Three mechanisms in the pathogenesis of pre-eclampsia suggested by over-represented transcription factor-binding sites detected with comparative promoter analysis

Microarray studies generating lists of genes with altered expression in placentas from pregnancies complicated with pre-eclampsia (PE) have so far been published in several different studies. Working under the assumption that altered gene expression in PE may be the result of altered expression of regulatory transcription factors (TFs), we looked for over-represented TF-binding sites (TFBSs)-which indicate the involvement of TFs in gene regulatory networks-in lists of genes (n = 143) compiled in these studies. We compared the prevalence of TFBSs in the promoter regions of 68 genes with the background prevalence of TFBSs in promoters of the human genome. The prevalence of the E47, sterol regulatory element binding protein (SREBP) and NFKB-p50 TFBSs was higher (P < 0.005) in the promoter sequences of the PE gene lists than in the background model. Each of these TFBSs could be implicated in the development of PE. The E47 protein is an E-protein or basic helix-loop-helix (bHLH) TF. Data support the role of bHLHs in the differentiation of placental tissue. SREBP-1, a lipid-sensing sterol regulatory element-binding protein, is a critical regulator of fatty acid homeostasis in the placenta. The target genes of NFKB-p50 determine inflammatory response, and aberrant cytokine homeostasis is a further sign of PE. These TFs may provide an insight into the pathogenesis of the disease

Akt enzim: új terápiás célpont rákban és cukorbetegségben? = Akt enzyme: new therapeutic target in cancer and diabetes?

A megváltozott sejthalál (apoptózis) számos betegség kialakulásában és progressziójában központi szerepet játszik. Az apoptózist reguláló fehérjék lehetséges terápiás célpontok, ezek egyik tagja az Akt enzim. Az Akt enzim a legtöbb sejtben jelen van. Növekedési faktorok és inzulin, valamint környezeti hatások, így oxigéntenzió-változás és magas hőmérséklet hatására aktiválódik. Az Akt a sejtek metabolizmusában és túlélésében játszik szerepet. Egyes betegségcsoportokban az Akt megváltozott működése figyelhető meg. Számos rosszindulatú daganatban, így prosztata-, emlő-, vastagbél- és hasnyálmirigyrákban, valamint rosszindulatú hematológiai betegségekben az Akt túlműködését igazolták. Diabéteszben egyrészt a béta-sejt-pusztulásban játszik szerepet, másrészt a sejtek inzulinszenzitivitását is befolyásolja. Több kutatási eredmény azt is bebizonyította, hogy a már forgalmazott gyógyszerek egy részének, így a statinoknak, tiazolidindionoknak és az ACE-gátlóknak egyaránt van Akt-moduláló hatása. Jelenleg kutatások folynak olyan Akt-gátlók kifejlesztésére, amelyek a kemoterápia hatékonyságát segíthetik. A perifozin és a triciribin két olyan, fázis I–II. stádiumban lévő Akt-gátló, amely kombinációban adva növelheti emlőrákban, petefészekrákban, gastrointestinalis stromatumorokban, szarkómákban, karcinómákban és hematológiai daganatokban a túlélési idő hosszát. | Alteration of apoptotic processes plays a central role in the development and progression of several chronic disorders. Proteins responsible for the regulation of apoptosis are therapeutic targets; these include the Akt enzyme. Akt enzyme is expressed in most cell types. Akt activation is regulated by growth factors, insulin, and also environmental factors as altered oxygen tension and high temperature. Akt is a central regulator of cellular metabolism and survival. Akt function is reportedly altered in some disorders. An increased activity of Akt has been described in prostate, breast, colon, and pancreatic cancer, as well as in hematological malignancies. Akt is also a factor in the pathomechanism of diabetes as it determines beta-cell apoptosis of Langerhans islets and insulin sensitivity of the cells. Several studies revealed that some of the marketed drugs including statins, thiazolidinediones and ACE inhibitors modulate Akt activity. There are efforts to develop specific Akt inhibitors that may improve the efficacy of chemotherapy. Triciribine and perifosine are two Akt inhibitors in developmental phase 1 and 2 that may improve survival in breast cancer, pancreas cancer, gastrointestinal stroma tumor, sarcoma and melanoma, and in hematological malignancy

Pregnancy Rates with Recombinant versus Urinary Human Chorionic Gonadotropin in In Vitro Fertilization: An Observational Study

Randomized clinical trials (RCTs) demonstrated the equal efficacy of urinary human chorionic gonadotropin (uhCG) and recombinant hCG (rhCG) products in in vitro fertilisation (IVF). However, limitations inherent with RCTs necessitate the reinforcement of RCT results in real-life. We retrospectively analyzed pregnancies after treatment with rhCG and uhCG products (n = 391, and 96, resp.). We found that laboratory-verified pregnancy occurred more frequently in rhCG patients than in those on uhCG (43% versus 30%, P = 0.02). The association remains significant (P = 0.002) after its adjustment for clinical characteristics. The prevalence of laboratory-verified pregnancies was higher with GnRH agonist use (P = 0.012) and BMI under 30 kg/m2 (P = 0.053) while decreased the age (P = 0.014) and the number of previous failed attempts (P = 0.08). Similar (but not significant) trends were observed with rates of pregnancy filled the 24th week. These results reinforce RCTs supporting the notion that rhCG is more efficient as uhCG during IVF

Characteristics of allergic colitis in breast-fed infants in the absence of cow’s milk allergy

AIM: To investigate the characteristics of mucosal lesions and their relation to laboratory data and long-term follow up in breast-fed infants with allergic colitis. METHODS: In this study 31 breast-fed infants were prospectively evaluated (mean age, 17.4 wk) whose rectal bleeding had not ceased after a maternal elimination diet for cow's milk. Thirty-four age-matched and breast-fed infants (mean age, 16.9 wk) with no rectal bleeding were enrolled for laboratory testing as controls. Laboratory findings, colonoscopic and histological characteristics were prospectively evaluated in infants with rectal bleeding. Long-term follow-up with different nutritional regimes (L-amino-acid based formula or breastfeeding) was also included. RESULTS: Iron deficiency, peripheral eosinophilia and thrombocytosis were significantly higher in patients with allergic colitis in comparison to controls (8.4 ± 3.2 μmol/L vs 13.7 ± 4.7 μmol/L, P < 0.001; 0.67 ± 0.49 G/L vs 0.33 ± 0.17 G/L, P < 0.001; 474 ± 123 G/L vs 376 ± 89 G/L, P < 0.001, respectively). At colonoscopy, lymphonodular hyperplasia or aphthous ulceration were present in 83% of patients. Twenty-two patients were given L-amino acid-based formula and 8 continued the previous feeding. Time to cessation of rectal bleeding was shorter in the special formula feeding group (mean, 1.4 wk; range, 0.5-3 wk) when compared with the breast-feeding group (mean, 5.3 wk; range, 2-9 wk). Nevertheless, none of the patients exhibited rectal bleeding at the 3-mo visit irrespective of the type of feeding. Peripheral eosinophilia and cessation of rectal bleeding after administration of elemental formula correlated with a higher density of mucosal eosinophils. CONCLUSION: Infant hematochezia, after cow's milk allergy exclusion, is generally a benign and probably self-limiting disorder despite marked mucosal abnormality. Formula feeding results in shorter time to cessation of rectal bleeding; however, breast-feeding should not be discouraged in long-lasting hematochezia

Adaptive Immunity in Ankylosing Spondylitis: Phenotype and Functional Alterations of T-Cells before and during Infliximab Therapy

Our aim was to assess the phenotype of T-cell subsets in patients with ankylosing spondylitis (AS), a chronic inflammatory rheumatic disease. In addition, we also tested short-term T-cell activation characteristics. Measurements were done in 13 AS patients before and during the intravenous therapy with anti-TNF agent infliximab (IFX). Flow cytometry was used to determine T-cell subsets in peripheral blood and their intracellular signaling during activation. The prevalence of Th2 and Th17 cells responsible for the regulation of adaptive immunity was higher in AS than in 9 healthy controls. Although IFX therapy improved patients' condition, immune phenotype did not normalize. Cytoplasmic and mitochondrial calcium responses of CD4+ and CD8+ cells to a specific activation were delayed, while NO generation was increased in AS. NO generation normalized sooner upon IFX than calcium response. These results suggest an abnormal immune phenotype with functional disturbances of CD4+ and CD8+ cells in AS

Immune phenotype in children with therapy-naïve remitted and relapsed Crohn’s disease

AIM To characterize the prevalence of subpopulations of CD4+ cells along with that of major inhibitor or stimulator cell types in therapy naive childhood Crohn s disease (CD) and to test whether abnormalities of immune phenotype are normalized with the improvement of clinical signs and symptoms of disease METHODS We enrolled 26 pediatric patients with CD 14 therapy naive CD children, of those, 10 children remitted on conventional therapy and formed the re mission group We also tested another group of 12 children who relapsed with conventional therapy and were given infliximab, and 15 healthy children who served as controls The prevalence of Th1 and Th2, naive and memory, activated and regulatory T cells, along with the members of innate immunity such as natural killer (NK), NK T, myeloid and plasmocytoid dendritic cells (DCs), monocytes and Toll like receptor (TLR) 2 and TLR 4 expression were determined in peripheral blood samples RESULTS Children with therapy naive CD and those in relapse showed a decrease in Th1 cell prevalence Simultaneously, an increased prevalence of memory and activated lymphocytes along with that of DCs and monocytes was observed In addition, the ratio of myeloid/plasmocytoid DCs and the prevalence of TLR2 or TLR4 positive DCs and monocytes were also higher in therapy naive CD than in controls The majority of alterations diminished in remitted CD irrespective of whether remission was obtained by conventional or biological therapy CONCLUSION The finding that immune phenotype is normalized in remission suggests a link between immune phenotype and disease activity in childhood CD Our observations support the involvement of members of the adaptive and innate immune systems in childhood CD (C) 2010 Baishideng All rights reserve

Intestinal alkaline phosphatase in the colonic mucosa of children with inflammatory bowel disease

AIM: To investigate intestinal alkaline phosphatase (iAP) in the intestinal mucosa of children with inflammatory bowel disease (IBD). METHODS: Colonic biopsy samples were taken from 15 newly diagnosed IBD patients and from 10 healthy controls. In IBD patients, specimens were obtained both from inflamed and non-inflamed areas. The iAP mRNA and protein expression was determined by reverse transcription-polymerase chain reaction and Western blotting analysis, respectively. Tissue localization of iAP and Toll-like receptor (TLR) 4 was investigated by immunofluorescent staining. RESULTS: The iAP protein level in the inflamed mucosa of children with Crohn's disease (CD) and ulcerative colitis (UC) was significantly decreased when compared with controls (both P < 0.05). Similarly, we found a significantly decreased level of iAP protein in the inflamed mucosa in CD compared with non-inflamed mucosa in CD (P < 0.05). In addition, the iAP protein level in inflamed colonic mucosa in patients with UC was decreased compared with non-inflamed mucosa in patients with CD (P < 0.05). iAP protein levels in the non-inflamed mucosa of patients with CD were similar to controls. iAP mRNA expression in inflamed colonic mucosa of children with CD and UC was not significantly different from that in non-inflamed colonic mucosa with CD. Expression of iAP mRNA in patients with non-inflamed mucosa and in controls were similar. Co-localization of iAP with TLR4 showed intense staining with a dotted-like pattern. iAP was present in the inflamed and non-inflamed mucosa of patients with CD, UC, and in control biopsy specimens, irrespective of whether it was present in the terminal ileum or in the colon. However, the fluorescent signal of TLR4 was more pronounced in the colon compared with the terminal ileum in all groups studied. CONCLUSION: Lower than normal iAP protein levels in inflamed mucosa of IBD patients may indicate a role for iAP in inflammatory lesions in IBD. Based on our results, administration of exogenous iAP enzyme to patients with the active form of IBD may be a therapeutic option

Emelkedett hepcidinszint nőgyógyászati műtéteket követő harmadik napon = Increased hepcidin levels three days after gynecological interventions

A hepcidin a vasfelszívódást és a plazmavasszintet közvetlenül csökkentő endogén vegyület. Technikai okok miatt meghatározása nem terjedt el, klinikai jelentőségére vonatkozóan korlátozottak az adatok. Munkánk során nő gyógyászati műtétek kapcsán elemeztük a bekövetkező hepcidinszint-változást. Vizsgálatunk során 17 nőgyógyá szati műtéten átesett nő esetében a műtét előtt közvetlenül, majd azt követően 3 nappal vett vérmintában határoztuk meg tömegspektrometriával a hepcidinszintet, valamint ELISA-módszerrel a legfontosabb hepcidininduktor, az interleukin-6 szintjét. A műtét után csökkent a szérumvasszint [medián, interkvartilis (17,85 [15,25–24,9] versus 10,1 [7,6–15,0] μmol/L, p<0,01)] és transzferrinszint [60,3 (55,93–67,18) versus 53,1 (49,7–60,0) μmol/L, p<0,01], míg nőtt a hepcidinszint [2,75 (2,24–3,51) versus 8,01 (6,8–9,67) μg/L, p<0,01) és az interleukin-6-szint (ND – nem detektálható) [ND [ND – 2.2] versus 8,15 (2,31–12,86), p<0,01]. Következtetés: A műtétet követő vasanyagcsere-változásokkal egyidejűleg a hepcidinszint – hasonlóan más akutfázis-fehérjékhez – gyorsan emelkedik. Eredményeink alapján a hepcidinszint emelkedése és a vasszint csökkenése közötti ok-okozati kapcsolat valószínűsíthető. A hepcidinszint mérésének a mindennapos gyakorlatban a műtétet követő vasanyagcsere-változás monitorozásában, esetleges előrejelzésében lehet szerepe. Elterjedése azonban rutin laboratóriumi tesztek hiányában egyelőre nem valószínű. Orv. Hetil., 2010, 43, 1790–1794. | Hepcidin is an endogenous substance that inhibits iron absorption and plasma iron levels. Due to technical reasons its levels are not routinely assessed and data regarding its clinical relevance are limited. We analyzed the alteration of hepcidin levels following gynecological interventions. Hepcidin levels were determined by mass spectrometry, along with the levels of interleukin-6, the main inductor of hepcidin with ELISA in 17 women undergoing gynecological intervention just prior to and three days after the surgery. The results were related to iron homeostasis parameters. A decrease in serum iron (median, interquartile range) (17.85 [15.25–24.9] versus 10.1 [7.6–15.0] μmol/l, p<0.01) and transferrin levels (60.3 [55.93–67.18] versus 53.1 [49.7–60.0], p< 0.01) μmol/l, simultaneously with an increase in hepcidin (2.75 [2.24–3.51] versus 8.01 [6.8–9.67] μg/l, p<0.01) and interleukin-6 levels (ND = not detected) (ND [ND – 2.2] versus 8.15 [2.31–12.86], p<0.01). Conclusion: As with other acute phase proteins postoperative hepcidin levels dramatically increase, simultaneously with other changes in iron homeostasis. These results indicate a possible causative relationship between increased hepcidin and decreased iron levels. In clinical practice, determination of hepcidin levels may be indicated for characterization and, possibly, prediction of postoperative iron homeostasis. However, measurement of hepcidin level in clinical practice is unlikely in the near future due to the lack of available kits for routine clinical laboratories. Orv. Hetil., 2010, 43, 1790–1794