A szöveti hidráció szabályozásának experimentális vizsgálata - különös tekintettel a perinatális időszakra = Experimental studies on the regulation of tissue hydratation with particular reference to the perinatal period

1. A vízterek perinatális átrendeződésének új koncepcióját dolgoztuk ki. Újszülött nyulakban és foetusokban igazoltuk, hogy a különböző mobilitású szöveti vízfrakciók aránya az érés során sajátosan változnak. Igazoltuk, hogy a foetális/neonatális agy- és tüdőszövetben a fizikai vízterek átrendeződését anyai steroid, terbutalin és amilorid kezelése nem befolyásolja. 2. Humán anyagban 14-40 hetes gesztációs korú magzatokban vizsgáltuk az agyszövet-specifikus aquaporin-4 (AQP4) és aquaporin1 (AQP1) membrán-csatorna fehérjék expresszióját és leírtuk azok intracellularis elhelyezkedésének és mennyiségének semi-kvantitatív változásait. Felhívtuk a figyelmet az AQP-k élettani és klinikai jelentőségére az agy fiziológiás dehidrációjának folyamatában. 3. Kimutattuk, hogy az angiotenzin konvertáló enzim (ACE) DD genotipusa protektív hatással bír alacsony súlyú koraszülöttekben a keringési elégtelenség kialakulása szempontjából. 4. Kongentiális szívfejlődési rendellenességgel született újszülöttek vérmintáinak retrospektív analízisével megállapítottuk, hogy a vaszkuláris endotheliális növekedési faktor (VEGF) génpolymorfizmusa növeli a szívfejlődési rendellenességek kialakulásának kockázatát. 5. Megállapítottuk, hogy az éretlen vese beszűkült koncentrálóképessége az eddigi ismert mechanizmusok melett a vese papilla/medulla magas hialuronsav tartalmával magyarázható. A szöveti hialuronsav az ADH-mediálta ozmotikus vízmozgást gátolja. | 1. A new concept of perinatal redistribution of body fluid compartments has been developed. In fetal/neonatal rabbit pups we demonstrated marked changes in the various physical water compartments which remained unaffected by maternal administration of steroid, terbutaline and amiloride. 2. The developmental changes in aquaporin-1 (AQP1) and AQP4 were investigared in human brain tissue during the period of 14-40 weeks of gestation. We demonstrated the progressive increase of their expression and the pattern of their distribution as the gestation advances. Furthermore, the role of AQP-s in the physiological brain dehydration has been established. 3. Evidences have been provided to indicate the protective effects of ACE DD genotype on the development of circulatory failure in low-birthweight neonates. 4. We have shown that infants born with congenital cardiac malformation have polimorphism for the vascular endothelial growth factor. 5. Indirect evidences have been provided that in addition to the well-known factors, the limited capacity of immature kidney to concentrate urine can be attributed to the high hyaluronic acid content of the renal medulla/papilla since HA limits ADH-mediated osmotic water flo

Disparities and relative risk ratio of preterm birth in six Central and Eastern European centers

Aim To identify characteristic risk factors of preterm birth in Central and Eastern Europe and explore the differences from other developed countries. Method Data on 33 794 term and 3867 preterm births (<37 wks.) were extracted in a retrospective study between January 1, 2007 and December 31, 2009. The study took place in 6 centers in 5 countries: Czech Republic, Hungary (two centers), Romania, Slovakia, and Ukraine. Data on historical risk factors, pregnancy complications, and special testing were gathered. Preterm birth frequencies and relevant risk factors were analyzed using Statistical Analysis System (SAS) software. Results All the factors selected for study (history of smoking, diabetes, chronic hypertension, current diabetes, preeclampsia, progesterone use, current smoking, body mass index, iron use and anemia during pregnancy), except the history of diabetes were predictive of preterm birth across all participating European centers. Preterm birth was at least 2.4 times more likely with smoking (history or current), three times more likely with preeclampsia, 2.9 times more likely with hypertension after adjusting for other covariates. It had inverse relationship with the significant predictor body mass index, with adjusted risk ratio of 0.8 to 1.0 in three sites. Iron use and anemia, though significant predictors of preterm birth, indicated mixed patterns for relative risk ratio. Conclusion Smoking, preeclampsia, hypertension and body mass index seem to be the foremost risk factors of preterm birth. Implications of these factors could be beneficial for design and implementation of interventions and improve the birth outcome

Az extrém alacsony születési súlyú koraszülöttek hyperglykaemiájának korai és késői szövődményei = Early and late complications of hyperglycemic extremely low birth-weight infants

Absztrakt: Bevezetés: Az újszülött intenzív osztályok működésének köszönhetően az extrém alacsony súlyú koraszülöttek perinatalis mortalitása jelentősen csökkent. Fontos feladat a korai és késői szövődmények felismerése. Célkitűzés: A hyperglykaemia (vércukorszint > 8,5 mmol/l) előfordulási gyakoriságát, a korai és késői komplikációkat feltárva kapcsolatot kerestünk a hyperglykaemia és a szövődmények kialakulása között. Módszer: A 2014. január 1. és 2017. december 31. közötti periódusban született, 1000 g alatti súlyú 188 koraszülött klinikai adatait elemeztük. Meghatároztuk a hyperglykaemia, a retinopathia, az agyvérzés, valamint a bronchopulmonalis dysplasia gyakoriságát. Állatkísérleteinket Sprague Dawley patkányokon végeztük. A hyperglykaemiás állapotot intraperitonealis sztreptozotocininjekció adásával értük el (100 mg/ttkg). A 7. életnapon az aortát eltávolítottuk, szövettani metszeteket készítettünk, melyeket hematoxilin-eozin oldatokkal festettünk. A falvastagságot a QCapture Pro 7 képelemző programmal mértük. Eredmények: Az 1000 g alatti születési súlyú koraszülöttek gesztációs kora és születési súlya 27,1 ± 2,2 hét, illetve 814,9 ± 151,9 g volt, közülük 33 exitált (17,5%). Hyperglykaemiát 62 esetben igazoltunk (32,9%), inzulinkezelést 43 esetben alkalmaztunk (22,8%). A hyperglykaemiás csoport gesztációs kora, születési súlya szignifikánsan alacsonyabb volt (p<0,001), a súlyos retinopathia előfordulása gyakoribb (p = 0,012), az inzulinkezeltek mortalitása magasabb (p = 0,02) volt, mint a normoglykaemiás koraszülötteké. A túlélő gyermekeket vizsgálva (n = 155) logisztikus regressziós analízissel megállapítottuk, hogy a hyperglykaemia jelentős kockázati tényező a súlyos retinopathia kialakulásában (p<0,001). Állatkísérletes modellen megfigyeltük, hogy a neonatalis hyperglykaemia az aortafal jelentős megvastagodását okozza. Következtetés: Retrospektív és állatkísérletes vizsgálataink eredményei arra hívják fel a figyelmet, hogy hyperglykaemia gyakran alakul ki extrém alacsony súlyú koraszülöttekben; gondozásuk során a szemészeti kontroll mellett a veseműködés és a vérnyomás ellenőrzése is fontos feladat. Orv Hetil. 2019; 160(32): 1270–1278. | Abstract: Introduction: During recent decades, the perinatal mortality of extremely low-birth weight infants has decreased. An important task is to recognize complications of prematurity. Aim: We made an attempt to explore the relationship between complications of prematurity and neonatal hyperglycemia. Method: From 1 January 2014 to 31 December 2017, 188 infants with birth weight below 1000 g were admitted. For each infant, the frequencies of hyperglycemia (blood glucose >8.5 mmol/l), retinopathy of prematurity, intraventricular hemorrhage, and bronchopulmonary dysplasia were determined. Animal studies were performed in Sprague Dawley rats. Hyperglycemia was achieved by intraperitoneal injection of streptozotocin (100 mg/kg). On the 7th day of life, aorta sections were prepared and stained with hematoxylin eosin. Wall thickness was measured using QCapture Pro 7 image analysis software. Results: The mean ± SD gestational age and birth weight were 27.1 ± 2.2 weeks and 814.9 ± 151.9 g; 33 infants (17.5%) died. Hyperglycemia was confirmed in 62 cases (32.9%), and insulin treatment was given to 43 infants (22.8%). The gestational age and birth weight of the hyperglycemic infants were significantly lower (p<0.001), the incidence of severe retinopathy (p = 0.012) and the mortality of insulin-treated patients were higher (p = 0.02) than in normoglycemic infants. Among survivors (n = 155), we found by logistic regression analysis that hyperglycemia was a risk factor for severe retinopathy (p<0.001). In the rat model, neonatal hyperglycemia caused significant thickening of the aortic wall. Conclusion: Our studies indicate that hyperglycemia is common in extremely low birth-weight infants. Monitoring of these infants for retinopathy of prematurity, kidney dysfunction, and hypertension is recommended. Orv Hetil. 2019; 160(32): 1270–1278

Validity of biomarkers of early circulatory impairment to predict outcome: a retrospective analysis

Objectives: The definition of circulatory impairment in the premature infant is controversial. Current research suggests overdiagnosis and overtreatment. We aimed to analyse which biomarkers move clinicians to initiate cardiovascular treatment (CVT). The prognostic capacity for adverse outcome (death and/or moderate-severe brain damage by cranial ultrasound at term equivalent) of these biomarkers was evaluated. Study Design: Retrospective data analysis from preterm infants enrolled in a placebo-controlled trial on dobutamine for low superior vena cava (SVC) flow, who showed normal SVC flow within the first 24 h (not randomized). Five positive biomarkers were considered: MABP 4 mmol/L; BE < −9 mmol/L; SVC flow <51 ml/kg/min. Results: Ninety eight infants formed the study cohort. Thirty six received CVT (2–95 h). Logistic regression models adjusted for gestational age showed a positive association between CVT and the risk of death or moderate-severe abnormal cranial ultrasound at term equivalent [(OR 5.2, 95%CI: 1.8–15.1) p = 0.002]. MABP 4 mmol/L were the most prevalent biomarkers at start of treatment. Low BE, high serum lactate and low SVC flow at first echocardiography showed a trend toward being associated with adverse outcome, although not statistically significant. Conclusions: Low blood pressure and high lactate are the most prevalent biomarkers used for CVT prescription. Lactic acidosis and low SVC flow early after birth showed a trend toward being associated with adverse outcome. These findings support using a combination of biomarkers for inclusion in a placebo-controlled trial on CVT during transitional circulation

New pseudononapeptide bombesin antagonists with C-terminal leu-psi(ch2n)tac-nh2 show high binding-affinity to bombesin/grp receptors on cfpac-1 human pancreatic-cancer cells.

It has been demonstrated that bombesin/GRP antagonist D-Tpi(6),Leu(13)psi(CH2NH) Leu(14)-BN(6-14) (RC-3095) inhibits effectively the growth of pancreatic cancer and other tumors in experimental animals and in cell cultures. In an attempt to develop antagonists with still greater antitumor activity, several new pseudononapeptide bombesin/GRP antagonists containing C-terminal Leu psi(CH2N)Tac-NH2 have been synthesized in our laboratory. In this study, we investigated the ability of four Leu(13)psi(CH2N)Tac(14)-BN(6-14) antagonists to inhibit the binding of bombesin to specific receptors for bombesin/GRP on CFPAC-1 human pancreatic cancer cells. Receptor binding assays were performed by incubating CFPAC-1 cells (5x10(4) cells/well) with 0.5 nM [I-125]-Tyr(4)-bombesin in the absence or presence of (1 pM to 10 mu M) unlabeled bombesin, GRP(14-27) and various antagonists for 2 h at 22 degrees C. Displacement assays showed that antagonist D-Tpi(6),Leu(13)psi(CH2N)Tac(14)-BN(6-14) (RC-3910-II) with a similar structure to RC-3095, but a different C-terminal, had a binding affinity to CFPAC-1 cells 15 times higher than RC-3095. Three other antagonists, RC-3925-II, RC-3940-II and RC-3950-II contained the same C-terminal Leu psi(CH2N)Tac-NH2 as RC-3910-II, but had different N-terminal residues: D-Cpa, Hca and D-Phe, respectively. Among them, Hca(6),Leu(13)psi(CH2N)Tac(14)-BN(6-14) (RC-3940-II) showed the highest binding affinity to the receptors on CFPAC-1 cells, which was 50 times higher than that of RC-3095 or 3 times greater than RC-3910-II. Our findings suggest the merit of further investigation of pseudononapeptide bombesin/GRP antagonist RC-3940-II ind related analogs for a possible development of a new hormonal therapy for pancreatic cancer

Epigenetic Effect of Maternal Methyl-Group Donor Intake on Offspring&rsquo;s Health and Disease

Maternal exposure to some dietary and environmental factors during embryonic development can affect offspring&rsquo;s phenotype and, furthermore, the risk of developing diseases later in life. One potential mechanism responsible for this early programming may be the modification of the epigenome, such as DNA methylation. Methyl-group donors are essential for DNA methylation and are shown to have an important role in fetal development and later health. The main goal of the present review is to summarize the available literature data on the epigenetic effect (DNA methylation) of maternal methyl-group donor availability on reproductivity, perinatal outcome, and later health of the offspring. In our literature search, we found evidence for the association between alterations in DNA methylation patterns caused by different maternal methyl-group donor (folate, choline, methionine, betaine) intake and reproductivity, birth weight, neural tube defect, congenital heart defect, cleft lip and palate, brain development, and the development of obesity and associated non-communicable diseases in later life. We can conclude that maternal methyl-group donor availability could affect offspring&rsquo;s health via alterations in DNA methylation and may be a major link between early environmental exposure and the development of diseases in the offspring. However, still, further studies are necessary to confirm the associations and causal relationships

Inhibitory effect of bombesin receptor antagonist RC-3095 on the growth of human pancreatic cancer cells in vivo and in vitro

L

Inhibitory Effect of Bombesin Receptor Antagonist RC-3095 on the Growth of Human Pancreatic Cancer Cells in Vivo and in Vitro

Abstract In this study, we investigated the effect of bombesin/GRP antagonist RC-3095 on the growth of CFPAC-1 human pancreatic cancer cells transplanted to nude mice or cultured in vitro. Nude mice bearing xenografts of the CFPAC-1 cell line received s.c. injections of RC-3095 (10 µg twice a day) or the vehicle (control) for 25 days. Chronic administration of RC-3095 inhibited the growth of CFPAC-1 tumors in nude mice as shown by a significant decrease in tumor volume throughout the period of treatment. Tbrnor volume doubling time was prolonged by RC-3095 treatment from 7.2 days to 10 days, and the tumor growth rate was decreased by 49%. In mice treated with RC-3095, the tumor growth delay time was 5.8 days. Treatment with RC-3095 decreased the final tumor weight by 37% and reduced DNA and protein contents in tumor tissues by 44 and 39.9%, respectively, compared to the controls. In cultures of the CFPAC-1 cell line, the addition of bombesin(1–14) (1 pm-0.1 µm) to the medium induced a dose-dependent increase in cell number. RC-3095 at 1 nm concentration effectively inhibited the bombesin-stimulated growth of CFPAC-1 cells in cultures. In the presence of 1 µm RC-3095 in the culture medium, the bombesin-induced growth of CFPAC-1 cells was totally suppressed. Bombesin was also shown to stimulate the DNA synthesis in CFPAC-1 cells in vitro as based on [3H]thymidine incorporation assay. When the cells were cultured in the presence of 1–100 nm bombesin, the uptake of [3H]thymidine by the cells was increased by 89-131%. RC-3095 inhibited both the basal and bombesin-stimulated DNA synthesis of CFPAC-1 cells. Addition of RC-3095 (10µ100 nm) alone to the cultures caused a 39µ40% decrease in the [3H]thymidine incorporation by the cells. Concomitant addition of RC-3095 (1 µm) and bombesin (1µ100 nm) to the cultures induced a significant reduction in the uptake of [3H]thymidine by the cells compared to the values obtained with bombesin alone. Receptor binding assays showed the presence of two classes of specific binding sites for bombesin on CFPAC-1 cells, one with high affinity (Kd = 4.25 ± 0.77 nm) and low capacity (Bmax = 0.268 ± 0.052 pmol/106 cells) and the other with low affinity (Kd = 321.70 ± 68.46 nm) and high capacity (Bmax = 3.991 ± 0.374 pmol/106 cells). Antagonist RC-3095 inhibited the binding of 125I-Tyr4-bombesin to CFPAC-1 cell membranes in a dose-dependent manner. These observations suggest that bombesin acts as a growth factor and stimulates proliferation of CFPAC-1 human pancreatic cancer through specific receptors for bombesin/GRP present on the cells. RC-3095 appears to inhibit the growth of CFPAC-1 cells by blocking the interaction of bombesin with its receptors. Bombesin/GRP receptor antagonist RC-3095 could be considered for the development of new approaches for treatment of human pancreatic cancers. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact