Čimbenici angiogeneze u zdravih i dijabetičnih trudnica

Vaskularni endotelni čimbenik rasta (VEGF), placentni čimbenik rasta (PlGF), inzulinu sličan čimbenik rasta (IGF-II) i topljivi receptor VEGF-1 imaju neposredan utjecaj na rast i funkciju fetoplacentnih krvnih žila. Cilj istraživanja je bio odrediti koncentraciju posteljičnih čimbenika angiogeneze (VEGF, PlGF, IGF-II) i topljivog receptora VEGFR-1 ili sFlt-1 u zdravih trudnica i trudnica s dijabetesom tipa-1. Sudionice i način istraživanja. U istraživanje su uključene 42 trudnice s dijabetesom tipa-1 (DM-1) i 34 zdrave trudnice (kontrolna skupina). Iz uzoraka krvi tijekom trudnoće kao i pupčane vene neposredno nakon porođaja određivani su VEGF, PlGF, IGF-II i sVEGFR-1 (sFlt-1). Rezultati. Vrijednosti PlGF-a i sVEGFR-1 su tijekom trudnoće nešto više u trudnica s DM-1, ali nisu nađene značajne razlike. Omjeri sVEGFR-1/PlGF su niski tijekom trudnoće u obje istraživane skupine (kontrolna skupina 9,6 i DM-1 9,4 između 16–20 tjedna trudnoće, a između 32–36 tjedna trudnoće: kontrolna skupina 4,6 i DM-1 3,7). Razina PlGF-a u pupčanoj veni je niža (kontrolna skupina medijan 29,6, a DM-1 medijan 27,2) u odnosu na razinu PlGF seruma majke (kontrolna skupina medijan 122,3, a DM-1 medijan 141,5). Zaključak. Tijekom trudnoće dolazi do značajnog porasta PlGF-a i VEGFR-1 u obje istraživane skupine. Omjeri između sVEGFR-1/PlGF su u obje istraživane skupine tijekom trudnoće bili niski i nisu predskazivali razvoj preeklampsije i IUGR. Ni jedna trudnica nije razvila gestacijsku hipertenziju, a ni preeklampsiju

Utjecaj čimbenika angiogeneze na razvoj posteljice

U ovom preglednom članku detaljno je opisan utjecaj angiogenih i antiangiogenih čimbenika na razvoj posteljice. Razvoj posteljice u prvom tromjesečju trudnoće jedan je od glavnih činitelja o kojima ovisi daljnji tijek i ishod trudnoće. Čimbenici rasta endotela krvnih žila (VEGF) i rasta placente (PlGF) su ključni čimbenici i u fiziološkim i patološkim uvjetima. VEGF i PlGF ispoljavaju svoje djelovanje preko svojih receptora (tirozin kinaze) VEGFR-1 (Flt-1) i VEGFR-2 (KDR) koji se nalaze u endotelnim stanicama. Kisik je glavni regulator ravnoteže VEGF i PlGF. Hipoksija smanjuje djelovanje PlGF, a hiperoksija povećava. Topljivi VEGFR-1 (Flt-1) je povišen u trudnice koja će razviti preeklampsiju. Uspješna placentacija dovodi do niskog otpora krvnih žila zbog transformacije spiralnih arterija

DIGOXIN I AMIODARON KOD TRAJNE FETALNE SUPRAVENTRIKULARNE TAHIKARDIJE I NEIMUNOLOŠKOG FETALNOG HIDROPSA

Supraventricular tachycardia is the most common and clinically significant form of sustained fetal tachyarrhythmia in pregnancy; depending on duration and high rate variability heart failure and nonimmune hydrops may develop which are associated with a high incidence of perinatal mortality. Doppler/echo diagnosis is usually accidental during second and third trimester of pregnancy. Therapeutic goals are cardioconversion to sinus rhythm and recovery of heart failure. We present a case of fetal supraventricualr tachycardia diagnosed at 29 weeks of gestation with nonimmune hydrops. Treatment with digoxin and amiodarone was successful. The heart rate restored to sinus rhythm and nonimmune hydrops resolved within three weeks of treatment. Therapy with two drugs that act synergistically may be more efficient than monotherapy in blocking likely atrio-ventricular reentry mechanism by accessory pathway in sustained supraventricular tachycardia, thus allowing resolution of hydrops with favorable management outcome.Supraventrikularna tahikardija je najčešći i klinički najznačajniji oblik fetalne tahiaritmije u trudnoći, a ovisno o trajanju i visini srčane aktivnosti mogu se razviti zatajenje srca i neimuni fetalni hidrops, oboje povezani s lošim perinatalnim ishodom. Tijekom drugog i trećeg tromjesečja dijagnoza se često slučajno postavlja ultrazvučnim doplerskim nalazom. Terapijski cilj je konverzija u sinus ritam i oporavak srčane funkcije. Donosimo prikaz slučaja fetalne supraventrikularne tahikardije s neimunim hidropsom, dijagnosticirane u 29. tjednu trudnoće. Terapija digoksinom i amiodaronom bila je uspješna. Ponovo je uspostavljen sinusni ritam srčane frekvencije, a neimuni hidrops se povukao unutar tri tjedna liječenja. Terapija dvama lijekovima sa sinergističkim djelovanjem može biti učinkovitija od monoterapije u blokiranju vjerojatno ponovnog ulaska atrio-ventrikularnog impulsa pomoću sporednog puta u supraventrikularnoj tahikardiji, time dopuštajući povlačenje hidropsa te bolji ishod

MULTI-MODAL ANALGESIA AFTER HYSTERECTOMY AND ADNEXECTOMY

Postoperativni bol je najčešći oblik akutnog bola, a nedovoljna analgezija može dovesti do niza komplikacija. Osnovni cilj našeg istraživanja bio je usporediti dvije metode analgezije multimodalnim pristupom i postići odgovarajući analgetski učinak primjenom obiju metoda. Analizirano je 50 slučajno odabranih bolesnica tijekom prvog operacijskog dana, nakon abdominalne histerektomije i adneksektomije. Prema Američkom društvu anesteziologa bolesnice su procijenjene na ASA status I-III. Kod prve skupine od 25 bolesnica, kontinuirano intravenski primijenjeni su metamizol i tramadol, a kod druge skupine od 25 bolesnica ketoprofen i tramadol. Razina boli u svih bolesnica praćena je u prvom, trećem, šestom i devetom postoperativnom satu i zabilježena u tablice pomoću vizualno analogne ljestvice (visual analogue scale – VAS). U obje skupine postignut je zadovoljavajući analgetski učinak. Bolesnice u drugoj skupini (s ketoprofenom) su ranije postigle granicu između umjerene i neznatne boli, te bi stoga, kao nesteroidni antiinflamatorni lijek prvog izbora preporučili ketoprofen kao dodatak tramadolu.Postoperative pain is the most common form of an acute pain and inadequate analgesia can lead to numerous complications. Our goal was to compare two different methods of analgesia by multimodal approach and to optimize pain control in both groups. During the first operative day, 50 randomly chosen patients undergoing abdominal hysterectomy with bilateral adnexectomy were analyzed. According to the American Society of Anesthesiologists (ASA) they were classified to Class I-III. In the first group of 25 patients, metamizol and tramadol were administered in continuous intravenous infusion and in the second group of 25 patients ketoprofen and tramadol were administered. Pain was registered during the first, third, sixth and ninth postoperative hour using visual analogue scale (VAS). In both groups the adequate level of analgesia was achieved, although the patients in the second group have reached moderate level of pain earlier than the second group did. Therefore, as the non-steriod antiiflammatory drug adjuvant to opioid drug we prefer ketoprofen to metamizole

PLACENTNI ČIMBENIK RASTA U MAJČINOJ I UMBILIKALNOJ KRVI TRUDNICA OBOLJELIH OD DIJABETESA TIPA-1 I ZDRAVIH TRUDNICA

Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are key factors in physiological and pathological conditions of pregnancy. We investigated whether serum levels of PlGF in mother’s and umbilical blood are different between healthy pregnant women and pregnant women suffering from type-1 diabetes mellitus. We performed a prospective study of 44 pregnant women with type 1 diabetes who did not have diabetic complications and of 34 healthy pregnant women of the adequate age and parity and the normal pregnancy course. Venous blood samples were collected from 8th weeks of pregnancy during the whole pregnancy, in distance from 4 weeks. Results are expressed as means±standard deviations. Statistical analysis was performed using ANOVA, Student t-test, linear regression, and non-parametrical Mann-Whitney U test. PlGF level in diabetic and healthy pregnant women from the 8th till the 15th week of pregnancy is comparatively low (23.16±4.94 pg/mL : 21.68 ±4.91 pg/mL), and after the 15th week of pregnancy it increases fast till the 31st week of pregnancy when the value is the highest (440.77±173.03 pg/ml : 390.41±138.07 pg/mL). After the 31st week of pregnancy there is a decrease of PlGF levels. Comparing PlGF values between the research groups in defined weeks of pregnancy no statistically significant difference was found. PlGF values in serum of healthy and diabetic pregnant women do not differ in same weeks of pregnancy. PlGF values in mother’s and fetal serum immediately after the birth are a bit lower (but not statistically significant) in diabetic pregnant women in relation to a control group. A statistically significant correlation coefficient was found between PlGF level and a newborns weight and between PlGF and placenta weight. A statistically significant correlation coefficient was found between PlGF level of mother’s blood and umbilical vein.Vaskularni endotelni čimbenik rasta (VEGF) i placentarni čimbenik rasta (PlGF) su ključni čimbenici u fiziološkim i patološkim trudnoćama. Cilj istraživanja je bio naći razliku razina PlGF-a u majčinoj i umbilikalnoj krvi između zdravih trudnica i onih koje boluju od dijabetsa tipa-1. Učinjeno je prospektivno istraživanje u 44 trudnice s dijabetesom tipa-1 i u 34 zdrave trudnice. Trudnice su bile istih dobnih skupina, pariteta i urednog tijeka trudnoće. Venska krv trudnica je skupljana od 8. tjedna trudnoće tijekom cijele trudnoće u vremenskim razmacima od 4 tjedna. Rezultati su prikazani srednjim vrijednostima ± standardne devijacije, a statistička analiza je učinjena sljedećim testovima: ANOVA, Student-t testom, linearnom regresijom i Mann-Whitneyevim U testom. Razina PlGF-a u dijabetičnih i zdravih trudnica je bila podjednako niska u vremenskom razdoblju od 8. do 15. tjedna trudnoće (23,16±4,94 pg/mL : 21,68±4,91 pg/mL), a nakon 15. tjedna dolazi do naglog povišenja razine sve do 31. tjedna trudnoće kada su vrijednosti bile i najviše (440,77±173,03 pg/ml : 390,41±138,07 pg/mL). Nakon 31. tjedna trudnoće dolazi do sniženja vrijednosti PlGF-a. Uspoređujući vrijednosti PlGF-a između istraživanih skupina u istim tjednima trudnoće nije nađena statistički znakovita razlika. Neposredno nakon poroda razina PlGF-a u majčinom i fetalnom serumu je bila nešto niža, ali ne i statistički znakovito niža u dijabetičnih trudnica u odnosu na zdrave trudnice. Nađene su statistički značajne korelacije između razina PlGF-a i porodne težine, između PlGF-a i težine placente i između razina PlGF-a seruma majke i seruma umbilikalne vene

PHARMACOLOGICAL COST-BENEFIT ANALYSIS OF VACCINATION OF ADOLESCENTS BY CERVARIX

Karcinom vrata maternice u svijetu je drugi po učestalosti u žena. U Hrvatskoj je na osmome mjestu zastupljenosti. Ova vrsta karcinoma je bolest mlađih žena. Cervikalne intraepitelijalne neoplazije i karcinom vrata maternice su povezani su s trajnom infekcijom visoko onkogenim sojevima HPV-a. Cijena liječenja bolesti ovisi o njenom stadiju. Cjepivo Cervarix, primijenjeno u još spolno neaktivnih djevojčica i djevojaka, je u multinacionalnim dvostruko slijepim randomiziranim studijama pokazalo svoju visoku učinkovitost u stvaranju cirkulirajućih protutijela u serumu te smanjenju prevalencije HPV infekcije, preinvazivnih lezija i karcinoma vrata maternice. Cjepivo Cervarix također smanjuje prevalenciju trajne infekcije HPV-om u spolno aktivnih žena. Korištenjem matematičkih modela, uz visoku učinkovitost cjepiva od 100%, predviđa se 60–75% smanjenje morbiditeta i mortaliteta od karcinoma vrata maternice. Analizom izravnih troškova liječenja karcinoma vrata maternice i neizravnih troškova te kvalitetom života i usporedbom s cijenom cijepljenja u Hrvatskoj bi se godišnje moglo uštedjeti oko 50 milijuna kuna.Cervical carcinoma is the second most fequent female carcinoma in the world. In Croatia it took the 8th place. Cervical intraepithelial neoplasms and cervical carcinoma are related to permanent infection caused by high oncogenic type of HPV. The cost of treatment and therapy depends on grade of disease. In multinational double blinded randomised studies Cervarix vaccine has demonstrated its high efficiency in production of circulating serum antibodies, and the decrement of prevalence of HPV infection, preinvasive lesions and cervical carcinoma when applied in sexually not active adolescents. Cervarix vaccine also decreases the prevalence of permanent infections caused by HPV in sexually active women. Using mathematical models and considering high vaccine efficiency, it is predicted decrease of morbidity and mortality due to cervical carcinoma by 60–75%. When direct and indirect costs of therapy of cervical carcinoma and life quality were compared to cost of vaccination by Cervarix, it could be saved more than 50 milions of kunas in Croatia annually

Čimbenici angiogeneze placente u zdravih i dijabetičnih trudnica

Diabetes is a syndrome which develops because of absolute or relative deficiency of insulin or because of its alternated way of acting, which results in a formation of hyperglycemia. Diabetes in pregnancy brings along numerous other problems for both a mother and a child. Diabetes includes hypoxia, hyperglycemia and may affect grow, preservation and function of fetoplacental blood vessels, angiogeneses. Any form of pathological changes of haemodinamic characteristics in mother, characteristics of maternal blood, and grow factors including: vascular endothelial grow factor VEGF, placental grow factor PlGF, insulin like grow factor IGF, free oxygen radicals, final products of glycolysation, cytokines and mediators of inflammation are known to damage function of endothelial barrier or have extreme angiogenic effect. Emphasis of this research is on the events which form fetoplacental vasculature, and the changes which result as a consequence of mothers diabetes mellitus (DM). Goal of this research is to determine levels of PlGF, VGEF and IGF-II in examined groups, to perform histopathological analysis of placental insertion and to compare it with PlGF values in complete, incomplete and absent transformation of blood vessels, to compare grow factors in a serum of a mother and umbilical serum, and to find a correlation between the weight of the placenta, newborn's weight and a level of individual grow factors. Materials and methods: this is a prospective study, which involves 42 pregnant women with a type 1 diabetes, while a control group consists of 34 healthy pregnant women. Blood samples were taken from pregnant women at regular examinations, in periods of 3 to 4 weeks during whole pregnancy, at the delivery and from the umbilical vein. From the serum VGEF, PlGF and IGF-2 were determined. Deliveries which were terminated with a C-section, a biopsy of placental bed was made and it was send for a histopathological examination. Type of the childbirth termination, newborn's weight, newborn's length, Apgar score, pH and acidobasic status from the umbilical vein were noted. Statistical analysis was performed with SPPS program. Results PlGF values progressively grow from the beginning of pregnancy up to the 31st week of pregnancy, when maximum values – level of PlGF were found between 27 -30 weeks of pregnancy. Values are not statistically significant in investigated groups. VEGF values during pregnancy are higher in pregnant women who suffered from diabetes then in healthy pregnant women, but statistically significant difference between investigated groups was found in a period of 27-31 weeks of pregnancy and immediately after the delivery. VEGFR-1 levels are higher in pregnant women with diabetes comparing to healthy pregnant women, but this was not found to be statistically significant. IGF values are higher in a group of pregnant women with diabetes comparing to healthy pregnant women, and they increase during pregnancy, but again this was not found to be statistically significant. General information, age of the pregnant woman, week when pregnancy was terminated, weight of the placenta, newborn's weight and Apgar score in investigated groups were found not to be of any statistical significance. PIGF levels show correlation in weeks of pregnancy, newborn's weight and weight of the placenta in pregnant women with diabetes and in healthy pregnant women. PlGF levels in umbilical vein are lower than PlGF levels from the mother's serum. Comparing values of the PlGF levels from the mother's serum and from the umbilical vein, a positive and statistically significant coefficient was obtained. A characteristic of the placental bed obtained from the pregnant women whose pregnancies were terminated by a C-section is that there were 17% of incomplete physiological changes. Characteristics of the placenta insertion, physiological changes comparing to the incomplete physiological changes are statistically significant comparing to the week of pregnancy was it was terminated, weight of the placenta and the newborn, PlGF levels in mother’s serum and from the umbilical vein. Conclusion: I must stress out great importance of regular monitoring of normoglycemia in pregnant women with diabetes, which results in minimal oscillations of hyperglycemia and hypoglycemia and by this in minimal oscillations of hypoxia, and a supervision of different pathological conditions in pregnancy, as well (hypertension etc.) which affect factors of placental angiogeneses, and by this prevalence of specific morphological appearance of the placenta in pregnant women with type 1 diabetes

Importance of macroprolactinemia in hyperprolactinemia

Macroprolactin is an antigen-antibody complex of higher molecular mass than prolactin (>150kDa), consisting of monomeric prolactin and immunoglobulin G. The term 'macroprolactinemia' is used when the concentration of macroprolactin exceeds 60% of the total serum prolactin concentration determined by polyethylene glycol precipitation. The gold standard technique for the diagnosis of macroprolactinemia is gel filtration chromatography. The prevalence of macroprolactinemia in hyperprolactinemic populations varies between 15% and 35%. Although the pathogenesis of these antibodies is not clear, it is possible that changes in the pituitary prolactin molecule represent increased antigenicity to the immune system, leading to the production of anti-prolactin antibodies. Mild hyperprolactinemia usually occurs because macroprolactin is not cleared readily from the circulation due to its higher molecular weight. Moreover, the hypothalamic negative feedback mechanism for autoantibody-bound prolactin is inactive because macroprolactin cannot access the hypothalamus, resulting in hyperprolactinemia. Reduced in-vivo bioactivity of macroprolactin may be the reason for the lack of hyperprolactinemic symptoms. It also seems that anti-prolactin autoantibodies may compete with prolactin molecules for receptor binding, resulting in low bioactivity. Additionally, the large molecular size of macroprolactin confined in the intravascular compartment prevents its passage through the capillary endothelium to the target cells, which may be the reason for the lack of symptoms. Macroprolactinemia is considered to be a benign clinical condition in patients with normal concentrations of bioactive monomeric prolactin, with a lack, or low incidence, of hyperprolactinemic symptoms and negative pituitary imaging. In such cases with resistance to anti-prolactinaemic drugs, no pharmacological treatment, diagnostic investigations or prolonged follow-up are required. However, macroprolactinemia may also occur in patients with conventional symptoms of hyperprolactinemia who cannot be differentiated from patients with true hyperprolactinemia. These symptoms are mainly attributed to excess levels of monomeric prolactin, and this is of concern. The diagnosis of macroprolactinemia is misleading and inappropriate. A multitude of physiological, pharmacological and pathological causes, including stress, prolactinomas, hypothyroidism, renal and hepatic failure, intercostal nerve stimulation and polycystic ovary disease, can contribute to increased levels of monomeric prolactin. It is important for patients with elevated monomeric prolactin levels to undergo routine evaluation to identify the exact pathological state and introduce adequate treatment, regardless of the presence of macroprolactin. In addition, macroprolactinemia occasionally occurs due to macroprolactin associated with pituitary adenomas, with biological activity of macroprolactin comparable with that of monomeric prolactin. In cases when excess macroprolactin occurs with clinical manifestations of hyperprolactinemia, macroprolactinemia should be regarded as a pathological biochemical variant of hyperprolactinemia. An individualized approach to the management of such patients with macroprolactinemia may be necessary, and pituitary imaging, dopamine treatment and prolonged follow-up should be applied