients (body high,
weight, circumference) at the Department of General Surgery, Clinical Hospital Center
,,Bežanijska kosa”, Belgrade. Biochemical parameters and the levels of inflammatory
and tumor markers CEA, CA 19-9, AFP, and CRP were registered and correlated with
the presence of MS.
Results: The values of BMI, waist circumference, systolic pressure, glucose, and
triglycerides were significantly increased in KRK patients with metabolic syndrome,
while the values of HDL-C were significantly decreased. A number of MS components
were significantly decreased 3 months after the surgical procedure. The values of
alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, direct and
total bilirubin, urea and creatinine were not differed significantly between examined
groups. The values of CRP were significantly increased 3 months after surgical
procedures in investigated groups. The values of AFP and CEA were increased and
above the limit values between patients with MS, but observed differences were not
statistically significant. The values of CA 19-9 were significantly increased in the group
with MS pre- and postoperatively, but its values were bellowed the limit.
Conclusions: This study showed possible correlation among MS and increased risk for
KRK. Large prospective population-based studies are needed to establish real benefit of
molecular markers for KRK screening in patients with MS. | true |
Značaj parametara ultrazvučne biometrije za predviđanje ishoda monohorionskih blizanačkih trudnoća | First trimester ultrasonographic parameters in prediction of the course and outcome of monochorionic twin pregnancies. | Uvod: Prema sadašnjim stavovima i preporukama, ultrasonografska fetalna
merenja u prvom i drugom trimestru
imaju najveću moć za predikciju daljih
komplikacija kao i samih ishoda monohorionskih trudnoća, ali su rezultati prethodnih
studija nekonzistentni ili nedovoljno pouzdani zbog male incidence monohorionskih
blizanaca, pa su dalja istraživanja na ovu temu još uvek potrebna.
Cilj: Ciljevi studije su bili analizirati tok i ishod monohorionskih blizanačkih
trudnoća,
a
zatim
ispitati
povezanost
i
potencijalnu
prediktivnu
vrednost
ultrasonografskih parametara koji se određuju u prvom i drugom trimestru trudnoće na
tok i ishod monohorionskih blizanačkih trudnoća.
Materijal i metod: Sprovedena je prospektivna kohortna studija svih trudnica sa
monohorionskim blizanačkim trudnoćama koje su kontrolisane i porođene u Klinici za
ginekologiju i akušerstvo Kliničkog centra Srbije u Beogradu, u periodu od 01. januara
2010. godine do 31. decembra 2015. godine. Svakoj pacijentkinji je već tokom prvog
pregleda uzeta kompletna anamneza sa podacima o godinama života, komorbiditetima,
paritetu, kao i načinu nastanka trudnoće. U prvom trimestru, između 11 i 14 nedelje
trudnoće za svakog blizanca su ultrazvučno izmereni dužina teme-trtica (crown-rump
lenght CRL) i debljina nuhalne translucence (NT). U periodu od 16 do 18 nedelje
trudnoće, ultrazvučnim pregledom za oba blizanca, određeni su biometrijski parametri:
biparijetalni
dijametar
(biparietal
diameter
BPD),
obim
trbuha
(abdominal
circumference AC) i dužina butne kosti (femur length FL). Redovno su registrovane sve
komplikacije trudnoće. Naročita pažnja se obraćala na pojavu intrauterinog zastoja u
rastu jednog ili oba blizanca (intrauterine growth restriction IUGR), interblizanačkog
transfuzionog sindroma (twin-to-twin transfusion syndrome TTTS), spontanog pobačaja
(pre 24. nedelje gestacije) ili prevremenog porođaja (pre 35. nedelje gestacije) i smrti
jednog ili oba blizanca. Kao osnovni pozitivni ishod trudnoće u našem istraživanju
smatrana je živorođenost (jednog ili oba blizanca). Ishod trudnoće je smatran kao dobar
ako je trudnoća završena nakon 35 nedelje gestacije i kada je Apgar skor blizanaca bio
iznad 7. Gestaciona nedelja u kojoj je došlo do porođaja, kao i način tj. tip porođaja
(vaginalni ili carski rez SC), su registrovani za svaku ispitanicu. Svi prikupljani podaci
su analizirani u skladu sa ishodom trudnoće i obrađeni metodama deskripcione i
analitičke statistike.
Rezultati: Studija je obuhvatila 39 monohorionskih blizanačkih trudnoća.
Trudnoće su se u proseku završavale u 32 nedelji gestacije (16 do 39 nedelja). Porođaj
je završen carskim rezom kod 61.5 % ispitanica. Od ukupnog broja trudnoća 30 je
završeno porođajem, od čega prevremenim 14, terminskim 16, a pobačajem 9 trudnoća.
Ukupan broj živorođene dece je 61, dok je broj mrtvorođene 17. Apgar skorovi na
rođenju, kako prvog tako i drugog gemela, su prosečno iznosili 5 (Apgar skor 0 do 9).
Nešto više od polovine blizanaca (51,28%) je bilo bez fetalnih komplikacija. Najčešće
komplikacije trudnoće u našem uzorku bile su diskordantni rast (25%), TTTS (20,5%) i
IUGR (9%). Ukupno je bilo 10 trudnoća sa poremećajem količine plodove vode.
Ruptura vodenjaka je obično nastupala u porođaju, a do PPROM-a je došlo kod 7
pacijentkinja.
Razlika CRL između blizanaca u 12. nedelji trudnoće veća od 10% može imati
pozitivnu prediktivnu vrednost u detekciji jednog broja komplikacija trudnoće. Pored
toga i debljina nuhalne translucence korelira pozitivno sa Apgar skorovima (p=0,025 I
gemel i p=0,017 II gemel) i telesnim težinama na rođenju (p=0,032 I gemel i p=0,029 II
gemel) monohorionskih blizanaca. U našoj studiji su postavljene i nove granične
vrednosti (cut off) za CRL i NT koje imaju bolju senzitivnost i specifičnost u predikciji
ishoda trudnoće. Razlika u CRL manja od 3,75 mm je dobar prediktor za živorođenost
monohorionskih blizanaca. Razlika NT veća od 1,3 mm je dobar prediktor za razvoj
komplikacija kod monohorionskih blizanaca.
Na osnovu ROC analize pokazano je da su AC (p=0.017) i FL (p=0.037) mereni
u drugom trimestru trudnoće dobri prediktori živorođenosti, dok BPD nije značajan za
ovu predikciju (p=0.757). Razlika u AC >17mm kao i razlika u FL >1,5mm između
blizanaca u 16. nedelji gestacije ima pozitivnu prediktivnost za pojavu kasnijih
komplikacija trudnoće kao i loših ishoda trudnoće. Diskordantnost u AC i FL merama u
drugom trimestru između blizanaca predviđa loš ishod trudnoće sa pouzdanošću od
76.1% za AC i 59.3% za FL.
Zaključak: Ukupno gledano, ishodi praćenih monohorionskih trudnoća su bili
sa živorođenošću oba gemela većom od 75% (30 parova blizanaca živorođeno) što se
može smatrati veoma dobrim ishodom. Rezultati studije potvrđuju potencijalnu
prediktivnu vrednost ultrasonografskih parametara koji se određuju u prvom i drugom
trimestru trudnoće na tok i ishod monohorionskih blizanačkih trudnoća. | Introduction:
According
to
current
positions
and
recommendations,
ultrasonographic fetal measurements in the first and second trimesters have the greatest
power to predict further complications as well as the outcomes of monochorionic
pregnancies, but the results of previous studies are inconsistent or insufficiently reliable
due to the small incidence of monochorion twins, so further research on this matter is
always necessary.
Objective: The aims of the study were to analyze the course and outcome of
monochorionic twin pregnancies, and then examine the connection and potential
predictive value of ultrasonographic parameters that are assessed in the first and second
trimester of pregnancy on the cource and outcome of monochorion twin pregnancies.
Material and Method: We conducted a prospective cohort study of all pregnant
women with monochorionic twin pregnancies checked-up and delivered at the Clinic for
Gynecology and Obstetrics Clinical Center of Serbia in Belgrade, in the period from
January 1, 2010 to December 31.2015. Already during the first examination, a complete
history was taken from every patient with data on age, comorbidity, parity, and the way
of pregnancy commencement. In the first trimester, between 11 and 14 weeks of
pregnancy for each twin, the crown-rump lenght (CRL) and the thickness of nuchal
translucency (NT) were measured ultrasonically. In the period from 16 to 18 weeks of
pregnancy, ultrasound examination for both twins determined biometric parameters:
biparietal diameter (BPD), abdominal circumference (AC) and femur length (FL). All
complications of pregnancy were registered regularly. Particular attention was paid to
the occurrence of intrauterine growth restriction (IUGR) in one or both twins, twin-to-
twin transfusion syndrome (TTTS), spontaneous abortion (before 24 weeks of gestation)
or premature labor (before 35 weeks of gestation) and the death of one or both twins.
The basic positive outcome of pregnancy in our study was the live birth (one or both
twins). The outcome of pregnancy was considered as good if the pregnancy was
completed after 35 weeks of gestation and when the Apgar score of the twins was above
7. The gestational week in which the delivery occurred and the way ie. type of labor
(vaginal or cesarean SC) were registered for each case. All collected data were analyzed
according to the outcome of pregnancy and processed by methods of descriptive and
analytical statistics.
Results: The study included 39 monochorionic twin pregnancies. Pregnancy
generally ended in the 32nd gestational week (16 to 39 weeks). The delivery was
completed by caesarean section in 61.5% of patients. Out of the total number of
pregnancies, 30 were completed by birth, of which 14 were premature, 16 were
terminated, and 9 were aborted. The total number of live-born children was 61, while
the number of stillborn was 17. The Apgar scores on delivery of both the first and the
second twin were on average 5 (Agar score 0 to 9). Just over half of twins (51.28%)
were without fetal complications. The most common complications of pregnancy in our
sample were discordant growth (25%), TTTS (20.5%) and IUGR (9%). In total, there
were 10 pregnancies with a disorder of the amount of amnionic fluid. Rupture of the
amnionic sac was usually performed during labour, while 7 patients had PPROM.
The difference in CRL between twins in the 12th week of pregnancy greater
than 10% may have a positive predictive value in detecting a number of complications
of pregnancy. In addition, the thickness of nuchal translucency correlates positively
with Apgar scores (p = 0.025 I gemel and p = 0.017 II gemel) and body weight at birth
(p = 0.032 I gemel and p = 0.029 II gemel) of monochorionic twins. In our study, new
cut-off values for CRL and NT have been set, which have better sensitivity and
specificity in the prediction of pregnancy outcome. The difference in CRL of less than
3.75 mm is a good predictor for having live born monochorion twins. The NT difference
greater than 1.3 mm is a good predictor for the development of complications in
monochorionic twin pregnancies.
Based on the ROC analysis, AC (p = 0.017) and FL (p = 0.037) measured in the
second trimester of pregnancy were good predictors of live birth, while BPD was not
significant for this prediction (p = 0.757). The difference in AC > 17mm as well as the
difference in FL > 1.5mm between the twins in the 16th week of gestation has a positive
predictive value for the onset of late complications of pregnancy and poor outcomes of
pregnancy. Discordance in AC and FL measures in the second trimester between twins
predicts a poor outcome of pregnancy with a confidence of 76.1% for AC and 59.3% for
FL.
Conclusion: Overall, the outcomes of monitored monochorionic pregnancies
were with the survival of both twins greater than 75% (30 pairs of twins live born),
which can be considered a very good outcome. The results of the study confirm the
potential predictive value of ultrasonographic parameters that are determined in the first
and second trimester of pregnancy on the course and outcome of monochorionic twin
pregnancies. | true |
In vitro interakcije jona bakra sa bilirubinom i [beta]-laktaminskim antibioticima | In vitro interactions of copper ions with bilirubin and [beta]-lactam antibiotics | Koncentracija jona bakra (Cu2+), kao esencijalnog mikroelementa neophodnog u
delovanju brojnih enzima ali i potencijalno toksičnog metala, u humanoj plazmi je
striktno regulisana. Poremećaj u koncetraciji jona bakra je opisan kod brojnih bolesti
poput neonatalne hiperbilirubinemije, infekcija, inflamatornih stanja, Vilsonove bolesti,
dijabetesa, oboljenja jetre. Sa stanovišta patoloških stanja redoks potencijal jona bakra,
mogućnost stupanja u koordinativne reakcije i formiranja kompleksa sa biomolekulima
pa i lekovima može uticati na tok i efekte terapije. Do sada je opisano nekoliko
mehanizama bakrom indukovanog ćelijskog oštećenja poput učestvovanja u stvaranju
reaktivnih kiseoničnih vrsta (ROS), redoks reakcija sa molekulima tiola i indirektni
uticaj na stvaranje ROS i formiranje koordinacionih kompleksa.
U pogledu infekcija potencijalne interakcije između jona bakra i antibiotika
mogu biti od velike važnosti. Praćenjem pomenutih interakcija ukazano je na postojanje
takozvanih bakar-zavisnih antibiotika za čiju aktivnost je neophodno prisustvo jona
bakra. Takođe studije izvedene u nefiziološkim uslovima su izučavale i mogućnost
nastanka kompleksa ili koordinativnih reakcija između bakra i brojnih antibiotika poput
fluorohinolona, aminoglikozida, pojedinih cefalosporina ali sa promenjivim rezultatima
na antimikrobnu aktivnost. Usled nedostatka ispitivanja u fiziološkim uslovima sam
mehanizam interakcija jona bakra i pojedinih antibiotika ostao je nedorečen. U
slučajevima neonatalne žutice, koja se javlja usled povišenog broja eritrocita i nezrelosti
jetre, ali i u slučajevima sepse kroz oštećenje eritrocita, interakcije bilirubina (BR) i
bakra mogu biti važne za objašnjenje toksičnih efekata nekonjugovanog (nevezanog za
albumin) bilirubina, ali i za uspešnost antibiotske terapije. Dokazi iz nekoliko studija
upućuju na značaj interakcija BR i bakra: neuralni defekti u slučajevima
hiperbilirubinemije se najčešće javljaju na nivou bazalnih ganglija gde je i koncentracija
bakra najviša; kod neonatusa sa hiperbilirubinemijom zabeleženi su povišeni nivoi jona
bakra i malondialdehida, kao markera lipidne peroksidacije. U slučajevima
hiperbilirubinemije kada je koncentracija teških metala povišena, pozitivne efekte na
ishod terapije je pokazala primena penicilamina, koji deluje kao helator bakra i
smanjuje nivo slobodnih radikala.
Cilj ovog istraživanja je bio da se opiše mehanizam in vitro interakcija jona
bakra sa BR i β-laktamskim antibioticima. Analize su urađene pomoću sledećih metoda:
ultraljubičaste/vidljive spektroskopije, elektron paramagnetne rezonancije, ciklične i
pulsne voltametrije, merenjem potrošnje kiseonika uz pomoć polarografije, merenjem
minimalne inhibitorne koncentracije na odabranim bakterijskim sojevima i merenjem
lipidne peroksidacije i hemolize.
Naše istraživanje je pokazalo da molekul BR redukuje Cu2+ do Cu1+, u odnosu
1:1, te da BR i Cu2+ ne formiraju stabilni kompleks. Stvoreni Cu1+ podleže spontanoj
oksidaciji u prisustvu kiseonika i ponovo se stvara Cu2+ uz istovremenu produkciju
vodonik peroksida i hidroksilnog radikala preko redukcije molekulskog kiseonika do
superoksida odnosno kroz Fentonovu reakciju. Upravo stvaranje pomenutih slobodnih
radikala nastalih kao posledica reakcije BR i Cu2+ može biti odgovorno za toksične
efekte u stanjima hiperbilirubinemije. U skladu sa ovim dobijenim rezultatom je i
oštećenje eritrocitnih membrana prilikom istovremenog izlaganja BR i Cu2+. Vezivanje
Cu2+ za fosfate u rastvoru, fosfatne grupe na lipozomima ili helirajući agens
penicilamin, dovodi do smanjenja štetnih efekata BR i Cu2+. U pogledu analize
interakcija sa β-laktamskim antibioticima, opaža se da penicilin G ne stupa u interakcije
sa Cu2+. Ampicilin, amoksicilin i cefaleksin i Cu2+ formiraju oktaedraelni kompleks sa
tetragonalnom distorzijom sa Cu2+. Rezultati našeg istraživanja upućuju na primarnu
amino grupu na bočnom lancu kao mesto vezivanja bakra za ove antibotike. Takođe tri
pomenuta antibiotika dovode do porasta u koncentraciji rastvorljivog Cu2+ u fosfatnom
puferu. Slične geometrije je i kompleks ceftazidima i Cu2+, s tim što je formiranje ovog
kompleksa praćeno stvaranjem organskog radikala. Ceftriakson- Cu2+ kompleks je bio
drugačije geometrije. Cefaklor redukuje Cu2+ do Cu1+ koji potom reaguje sa kiseonikom
i dovodi do stvaranja vodonik peroksida. Meropenem se razgradio u prisustvu Cu2+. Svi
ispitivani antibiotici koji stvaraju komplekse sa Cu2+ su u 1:1 stehiometrijskom odnosu.
Analizom minimalne inhibitorne koncentracije na sojevima E. coli i S. aureus uočava se
da prisustvo Cu2+ slabi antimikrobni potencijal ampicilina, amoksicilina, ceftriaksona i
meropenema dok je delovanje cefaleksina i cefaklora blago pojačano u prisustvu Cu2+.
U zaključku možemo istaći da in vitro opisani mehanizmi interakcija Cu2+ i BR,
kao i Cu2+ i β-laktamskih antibiotika mogu biti od kliničkog značaja u stanjima koja
karakterišu promene u koncentraciji Cu2+. Sveukupni rezultati upućuju na potrebu
nastavka ispitivanja, od in vitro ka in vivo studijama. | The concentration of copper ions (Cu2+) in human body plasma is tightly
regulated since they are cofactors of numerous enzymes, but also highly toxic to the
cell. Cu2+ disbalans can be seen in neonatal hyperbilirubinemia, infections,
inflammatory diseases, Wilson’s disease, diabetes mellitus, liver disorders.
Coordination, redox interactions or formation of complexes between copper and
biomolecules can affect therapy. So far, several mechanisms of copper induced cell
damage had been proposed such as increased ROS production, redox reactions with
thiols and indirect ROS creation, and formation of coordination complexes.
In case of infection, possible ineractions of Cu2+ and antibiotics could be of great
importance. Detailed analysis of mentioned interactions showed existance of so-called
copper-dependant antibiotics. These antibiotics are only active in presence of copper
ions. Also, previous studies conducted in non-physiological conditions reported possible
coordinative interactions or formation of complexes between Cu2+ and antibiotics such
as fluoroquinolones, aminoglycosides, several cephalosporins but with inconsistent
results regarding antimicrobial activity. Still, studies of interaction between copper ions
and antibiotics under physiological conditions are lacking. This leads to poor
understanding of mechanism and undetermined clinical impact of copper interactions
with antibotics in everyday use. In cases of neonatal jaundice which can occur due to
higher number of erythrocytes, immaturity of liver or in case of erythrocytes damage in
sepsis, interactions of Cu2+ with bilirubin (BR) may be an important part of toxicity
caused by unconjugated BR (not bound to albumin). Also, these interactions may have
impact on the effectiveness of antibiotic therapy. Results from several studies showed
indirect evidence for this: neural injury in hyperbilirubinemia occurs primarily in basal
ganglia, which showed higher copper content compared to other brain regions; neonates
with
hyperbilirubinemia
showed
increased
plasma
levels
of
copper
and
malondialdehyde, marker of lipid peroxidation. Penicillamine, as copper-chelation agent
which reduces ROS levels showed beneficial effects in neonatal hyperbilirubinemia.
The aim of this study was to investigate mechanism of in vitro interactions of
copper and BR and β-lactam antibiotics. Set of experiments was conducted at
physiological pH 7.4 using following methods: UV-VIS spectrophotometry, electron
paramagnetic resonance, cyclic and differential pulse voltammetry, measuring
concentration of oxygen using polarography, defining minimum inhibitory
concentration on selected bacterial strains and measuring malondialdehid and
hemoglobin as markers of lipid peroxidation and hemoliysis.
Our study showed that BR reduces Cu2+ to Cu1+, in 1:1 stoichiometry, whereby
BR and Cu2+ do not form stable complexes. Cu1+ undergoes spontaneous oxidation by
O₂ which results with Cu2+ and with production of hydrogen peroxide and hydroxyl
radical through reduction of molecular oxygen to superoxide via Fenton-like reaction.
Copper and BR induced oxidative stress can be responsible for toxic effects observed in
neonatal hyperbilirubinemia and for damaging effects on erythrocytes membranes. The
binding of Cu2+ to phosphates in solution, liposomal phosphate groups, or to chelating
drug penicillamine, impedes redox interactions with BR. Regarding copper interactions
with β-lactam antibiotics, it is observed that penicillin G does not interact with Cu2+.
Ampicillin, amoxicillin and cephalexin formed stable complexes with Cu2+ with
octahedral coordination environment and tetragonal distortion. Primary amine group on
side-chain was marked as the site of coordinate bond formation. These three β-lactams
increased the solubility of Cu2+ in the phosphate buffer. Ceftazidime and Cu2+ formed a
complex with a similar geometry and gave rise to an organic radical. Ceftriakson- Cu2+
exhibited different geometry. Cefaclor reduced Cu2+ to Cu1+ that further reacted with
molecular oxygen to produce hydrogen peroxide. Meropenem underwent degradation in
the presence of copper. All antibiotics that formed complex with Cu2+ showed 1:1
stoichiometry. The analysis of minimum inhibitory concentration against E. coli and S.
aureus showed that the effects of ampicillin, amoxicillin, ceftriaxone and meropenem
were significantly hindered in the presence of copper ions, while the effects of
cephalexin and cefaclor were slightly increased.
In conclusion, we may emphasize that described mechanism of interactions of
BR and β-lactam antibiotics with copper ions can be of great impact in conditions
characterized with copper disbalans. The elucidated mechanisms warrant further
research on this topic, from in vitro to in vivo studies. | true |
Analiza mikrovaskularizacije i imunohistohemijskih karakteristika ganglijskih i ektopičnih ganglijskih ćelija trigeminalnog nerva | Analysis of microvascularization and immunohistochemicalcharacteristics of ganglion and ectopic ganglion cells of trigeminal nerve | Posebne mikromorfološke karakteristike vaskularizacije trigeminalnog nerva i
gangliona i bliski neurovaskularni odnosi sa okolnim sudovima, kao i njihov mogući klinički
značaj bili su prvi razlozi ove studije. Drugi cilj studije bio je da se prouče morfološke i
imunohistohemijske karakteristike ektopičnih i ganglijskih neurona u trigeminalnom nervu i
ganglionu.
Krvni sudovi 25 trigeminalnih nerava odraslih osoba, posle injiciranja mešavine tuša i
želatina u arterijski sistem, mikrodisekovani su i proučavani pod stereomikroskopom.
Četrdeset humanih trigeminalnih nerava i gangliona poreklom od 20 osoba, dobijenih
rutinskom obdukcijom, proučavani su posle histološkog bojenja metodom Klüver-Barrera,
trihromnih bojenja Azan i Masson tehnikom i imunohistohemijskih reakcija na neke od
neuronskih markera, neuropeptida i neurotransmitera.
Trigeminalne grančice namenjene nervu, od dve do pet, polazile su od dve ili tri od
sledećih arterija: superolateralna pontinska (92%), a. cerebelli inferior anterior (ACIA)
(88%), inferolateralna pontinska (72%) i a. cerebelli superior (ACS) (12%). Trigeminalne
arterijice su bile prosečnog prečnika od 0,220 mm. Jedan sud je vaskularizovao bilo motorni
deo trigeminalnog stabla, ili senzorni deo ili oba. Trigeminalni sudovi su formirali
proksimalni i distalni arterijski prsten oko nerva. Proksimalni prsten se nalazio u nivou spoja
korenog dela nerva i ponsa. Njegove centralne grane su pratile trigeminalni nerv na putu ka
glavnom senzornom i motornom jedru, dok su periferne longitudinalne grančice pratile
snopove nerva ka ganglionu. Distalni arterijski prsten, često nekompletan, obuhvatao je
središnji deo nerva, neposredno pre njegovog ulaska u arahnoidni omotač. Najčešće uočen
neurovaskularni kontakt trigeminalnog nerva bio je sa ACS (20%), sa petroznom ili
Dendijevom venom (24%) i sa ACIA (12%). Inferolateralno stablo i meningohipofizialno
stablo, koja polaze od unutrašnje karotidne arterije, kao i grane srednje moždanične arterije
su bili glavni sudovi koji su vaskularizovali trigeminalni ganglion. Trigeminalne arterijice
koje su od njih polazile su bile prosečnog prečnika od 0,220 mm.
Ukupno 73 izmeštena (ektopična) neurona je tokom naših istraživanja pronađeno u
90% izučavanih osoba. Ektopični neuroni su uočeni u 65% trigeminalnih nerava, bilo u
senzornom delu (32,5%), motornom delu (22,5%) ili u oba (10,0%). Dijametri ćelija varirali
su od 12,325,1 μm do 45,166,7 μm (prosečno, 27,242,4 μm), a površine od 247 do 2256
μm2 (prosečno, 945 μm2). Neurone je okruživalo 2 do 17 izduženih satelitskih ćelija po
preseku. Na svim studiranim neuronima imunska reakcija je bila pozitivna na neuron
specifičnu enolazu (NSE), protein genski product 9.5 (PGP9.5), neurofibrilarni protein (NFP) i
sinaptofizin (Sy), a u nekim neuronima na peptid regulisan kalcitoninskim genom (CGRP)
(24,14%), holecistokinin (CCK) (13,79%), somatostatin (SST) (17,24%), supstancu P (SP)
(15,52%), vazoaktivni intestinalni polipeptid (VIP) (8,62%), neuropeptid Y (NPY) (10,34%)
i serotonin (Ser) (10,34%). Najčešće prisutna je bila imunska reakcija na CGRP, SST, SP i CCK.
Poredili smo dobijene rezultate sa rezultatima dobijenim primenom sličnih merenja, kao i
imunohistohemijskih reakcija na ganglijskim ćelijama trigeminalnog gangliona.
Proučavane karakteristike vaskularizacije trigeminalnog nerva mogu da budu korisna
osnova u dekompresionoj neurovaskularnoj hirurgiji. Zaključili smo da su izmešteni neuroni
u trigeminalnom nervu morfološki i imunohistohemijski identični senzornim neuronima u
trigeminalnom ganglion. | Specific micromorphological characteristics of the trigeminal nerve and ganglion blood
supply and close neurovascular relationships with surrounding vessels, as well as their possible
clinical significance were the first reasons for this study. The second aim of this study was to
examine the morphology and the immunohistochemical features of displaced and ganglion cells
in the trigeminal nerve and ganglion.
The vasculature of 25 adult trigeminal nerves and ganglions were microdissected and
examined under the stereoscopic microscope, after injecting their arteries with a mixture of India
ink and gelatin. Forty human trigeminal nerves and ganglions of twenty persons, obtained during
routine autopsy, were examined following Klüver-Barrera, Azan and Masson trichrome
histological stainings, and immunohistochemical reactions against certain neuronal markers,
neuropeptides and neurotransmitters.
The trigeminal nerve vessels, which varied between two and five in number, arose from
two or three of the following arteries: the superolateral pontine (92%), anterior inferior cerebellar
(AICA) (88%), inferolateral pontine (72%), and superior cerebellar (SCA) (12%). The trigeminal
vascular twigs had a mean diameter of 0.220 mm. A single vessel may supply either the motor
portion of the nerve root, or the sensory portion or both. The trigeminal vasculature formed the
proximal and distal rings. The proximal ring was located at the trigeminal root entry zone. Its
central branches extended along the trigeminal nerve to the principal sensory and motor
trigeminal nuclei while its peripheral longitudinal twigs followed the trigeminal nerve fascicles.
The incomplete distal arterial ring embraced the middle portion of the trigeminal nerve before
the level of its entrance into the arachnoid sleeve. The most frequent contact of the trigeminal
nerve was noticed with the SCA (20%), the petrosal or Dandy’s vein (24%), and the AICA
(12%). The inferolateral trunk, the meningohypophyseal trunk, branches of the internal carotid
artery, and the middle meningeal artery were the main vessels supplying the trigeminal ganglion.
The trigeminal vascular twigs had a mean diameter of 0.220 mm.
A total number of 73 displaced (ectopic) neurons were investigated, which were present
in 90% of individuals studied. Displaced neurons were found in 65.0 % of the nerves, either in
the sensory portion (32.5%), motor portion (22.5%) or both (10.0%). Neuronal diameter varied
from 12.325.1 μm to 45.166.7 μm (mean, 27.242.4 μm), and in area between 247 and 2256
μm2 (mean, 945 μm2). Each neuron was surrounded by 2 to 17 elongated satellite cells per slice.
The immune reaction was positive in all the neurons studied for neuron-specific enolase (NSE),
protein gene product 9.5 (PGP9.5), neurofilament protein (NFP) and synaptophysin (Sy), and in
some neurons for calcitonin gene-related peptide (CGRP) (24.14%), cholecystokinin (CCK)
(13.79%), somatostatin (SST) (17.24%), substance P (SP) (15.52%), vasoactive intestinal
polypeptide (VIP) (8.62%), neuropeptide Y (NPY) (10.34%), and serotonin (Ser) (10.34%). The
immune reactions were most frequent against the CGRP, SST, SP and CCK. We compared
obtained data with the results of the similar measurements and immunohistochemical reactions
performed on ganglion cells bodies in the trigeminal ganglion.
The observed characteristics of the trigeminal nerve vasculature could be the useful basis
for decompressive neurovascular surgery. We concluded that displaced neurons in the trigeminal
nerve morphologically and immunohistochemically were identical with the sensory neurons in
the trigeminal ganglion. | true |
Korelacija obrazaca ponašanja fokalnih epileptičnih napada i lokalizacije epileptogene lezije | Correlation of the patterns of behavior in focal epileptic seizures and localization of the epileptic lesions | Aktivnost anatomski definisanih regiona humanog cerebralnog korteksa, kroz konektivnost, proizvodi funkcionalnu heterogenost reprezentovanu kroz bihejvioralni aspekt. Bazični fiziološki supstrat interkonekcije anatomskih podregiona predmet je stalnih istraživanja. Fokalna epilepsija, kao eksluzivna kortikalna bolest, odličan je model za eksploraciju neurobiološke osnove funkcionalne anatomije. Tačnije, iritativni kortikalni fenomen u jednom regionu (finalni patofiziološki produkt epileptogeneze u epileptogenoj leziji), pored inicijalnog simptoma, dovedi do većeg broja različitih, vremenski uslovljenih, kombinacija kliničkih simptoma i znakova – obrazaca ponašanja tokom epileptičnog napada. Sekvencijalni raspored simptoma i znakova determinisan je propagacijom abnormalne električne aktivnosti kroz korteks i anatomske puteve, od generatora do bliskih i udaljenih moždanih regiona. Preferencijalni put propagacije deo je neurodiveziteta epileptične mreže i dominantno je uniforman na individualnom nivou. Iako su poznate i manje inter-individualne varijacije, veruje se da je broj kombinacija u obrascu ponašanja tokom fokalnog epileptičnog napada, u ljudskoj vrsti, konačan. Primarni cilj doktorske disertacije bio je utvrđivanje korelacije klinički definisanih epileptičnih simptoma i znakova (semiologije) i lokalizacije epileptogene lezije. Učinjena je kliničko-anatomska korelacija na reprezentativnom uzorku bolesnika sa fokalnom epilepsijom, obrađenih na Klinici za neurologiju Kliničkog Centra Srbije, shodno, trendovima moderne epileptologije. Rezultati na analiziranom materijalu demonstriraju kompleksnost epileptične mreže nadgrađene na fiziološkom nivou konektivnosti, ali i izvesne zakonomernosti, koje podupiru postojeći neurobiološki koncept funkcionalne anatomije i utvrđuju klinička uverenja u modernoj epileptologiji. Koherentna i oscilatorna epileptična aktivnost generiše bihejvioralne fenomene, poput potpunog prestanka motorne aktivnosti ili oroalimentarnih automatizmama, znakova koji su najčešći u analiziranoj populaciji. Bihejvioralni arest, rani znak, sugeriše na limitiranu aktivnost u cerebralnom korteksu, uz verovatnu disrupciju kortiko-subkortiko-spinalnih veza. Oroalimentarni automatizmi, fenomen druge polovine epileptičnog napada, mogući su proizvod aktivacionih i inhibitornih stimulusa više kortikalnih regiona sa finalnom rezultantom u arhaičnom ponašanju. Epigastrična i psihička aura najfrekventniji su među subjektivnim doživljajima analiziranih bolesnika; centralna autonomna mreža, viscerotopna prezentacija usko lokalizovanog korteksa i međuigra paleo- i neo-korteksa verovatni su patofiziološki mehanizmi ovih simptoma... | Activity of anatomically defined regions of the human cerebral cortex, through connectivity produces functional heterogeneity represented by behavioral aspect. Basic physiological substrate of the interconnection between anatomical subregions is a subject of continuous research. Focal epilepsy, exclusive cortical disease, is an excellent model for the exploration of the neurobiological basis of functional anatomy. Specifically, cortical irritative phenomenon in a region (the final pathophysiological product of epileptogenesis in epileptogenic lesion), in addition to the initial symptoms, leads to a large number of different, time-conditioned, combination of the clinical symptoms and signs - behavior patterns during epileptic seizure. Sequential arrangement of signs and symptoms is determined by the propagation of abnormal electrical activity in the cortex and anatomical pathways from the generator to the close and distant brain regions. Preferential path of the propagation is part of the epileptic network’s neurodiversity that is dominantly uniform at the individual level. Although minor inter-individual variations has been given, it is believed that the number of combinations in the pattern of behavior in focal seizures in the human species is final. The primary goal of the doctoral dissertation was to determine the clinical correlation between defined epileptic symptoms and signs (semiology) and localization of epileptogenic lesions. We performed a clinical-anatomic correlation of a representative sample of patients with focal epilepsy, treated at the Department of Neurology, Clinical Center of Serbia, according to modern trends in epileptology. The results of the material analyzed demonstrate the complexity of the epileptic network upgraded to a physiological level of connectivity, as well as certain regularities, which support existing neurobiological concept of functional anatomy and determine the clinical belief in modern epileptology. Coherent oscillations and epileptic activity generates behavioral phenomena, such as the complete cessation of motor activity or oroalimentary automatisms, most common signs in the analyzed population. Behavioral arrest, an early sign, suggests the limited activity of the cerebral cortex, with the probable disruption in cortico-subcortico-spinal pathways. Oroalimentary automatisms, the phenomenon of the second half of seizures, are possible product of the activation and inhibitory stimuli in wider cortical regions with the final resultant in the archaic behavior. Epigastric and psychic aura are among the most frequent subjective experiences in analyzed patients; central autonomic network, viscerotopic presentation in narrowly localized cortex and interplay of paleo-and neo-cortex are likely pathophysiological mechanisms of these symptoms... | false |
Procena kvaliteta života kod dece i omladine sa primarnim imunodeficijencijama | Quality of life assessment in children and adolescents with primary immunodeficiencies | Uvod: Kvalitet ţivota povezan sa zdravljem (engl. health-related quality of life,
HRQOL) predstavlja multidimenzionalni koncept i obuhvata fizičku, emocionalnu,
psihosocijalnu i bihejvioralnu komponentu blagostanja i funkcionisanja, te se danas sve
više prepoznaje kao deo multimodalne procene zdravlja i ishoda lečenja dece sa
hroničnim bolestima, uključujući i decu sa primarnim imunodeficijencijama (PID).
Cilj: Osnovni cilj istraţivanja je bio da se proceni HRQOL, nivo anksioznosti i
depresivnosti kod dece sa PID, kao i da se utvrdi na koji način emocionalni problemi
ove dece utiču na njihov kvalitet ţivota.
Metode: Istraţivanje je sprovedeno po tipu studije preseka i obuhvatilo je 25 bolesnika
sa PID i njihovih roditelja. Kontrolnu grupu obolelih sačinjavalo je 50 bolesnika sa
juvenilnim idiopatskim artritisom (JIA) i 89 zdrave dece i njihovih roditelja. Kao
instrument istraţivanja korišćen je pedijatrijski upitnik o kvalitetu ţivota (eng. Pediatric
Quality of Life InventoryTM version 4.0, PedsQLTM), upitnik za pretragu anksioznosti
(eng. Screen for Child Anxiety Related Emotional Disorders Questionnaire, SCARED),
upitnik za pretragu raspoloţenja i osećanja (Mood and Feeling Questionnaire, MFQ),
svi sa proverenim psihometrijskim karakteristikama.
Rezultati: Bolesnici sa PID su imali lošiji ukupni skor kvaliteta ţivota u odnosu na
bolesnike sa JIA i zdravu decu, i to kako na osnovu dečje samoprocene (p = 0,02) tako i
na osnovu roditeljske procene (p < 0,001). Osim toga, deca sa PID su imala značajno
lošije emocionalno funkcionisanje u odnosu na decu sa JIA i socijalno funkcionisanje u
odnosu na obe grupe dece i to kako na osnovu samoprocene tako i na osnovu roditeljske
procene. Deca sa PID se prema sopstvenoj proceni nisu razlikovala u pogledu školskog
funkcionisanja u odnosu na druge dve grupe dece. MeĎutim, roditeljska procena je
pokazala de su deca sa PID imala statistički signifikantno lošije školsko funkcionisanje
u odnosu na decu sa JIA i zdravu decu. Prema roditeljskoj proceni, svako četvrto (24%)
dete sa PID imalo je anksiozne simptome u klinički relevantnom opsegu, što je bilo
statistički značajno više u odnosu na decu sa JIA i zdravu decu (p = 0,05). Osim toga,
Procena kvaliteta života kod dece i omladine sa primarnim imunodeficijencijama
na osnovu dečje samoprocene, utvrĎeno je i da svako peto (20%) dete sa PID ima
depresivne simptome u klinički relevantnom opsegu, što je ukazivalo na neophodnost
ekspertske pomoći. TakoĎe je utvrĎena značajna povezanost anksioznih simptoma sa
kvalitetom ţivota dece sa PID.
Zaključak: S obzirom da su deca sa PID imala lošiji kvalitet ţivota i dva do tri puta veći
rizik za anksiozne poremećaje, zaključeno je da je potrebno da procena HRQOL i
skrining emocionalnih poremećaja postanu deo multimodalne procene zdravlja i ishoda
lečenja dece sa PID, u skladu sa već publikovanim podacima kod brojnih hroničnih
bolesti. | Introduction: Health-related quality of life (HRQOL), as a multidimensional construct
covering physical, emotional, mental, social, and behavioral components of well-being
and functioning, has been recognized as one of the most important PRO measures for
evaluating the outcome of a chronic pediatric condition. Considering that HRQOL data
provides direct information about the impact of a disorder and its treatment, HRQOL
assessments could be a part of multimodal assessment and treatment approach in
children with primary immunodeficiency disease (PID) as well.
Objective: The aims of the study were to evaluate levels of health-related quality of life
(HRQOL) and the presence of anxiety and depressive symptoms in children with PID in
Serbia.
Methods: Self- and parent-rated data from 25 children with PID were available. As
controls, data from 50 children with juvenile idiopathic arthritis (JIA) and 89 healthy
children were included. The Pediatric Quality of Life Inventory (PedsQL) was used for
HRQOL assessments. Anxiety symptoms were identified using the Screen for Child
Anxiety Related Emotional Disorders Questionnaire (SCARED), while depressive
symptoms were identified using the Mood and Feeling Questionnaire (MFQ).
Results: Children with PID had significantly lower PedsQL total score compared to
children with JIA and healthy children as child-rated (p = 0.02) and parent-rated (p <
0.001). Specifically, they had significantly lowered emotional functioning compared to
children with JIA, and social functioning compared to both, children with JIA and
healthy children. However, school functioning was significantly lower among children
with PID as only parent-rated. As parent-rated, 6 (24%) out of 25 children with PID had
significant anxiety symptoms, while 5 (20%) children had significant depressive
symptoms, which was statistically higher than among children with JIA and healthy
controls (p = 0.05).
Conclusion: HRQOL could be significantly compromised in children with PID,
particularly across psychosocial domains, such as emotional, social, and school. These
Procena kvaliteta života kod dece i omladine sa primarnim imunodeficijencijama
children were also found to be at an increased risk for suffering significant anxiety and
depressive symptoms. The differences between children and parents were also found
when reporting the HRQOL and emotional problems. This implies that HRQOL data
should be routinely collected for every child with chronic illness, including PID, as a
part of multimodal assessment and treatment approaches. | true |
Farmakološka analiza tipova muskarinskih receptora u glatkom mišiću tela želuca | Pharmacological analysis of muscarinic receptor subtypes in smooth muscle from the body of the stomach | Mada su M1, M2 i M3 podtipovi muskarinskog receptora bili identifikovani u glatkim mišićima želuca žabe, pacova, psa i svinje, podtipovi ovog receptora nisu bili ispitani u želucu čoveka i mačke. Cilj ove teze je bio da se identifikuju i okarakterišu podtipovi muskarinskog receptora u longitudinalnom i cirkularnom mišićnom sloju tela želuca čoveka i mačke. Farmakološka analiza podtipova muskarinskog receptora je sprovedena na izolovanim preparatima cirkularnog i longitudinalnog mišićnog sloja tela želuca čoveka (42 uzorka) i mačke (109 uzoraka). Actilholinom-indukovane toničke kontrakcije cirkularnog mišićnog sloja tela želuca čoveka su snažno blokirali heksociklijum (pA2=9.92), telenzepin (pA2=9.86), skopolamin butilbromid (pA2=9.68), triheksifenidil (pA2=9.42) i atropin (pA2=8.91), umereno pirenzepin (pA2=7.41) i slabo galamin (pA2=5.60) i pFHHSiD (pA2=5.84). Toničke kontrakcije longitudinalnog mišićnog sloja tela želuca čoveka su snažno blokirali heksociklijum (pA2=9.19), telenzepin (pA2=9.37), skopolamin butilbromid (pA2=8.67), triheksifenidil (pA2=9.72) i atropin (pA2=8.56), umereno galamin (pA2=7.18) i slabo pirenzepin (pA2=6.25) i pFHHSiD (pA2 nije izračunato). Toničke kontrakcije cirkularnog mišićnog sloja tela želuca mačke su blokirali snažno triheksifenidil (pA2=9.20), atropin (pA2=8.96), heksociklijum (pA2=8.94), skopolamin butilbromid (pA2=8.38) i pFHHSiD (pA2=7.98), a umereno galamin (pA2=7.32), pankuronijum (pA2=7.28), pirenzepin (pA2=7.14) i telenzepin (pA2=7.09). Toničke kontrakcije longitudinalnog mišićnog sloja tela želuca mačke su blokirali snažno atropin (pA2=9.57), heksociklijum (pA2=9.43), triheksifenidil (pA2=9.13), telenzepin (pA2=8.65) i pFHHSiD (pA2=8.88), umereno galamin (pA2=7.97) i pankuronijum (pA2=8.06), a slabo pirenzepin (pA2=6.87) i skopolamin butilbromid (pA2=6.41). U cirkularnom i longitudinalnom mišićnom sloju želuca čoveka dominira M1 podtip muskarinskog receptora, dok su u cirkularnom i longitudinalnom mišićnom sloju želuca mačke dominantni M1 i M3 podtipovi. | Although M1, M2 and M3 muscarinic receptor subtypes were identified in smooth muscles of the stomach from frog, rat, dog and swine, subtypes of this receptor were not characterized in human and feline stomach. The aim of this thesis was to identify and characterize muscarinic receptor subtypes in longitudinal and circular smooth muscle layers from the body of human and feline stomach. Pharmacological analysis of muscarinic receptor subtypes was conducted on isolated preparations of circular and longitudinal smooth muscle layer from the body of human (42 specimens) and feline (109 specimens) stomach. Acetylcholine-induced tonic contractions of circular muscle layer from the body of human stomach were blocked strongly by hexocyclium (pA2=9.92), telenzepine (pA2=9.86), scopolamine butylbromide (pA2=9.68), trihexyphenidyl (pA2=9.42) and atropine (pA2=8.91), moderately by pirenzepine (pA2=7.41) and weakly by gallamine (pA2=5.60) and pFHHSiD (pA2=5.84). Tonic contractions of longitudinal muscle layer from the body of human stomach were blocked strongly by hexocyclium (pA2=9.19), telenzepine (pA2=9.37), scopolamine butylbromide (pA2=8.67), trihexyphenidyl (pA2=9.72) and atropine (pA2=8.56), moderately by gallamine (pA2=7.18) and weakly by pirenzepine (pA2=6.25) and pFHHSiD (pA2 not calculated). Tonic contractions of circular muscle layer from the body of feline stomach were blocked strongly by trihexyphenidyl (pA2=9.20), atropine (pA2=8.96), hexocyclium (pA2=8.94), scopolamine butylbromide (pA2=8.38) and pFHHSiD (pA2=7.98) and moderately by gallamine (pA2=7.32), pancuronium (pA2=7.28), pirenzepine (pA2=7.14) and telenzepine (pA2=7.09). Tonic contractions of longitudinal muscle layer from the body of feline stomach were blocked strongly by atropine (pA2=9.57), hexocyclium (pA2=9.43), trihexyphenidyl (pA2=9.13), telenzepine (pA2=8.65) and pFHHSiD (pA2=8.88), moderately by gallamine (pA2=7.97) and pancuronium (pA2=8.06), and weakly by pirenzepine (pA2=6.87) and scopolamine butylbromide (pA2=6.41). Circular and longitudinal muscle layers from the human stomach are dominated by M1 muscarinic receptor subtype, while in the circular and longitudinal muscle layers from the feline stomach dominant subtypes of muscarinic receptor are both M1 and M3. | false |
Procena kvaliteta života bolesnika sa cirozom jetre | Quality of life in patients with liver cirrhosis | Kvalitet života je snižen kod bolesnika sa cirozom jetre. Pacijenti sa ovom bolešću imaju
veliki broj onesposobljujućih simptoma, što dovodi do redukcije kvaliteta života povezanog
sa zdravljem (HRQoL) i blagostanja. U sprovođenim studijama, uglavnom je ispitivan
uticaj etiologije i težine bolesti na HRQoL. Od sociodemografskih i kliničkih karakteristika
evaluiran je uticaj pola, starosti, ascitesa, hepatične encefalopatije, depresije, anksioznosti i
zamora. Podaci o uticaju: nivoa obrazovanja, zanimanja, zaposlenja, bračnog stanja, dece,
konzumiranja
alkohola,
pušenja,
dužine
trajanja
bolesti
jetre
i
predhodnog
gastrointestinalnog krvarenja, na HRQoL kod ovih pacijenata, su oskudni ili ne postoje.
Takođe, relativni doprinos sociodemografskih, kliničkih i bihejvioralnih faktora u redukciji
HRQoL, nije do kraja razjašnjen. Najčešće korišćen specifični upitnik za pacijente sa
hroničnom bolešću jetre je CLDQ. Ovaj upitnik do sada nije validiran za upotrebu na
srpskom jeziku.
Ciljevi ovog istraživanja su: validacija srpske verzije CLDQ upitnika; ispitivanje kvaliteta
života bolesnika sa cirozom jetre SF-36 upitnikom i evaluaciju demografskih i kliničkih
karakteristika u smislu potencijalnih prediktora kvaliteta života.
Prikupljani su sociodemografski, klinički i laboratorijski podaci, pacijenata sa cirozom
jetre. Kvalitet života je procenjivan SF-36 i CLDQ upitnicima. Bihejvioralne karakteristike
su procenjivane HDRS, HARS i FSS skalama.
Srpska verzija CLDQ upitnika ima relijabilnost, diskriminatornu, transkurturalnu i
konvergentnu validnost, koja je u skladu sa literaturnim podacima. Konstruktorna validnost
ovog upitnika je potvrdila šestofaktorsku strukturu CLDQ upitnika, uz delimično
preklapanje sa originalnim domenima, i uvođenjem dva nova domena i to "Spavanje" i
"Ishrana", od kojih se "Ishrana" prvi put pojavljuje u literaturi.
Na pojedine domene kvaliteta života utiču: pol, starost, nivo obrazovanja, zaposlenje,
bračno stanje, težina bolesti, ascites i hepatična encefalopatija, pojedini laboratorijski
parametri, skor depresije, anksioznosti i zamora. Prediktori fizičke komponente kvaliteta
života su: pol, koncentracija uree u serumu, depresija i zamor, dok su prediktori mentalne
komponente ascites, urea, depresija i zamor. Prediktori kvaliteta života, određivanog CLDQ
upitnikom su: encefalopatija, urea, depresija i zamor.
U zaključku se može navesti da je srpska verzija CLDQ upitnika prihvatljiva za primenu
kod pacijenata sa cirozom jetre, na našim prostorima. Od ispitivanih sociodemografskih,
kliničkih i laboratorijskih parametara samo pojedini imaju uticaja na kvalitet života u ovoj
populaciji. Najvažniji prediktori kvaliteta života su bihejvioralni faktori, što ukazuje na
potrebu adekvatnog terapijskog delovanja u cilju poboljšanja kvaliteta života kod ovih
pacijenata. | The Quality of life is decreased in patients with liver cirrhosis. Patients with this disease
have a numerous disabling problems which leading to a reduced health related quality of
life (HRQoL) and well-being. Most studies were based on the importance of etiology and
disease severity on HRQoL. From the socio-demographic and clinical characteristics most
often evaluated the effects of gender, age, ascites, hepatic encephalopathy, depression,
anxiety and fatigue. Information about the importance of numerous factors (education level,
occupations, employment and marital status, children status, alcohol consumption,
smoking, duration of liver disease and previous gastrointestinal bleeding) on the HRQoL,
are scarce or do not exist. Also, the relative contribution of socio-demographic, clinical,
and behavioral factors in the reduction of HRQoL is not clear. CLDQ is commonly used
specific questionnaire for patients with chronic liver disease. This questionnaire has not
been validated for use in the Serbian language.
The objectives of this research are: validation of Serbian version CLDQ questionnaires;
testing the quality of life in patients with cirrhosis of the liver with the SF-36 questionnaire
and evaluation of socio-demographic and clinical characteristics as potential predictors of
quality of life. We collected clinical, socio-demographic and laboratory data, in patients
with liver cirrhosis. Quality of life was assessed by SF-36 and CLDQ questionnaires.
Behavioral characteristics were evaluated by HDRS, HARS and FSS scales.
Serbian version CLDQ questionnaire has the reliability, discriminatory, transcurtural and
convergent validity, which is consistent with previously published data. Constructory
validity of the CLDQ questionnaire was confirmed original six-factors structure, with
partially overlapping with the original domain, and the addition of two domains and the
"Sleep" and "Nutrition", of which "Nutrition" for the first time in the literature.
Some domains of quality of life, were significantlly affected by following factors: gender,
age, education level, employment status, marital status, severity of the disease, ascites,
hepatic encephalopathy, a some laboratory parameters, scores of depression, anxiety and
fatigue. Predictors of physical components of quality of life are: gender, serum urea
concentration, depression and fatigue, and predictors of mental components are: ascites,
urea, depression and fatigue. Predictors of quality of life, estimated by CLDQ questionnaire
are: encephalopathy, urea, depression and fatigue.
In conclusion, the Serbian version of the CLDQ questionnaire is acceptable for use in
patients with liver cirrhosis in our region. The tested socio-demographic, clinical and
laboratory parameters have a certain impact on the quality of life in this population. The
most important predictors of quality of life are behavioral factors, suggesting the need for
adequate therapeutic action in order to improve the quality of life in these patients. | true |
Odgovornost države za zaštitu stranih direktnih ulaganja | Predmet doktorske disertacije predstavlja istraživanje pravnog režima, sadržaja i pravnih posledica odgovornosti države za zaštitu stranih direktnih ulaganja. U tom smislu detaljno se ispituju specifičnosti teorijskog određenja odgovornosti države za zaštitu stranih direktnih ulaganja, posebnosti u pogledu određivanja merodavnog prava za različite aspekte odgovornosti, uticaj različitih načina definisanja pojma stranog direktnog ulaganja na domašaj odgovornosti države prijemnice za njegovu zaštitu, sadržaj i dejstvo konstitutivnih elemenata, odnosno uslova odgovornosti, načini ispoljavanja uslova isključenja odgovornosti u međunarodnom pravu zaštite stranih direktnih ulaganja, kao i posledice postojanja odgovornosti države prijemnice u slučaju povrede obaveze zaštite stranih direktnih ulaganja na njenoj teritoriji. Ovako postavljen predmet istraživanja uslovljen je rastućim značajem stranih direktnih ulaganja za razvoj nacionalnih privrednih sistema, što je međunarodni trend u pogledu kojeg naša država nije izuzetak. Međutim, nastojanje da se privuku strana direktna ulaganja nije uvek praćeno dovoljno pažljivim promišljanjem o pravnim posledicama jemstava datih stranim ulagačima. O tome jasno svedoči izrazita heterogenost sadržaja izvora međunarodnog prava zaštite stranih direktnih ulaganja. Upravo uticaj te heterogenosti međunarodnih i unutrašnjih izvora prava zaštite stranih direktnih ulaganja, kao i specifičnosti koje proizlaze iz hibridne prirode međunarodnog prava stranih ulaganja na režim odgovornosti država prijemnica, predstavljaju okosnicu problematike ove disertacije. Shodno tome, opšti cilj istraživanja predstavlja utvrđivanje faktora koji uobličavaju odgovornost države za zaštitu stranih direktnih ulaganja i ispitivanje njihovog dejstva, kako bi se izučavani institut bolje teorijski razumeo i pravilnije praktično primenjivao. Iz ovog opšteg cilja proističe i nekoliko konkretnih zadataka istraživanja, a to su: davanje pregleda i sistematizovanje izvora prava u oblasti odgovornosti države za zaštitu stranih direktnih ulaganja, utvrđivanje aktuelnih tendencija u pravu stranih ulaganja u vezi sa odgovornošću države za zaštitu stranih direktnih ulaganja, ispitivanje usaglašenosti izvora prava stranih ulaganja na snazi u Republici Srbiji sa tim tendencijama i formulisanje predloga za izmene pravila čija bi primena mogla da dovede do preteranog širenja odgovornosti države, odnosno do nemogućnosti stranog ulagača da zaštiti svoja legitimna ulagačka prava i interese. | The subject-matter of this doctoral dissertation is the research of legal regime, content and consequences of State responsibility for the protection of foreign direct investments. To that effect, the author examines in detail the elements of theoretical definition of the notion of State responsibility for the protection of foreign direct investments, the specificities with respect to the determination of the law applicable to different aspects of responsibility, the influence of various methods of defining the notion of investment to the scope of responsibility for its protection, the content and effects of elements and preconditions for responsibility, the circumstances excluding the responsibility as well as the legal consequences of responsibility of the host State in case of violation of its obligation to protect foreign direct investments in its territory. This choice of subject-matter of the doctoral dissertation is governed by the increasing importance of foreign direct investments for the development of national economies, which is a world-wide trend also present in Serbia. However, attempts to attract foreign investments are not always accompanied by careful considerations of legal consequences and potential practical repercussions of guarantees given to foreign investors. This is clearly proved by the diversity and heterogeneous content of sources of foreign direct investment law which, along with the specificities caused by the hybrid nature of international regime of investment protection, represent the focus of this dissertation. Accordingly, the general aim of the research is the identification of factors that shape State responsibility for protection of foreign direct investments and the exploration of their effects in order to enable better theoretic understanding and practical application of the rules studied in the thesis. This general aim induces several special aims of the study: providing an overview and describe the system of legal sources of foreign direct investment protection, identifying current tendencies in the law of foreign direct investment with respect to the State responsibility for protection of foreign direct investments, establishing the level of harmonization of sources of foreign direct investment protection applicable in Serbia with the international standards and suggesting the changes of the currently applicable regulatory framework in order to avoid both the overly extension of scope of State responsibility and the impossibility of foreign investors to protect their legitimate rights, interests and expectations. | false |
|
Procena efikasnosti hirurškog lečenja kod dece sa ekstrahepatičnom portnom hipertenzijom | Assessing the effectiveness of surgical treatment in children with extrahepatic portal hypertension | Portna hipertenzija predstavlja stanje stalno povišenog pritiska u portnom venskon sistemu koji prelazi 10 mm Hg stuba odnosno 17 cm vodenog stuba. Izučavanje problematike portne hipertenzije u dečjem uzrastu predstavljalo je veliki izazov za generacije pedijatara i dečijih hirurga.Tretman ekstrahepatčke forme hipertenzije, najčešće forme portne hipertenzije u pedijatrijskoj populaciji bio je tokom proteklih decenija predmet mnogobrojnih diskusija i razmimoilaženja kada je u pitanju inicijalni tretman i izbor najbolje hirurške procedure ze lečenje ovih bolesnika. Kontroverze i dalje postoje kada je u pitanju inicijalna terapija pacijenata sa krvarećim gastroezofagealnim variksima, najčešće i najopasnije komplikacije portne hipertenzije. Tretman dece sa krvarećim variksima kod ekstrahepatične portne hipertenzije, kao posledicom portne venske tromboze se promenio razvojem endoskopije tokom osamdesetih godina prošlog veka. Endoskopska sklerozacija i ligacija variksa postale su inicijalna terapija za krvareće varikse u dečijem uzrastu, što je dovelo čak i do napuštanja šant hirurgije u većini pedijatrijskih centara. Endoskopska skleroterapija ili ligacija variksa preporučivale su se od strane izvesnog broja autora čak i kao metoda izbora u lečenju potne hipertenzije. Njihove preporuke se bazirale su se na zapažanju da se rizik od ponavljanih variksnih krvarenja smanjuje vremenom sa rastom deteta i razvojem spontanih portosistemskih kolaterala, odnosno prirodnih šantova, te da deca „prerastu“ krvarenje iz variksa. Ovaj koncept medjutim ima osnova za kritike. Naime, istraživanja su pokazala da prirodnim spontanim kolateralama, čak i ukoliko nastanu, potrebno je izvesno vreme da se razviju, koje se ne retko meri u godinama. Za sve to vreme medjutim, pacijent je pod velikim rizikom od iznenadnih ponavljanih obilnih krvarenja iz variksa jednjaka, koja se mogu pojaviti i posle nekoliko godina nakon endoskopske ligacije ili sklerozacije variksa. Ova činjenica predstavlja naročito veliki problem za pedijatrijske pacijente koji žive daleko od specijalizovanih medicinskih centara. Dalje, skleroterapija se pokazala kao neadekvatna u kontroli krvarenja iz gastričnih variksa koji predstavljaju prirodni tok u evoluciji portne hipertenzije kao dinamičkog i progresivnog procesa, zatim iz variksa u slučaju postojanja Roux-en-Y anastomoze ili intestinalnih variksa. Progresivni hipersplenizam takodje ostaje kao problem koji nije moguće rešiti ponavljanim endoskopskim sklerozacijama ili ligacijama variksa. Sve ovo navodi na razmišljanje o ranom izvodjenju šant operacije kod pacijenata sa ekstrahepatičkom portnom hipertenzijom... | Portal hypertension is a condition of continuous high blood pressure in the portal venous system exceeding 10 mm Hg or 17 cm of water column. The treatment of portal hypertension in children has always been a challenge for generations of pediatricians and pediatric surgeons. In recent decades, the treatment of extrahepatic portal hypertension, the most common form of portal hypertension in the pediatric population has been the subject of many discussions and disagreements when it comes to the choice of initial treatment and surgical procedures. Controversy continues to exist when it comes to initial treatment of patients with bleeding gastroesophageal varices, the most often and dangerous complication of portal hypertension. Treatment of children with bleeding varices in extrahepatic portal hypertension has changed throughout the eighties of the last century. Endoscopic variceal ligation and sclerotherapy became the initial treatment for bleeding varices in children, which led to the abandonment of shunt surgery in most pediatric centers. Endoscopic procedures were recommended by a number of authors as a single method of choice in the treatment of portal hypertension. Their recommendations were based on the observation that the risk of recurrent variceal bleeding decreases over time as the child grow older with the development of spontaneous portosystemic collaterals or natural shunts, and that the children will "grow out" the variceal bleeding. However, there is a place for criticism of this concept. In fact, studies have shown that natural spontaneous collaterals, even if they occur need some time to develop, which is very often measured in years. However, during this period the patient is at risk of recurrent sudden heavy bleeding from esophageal varices, which may occur several years after endoscopic variceal ligation or sclerotherapy. This fact is very difficult, especially for pediatric patients who lived far from specialized medical centers. Furthermore, sclerotherapy has proved to be inadequate in controlling bleeding from gastric varices, which are in the natural course of evolution of portal hypertension as a dynamic and progressive process, and also from varices in case of a Roux-en- Y anastomosis, or intestinal varices. Progressive hypersplenism also remains a problem that can not be solved with repeated endoscopic variceal ligation or sclerotherapy. All this leads to consideration of performing early shunt surgery in patients with extrahepatic portal hypertension... | false |
Korelacija između genotipa i fenotipa bolesnika sa hiperfenilalaninemijom na teritoriji Srbije | Genotype-phenotype corelation in Serbian patients with hyperphenylalaninemia | Cilj rada: Ispitivana je korelacija genotipa i fenotipa bolesnika sa hiperfenilalninemijom. Utvrðena je incidencija hiperfenilalninemije u našoj populaciji. Prikazana je učestalost najčešćih mutacija u PAH genu i njihov uticaj na fenotip. Posebna pažnja je poklonjena ispitivanju metaboličkog i kliničkog fenotipa najčešće mutacije u našoj populaciji. Izneti su zaključci praćenja metaboličke kontrole kod naših bolesnika. Materijal i metode: Za ispitivanje incidencije hiperfenilalaninemije korišćeni su rezultati Republičkog zavoda za statistiku. Korišćena je medicinska dokumentacija Instituta za zdravstvenu zaštitu majke i deteta i rezultati Instituta za molekularnu genetiku i genetičko inženjerstvo. Biohemijske analize raðene su Guthrievim testom, Enzimskom metodom i Aminoanalizatorom. Za analizu dobijenih rezultata korišće su deskriptivne i analitičke statističke metode. Rezultati: Incidencija hiperfenilalninemije na našim prostorima iznosi 1: 15 130. Najveći broj bolesnika (62%) ima klasičnu fenilketonuriju. Najčešće mutacije PAH gena u našoj populaciji su: p.L48S, p.R4OW, p.P281L, p.E3906 i p.1306V, i javljaju se u 2/3 svih bolesnika. Interesantno je da je naša najčešća mutacija L48S prisutna kod 31% obolelih, što do sada nije zabaleženo ni u jednoj populaciji. Homozigoti i funkcionalni hemizigoti za L48S mutaciju se mogu javiti kod svih kategorija hiperfenillaninemije (blaga hiperfenilalaninemija, srednje teška fenilketonurija i klasična fenilketonurija). Pokazali smo i da tip mutacije nije značajan za konačan IQ bolesnika sa hiperfenilalaninemijom, već kontinuirano održavanje koncentracije fenilalnina u krvi u dozvoljenim granicama. Zaključak: Naša zemlja pripada grupi sa srednjom incidencijom hiperfenilalaninemija u svetu. S obzirom da naša najčešća mutacija pripada grupi mutacija sa rezidualnom enzimskom aktivnosti, koja izgleda zavisi od brojnih faktora, tolerancija fenilalanina je najbolji način za kategorizaciju ovih bolesnika. Odluka oko primene terapije i dalje treba da se zasniva na koncentraciji fenilalnina u krvi, a ne na osnovu mutacije u PAH genu. Na osnovu analize genotipa, preko 50% naših bolesnika su kandidati za BH4 terapiju. | Goal: Correlation between genotype and phenotype was tested in patients with hyperphenylalaninemia. Incidence of hyperphenylalaninemia in our population was calculated. Frequency of most common mutations in PAH gene was presented, along with it's impact on phenotype. Special focus was put directed on exploration of metabolic and clinical phenotype of the most prevalent mutation in our population. Conclusions derived from metabolic follow-up of our patients were presented as well. Matherials and methods: To determine incidence of hyperphenylalaninemia, data from Statistical Office of the Republic of Serbia. Medical documentation of Mother and Child Health Care Institute for used along with genetic findings of Institute for Molecular Genetics and Genetical Engineering. Biochemical analysis were performed using Guthrie test, Enzyme assay and Aminoacid analyser. Statistical analysis included both descriptive and analytical methods. Results: Incidence of hyperphenylalaninemia in our population was estimated at 1: 15 130. Majority of patients (62%) have classic phenylketonuria. Most common mutations in PAH gene in Serbia are: p.L48S, p.R4OW, p.P281L, p.E3906 i p.1306V, found in 2/3 of all patients. Interesting finding refers to L48S being the most prevalent mutation (found in 31%), which is unparalleled finding worldwide. Homozygous and functionaly hemizigous L48S carriers are found among all types of hyperphenylalaninemia (mild hyperphenylalaninemia, moderate hyperphenylalaninemia and classic phenylketonuria). It was also shown in these results that mutation type is not a valuable predictor for final IQ status of patients with hyperphenylalaninemia; on the other hand, metabolic control of disease was found as significant factor of final outcome. Conclusion: Our country can be considered as having an average incidence of hyperphenylaninemia. Considering the fact that most common mutation in Serbia relates to residual enzyme activity (determined by multitude of factors), tolerance of phenylalanine is the best way to classify severity of the disease. Thus, decision over treatment should be based on phenylalanine blood concentrations, and not on PAH gene mutation. According to genotype profiling, more than 50% of our patients could be candidates for tetrahydrobiopterine (BH4) treatment. | false |
Regenerativne osobine tetiva mišića semitendinozusa i gracilisa kod hirurške rekonstrukcije prednjeg ukrštenog ligamenta kolena | Regenerative features of semitendinosus and gracilis muscle tendons after anterior cruciate ligament reconstruction | Uvod: Tretman povrede prednjeg ukrštenog ligamenta se zahvaljujući
saznanjima bazičnih i kliničkih istraživanja, razvijao od neoperativnog, preko
ekstrakapsularne
stabilizacije
i
primarne
reparacije
ligamenta,
do
rekonstrukcije. Tetive mišića semitendinozusa i gracilisa (StG) su prisutne u
hirurškoj rekonstrukciji kao alternativni izvor grafta još od sredine
prošlog veka, a danas obezbeđuje više snopova čime se približava normalnoj
anatomiji uz upitan kvalitet prorastanja grafta u koštanim tunelima i
odsustvo
rigidne
koštane
fiksacije.
Savremena
hirurška
tehnika
rekonstrukciju prednje ukrštene veze sagledava veoma kompleksno od dijagnoze,
preko, individualnih, pacijentu prilagođenih anatomskih parametara u izboru
grafta i pozicioniranju tunela, do načina fiksacije i rehabilitacije. S
obzirom da je upotreba tetive mišića semitendinozusa i gracilisa postala sve
popularnija pri rekonstrukciji prednjeg ukrštenog ligamenta, povećana je i
pažnja na morbiditet donorske regije i kvalitet koštane fiksacije, a mogućnost
da dođe do potpune regeneracije nakon resekcije pune dužine i debljine tetiva
čini se čudesnom pojavom.
Ciljevi:
(I) Pokazati regenerativni potencijal tetiva mišića
semitendinozusa i gracilisa nakon njihove resekcije i upotrebe kao
autotransplantata kod rekonstrukcije prednjeg ukrštenog ligamenta (LCA)
kolena: ultrazvučna, morfološka i MR analiza. (II) Definisati potencijal i
karakteristike prorastanja tetivnih autotransplatata mišića semitendinozusa
i gracilisa u koštanim tunelima tibije i/ili femura nakon rekonstrukcije
prednjeg ukrštenog ligamenta kolena. (III) Izvršiti analizu ishoda lečenja
tokom rane faze rehabilitacije i srednjeročnog – dvogodišnjeg praćenja
pacijenata nakon rekonstrukcije prednjeg ukrštenog ligamenta kolena: poređenje
dve vrste fiksacije u femoralnom koštanom tunelu (transkondilarna fiksacija
i interferentni zavrtanj) sa pretpostavkom o superiornosti transkondilarne
fiksacije
Materijal i metodologija: U periodu od 2009 do 2011, od 150 pacijenata,
kod kojih je učinjena rekonstrukcija prednjeg ukrštenog ligamenta sa
dvostrukim graftom St/G ili trostrukim do četvorostrukim St, prospektivno je
praćeno 50 pacijenata koji su pristali da se uključe u studiju, a zadovoljili su
kriterijume: jednostrana povreda prednje ukrštene veze ne starija od 6 meseci
kod pacijenata od 18 do 40 godina starosti koja je potvrđena artroskopski ili na
MR. Pacijentima je rađen ultrazvučni pregled i parametarski i klinički
testovi u određenim vremenskim intervalima: preoperativno, i nakon 1, 3, 6, 12,
18 i 24 meseca nakon operacije. Rađena su dva istraživanja: prvo istraživanje se
odnosilo na regenerativne osobine tetiva semitendinozusa i gracilisa, uz
poseban naglasak na regeneraciju tetive semitendinozusa usled kvaliteta i
tehničkih mogućnosti istraživanja; drugo istraživanje se odnosilo na kvalitet
femoralne fiksacije tetivnog grafta, odnosno prednost transkondilarne
fiksacije („BioTransfix“, Arthrex, Inc) u odnosu na interferentni zavrtanj
(„PLLA Bioabsorbable srew“, Arthrex, Inc).
Sve procedure su usaglašene sa etičkim standardima odbora na
Medicinskom fakultetu Univerziteta u Beogradu (odluka broj 444/V – 9).
Pacijenti su adekvatno informisani o procedudarama i razlozima ispitivanja i
kod pacijenata koji su dali pismenu saglasnost, a gde je potvrđeno prisustvo
regenerata (klinički, ultrazvuk i/ili MR), izvršena je hirurška biopsija
novoformiranih tetiva. Razlike između postoperativnih i intraoperativnih
vrednosti, kao i između operisane i neoperisane noge su analizirane upotrebom
Studentovog t-testa za zavisne uzorke; razlike između pacijenata sa
regenerisanim tetivama semitendinozusa i gracilisa i onih bez regenerata su
testirani ANOVA testom za ponavljana merenja sa pre i postoperativnom
razlikom, kao i pri testiranju razlika pri upotrebi jedne odnosno obe tetive,
odnosno dve tehnike fiksacije grafta.
Rezultati: Prva kategorija se odnosila na regenerativne osobine tetiva
semitendinozusa i gracilisa, uz poseban naglasak na regeneraciju tetive
semitendinozusa usled kvaliteta i tehničkih mogućnosti istraživanja. Druga
grupa se odnosila na kvalitet, odnosno prednost transkondilarne fiksacije
(BioTransfix) u odnosu na intereferntni zavrtanj (PLLA Bioabsorbable srew):
poređenje ishoda lečenja nakon resekcije jedne ili dve tetive, sa jedne strane
odnos upotrebe dve različite vrste femoralne fiksacije, nisu dali statistički
značajne razlike, odnosno prednost jednoj ili drugoj metodi. U slučaju izolovane
resekcije St, stepen regeneracije kao i pripajanje „neotetive“ je bio distalno od
zglobne linije u preko 80% slučajeva (83.3%); nivo propoja nakon resekcije obe
tetive je bio u 60% slučajeva iznad nivoa zglobne linije: ultrasonografski je
pokazana regeneracija i proksimalna insercija „neotetiva“ u slučajevima kada
su resecirane obe tetive, tj u 15 slučajeva (60%) ukupno regenerisanih tetiva, a
od toga u 9 pacijenata (60%) iznad nivoa zglobne linije, na poplitealnoj
fasciji; u slučajevima kada je resecirana samo jedna tetiva (St), uz očuvanu
tetivu gracilisa, neotetiva se razvila u preko 80% slučajeva, i mesto insercije
je u većini bilo ispod nivoa zglobne linije, ali ipak nešto iznad anatomske
insercija na pes anserinusu, kod 12 pacijenata (67%). Naša anatomska
ispitivanja pokazuju da je vaskularizacija okolnog tetivnog tkiva dobro
razvijena i može imati ključnu ulogu u procesu regeneracije. Složili bi se da
hirurška tehnika mora biti što poštednija kako bi se očuvala normalana
vaskularna anatomija u zoni resekcije te očekivao proces regeneracije. Na
našem materijalu nije uočena statistički značajna razlika u kliničkim
parametrima kod dve vrste fiksacije: PLLA Bioabsorbable screw / BioTransfix u
femoralnom koštanom tunelu, kako po tipu vrste fiksacije tako i u različitim
testovima između grupa (Lysholm, Tegner, IKDC), ali je svakako postignuto
značajno poboljšanje tegoba i funkcije nakon rekonstruktivne procedure.
Zaključak: Potrđena je hipoteza da se može očekivati regeneracija tetiva
semitendinozusa i gracilisa nakon njihove potpune resekcije u pripremi grafta
za rekonstrukciju prednje ukrštene veze. Regenerisana tetiva („neotetiva“) ne
samo da ima morfološke sličnosti sa nativnom tetivom, na ultrazvučnom i
kliničkom pregledu, već se i histološke karakteristike skoro izjednačuju sa
originalnom tetivom u karakteru i orijentaciji kolagenih vlakana, rasporedu
fibrocita i razvoju novih krvnih sudova. Na osnovu funkcionalnih kliničkih
i parametarskih testova, može se reći da se ne iskazuje gubitak mišićne snage
nakon resekcije, ali svakako postoji nedostatak studije u odsustvu objektivnih
izokinetičkih testova funkcionalnosti regenerata. Prisutna je mogućnost
ponovnog korišćenja regenarata, ali ostaje otvoreno pitanje o karakteru i
kvalitetu, odnosno biomehaničkim paramaterima prilikom ponovne upotrebe u
rekonstruktivnoj hirurgiji. Pokazalo se da se preciznom hirurškom tehnikom,
pripremom trostrukog/četvorostrukog grafta izolovane tetive semitendinozusa,
bez obzira na način fiksacije u femoralnom koštanom tunelu, obezbeđuje
kvalitetan ishod lečenja nakon rekonstrukcije prednje ukrštene veze uz veliki
potencijal regeneracije sa morfološkim i biološkim karakteristikama
sličnim nativnoj tetivi. Mogućnost ponovne upotrebe regenerata („neotetive“)
u novim rekonstruktivnim ili čak revizionim procedurama daje prednost
upotrebi tetivnog autografta u artroskopski asistiranoj hirurgiji zgloba
kolena. | Objective: The treatment оf the anterior cruciate ligament rupture was
developed from non-operating, through extracapsular stabilization and primary ligament
repair to reconstruction, after knowledge of basic and clinical research. Semitendinosus
and gracilis muscle tendons (StG) are alternative source of graft since mid of last
century, but nowdays provides two bundles similar to normal ACL anatomy even with
questionable graft tunnels ingrowth and the absence of rigid bone fixation. Modern
surgical techniques are considering diagnosis, individual, patient anatomical parameters
in the selection of graft and positioning of the tunnel, and the way of fixation and
rehabilitation. Since semitendinosus and gracilis muscle tendons became more popular
in the reconstruction of the anterior cruciate ligament, there is increased attention on the
morbidity and the quality of tendon bone fixation. a Complete regeneration possibility
after resection of full length and thickness seems like miracle in human anatomy
Aims: (I) to analyze the regenerative potential of semitendinosus and gracilis
muscle tendon after their resection and use as a autograft in reconstruction of the
anterior cruciate ligament (ACL): diagnostics with ultrasound, MRI and biopsy; (II) to
demonstrate the potential and characteristics of tendon's ingrowth in bone tunnels after
reconstruction of the anterior cruciate ligament; (III) to analyze treatment outcome
during the early stages of rehabilitation and medium-term - a two-year follow-up of
patients after reconstruction of the anterior cruciate ligament: comparison of two types
of fixation in the femoral bone tunnel (transcondylar and interference screw fixation)
with the assumption of transcondylar fixation superiority.
Methodology: From 2009 to 2011, among 150 patients with anterior cruciate
ligament reconstruction (double graft St / G or triple to quadruple St) we prospectively
followed 50 patients who agreed to participate in the study, and meet the criteria:
unilateral anterior cruciate ligament injuries less than than 6 months old, 18 to 40 years
of age, lesion confirmed on arthroscopy or MRI. Ultrasound exams and parametric and
clinical tests at specified time intervals were performed: preoperatively, 1, 3, 6, 12, 18
and 24 months after surgery. All procedures were in compliance with ethical standards
committee in the School of Medicine, University of Belgrade (Decision No. 444 / V -
9). Patients are adequately informed about the reasons of tests and with regenerate
presence confirmation (clinical, ultrasound and / or MRI) surgical biopsy was
performed on newly formed tendon. Differences between intraoperative and
postoperative values, as well as between the operated and unoperated leg were analyzed
using Student's t-test for paired samples; differences between patients with regenerated
tendons and those without regenerate are tested ANOVA for repeated measurements
with pre and postoperative difference, as well as in testing the difference in the use of
one or both tendons, or two graft fixation techniques.
Results: The first category is related to the regenerative properties of
semitendinosus and gracilis tendons, with a special emphasis on the regeneration of St
due to the quality and technical possibilities of research. The second group is related to
the quality or the advantage transcondylar fixation (“BioTransfix”, Arthrex, Inc)
compared to interference screw (“PLLA Bioabsorbable srew”, Arthrex, Inc.):
comparison of treatment outcome after resection of one or two tendons on the one hand
and the ratio of the use of two different types of femoral fixation, did not provide
statistically significant differences or favor one or another method. In the case of
resection of the isolated St, the degree of the regeneration as well as the coupling of a
"neotendon" was distal to the joint line in more than 80% of cases (83.3%); insertion
level after resection of both tendon was in 60% of cases above the level of joint line:
ultrasound has shown regeneration of the proximal insertion "neotendon" in cases where
both resected tendon, i.e. in 15 cases (60%) of regenerated tendons, of which in 9
patients (60%) above the joint line, to the popliteal fascia; in cases where was resected
only one tendon (St), while maintaining gracilis tendon, „neotendon“ develop in over
80% of cases, and the insertion site is below the level of the joint line, but still slightly
above the anatomical insertion of the pes anserinus, in 12 patients (67%). Our
anatomical studies showed that vascularization surrounding tendon tissue is well
developed and can play a key role in the process of regeneration. We agreed that the
surgical technique should be as meticulous to preserve a normal vascular anatomy in the
zone of resection and the expected regeneration process. In our material there are is no
statistically significant difference in clinical parameters in two types of fixation: PLLA
Bioabsorbable screw / BioTransfix femoral bone tunnel, both by type and kind of
fixation in various tests between groups (Lysholm, Tegner, IKDC), but it certainly
achieved significant improvement in symptoms and function after reconstructive
procedure.
Conclusion: Study confirmed hypothesis of expected regeneration and recovery
of semitendinosus and gracilis tendons after their complete resection in the preparation
of anterior cruciate ligament. Regenerated tendon ("neotendon") has the morphological
similarities with the native tendon on ultrasound and clinical examination, but also the
histological features almost equated with the original string in the character and
orientation of collagen fibers, fibrocytes pattern and development of new blood vessels.
On the basis of clinical, functional and parametric tests, we can say that there is no loss
of muscle strength after resection, but definitely point out the lack of this study is in the
absence of objective isokinetic functional tests on regenerate tendon. The possibility of
„neotendon“ re-use is certain, but the question remains about the character and quality
or biomechanical parameters when used again in reconstructive surgery. It turned out
that precise surgical technique, preparation of the triple / quadruple isolated
semitendinosus tendon graft, regardless of the method of fixation in the femoral bone
tunnel, provide an excellent outcome after ACL reconstruction with great potential for
regeneration with morphological and biological characteristics similar to native tendon.
The possibility of regenerative tendon re-use in the new reconstructive or even revision
procedures, favor the use of tendon autograft in arthroscopic assisted knee surgery. | true |
Nivoi međućelijskog adhezionog molekula-1 i vaskularnog ćelijskog adhezionog molekula-1 u serumu obolelih od bipolarnog afektivnog poremećaja i shizofrenije | The levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in sera of patients with bipolar disorder or schizophrenia | Uvod. Ćelijski adhezioni molekuli imaju važnu ulogu u inflamatornim
procesima za koje se veruje da posreduju u nastanku psihotičnih i afektivnih duševnih
oboljenja.
Ciljevi istraživanja. Ciljevi sitraživanja bili su: odredjivanje nivoa serumskih
koncentracija solubilnog medjućelijskog adhezionog molekula-1 (sICAM-1) i
solubilnog vaskularnog ćelijskog molekula-1 (sVCAM-1) kod obolelih od bipolarnog
afektivnog poremećaja (BAP) i shizofrenije (SCH) i zdravih ispitanika; poredjenje
serumskih koncentracija sICAM-1 i sVCAM-1 obolelih u odnosu na zdrave ispitanike;
ispitivanje promene serumskih koncentracija sICAM-1 i sVCAM-1 u remisiji u odnosu
na akutnu fazu bolesti kod BAP/SCH; i finalno, ispitivanje povezanosti nivoa sICAM-1
i sVCAM-1 sa stepenom psihopatologije, kliničkim karakteristkama toka bolesti i
primenjenim farmakoterapijskim protokolima.
Materijal i metod. Istraživanje predstavlja kliničku, prospektivnu, otvorenu,
eksperimentalnu studiju ispitivanja serumskih nivoa sICAM-1 i sVCAM-1 kod obolelih
od BAP (n = 82) i SCH (n = 66) u akutnoj fazi bolesti i remisiji, u odnosu na i zdrave
ispitanike (n = 73). Podaci su prikupljeni putem sledećih upitnika: polu-strukturisani
psihijatrijski upitnik, skala opšteg kliničkog utiska, skala globalne ocene funkcionisanja,
kratka skala za psihijatrijsku procenu, skala za procenu pozitivnog i negativnog
sindroma shizofrenije, Montgomeri-Ašberg skala za procenu depresivnosti, Jangova
skala za procenu manije, skala za procenu shizo-bipolarnosti. Odredjivanje serumskih
nivoa koncentracije adhezionih molekula vršeno je ELISA metodom. U okviru studije
obavljena je procene težine bolesti, prisutne psihopatologije, toka bolesti i akutne i
longitudinalne primene farmakoterapije. U statističkoj obradi podataka su korišćene
metode deskriptivne statistike, metode bivarijatne analitičke statistike (Studentov t-test
za nezavisne uzorke, χ2- test, korelaciona analiza) i multivarijatne metode (parcijalna
korelaciona analiza, linearna regresiona analiza, ANCOVA analiza, analiza
medijatorskih i moderatorskih efekata). Kao kovarijate upotrebljeni su pol, pušacki
status, indeks telesne mase i starost.
Rezultati. Rezultati istraživanja ukazuju da se nivoi sVCAM-1 razlikuju kod
obolelih od BAP i SCH u akutnoj fazi i remisiji bolesti, dok medju ispitivanim grupama
ne postoji razlika u nivoima sICAM-1. Nivoi ispitivanih imunskih medijatora razlikuju
se kod obe grupe obolelih u odnosu na zdrave ispitanike, dok u fazi remisije dolazi do
normalizacije nivoa sICAM-1 i to samo kod obolelih od BAP. Izmene u sICAM-1 i
sVCAM-1 povezane sa akutnim i longitudinalnim kliničkim karakteristikama bolesti.
Dodatno, rezultati ukazuju da postoji akutno i dugoročno imunomodulatorno delovanje
psihofarmaka iz grupe stabilizatora raspoloženja na nivoe sVCAM-1 i atipičnih
antipsihotika i antidepresiva na nivoe sICAM-1. U okviru analize celokupnog uzorka
obolelih sniženje sVCAM-1 bilo je povezano sa psihotičnom, pozitivnom
simptomatologijom, praćenom kognitivnim oštećenjem, kao i izraženijom tendencijom
ka pripadnosti shizofrenim nasuprot afektivnim poremećajima. Takodje, sVCAM-1
predstavlja prediktor pripadnosti dijagnostičkoj kategoriji, a njegova uloga može biti
potencirana moderatorskom ulogom herediteta na afektivne poremećaje.
Zaključak. Ćelijski adhezioni molekuli igraju značajnu ulogu u biološkim
procesima koji se nalaze u delimično zajedničkoj osnovi afektivnih i psihotičnih
poremećaja, i koji su podložni longitudinalnim izmenama u inflamatornom statusu
obolelih. Studija ukazuje da je sagledavanje BAP i SCH neophodno, kroz njihove
delimično zajedničke neurobiološke determinante i psihopatologiju, ali uz distinkciju
izmedju ova dva poremećaja kada su u pitanju faktori vezani za progresiju bolesti,
terapiju i terapijski odgovor. | Background. Adhesion molecules play an important role in inflammatory
processes that underlie etiopathogenesis of psychotic and affective disorders.
Aims. The aims of the study were to: assess the differences in serum
concentrations of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble
vascular cell adhesion molecule-1 (sVCAM-1) among patients with bipolar disorder
(BAP) and schizophrenia (SCH); compare the serum concentrations of sICAM-1 and
sVCAM-1 among patient groups and healthy controls; assess the alterations in serum
concentrations of sICAM-1 and sVCAM-1 in acute phase and remission of the
disorders; and to assess the association between sICAM-1/sVCAM-1 and current
psychopathology, clinical characteristics of the disorder and pharmacotherapeutic
treatment.
Material and method. The study was designed as clinical, prospective, open,
experimental study assessing the serum levels of sICAM-1 and sVCAM-1 in patients
with BAP (n = 82) and SCH (n = 66) in acute phase and remission, and compared to
healthy controls (n = 73). The data were collected by: semi-structured psychiatric
interview, Clinical Global Impression, Global Assessment of Functioning, Brief
Psychiatric Rating Scale, Positive and Negative Syndrome Scale for Schizoprenia,
Montgomery-Asberg Depression Rating Scale Young Mania Rating Scale, Schizo-
Bipolar Scale. Serum levels of adhesion molecules were measured by ELISA. The
severity of the disorder, current psychopathology, course of ilness and acute and
longitudinal treatment were assessed within the study. Methods of descriptive statistics,
bivariant analytical statistic (Student’s t-test, χ2- test, correlation analysis) and
multivariant statistic (partial corelation, linear regression analysis, ANCOVA analysis,
analysis od mediating and moderatory effect) were used to analyze the data. Gender,
smoking habits, body mass index and age were used as covariates.
Results. The results show that the levels of sVCAM-1 differ between BAP and
SCH in the acute phase and remission. The differences in the levels of sICAM-1 were
not observed. The levels of adhesion molecules were altered in both patient groups
when compared to healthy controls. Moreover, the normalization of immune mediators
was observed only in sICAM-1, in BAP, in remission. Alterations of the sICAM-1 and
sVCAM-1 were associated with both acute and longitudinal clinical characteristics of
the disorders. In addition, the results indicate that there is an acute and long-term
immunomodulatory effect of psychotropic medication such as mood stabilizers on
sVCAM-1 levels, while atypical antipsychotics and antidepressants were related to the
similar changes of sICAM-1. The analysis of the entire sample revealed that sVCAM-1
was associated with psychotic, positive symptomatology, accompanied by cognitive
impairment, as well as a marked predisposition towards schizophrenic versus affective
disorders. Also, sVCAM-1 was a predictor of predisposition towards diagnostic
category, while its role was moderated by heredity on affective disorders.
Conclusion. Cell adhesion molecules play a pivotal role in biological processes
at the common basis of affective and psychotic disorders. Moreover, their levels are
vulnerable to longitudinal changes in the inflammatory states observed in patients. The
study indicates that the perception of BAP and SCH should include shared
neurobiological determinants and psychopathology, but also the distinction between the
two disorders in terms of their progression, treatment and treatment response. | true |
Prognostički značaj molekularnih markera, kliničkih i patohistoloških parametara kod bolesnika operisanih zbog karcinoma rektuma u ranom stadijumu | Prognostic significans of molecular markers, clinical and pathological parameters in patients operated for early rectal cancer | Karcinom rektuma zbog visoke incidence i trenda njenog rasta u budućnosti, predstavlja veliki
javnozdravstveni problem. Hirurško lečenje je i dalje primarno u tretmanu ove bolesti ali se dobri rezultati
mogu očekivati samo multidisciplinarnim pristupom odnosno kombinovanom, miltimodalnom terapijom.
U tom cilju nameće se potreba za pronalaženjem prognostičkih biomarkera uz pomoć kojih se mogu
predvideti bolesnici sa visokim rizikom za recidiv odnosno kandidati za intenzivnije postoperativno
praćenje i agresivnije terapijske modalitete.
Cilj ove studije je da se zajedno sa kliničko-patološkim parametrima ispita prognostički potencijal
vaskularnog endotelijalnog faktora rasta (VEGF), receptora epidermalnog faktora rasta (EGFR) i CD44v6
kod pacijenata sa T3N0 karcinomom rektuma.
Materijal i metode. Ovo je studija preseka koja obuhvata 163 bolesnika sa T3N0 karcinomom rektuma,
koji su kurativno operisani na III odeljenju, Klinike za digestivnu hirurgiju – Prve hirurške klinike,
Kliničkog centra Srbije u periodu 2003-2013 godina. VEGF, EGFR i CD44v6 ekspresija je ispitivana
imunohistohemijski. Kao parametri od interesa definisani su: pojava lokalnog recidiva, distalnih metastaza
i preživljavanje bolesnika.
Reziltati.U studiji je bilo 102 bolesnika muškog i 61 bolesnik ženskog pola. Prosečna starost bila je 62
godine (31-88 godina) a postoperativno su praćeni u proseku 81 mesec (4-177 meseci). Kod 6 bolesnika je
dijagrostikovan lokalni a kod 31 distalni recidiv bolesti. Kod bolesnika sa pozitivnom VEGF i CD44v6
ekspresijom preživljavanje je bilo lošije u odnosu na bolesnike sa negativnom VEGF i CD44v6
ekspresijom. Kliničkopatološki parametri (mucinozni tip adenocarcinoma, vaskularna invazija, invazija
limfatika i perineuralna invazija, gradus tumora, način rasta tumora, uznapredovali T3 stadijumi,
intraoperativna perforacija tumora) takođe značajno utiču na prognozu bolesti.
Zaključak: Povišena VEGF i CD44v6 ekspresija kod T3N0 karcinoma rektuma zajedno sa standardnim
histopatološkim karakteristikama tumora može dati dovoljno informacija za definisanje pacijenata sa
visokim rizikom za pojavu recidiva bolesti i lošijom prognozom. | Rectal carcinoma still presents major health problem. Besides the need for
individualized and meticulous preoperative staging there is sometimes a problem in choosing the
optimal mode of treatment. Today’s problem presents a group of rectal cancer patients in
T3N0M0 stage. These patients may not benefit from aggressive neoadjuvant and adjuvant
approach. Nevertheless, we still have around 20% of patients in this group who develop distant or
local relapse of the disease. There is a need for predictive and prognostic markers that could help
us determine the subgroup of patients with high risk of relapse.
The aim of this study is to determine the prognostic potential of VEGF, EGFR,CD44v6 and
clinicopathological parameters in patients with T3N0 rectal carcinoma in the absence of
neoadjuvant treatment.
Methods. This was retrospective analysis of 163 selected T3N0 rectal cancer patients, operated
on the Department for Colorectal Surgery of the Clinic for Digestive Surgery-First Surgical
Clinic,
Clinical
Centre
of
Serbia.
VEGF,
EGFR
and
CD44v6
expression
was
immunohistochemically assessed. Parameters of interest were: Local recurrence, distant
metastases, disease free survival, disease specific and overall survival.
Results.There were 102 men and 61 women. The median age was 62 years (range, 31-88 years).
Median follow-up interval was 81 months (range, 4-177 months). During the follow-up period 6
patients developed local recurrence, in 31 patients we discovered distant metastases.
Disease free survival, disease specific and ovareall survival were lower in VEGF and CD44v6
positive tumors. Clinicopathological parameters (mucinous type of adenocarcinoma, vascular
invasion, lymphatic invasion, perineural invasion, tumor diferentiation, tumor growth, advanced
T3 stages, intraoperative tumor perforation) also significantly affect the prognosis of the disease.
Conclusion. Elevated VEGF and CD44v6 expression in T3N0 rectal carcinoma together with the
standard histopathological characteristics, can provide enough information to define patients with
high risk for recurrence and poor prognosis. | true |
Uticaj terapije gvožđem i eritropoetinom i polimorfizma ACE D/I na suzbijanje anemije kod bolesnika na hroničnoj hemodijalizi | Impact of iron and erythropoietin threatment associated with ACE D/I polymorphism on anemia management in chronic hemodialysis patients. | Uvod: Anemija je jedna od glavnih komplikacija koja se javlja u hroniĉnoj bolesti bubrega (CKD), terminalnoj bolesti bubrega (ESRD) i na dijalizi i nezavistan je prediktor morbiditeta i mortaliteta kod ovih bolesnika (10,11). Smanjena produkcija endogenog eritropoetina (Epo) i nedostatak gvoţĊa (Fe) dva su neodvojiva razloga usporavanja i prekida diferencijacije i maturacije eritrocita u kostnoj srţi i predstavljaju glavne razloge koji dovode do smanjene eritropoeze u bolesnika na dijalizi. Korekcija statusa feremije redovnom nadoknadom Fe od kljuĉne je vaţnosti u leĉenju anemijskog sindroma kod bolesnika sa CKD, ESRD i na dijalizi. Svakako opravdano, primena preparata Fe je u porastu, zajedno sa primenom rekombinantnog humanog eritropoetina (rHu Epo), (49), a preporuĉen ciljni hemoglobin (HGB) je korigovan sa 130 na 105-110 g/L, na osnovu utvrĊenog bezbedonosnog profila rHu Epo za bolesnike sa CKD (50-52). Aktuelni vodiĉi leĉenja anemije na hemodijalizi (K/DIGO) liberalizuju upotrebu Fe kod bolesnika sa CKD (53). Angiotenzin II direktno povećava proliferaciju eritroidnih progenitora u in vitro uslovima (41,42). Pokazana je veća potreba za koliĉinom rHuEpo kod bolesnika sa ACE genotipom II za postizanje adekvatne korekcije krvne slike, u odnosu na bolesnike sa DD genotipom na hroniĉnoj ambulatornoj peritonealnoj dijalizi (44). Kardiovaskularni status bolesnika na hemodijalizi je pod snaţnim uticajem stepena anemije i medijatora iz sistema renin-angiotenzin, koji se moduliraju pod uticajem polimorfizma konvertaze angiotenzina I (ACE) genotipa. Hipertrofija leve komore (HLK) veoma je ĉesta u CKD (do 40% bolesnika), a prema pojedinim istraţivanjima i do 75% bolesnika na dijalizi razvije HLK (158,173). U literaturi nema podataka o meĊudejstvu modaliteta supstitucije Fe (IV prema peroralnom), ACE genotipa i odgovora na terapiju rHu Epo kod bolesnika na hemodijalizi, što je od kliniĉkog interesa za modulaciju protokola terapije anemije... | Introduction: Anemia is one of the major complications which occurs in chronic kidney disease (CKD), end-stage renal disease (ESRD) and on dialysis and is an independent predictor of morbidity and mortality in these patients (10,11). Decreased production of endogenous erythropoietin (Epo) and iron deficiency (Fe) are the two inseparable reasons of slowdown and disruption of differentiation and maturation of red blood cells in the bone marrow and are the main reasons that lead to reduced erythropoiesis in dialysis patients. Correction of the feremia status with regular compensation of Fe is crucial in treating anemia syndrome in patients with CKD, ESRD and dialysis. Certainly justified, the use of Fe medicines is on the rise, along with the implementation of recombinant human erythropoietin (rHu Epo), (49), and the recommended target HGB is adjusted from 130 to 105-110 g / L, based on the established complex security profile rHu Epo in patients with CKD (50-52). The current guideline of the treatment of anemia in hemodialysis patients (K/DIGO) liberalizes the use of Fe in patients with CKD (53). Angiotensin II directly increases the proliferation of erythroid progenitors in in vitro conditions (41,42). A greater need is expressed for the amount of rHu Epo in patients with ACE genotype II to achieve adequate correction of the blood count, compared to patients with the DD genotype on chronic ambulatory peritoneal dialysis (44). The cardiovascular status of patients on hemodialysis is strongly influenced by the degree of anemia and mediators of the renin-angiotensin system, which can be modulated by the influence of angiotensin converting polymorphism I (ACE) genotype. Left ventricular hypertrophy (LVH) is very common in CKD (up to 40% of patients), and according to some studies up to 75% of patients on dialysis develop LVH (158,173). In the literature there is no data on interacting modalities of Fe substitution (IV towards peroral), ACE genotype and responses to rHu Epo therapy in hemodialysis patients, which is of clinical interest in the protocol modulation of anemia therapy... | false |
Sistematski pregled sa meta-analizom pouzdanosti i valjanosti psihijatrijskih skala u longitudinalnim studijama | Systematic review and meta-analysis of reliability and validity of psychiatric scales in longitudinal studies | Uvod: Psihijatrijske skale omogućavaju da se registruje prisustvo ili odsustvo simptoma
psihijatrijskih oboljenja, da se njihov intenzitet izrazi brojevima i upotrebi u kliničke ili
istraživačke svrhe. Samim tim, važan aspekt skala u psihijatriji jesu njihove metrijske
osobine, odnosno njihova merna adekvatnost što obuhvata pouzdanost i valjanost.
Pouzdanost označava do koje mere se metoda merenja (test) konzistentno ili postojano
ponaša, a valjanost je odnos između onog što se pretpostavlja da bi instrument (test)
trebalo da meri i onog što on stvarno meri. Postoje tri standardna načina za ocenu
pouzdanosti: interna konzistentnost, međuposmatračka pouzdanost i test-retest
pouzdanost. Tri glavna tipa valjanosti su sadržinska, konstruktivna i kriterijumska.
Uobičajeno se pouzdanost i valjanost ocenjuje primenom nekog od koeficijenata u
studijama preseka, najčešće jedanput. U longitudinalnim studijama eliminiše se
varijabilnost koja je posledica interindividualnih razlika pa se povećava verovatnoća za
uočavanje značajne razlike nivoa faktora. Ponovljenim ocenama pouzdanosti i valjanosti
dobiće se informacije o stabilnosti tih ocena u vremenu, a samim tim i pouzdanost i
valjanosti skorova dobijenih primenom skala.
Cilj: Ciljevi ovog istraživanja bili su: (1) Uraditi sistematski pregled literature i meta-
analitičko objedinjavanje ocena pouzdanosti i valjanosti psihijatrijskih skala saopštenih u
različitim vremenima tokom longitudinalnih studija. (2) Proceniti promene ocena
pouzdanosti i valjanosti psihijatrijskih skala saopštenih u različitim vremenima tokom
longitudinalnih studija. (3) Generisati moderatore / prediktore prethodno navedenih ocena
i njihovih promena.
Materijal i metode: Postavljeni cilj ovog istraživanja realizovan je u studiji slučaja
sistematskog pregleda i meta-analize ocena pouzdanosti i valjanosti Hamiltonove skale
za procenu depresivnosti (HAMD) i Montgomeri–Ašbergove skale za procenu
depresivnosti (MADRS). Ove dve skale su odabrane jer su najkorišćeniji psihijatrijski
instrumenti koji se koriste od strane ocenjivača. Jedinice posmatranja su literaturne
jedinice (publikovani radovi) koje su dobijene sistematskim pregledom literature u cilju
identifikacije publikovanih istraživanja u kojima su saopštene ocene o pouzdanosti i/ili
valjanosti skala HAMD i MADRS. Pretraživanje literature sprovedeno je u dve faze. U
prvoj fazi pretražene su dve bibliografske (indeksno-abstraktne) baze podataka:
MEDLINE i PsycINFO. Vremenski period obuhvaćen pretraživanjem proteže se od
početka primene HAMD (1960. godine) i MADRS (1979. godine) skala, do kraja 2013
godine. Pretraživanjem baza podataka koje sadrže kompletan tekst objavljenih studija u
elektronskoj formi (HINARI, EBSCO, ProQuest i Science Direct) identifikovane su i
locirane dodatne studija za skale HAMD i MADRS. Rezultati pretraživanja su spojeni, a
zatim su uklonjeni duplikati i lažno pozitivni nalazi. Ukupan broj prikupljenih studija u
punom tekstu u kojima je korišćena HAMD skala iznosio 6590, a u kojima je korišćena
MADRS skala iznosi 2051. U drugoj fazi izvršeno je pretraživanje ocena pouzdanosti i
valjanosti u prikupljenim radovima u celini. Primarne studije pregledane su od strane dva
nezavisna istraživača koji su u unapred pripremljen formular ekstrahovali podatke koji se
odnose na ocene pouzdanosti i valjanosti HAMD i MADRS skala, kao i podatke koji se
potencijalno mogu upotrebiti u analizi varijabli moderatora. Sistematski pregled i meta-
analiza biće izvedeni za sve ocene pouzdanosti i valjanosti saopštene u dva vremena u
longitudinalnim studijama. Veličina efekta u slučaju ocena pouzdanosti i koeficijenata
korelacije između skala biće njihova zed transformisana vrednost. U cilju otkrivanja
potencijalnih varijabli moderatora biće izvedena meta-regresija. Meta-analitičkim
metodom robusne ocene varijanse modelovane su promene koeficijenata pouzdanosti i
konkuretne valjanosti u vremenu, kao i povezanost tih promena sa potencijalnim
prediktorima, dok su metodom recipročne varijanse objedinjeni koeficijenti pouzdanosti
i konkurentne valjanosti u pojedinačnim vremenima.
Rezultati: Od 6590 prikupljenih i pregledanih studija za HAMD skalu 98 (1,5%) su
identifikovane kao studije u kojima su saopšteni podaci o pouzdanosti ili valjanosti. Od
2051 prikupljenih i pregledanih studija za MADRS skalu 38 (1,9%) je identifikovano kao
studije u kojima su saopšteni podaci o pouzdanosti ili valjanosti. Vrednosti Alfa
koeficijenta za HAMD skalu više su na poslednjoj proceni kod 22 od 24 uključene studije.
Postoje statistički značajne promene u vremenu zed transformisanih vrednosti alfa
koeficijenata za HAMD skalu (p<0,001). Povećanje vrednosti alfa koeficijenta povezano
je sa smanjenjem skora depresivnosti i povećanjem njegovog varijabiliteta. Vrednost zed
transformisanih Loevingerinih koeficijenta za HAMD skalu raste u vremenu i taj porast
je statistički značajan (p=0,002). Nisu dobijene statistički značajne promene u vremenu
za vrednosti zed transformisanih alfa i Loevingerinih koeficijenata za MADRS skalu, što
je verovatno posledica malog uzorka. Postoji statistički značajan porast u vremenu zed
transformisanih vrednosti intraklasnog koeficijenta korelacije za HAMD skalu (p=0,025).
U poređenju sa početnim merenjima, vrednosti intraklasnog koeficijenta korelacije za
MADRS skalu više su na poslednjoj proceni. U poređenju sa početnim merenjima,
vrednosti zed transformisanih koeficijenata test-retest pouzdanosti za HAMD skalu više
su na poslednjoj proceni. Korelacije između skala za procenu depresivnosti povećavaju
se tokom vremena kod 52 od 61 studije uključene u meta-analize. Statistički značajne
promene u koeficijentima korelacije nađene su između skala HAMD i BDI (p<0,001) i
za korelacije između skala HAMD i MADRS (p<0,001). Povećanje korelacija između
skala povezano je sa smanjenjem skora depresivnosti i povećanjem njegovog
varijabiliteta. Mali broj podataka nije mogao dovesti do zaključka o promenama
dijagnostičke i faktorske valjanosti, kako za HAMD tako i za MADRS skalu.
Zaključci: Zaključci koji se odnose na meta-analitički metod ispitivanja promena
pouzdanosti i valjanosti psihijatrijskih skala u vremenu su: (1) Postojećim meta-
analitičkim metodama adekvatno se mogu oceniti pokazatelji pouzdanosti i valjanosti
psihijatrijskih instrumenata u longitudinalnim studijama. (2) Meta-analiza ocena
pouzdanosti i valjanosti u longitudinalnim studijama pruža objektivnu osnovu za
generisanje preporuka njihove prihvatljive vrednosti koje su specifične za
instrument/oblast i vreme primene. (3) Niska učestalost saopštavanja podataka o
pouzdanosti i valjanosti primenjenih psihijatrijskih instrumenata predstavlja glavni
problem za efektivno korišćenje meta-analitičkog metoda u istraživanju promena merne
adekvatnosti u longitudinalnim studijama. Zaključci koji se odnose na meta-analizu
promena ocena pouzdanosti i valjanosti za Hamiltonovu skalu za procenu depresivnosti i
Montgomeri-Ašbergovu skalu za procenu depresivnosti: (1) Pouzdanost Hamiltonove
skale za procenu depresivnosti, interna konzistenost, iskazana u vidu Cronbachovih alfa
koeficijenata i Loevingerinih koeficijenata, kao i međuposmatračka pouzdanost, iskazana
u vidu intraklasnih koeficijenata korelacije, pokazuje povećanje u vremenu u
longitudinalnim studijama. (2) Koeficijenti konkurentne valjanosti Hamiltonove skale za
procenu depresivnosti i Montgomeri-Ašbergove skale za procenu depresivnosti iskazani
u vidu koeficijenata korelacija, kao i koeficijenti korelacije sa Bekovom skalom za
procenu depresivnosti pokazuju trend povećanja u longitudinalnim studijama. Njihove
vrednosti su za oko trećinu veće na kraju studija u odnosu na početak. Iz navedenog se
može zaključiti da je mali broj publikovanih podataka u ovom tipu istraživanja glavna
prepreka za dostizanje opšteg zaključka o promenama pouzdanosti i valjanosti
psihijatrijskih skala u vremenu u longitudinalnim studijama. | Introduction: Rating scales in psychiatry make it possible to detect the presence or lack
of symptoms of the psychiatric disorders, to express the intensity of symptoms in numbers
and to use it for clinical or research purposes. Thus, an important aspect of these scales
are their metric characteristics, their measurement adequacy what includes reliability and
validity. While reliability indicates the extent to which the method of measurement (test)
behaves consistently and steadily, the validity is the ratio between what the instrument
(test) is supposed to measure and what it really measures. There are three standard ways
of evaluating reliability: internal consistency reliability, inter-rater reliability and test-
retest reliability. Three main types of validity are content validity, construct validity and
criterion-related validity. Commonly reliability and validity are evaluated by using one
of the coefficients in the cross-sectional studies, usually once. In longitudinal studies,
variability which is a consequence of interindividual differences is eliminated and thus
the chance of spotting significant difference in factor levels is increased. By repeated
assessments of reliability and validity information on score stability over time will be
obtained, and consequently the reliability and validity of the scores obtained by used
scales.
Aims of study: The aims of this study were to: (1) Conduct a systematic review and meta-
analysis of the reliability and validity scores of psychiatric scales used in longitudinal
studies at different points in time. (2) Evaluate changes in the reliability and validity
scores in longitudinal studies at different points in time. (3) Generate
moderators/predictors of mentioned scores and their changes.
Material and methods: The aim of research was carried out through case study of
systematic review and meta-analysis of the reliability and validity of Hamilton
Depression Rating Scale (HAMD) and Montgomery-Asberg Depression Rating Scale
(MADRS). These two rating scales were chosen because they are the psychiatric
instruments most widely used by the assessors. The units of analysis were an individual
studies (published papers) obtained by systematic review of the literature in order to
identify published research in which the assessment of the reliability and/or validity of
HAMD and MADRS rating scales is reported. Literature search was performed in two
stages. In Stage I, we searched two bibliographic (index-abstract) databases: MEDLINE
and PsycINFO. Period covered by search extends from the beginning of implementation
of HAMD (1960) and MADRS (1979) rating scales to the end of the year 2013. By
searching databases containing the entire text of published studies in electronic format
(HINARI, EBSCO, ProQuest and Science Direct) additional studies for HAMD and
MADRS rating scales have been identified and located. After results were pooled, false
positive records were removed and duplicates resolved. The total number of collected
articles in full text was 6590 for HAMD rating scale and 2051 for HAMD rating scale.
In Stage II, pooled full-text papers were searched for reliability and validity scores.
Primary studies were reviewed independently by two researchers who extracted
information related to the assessment of the reliability and validity of HAMD and
MADRS rating scales in pre-prepared form, as well as data that can potentially be used
in the analysis of moderator variables. A systematic review and meta-analysis was
performed for all ratings of reliability and validity reported in two time points in
longitudinal studies. Effect sizes of reliability scores and correlation coefficients between
scales was their z-transformed value. In order to detect potential moderator variables
meta-regression was applied. Relationship between changes in coefficients of reliability
and concurrent validity in time with potential predictors were modelled using robust
variance meta-regression, while the pooled coefficients of reliability and concurrent
validity in individual points of time were obtained by the inverse variance meta-analytic
method.
Results: Out of 6590 collected and reviewed studies for HAMD rating scale 98 (1.5%)
were identified as studies in which data on reliability and validity were given. At the same
time out of 2051 collected and reviewed studies for MADRS rating scale 38 (1.9%) were
identified as studies in which data on reliability or validity were provided. Alpha
coefficient values for HAMD rating scale were higher at last evaluation in 22 out of 24
included studies. Significant changes in time of z-transformed alpha coefficient values
for HAMD rating scale (p<0.001) were found. Increase in the alpha coefficient value is
associated with a decrease in depression score and increase in its variability. Value of z-
transformed Loevinger coefficients for HAMD rating scale is increased in time and the
increase is statistically significant (p=0.002). Changes in z-transformed alpha and
Loevinger coefficients values in time for MADRS rating scale were not statistically
significant, most probably due to small sample size. Increase of z-transformed values of
intraclass correlation coefficient in time for HAMD rating scale is statistically significant
(p=0.025). In comparison to initial measurements, values of intraclass correlation
coefficient for MADRS rating scale are higher at last evaluation. In comparison to initial
measurements, values of z-transformed coefficient for test-retest reliability for HAMD
rating scale are higher at last evaluation. Correlation coefficients between depression
scales increase over time in 52 out of 61 studies included in meta-analysis. Statistically
significant changes in correlation coefficients are found between HAMD and BDI rating
scales (p<0.001), and between HAMD and MADRS rating scales (p<0.001). Increase in
correlation between rating scales is associated with a decrease in depression score and
increase in its variability. Due to small sample size conclusion on changes of diagnostic
and factorial validity for both HAMD and MADRS rating scales could not be drawn.
Conclusions: Conclusions related to meta-analytic method in assessment of changes in
reliability and validity of psychiatric rating scales over time are: (1) Existing meta-
analytic methods can adequately be used in assessment of reliability and validity
indicators of psychiatric instruments in longitudinal studies. (2) Meta-analysis evaluation
of reliability and validity in longitudinal studies provides fair basis for creation of
recommendation on their acceptable value which are specific for instrument/field and
time of their implementation. (3) Low frequency of reporting data on reliability and
validity of applied psychiatric instruments is a major problem for the effective use of
meta-analytic methods in the study of changes in measurement adequacy in longitudinal
studies. Conclusions related to meta-analysis of changes in reliability and validity
assessments for Hamilton rating scale for depression and Montgomery-Asberg depression
rating scale: (1) The reliability of the Hamilton rating scale for depression, internal
consistency, expressed as Cronbach's alpha coefficients and Loevinger coefficients as
well as and inter-rater reliability, expressed as intraclass correlation coefficients, indicates
an increase over time in longitudinal studies. (2) Concurrent validity coefficients for
Hamilton rating scale for depression and Montgomery-Asberg depression rating scale
expressed as correlation coefficients, as well as correlation coefficients with Beck
depression inventory show rising trend in longitudinal studies. Their values are about a
third higher at the end of the study compared to beginning. From the above mentioned it
can be concluded that the small number of published data in this type of research is the
main obstacle in reaching a general conclusion about the changes in the reliability and
validity of psychiatric rating scales over time in longitudinal studies. | true |
Limfadenektomija kod karcinoma hipofarinksa - korelacija mikrometastatskog širenja sa prediktivnim molekularnim faktorima terapijskog odgovora | Lymphadenectomy in hypopharyngeal cancer % correlation of micrometastatic spread with predictive molecular markers of therapeutic response | Uvod: Skvamocelularni karcinom hipofarinksa (SKH) predstavlja jednu od najagresivnijih neoplazmi glave i vrata. Petogodišnje preţivljavanje kod ovog oboljenja u većini studija je ispod 30%. Zahvaćenost limfnih ţlezda prepoznata je kao nabitniji prognostiĉki faktor za SKH. Hirurško leĉenje SKH stoga treba orijentisati prema odstranjenju primarnog tumora, ali i adekvatnoj limfonodalnoj disekciji, ĉime bi se postigao potencijalni kurativni efekat, ali i odredio taĉan stadijum i prognoza oboljenja. Uniformno radikalno operisana grupa bolesnika i veliki broj odstranjenih limfnih nodusa omogućio nam je adekvatno odreĊivanje distribucije limfonodalnih metastaza, procene N stadijuma bolesti, ali i dodatnu imunohistohemijsku analizu na prisustvo mikrometastaza u odstranjenim limfnim nodusima. Dodatnim ispitivanjem pokušali smo da ustanovimo korelaciju ekspresije molekularnih markera p53 i EGFR sa preţivljavanjem, i stadijumom bolesti odraţenim prevashodno kroz N stadijum bolesti. Metodologija: U studiju je ukljuĉeno ukupno 55 bolesnika kod kojih je naĉinjena faringolaringoezofagektomija sa funkcionalnom disekcijom vrata i rekonstrukcija visceralnim transplantatom. Disekcija obe strane vrata je uĉinjena primenom lateralne selektivne disekcije koja je obuhvatala uklanjanje limfnih nodusa iz nivoa II, III, IV i VI . Prilikom patohistološke obrade preparata posebna paţnja je obraćena na sledeće parametre:1. Primarna lokalizacija tumora (mukozna distribucija i dubina infiltracije, diferencijacija, invazija vaskularnih, limfatiĉnih i neuralnih elemenata), 2. Nodalni status (ukupan broj odstranjenih nodusa, ukupan broj pozitivnih nodusa, prisustvo ektrakapsularnog rasta, veliĉina nodusa). Dodatnom imunohistohemijskom analizom ispitivani su limfni nodusi na prisustvo mikrometastaza i izolovanih tumorskih ćelija, odnosno uĉinjena je semikvantitativna procena ekspresija ispitivanih 6 markera (p53 i EGFR). Statistiĉkim analizama naĉinjena je korelacija gore navedenih parametara sa ukupnim preţivljavanjem i kliniĉkim ishodom pri završetku studije... | Introduction: Hypopharyngeal squamocellular carcinoma (HSCC) represents one of the most aggressive neoplastic diseases of head and neck. Most of the studies reports 5 year survival rate to be below 30%. Lymph node involvement in HSCC has been recognized as the most important prognostic factor. Surgical treatment of HSCC therefore should be oriented towards removal of the primary tumor, together with the adequate lymhonodal dissection, by which one accomplishes curative intent, both with the proper definite disease staging and prognosis. Uniformly radically operated group of patients and a large number of dissected lymph nodes provided us with a possibility of accurate estimation of lymph node distribution, accurate N staging and also allowed us additional immunohistochemical analyzes for presence of micrometastases in lymph nodes. With further investigation we will try to estimate the correlation between molecular expression of p53 and EGFR with the overall survival, and the disease stage. Methodology: Overall, in this study we included 55 patients in whom pharyngolaryngoesophagectomy with selective lymph node dissection and reconstruction with the visceral substituent was performed. We performed bilateral selective lymph node dissection, which included levels II, III, IV and VI. During the pathohistologic work up special emphasis was given upon: 1. primary tumor (mucosal distribution and the depth of infiltration, differentiation and invasion of vascular, lymphatic and neural elements), 2. nodal status (overall number of harvested lymh nodes, overall number of positive lymph nodes, size and presence of extracapsular growth). Immunohistochemistry was performed in order to determine presence of micrometastases and isolated tumor cels (ITC) in lymph nodes, and also to determine the expression of p53 and EGFR. Statistical analyzes were performed with the intent to determine the correlation of the aforementioned parameters with the overall survival rate. Results: In this study there was no intrahospital mortality. Overall survival median was 18.00 months (11,89 - 24,11). 42 (76%) patients died and 13 (24%) was alive when we ended the study. Two year survival was marked in 27 patients (46.5%). N0 stage was present in 17 patients, 8 9 patients had N1 stage while N2 stage was present in 30 patients... | false |
Kliničke karakteristike, dugoročna prognoza i funkcionalni ishod kod obolelih od neuroinvanzivnog oblika Groznice Zapadnog Nila | Clinical characteristics, long-term prognosis and functional outcome in patients with West Nile virus neuroinvasive disease | Uvod: Virus Zapadnog Nila (engl. West Nile virus - WNV) je neurotropni
arbovirus, čija se cirkulacija u prirodi održava uspostavljanjem enzootskog
ciklusa između komaraca i ptica a čovek predstavlja zadesnog, terminalnog
domaćina infekcije. WNV je prvi put identifikovan u oblasti West Nile u
Ugandi, 1937. godine, a povoljna ekološka situacija u oblasti Mediterana i
Balkana dovodi do širenja WNV u ovu oblast i pojave epidemija u Italiji 2008-
2009, Grčkoj i Rumuniji 2010, Grčkoj i Italiji 2011, Srbiji i Hrvatskoj 2012. godine.
Do simptomatske WNV infekcije dolazi kod oko 20% inficiranih osoba, a kod
manje od 1% inficiranih dolazi do pojave neuroinvazivnog oblika WNF (engl.
West Nile virus neuroinvasive disease-WNND). WNND se klinički najčešće
manifestuje kao meningitis (engl. West Nile meningitis- WNM), encefalitis
(engl. West Nile encephalitis- WNE) i/ili akutna flakcidna slabost (engl. Acute
flaccid paralysis – AFP). Serološke analize krvi i CST (engl. enzyme-linked
immunosorbent assay - ELISA test) predstavljaju zlatni standard u dijagnostici
humane WNV infekcije. U ovom trenutku ne postoji zvanično prihvaćena
vakcina niti terapija specifična za humanu WNV infekciju. Najveći procenat
smrtnih ishoda povezan sa WNV infekcijom u vezi je sa WNND, a veći
mortalitet se uočava kod bolesnika sa encefalitisom (oko 20%) i sa AFP (10-50%)
nego kod bolesnika sa meningitisom (1%). Perzistirajuće neurološke sekvele i
nepotpun funkcionalni oporavak mogu se održavati mesecima i godinama
posle WNND, a kod ovih bolesnika česti su simptomi poput malaksalosti,
mišićne slabosti, glavobolje, otežanog pamćenja i depresije.
Cilj: Utvrditi faktore povezane sa razvojem encefalitisa kao teške kliničke forme
WNND, faktore povezane sa nepovoljnom kratkoročnom i dugoročnom
prognozom i funkcionalnim ishodom i ispitati prediktivni značaj navedenih
faktora.
Materijal i metode: U ispitivanje su uključeni bolesnici koji su lečeni u Klinici
za infektivne i tropske bolesti Kliničkog Centra Srbije u Beogradu, tokom 2012. i
2013. godine i koji su ispunjavali kliničke i laboratorijske kriterijume za
dijagnozu WNND. Na osnovu kliničke forme WNND, bolesnici su podeljeni u
kategoriju sa meningitisom i kategoriju sa encefalitisom. Bolesnici sa
meningitisom i encefalitisom svrstavani su u kategoriju bolesnika sa
encefalitisom. Bolesnici sa znacima AFP udružene sa meningitisom ili
encefalitisom svrstavani su u jednu od te dve kategorije. Kratkoročnom
prognozom se označavao ishod na kraju hospitalizacije, na osnovu kog su
bolesnici podeljeni u dve kategorije: preživeli i umrli. Dugoročnom prognozom
podrazumevala se prognoza bolesnika sa WNND godinu dana po otpustu iz
bolnice i funkcionalni ishod je procenjen uz pomoć modifikovane Rankin Skale
(mRS) i Barthel indeksa, a povoljnim funkcionalnim ishodom smatrao se
potpuni oporavak.
Rezultati: Kriterijume za uključivanje u istraživanje ispunilo je 207 bolesnika.
Prosečna starost obolelih od WNND bila je 64.9 godina, a 72% obolelih bilo je
uzrasta 60 i više (≥60) godina. Uzrast ≥60 godina registrovan je kod 129 (80.1%)
bolesnika sa encefalitisom i 20 bolesnika (43.4%) sa meningitisom (p<0.001).
Odmakla životna dob (uzrast ≥60 godina) u univarijantnoj analizi predstavljala
je faktor povezan sa nepovoljnom kratkoročnom prognozom WNND (p=0.002).
Uzrast ≥60 godina je bio povezan i sa nepovoljnom dugoročnom prognozom i
funkcionalnim ishodom (p<0.001). Faktor rizika statistički značajno povezan sa
razvojem encefalitisa bila je arterijska hipertenzija (p=0.001). Odsustvo
hroničnih bolesti kod obolelih od WNND bio je faktor povezan sa manjim
rizikom od razvoja encefalitisa (p<0.001). Arterijska hipertenzija, hronična
bubrežna insuficijencija i cerebrovaskularno oboljenje predstavljali su faktore
povezane sa nepovoljnom kratkoročnom prognozom, a arterijska hipertenzija,
koronarna bolest i imunosupresija faktore povezane sa nepovoljnom
dugoročnom prognozom i funkcionalnim ishodom WNND. Odsustvo
hroničnih bolesti je bio faktor povezan sa povoljnijom i kratkoročnom i
dugoročnom prognozom. Prosečna vrednost serumskog CRP bila je značajno
veća kod bolesnika sa encefalitisom (50.7±4.9 mg/L) nego kod bolesnika sa
meningitisom (25.2±4.7 mg/L) (p=0.001), vrednosti CRP>100 mg/L bile su
prediktor smrtnog ishoda (OR 12.07; 95% CI 2.43-60.02). Na osnovu analize
cerebrospinalne tečnosti obolelih od WNND, registrovane su prosečne
vrednosti leukocita od 146/mm3, sa blagom predominacijom limfocita (52%),
prosečnom proteinorahijom 1.04g/L i glikorahijom 4.0 mmol/L. Prosečna
vrednost proteinorahije kod bolesnika sa encefalitisom (1.1±0.53 g/L) bila je
značajno veća nego kod bolesnika sa meningitisom (0.86±0.48 g/L) (p=0.015), a
proteinorahija >1g/L bila je nezavisni prediktor smrtnog ishoda (OR 7.21; 95%
CI 1.56-33.8). Nuklearna magnetna rezonanca endokranijuma kod 6 bolesnika
sa encefalitisom ukazala je na hiperintenzne T2W/FLAIR lezije u regijama
tipičnim za WNND. Najteža komplikacija 15.5% kod bolesnika sa WNND bila
je respiratorna insuficijencija sa potrebom mehaničkom ventilacionom
potporom. Kod 161 bolesnika (78%) je registrovan encefalitis, a 46 bolesnika
(22%) imalo je meningitis. AFP je registrovana kod 30 obolelih od WNND
(14.5%) i kod svih je bila udružena sa encefalitisom, a prisustvo AFP je bilo
povezano sa produženom hospitalizacijom i primenom mehaničke ventilacije.
Klinički znaci rombencefalitisa registrovani su kod 84 bolesnika (40.6%). Svih 33
bolesnika (15.9%) sa smrtnim ishodom imalo je encefalitis. Potpuni funkcionalni
oporavak posle godinu dana od otpusta zabeležen je kod 33/39 (84.6%)
bolesnika sa meningitisom i kod 33/117 (28.2%) bolesnika sa encefalitisom
(p<0.001).
Zaključak: WNND je sezonsko oboljenje koje je u Srbiji uzrokovano linijom 2
WNV, najčešće se javlja u Beogradskom okrugu u letnjem periodu, prenosi se
ubodom komaraca, a boravak pored reke je najčešći rizik. Razvoj WNND je
najčešći kod muškaraca uzrasta ≥ 60 godina, obolelih od arterijske hipertenzije,
diabetes mellitusa ili koronarne bolesti. Uzrast ≥ 60 godina kod obolelih od
WNND povezan je razvojem encefalitisa, nepovoljnom kratkoročnom i
dugoročnom prognozom i funkcionalnim ishodom. Arterijska hipertenzija
predstavlja faktor povezan sa razvoj WNE, a arterijska hipertenzija, hronična
bubrežna insuficijencija i prethodno cerebrovakularno oboljenje predstavljaju
faktore povezane sa smrtnim ishodom. Arterijska hipertenzija, koronarna bolest
i imunosupresija su komorbiditeti povezani sa nepovoljnom dugoročnom
prognozom i funkcionalnim ishodom, dok je odsustvo hroničnih bolesti faktor
povezan sa povoljnom dugoročnom prognozom i funkcionalnim ishodom.
WNM se češće javlja kod mlađih bolesnika bez hroničnih bolesti, a karakterišu
ga povoljna kratkoročna prognoza bez registrovanih smrtnih ishoda, povoljna
dugoročna prognoza i uglavnom potpuni oporavak. Bolesnici sa WNE imaju
nepovoljnu kratkoročnu i dugoročnu prognozu, sa potpunim oporavkom kod
trećine obolelih. Razvoj encefalitisa predstavlja prediktor nepovoljne dugoročne
prognoze. AFP kod obolelih od WNND je povezana sa dugotrajnom
hospitalizacijom, respiratornom insuficijencijom, većom učestalošću smrtnog
ishoda i nepovoljnom dugoročnom prognozom. Rombencefalitis je česta
klinička forma kod obolelih od WNND u Srbiji, koji je povezan sa povoljnom
kratkoročnom prognozom (izuzev obolelih sa encefalitisom moždanog stabla),
ali i sa nepovoljnom dugoročnom prognozom i svega trećinom bolesnika sa
potpunim oporavkom. | Introduction: West Nile virus (WNV) is neurotropic arbovirus, which is
maintained in nature by enzootic cycle between mosquitoes and birds. Humans
are involved in this cycle as an inccidental dead-end hosts. WNV was first
identified in West Nile district in Uganda in 1937. Favored by the changes in
ecologic situation, WNV emerged in Mediterranean and Balkan region and
caused outbreaks in Italy in 2008-2009, Greece and Romania 2010, Greece and
Italy 2011, Serbia and Croatia 2012. WNV infection is symptomatic in
approximately 20% of those infected and less than 1% infected develops West
Nile virus neuroinvasive disease (WNND). WNND is usually manifested as
meningitis (WNM), encephalitis (WNE) and/or acute flaccid paralysis (AFP).
Enzyme-linked immunosorbent assay (ELISA) of blood and cerebrospinal fluid
remains the gold standard in diagnostics of WNV infection. There is no
registered vaccine or WNV specific therapy so far. Mortality from WNV
infection is mostly associated with WNND, and fatality rate is bigger in WNE
(20%) and AFP (10-50%) than in WNM (1%) cases. Persistent neurologic
sequelae and incomplete functional recovery could be present months and
years after the initial episode of WNND, and malaise, muscle weakness,
headache, memory loss and depression are common symptoms.
Aim: To discover factors associated with encephalitis as the most severe form of
WNND, factors associated with unfavorable short-term and long-term
prognosis and functional outcome; to investigate predictive significance of
these factors.
Methods: All the patients treated during 2012. and 2013. at Clinic for Infectious
and Tropical Diseases, Clinical Center of Serbia, Belgrade, who met the clinical
and laboratory criteria for WNND were included. Patients were divided in two
categories based upon the clinical form of WNND: patients with meningitis and
patients with encephalitis. Patients with meningoencephalitis were classified in
the encephalitis group. Patients with AFP associated with meningitis or
encephalitis were classified in one of those groups. Short–term prognosis was
considered as the outcome at discharge, and cases were categorized in two
groups: survived and dead. Long-term prognosis was considered as the
functional outcome one year after the discharge, and it was estimated using
modified Rankin Scale (mRS) and Barthel index. Complete recovery was
considered as a favorable long-term functional outcome.
Results: Entry criteria were met by 207 patients. Mean age of WNND cases was
64.9, and 72% were 60 years and above (≥60). Age ≥60 was registered in 129
(80.1%) patients with WNE and 20 patients (43.4%) with WNM (p<0.001).
Advanced age was the factor associated with unfavorable short-term prognosis
using the univariate analysis (p=0.002). Age ≥60 was also associated with
unfavorable long-term prognosis and functional outcome (p<0.001). Arterial
hypertension was found to be the risk factor associated with encephalitis
development (p=0.001). Lack of chronic illness in patients with WNND was
found to be the factor associated with lower risk of encephalitis development
(p<0.001). Arterial hypertension, chronic renal insufficiency and history of
cerebrovascular disease were stongly associated with death, and arterial
hypertension, coronary disease and immunosuppression were stongly
associated with unfavorable long-term prognosis and functional outcome. Lack
of chronic illness was found to be associated with favorable short-term and
long-term prognosis. Mean value of serum CRP was significantly higher in
WNE patients (50.7±4.9 mg/L) than in those with WNM (25.2±4.7 mg/L)
(p=0.001) and value of CRP>100 mg/L was the predictor of fatal outcome (OR
12.07; 95% CI 2.43-60.02). WNND patients cerebrospinal fluid analysis revealed
the mean pleocytosis of 146/mm3, with mild lymphocytic predomination (52%),
mean proteinorrhachia of 1.04g/L and glycorrhachia of 4.0 mmol/L. Mean
proteinorrhachia in WNE patients (1.1±0.53 g/L) was significantly higher than
in WNM (0.86±0.48 g/L) (p=0.015), and proteinorrhachia >1g/L was found to
be the independent predictor of fatal outcome (OR 7.21; 95% CI 1.56-33.8). Brain
nuclear magnetic resonance revealed hyperintense T2W/FLAIR lesions in
typical areas in 6 patients with WNE. Respiratory failure was the most severe
complication which was registered in 15.5% of patients with WNND. WNE was
registered in 161 patients (78%) and 46 (22%) patients had WNM. AFP was
registered in 30 patients with WNE and the presence of AFP was associated
with prolonged hospitalization and mechanical ventilation. Clinical signs of
rhombencephalitis were registered in 84 patients (40.6%). All 33 patients (15.9%)
with fatal outcome had encephalitis. Complete functional recovery one year
after discharge was registered in 84.6% of WNM patients and 28.2% of WNE
patients (p<0.001).
Conclusion: WNND is a seasonal disease which is caused by lineage 2 WNV in
Serbia, and it is most commonly present in Belgrade district during summer.
WNV is transmitted by mosquitoes and the time spent near the river banks is
the most frequent risk. WNND is more frequent in men ≥ 60 years with arterial
hypertension, diabetes mellitus or coronary disease. Age ≥ 60 among patients
with WNND is associated with more frequent encephalitis development,
unfavorable short-term and long-term prognosis and functional outcome.
Arterial hypertension is the risk factor for WNE, and arterial hypertension,
chronic renal insufficiency and history of cerebrovascular disease are factors
associated with fatal outcome. Arterial hypertension, coronary disease and
immunosuppression are comorbidities associated with unfavorable long-term
prognosis and functional outcome, while the lack of chronic illness is associated
with higher chances for complete recovery. WNM is more common among
younger patients without chronic illnesses, and it is characterized by favorable
short-term prognosis without fatal outcomes and favorable long-term prognosis
with complete recovery in the majority of cases. WNE is the most common form
of WNND and it is associated with unfavorable short-term and long-term
outcome and complete recovery in only third of all cases. WNE development is
the independent predictor of bad long-term prognosis. The presence of AFP
among patients with WNND is associated with prolonged hospitalization,
higher fatality rate, respiratory failure and unfavorable long-term prognosis.
Rhombencephalitis is frequent form of WNND in Serbia and it is associated
with favorable short-term prognosis (with the exception of brainstem
encephalitis) but unfavorable long-term prognosis. | true |
Efekti redukcije telesne mase na promene androgenog statusa, metaboličkog i opstruktivnog apneja sindroma u izrazito gojaznih muškaraca | Effects of weight loss on androgen status, metabolic and obstructive sleep apnea syndrome in severely obese men | Uvod: Prevalencija gojaznosti se dramatično povećava poslednjih 30 godina, kako u
razvijenim zemljama, tako i u zemljama u razvoju. Novije studije sve više ukazuju da je u
gojaznih muškaraca snižen ne samo ukupni (T), nego i slobodni testosteron (FT)
proporcionalno stepenu gojaznosti. Poslednjih godina sve više naučne pažnje se
posvećuje interakciji hipogonadizma, gojaznosti, metaboličkog sindroma (MetS),
insulinske rezistencije i diabetes mellitus-a tip 2 u muškaraca. Danas se sve više govori o
opstruktivnom apneja sindromu (OSAS), kao jednom od razloga snižene koncentracije
testosterona u gojaznih muškaraca. Redukcija telesne mase (TT) je zajednički imenitelj
terapije hipoandrogenizma, MetS, insulinske rezistencije i OSAS u gojaznih muškaraca.
Cilj ove doktorske disertacije je bio ispitivanje povezanosti koncentracije testosterona u
serumu, MetS, insulinske rezistencije i OSAS, kao i ispitivanje uticaja redukcije telesne
mase higijensko dijetetskim režimom na koncentraciju testosterona u serumu, MetS,
insulinsku rezistenciju i OSAS u uzorku izrazito gojaznih muškaraca.
Materijal i metode: U prospektivnu eksperimentalnu studiju sprovedenu na Klinici za
endokrinologiju, dijabetes i bolesti metabolizma, KCS su bili uključeni izrazito gojazni
muškaraci, indeksa telesne mase (BMI)≥35kg/m2 i starosti između 20 i 60godina. U
terapijski program koji se sastojao od naizmenične veoma nisko kalorijske dijete (VLCD)
u bolničkim uslovima i nisko kalorijske dijete (LCD) uz doziranu svakodnevnu fizičku
aktivnost u vanbolničkim uslovima su učestvovala 82 izrazito gojazna muškarca. Na
prijemu su mereni antropometrijski parametri, krvni pritisak, koncentracija lipida i polnih
hormona. Rađen je test oralnog opterećenja glukozom u cilju izračunavanja insulinske
rezistencije i insulinske senzitivnosti. Svim ispitanicima je rađena polisomnografija.
Uslov za ponovno testiranje po istom protokolu je bila redukcija TT za najmanje 10% u
odnosu na početnu.
Rezultati: U ispitivanoj populaciji, analizirani komorbiditeti gojaznosti su imali sledeće
procentualne učestalosti: OSAS-95.12%, MetS-75.61%, diabetes mellitus tip 2-23.2%.
Sniženu koncentraciju ukupnog testosterona je imalo 40.24% muškaraca, a sniženu
koncentraciju slobodnog testosterona 12.2% ispitanika. Utvrđena je značajna povezanost
abdominalne gojaznosti sa izraženošću MetS (p=0.01), težinom OSAS (p<0.001),
koncentracijom T (p<0.001), kao i sa koncentracijom FT (p=0.001). Gojaznost i starost,
nisu uticali na povezanost krvnog pritiska (za razliku od drugih parametara MetS) sa
nekim od parametara OSAS (p<0.05). Na povezanost koncentracije T sa koncentracijom
triglicerida u krvi, kao i sa vrednošću dijastolnog krvnog pritiska, nisu imali uticaj
gojaznost i godine izrazito gojaznih muškaraca (p<0.05). Linearnom regresionom
analizom smo pokazali da su Apneja hipopneja indeks (AHI) i obim struka osnovni
prediktori varijabiliteta koncentracije ukupnog testosterona (p<0.05), a da su AHI i
godine osnovni prediktori varijabiliteta koncentracije slobodnog testosterona (p<0.05) u
izrazito izrazito gojaznih muškaraca. AHI je nezavisni prediktor koncentracije ukupnog
testosterona (p=0.002) i slobodnog testosterona (p=0.019) u izrazito izrazito gojaznih
muškaraca. Pacijenti uključeni u istraživanje tokom tronedeljne VLCD nisu imali
značajne neželjene efekte. Zbog loše komplijanse, 29 izrazito gojaznih pacijenata nije
nastavilo učešće u studiji. Niko nije zbog neželjenih efekata isključen iz protokola. 53
pacijenta, starosti 43.74±11.20 godina, TT 143.32±19.33kg, BMI 45.75±5.38 kg/m2, su
nastavila sa redukcijom TT i u vanbolničkim uslovima, i time ispunili uslov za ponovnu
hospitalizaciju, retestiranje i nastavak lečenja. Smanjena je bila TT pacijenata u proseku
za 24.5kg, t.j. 18% (p<0.001), praćeno značajnim smanjenjem insulinske rezistencije
(p<0.001), učestalosti MetS kao celine (p<0.001), učestalosti svih parametara MetS
(p<0.01), kao i OSAS parametera (p<0.001). Navedeni program redukcije TT je imao za
rezultat značajno povećanje koncentracije T (p<0.001) kao i FT (p<0.001) u izrazito
gojaznih muškaraca.
Zaključak: Ova studija je pokazala da je OSAS nezavisni prediktor koncentracije
ukupnog i slobodnog testosterona u izrazito izrazito gojaznih muškaraca. Redukcija
telesne mase značajno smanjuje hipoandrogenizam, MetS, insulinsku rezistenciju i OSAS
u izrazito gojaznih muškaraca. Kombinovana terapija koja se sastoji iz VLCD pod
medicinskim nadzorom i LCD sa balasiranom restrikcijom unosa hrane, promenom
načina života i povećanom svakodnevnom fizičkom aktivnošću bi bila jedna od
savetovanih opcija u lečenju komorbiditeta izrazito gojaznih muškaraca. | Introduction: Obesity has increased dramatically worldwide over the past 30 years, in
both developing and developed countries. Recent studies indicate that obese men have
not only low testosterone (T) but also low free testosterone (FT), in proportion to degree
of obesity. Many recent reviews pay attention to the link between hypogonadism, obesity,
metabolic syndrome (MetS), insuline resistance and type 2 diabetes in male. Obstructive
sleep apnea syndrome (OSAS) is emerging as new area of interest that can help to
explain low testosterone in obese male. The weight loss have been demonstrated to play a
cardinal role in significant improving not only testosterone concentration but also MetS,
insulin resistance and OSAS in obese men.
The aim of this doctoral dissertation was to analyze the relationship between MetS,
serum sex hormone concentrations, OSAS and to evaluate the influence of non-surgical
weight reduction on sex hormone levels, MetS and OSAS in severely obese men.
Material and methods: This was a prospective clinical study at the Clinic for
Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, which
included 20-60 year old severely obese men with Body Mass Index (BMI)≥35kg/m2.
Eighty-two extremely obese men, started the therapeutic program, which consisted of two
alternating phases: very low calorie diet (VLCD) in hospital conditions and the low
calorie diet (LCD) with dosed physical activity in outpatient conditions. Anthropometric
parameters, blood pressure, lipid profile and reproductive hormones were measured.
Subjects were underwent an oral glucose tolerance test and insulin resistance/sensitivity
was evaluated by the homeostasis model assessment and the oral glucose insulin
sensitivity. All patients were subjected to polysomnography. After weight reduction by at
least 10%, all mentioned assessments were repeated.
Results: The prevalence of obesity-related comorbidities in the study population was as
following: OSAS 95.12%, MetS 75.61%, type 2 diabetes 23.2%. Total testosterone was
subnormal in 40.24% and free testosterone in 12.2% of the subjects. There was
significant correlation between abdominal obesity and MetS score (p=0.01), severity of
OSAS (p<0.001), T levels (p<0.001), as well as FT levels (p=0.001). After correction for
BMI and age some sleep parameters only correlated with blood pressure (p<0.05) among
all MetS parameters. The correlation between T levels with triglyceride levels and with
diastolic blood pressure was independent of the age and BMI (p<0.05). A linear
regression model demonstrated Apnea Hypopnea Index (AHI) and waist circumference
as statistical significant predictors (p<0.05) of T level and AHI as well as age as
statistical significant predictors (p<0.05) of FT level. This study confirmed the
independent association of the AHI with FT (p=0.019) and T (p=0.002) after correction
for age and BMI. None of the patients included in the study during the VLCD had
significant adverse events. Twenty-nine of obese men abandoned further participation in
the study due to poor compliance. None is excluded due to side effects. Fifty-three men
aged 43.74±11.20 years, weighting 143.32±19.33kg and with BMI 45.75±5.38 kg/m2
completed the study. The mean weight loss was 24.5kg or 18% of the initial weight
(p<0.001), which was followed by a significant decrease of the insulin resistance
(p<0.001), the overall prevalence of MetS (p<0.001), all MetS (p<0.01), and OSAS
parameters (p<0.001). This weight loss program substantially improved T levels
(p<0.001) as well as FT levels (p<0.001) in extremely obese men.
Conclusion: This study shows that OSAS appears to be an independent predictor for low
testosterone levels in severely obese men. Our results demonstrates that weight loss is the
crucial determinant of the drastic improvement in MetS, insulin resistance, OSAS, total
testosterone levels as well as free testosterone levels in severely obese men. The program
consisting of the VLCD under a medical supervision which alternates with the prescribed
LCD and a gradual increase of physical activity in outpatient conditions should be
considered as a therapeutic option in the treatment of comorbidities of severely obese
men. | true |