Everolimus augments the effects of sorafenib in a syngeneic orthotopic model of hepatocellular carcinoma

Sorafenib targets the Raf/mitogen-activated protein kinase, VEGF, and platelet-derived growth factor pathways and prolongs survival patients in advanced hepatocellular carcinoma (HCC). Everolimus inhibits the mammalian target of rapamycin, a kinase overactive in HCC. To investigate whether the antitumor effects of these agents are additive, we compared a combined and sequential treatment regimen of everolimus and sorafenib with monotherapy. After hepatic implantation of Morris Hepatoma (MH) cells, rats were randomly allocated to everolimus (5 mg/kg, 2×/week), sorafenib (7.5 mg/kg/d), combined everolimus and sorafenib, sequential sorafenib (2 weeks) then everolimus (3 weeks), or control groups. MRI quantified tumor volumes. Erk1/2, 4E-BP1, and their phosphorylated forms were quantified by immunoblotting. Angiogenesis was assessed in vitro by aortic ring and tube formation assays, and in vivo with Vegf-a mRNA and vascular casts. After 35 days, tumor volumes were reduced by 60%, 85%, and 55%, relative to controls, in everolimus, the combination, and sequential groups, respectively (P < 0.01). Survival was longest in the combination group (P < 0.001). Phosphorylation of 4E-BP1 and Erk1/2 decreased after everolimus and sorafenib, respectively. Angiogenesis decreased after all treatments (P < 0.05), although sorafenib increased Vegf-a mRNA in liver tumors. Vessel sprouting was abundant in control tumors, lower after sorafenib, and absent after the combination. Intussusceptive angiogenic transluminal pillars failed to coalesce after the combination. Combined treatment with everolimus and sorafenib exerts a stronger antitumoral effect on MH tumors than monotherapy. Everolimus retains antitumoral properties when administered sequentially after sorafenib. This supports the clinical use of everolimus in HCC, both in combination with sorafenib or after sorafenib.

Functional Imaging of Pheochromocytoma with Ga-DOTATOC and C-HED in a Genetically Defined Rat Model of Multiple Endocrine Neoplasia

Rats affected by the MENX multitumor syndrome develop pheochromocytoma (100%). Pheochromocytomas are uncommon tumors and animal models are scarce, hence the interest in MENX rats to identify and preclinically evaluate novel targeted therapies. A prerequisite for such studies is a sensitive and noninvasive detection of MENXassociated pheochromocytoma. We performed positron emission tomography (PET) to determine whether rat pheochromocytomas are detected by tracers used in clinical practice, such as 68Ga-DOTATOC (somatostatin analogue) or (11)C-Hydroxyephedrine (HED), a norepinephrine analogue. We analyzed four affected and three unaffected rats. The PET scan findings were correlated to histopathology and immunophenotype of the tumors, their proliferative index, and the expression of genes coding for somatostatin receptors or the norepinephrine transporter. We observed that mean 68Ga-DOTATOC standard uptake value (SUV) in adrenals of affected animals was 23.3 ± 3.9, significantly higher than in control rats (15.4 ± 7.9; P = .03). The increase in mean tumor-to-liver ratio of (11)C-HED in the MENX-affected animals (1.6 ± 0.5) compared to controls (0.7 ± 0.1) was even more significant (P = .0016). In a unique animal model, functional imaging depicting two pathways important in pheochromocytoma biology discriminated affected animals from controls, thus providing the basis for future preclinical work with MENX rats.

Stress and Strain Adaptation in Load-Dependent Remodeling of the Embryonic Left Ventricle

Altered pressure in the developing left ventricle (LV) results in altered morphology and tissue material properties. Mechanical stress and strain may play a role in the regulating process. This study showed that confocal microscopy, three-dimensional reconstruction, and finite element analysis can provide a detailed model of stress and strain in the trabeculated embryonic heart. The method was used to test the hypothesis that end-diastolic strains are normalized after altered loading of the LV during the stages of trabecular compaction and chamber formation. Stage-29 chick LVs subjected to pressure overload and underload at stage 21 were reconstructed with full trabecular morphology from confocal images and analyzed with finite element techniques. Measured material properties and intraventricular pressures were specified in the models. The results show volume-weighted end-diastolic von Mises stress and strain averaging 50–82% higher in the trabecular tissue than in the compact wall. The volume-weighted-average stresses for the entire LV were 115, 64, and 147Pa in control, underloaded, and overloaded models, while strains were 11, 7, and 4%; thus, neither was normalized in a volume-weighted sense. Localized epicardial strains at mid-longitudinal level were similar among the three groups and to strains measured from high-resolution ultrasound images. Sensitivity analysis showed changes in material properties are more significant than changes in geometry in the overloaded strain adaptation, although resulting stress was similar in both types of adaptation. These results emphasize the importance of appropriate metrics and the role of trabecular tissue in evaluating the evolution of stress and strain in relation to pressure-induced adaptation.

Postoperative splanchnic blood flow redistribution in response to fluid challenges in the presence and absence of endotoxemia in a porcine model

We hypothesized that fluid administration may increase regional splanchnic perfusion after abdominal surgery-even in the absence of a cardiac stroke volume (SV) increase and independent of accompanying endotoxemia. Sixteen anesthetized pigs underwent abdominal surgery with flow probe fitting around splanchnic vessels and carotid arteries. They were randomized to continuous placebo or endotoxin infusion, and when clinical signs of hypovolemia (mean arterial pressure, <60 mmHg; heart rate, >100 beats · min(-1); urine production, <0.5 mL · kg(-1) · h(-1); arterial lactate concentration, >2 mmol · L(-1)) and/or low pulmonary artery occlusion pressure (target 5-8 mmHg) were present, they received repeated boli of colloids (50 mL) as long as SV increased 10% or greater. Stroke volume and regional blood flows were monitored 2 min before and 30 min after fluid challenges. Of 132 fluid challenges, 45 (34%) resulted in an SV increase of 10% or greater, whereas 82 (62%) resulted in an increase of 10% or greater in one or more of the abdominal flows (P < 0.001). During blood flow redistribution, celiac trunk (19% of all measurements) and hepatic artery flow (15%) most often decreased, whereas portal vein (10%) and carotid artery (7%) flow decreased less frequently (P = 0.015, between regions). In control animals, celiac trunk (30% vs. 9%, P = 0.004) and hepatic artery (25% vs. 11%, P = 0.040) flow decreased more often than in endotoxin-infused pigs. Accordingly, blood flow redistribution is a common phenomenon in the postoperative period and is only marginally influenced by endotoxemia. Fluid management based on SV changes may not be useful for improving regional abdominal perfusion.

Impact of a nurse vaccination program on hepatitis B immunity in a Swiss HIV clinic

We evaluated the impact of a nurse program for hepatitis B virus vaccination in a center from the Swiss HIV Cohort Study. Immunity (anti-HBs >10 IU/mL) increased from 32% to 76% in the intervention center (n = 238) where vaccine management was endorsed by nurses, but only from 33% to 39% in control centers (n = 2712, P < 0.001) where management remained in charge of physicians. Immunity against HBV in the HIV population is insufficient in Switzerland. Specific nurse vaccination program may efficiently improve health care.

SNPs in DNA repair genes associated to meningitis and host immune response

In vitro and in animal models, APE1, OGG1, and PARP-1 have been proposed as being involved with inflammatory response. In this work, we have investigated if the SNPs APE1 Asn148Glu, OGG1 Ser326Cys, and PARP-1 Val762Ala are associated to meningitis. The patient genotypes were investigated by PIRA-PCR or PCR-RFLP. DNA damages were detected in genomic DNA by Fpg treatment. IgG and IgA were measured from plasma and the cytokines and chemokines were measured from cerebrospinal fluid samples using Bio-Plex assays. A higher frequency (P<0.05) of APE1 Glu allele in bacterial meningitis (BM) and aseptic meningitis (AM) patients was observed. The genotypes Asn/Asn in control group and Asn/Glu in BM group was also higher. For the SNP OGG1 Ser326Cys, the genotype Cys/Cys was more frequent (P<0.05) in BM group. The frequency of PARP-1 Val/Val genotype was higher in control group (P<0.05). The occurrence of combined SNPs is significantly higher in BM patients, indicating that these SNPs may be associated to the disease. Increasing in sensitive sites to Fpg was observed in carriers of APE1 Glu allele or OGG1 Cys allele, suggesting that SNPs affect DNA repair activity. Alterations in IgG production were observed in the presence of SNPs APE1 Asn148Glu, OGG1 Ser326Cys or PARP-1 Val762Ala. Moreover, reduction in the levels of IL-6, IL-1Ra, MCP-1/CCL2 and IL-8/CXCL8 was observed in the presence of APE1 Glu allele in BM patients. In conclusion, we obtained indications of an effect of SNPs in DNA repair genes on the regulation of immune response in meningitis.

Flow experience during Taiji practice - an oberservational study in healthy subjects

Background: Taiji is a mind-body practice, characterised by gentle and mindful body movements originating from Chinese martial arts. Studies investigating the reasons why people engage into Taiji and maintain their practice routine have emphasised extrinsic motivational outcome related aspects. The relevance of intrinsic motivation (i.e. motivation that comes from inside an individual and is driven by an interest or enjoyment in the performed activity itself) has not yet been examined. The autotelic aspect of intrinsic motivation is an essential precondition for experiencing flow, a state where subjects fully immersed into the performance of an activity report to be highly concentrated, optimally challenged and in control of the action. The aim of our study was to assess to which degree flow was experienced in the course of a 3 month Taiji-beginners class and to examine the relationship between the degree of flow experience at the end of the course and the Taiji practice behaviour. Materials and Methods: 28 healthy subjects participated in a Taiji beginners course (2 x 1h per week for 3 months). Flow values were measured at week 1, 6 and 12 by using the Flow-Kurz-Skala (FKS) questionnaire. Data were analysed by using ANOVA with repeated measurements, students t-Tests for comparison with normative values, and pearson correlation coefficients were calculated. Results: In the course of the 12 weeks Taiji training, mean flow values increased continuously (F(1.34, 8.92) = 19.49; p < .001). The mean value for experienced flow during Taiji practice at week 12 (M = 5.54; SD = ±.77) was significantly above the norm value (t = 3.705; df = 27; p < .01). Since average course attendance rate was high (86.8 %), a ceiling effect is assumed, thus flow values did not correlate with course adherence (r = .236; p = .227). However, a significant correlation was found between flow values at week 12 and practice at home (r = .439; p < .05). Conclusion: Our findings emphasise the potential value of intrinsic motivational aspects inherent in Taiji practice for developing a regular practice routine. The impact of increased flow experience on health related outcome measures, and its relevance in clinical trials is subject of further research.

Effects of induced parturition in goats on immunoglobulin G and chitotriosidase activity in colostrum and plasma and on plasma concentrations of prolactin

The effect of induction of parturition with a PGF(2)alpha analog on plasma concentration of prolactin (PRL) and its effects on colostrum concentration of IgG and chitotriosidase (ChT) activity were studied in 16 pregnant Majorera goats. Treated goats, those in which parturition was induced, had greater concentrations of PRL than control goats 24 h before parturition (P < 0.05) and 48 h after parturition (P < 0.05). Control goats had greater concentrations of PRL than treated goats 96 h after parturition (P < 0.05). Plasma concentration of IgG did not differ between groups during the experimental period, but colostrum concentrations of IgG were greater in control goats than in treated goats at parturition (P < 0.05). Plasma ChT activity decreased during the period 72 h before parturition to 24 h after parturition in control and treated goats. Time evolution after partum affected the colostrum ChT activity, being greater at parturition than after parturition in both groups (P < 0.05). In summary, concentration of IgG in colostrum is slightly diminished if parturition is induced. Induction of parturition causes an early increase in PRL, which is most likely responsible for preterm suppression of IgG transport into mammary secretions. (C) 2011 Elsevier Inc. All rights reserved.

Myoelectric activity of the ileum, cecum, proximal loop of the ascending colon, and spiral colon in cows with naturally occurring cecal dilatation-dislocation

OBJECTIVE: To analyze myoelectric activity of the ileum, cecum, proximal loop of the ascending colon (PLAC), and spiral colon in cows with naturally occurring cecal dilatation-dislocation (CDD) and compare findings with those in healthy cows. ANIMALS: 8 CDD-affected and 6 healthy control cows. PROCEDURES: Immediately after diagnosis, CDD-affected cows underwent surgery; control cows underwent a similar surgical procedure. Before completion of surgery, 8 bipolar silver electrodes were implanted in the ileum (n = 2), cecum (1), PLAC (1), and spiral colon (4) of each cow. Beginning the day after surgery, intestinal myoelectric activity was recorded daily (8-hour period) for 4 days; data were analyzed by use of specialized software programs. Quantitative variables of myoelectric activity were compared between groups. RESULTS: Cows of both groups recovered without complications after surgery. In control cows, physiologic myoelectric activity was recorded in all intestinal segments on all days after surgery. Apparently normal myoelectric activity was evident in the ileum of CDD-affected cows on the first day after surgery, but myoelectric activity patterns in the cecum, PLAC, and spiral colon were variable with no organized cyclic myoelectric patterns, incomplete or normally organized migrating myoelectric complexes, and slow normalization over time. CONCLUSIONS AND CLINICAL RELEVANCE: After surgery for CDD, normal myoelectric patterns were disrupted in the large intestine of cows, especially in the spiral colon. Clinical recovery with effective transit of ingesta occurred before normalization of myoelectric activity in the large intestine. Therapeutic protocols for restoration or normalization of spiral colon motility should be developed for treatment of CDD-affected cattle.

Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma

Abberrant DNA methylation is one of the hallmarks of cancerogenesis. Our study aims to delineate differential DNA methylation in cirrhosis and hepatic cancerogenesis. Patterns of methylation of 27,578 individual CpG loci in 12 hepatocellular carcinomas (HCCs), 15 cirrhotic controls and 12 normal liver samples were investigated using an array-based technology. A supervised principal component analysis (PCA) revealed 167 hypomethylated loci and 100 hypermethylated loci in cirrhosis and HCC as compared to normal controls. Thus, these loci show a "cirrhotic" methylation pattern that is maintained in HCC. In pairwise supervised PCAs between normal liver, cirrhosis and HCC, eight loci were significantly changed in all analyses differentiating the three groups (p < 0.0001). Of these, five loci showed highest methylation levels in HCC and lowest in control tissue (LOC55908, CELSR1, CRMP1, GNRH2, ALOX12 and ANGPTL7), whereas two loci showed the opposite direction of change (SPRR3 and TNFSF15). Genes hypermethylated between normal liver to cirrhosis, which maintain this methylation pattern during the development of HCC, are depleted for CpG islands, high CpG content promoters and polycomb repressive complex 2 (PRC2) targets in embryonic stem cells. In contrast, genes selectively hypermethylated in HCC as compared to nonmalignant samples showed an enrichment of CpG islands, high CpG content promoters and PRC2 target genes (p < 0.0001). Cirrhosis and HCC show distinct patterns of differential methylation with regards to promoter structure, PRC2 targets and CpG islands.

Increased placental phospholipid levels in pre-eclamptic pregnancies

Physiological pregnancy is associated with an increase in lipids from the first to the third trimester. This is a highly regulated response to satisfy energy and membrane demands of the developing fetus. Pregnancy disorders, such as pre-eclampsia, are associated with a dysregulation of lipid metabolism manifesting in increased maternal plasma lipid levels. In fetal placental tissue, only scarce information on the lipid profile is available, and data for gestational diseases are lacking. In the present study, we investigated the placental lipid content in control versus pre-eclamptic samples, with the focus on tissue phospholipid levels and composition. We found an increase in total phospholipid content as well as changes in individual phospholipid classes in pre-eclamptic placental tissues compared to controls. These alterations could be a source of placental pathological changes in pre-eclampsia, such as lipid peroxide insult or dysregulation of lipid transport across the syncytiotrophoblast.

The Presidential Institution in Bulgaria, Albania and Romani: An Attempt at Comparison"

Bulgaria, Albania and Romania are all parliamentary republics with a president as head of state. Although the Albanian president is elected by Parliament, he is arguably the strongest of the three, both in terms of the powers allowed by the provisional constitution and of Mr. Berisha's political practice. The constitutional reform underway in the country will however change the status quo. In Bulgaria and Romania the presidents are elected directly by popular vote, but their powers are relatively small as compared to the democratic legitimisation implied by direct elections. Actual presidential powers should however be assessed with caution as some of them are set by law or interpretations of constitutional texts, rather than by the constitutions themselves. There is also variation in the degree to which the presidents in office have exploited their constitutional powers or taken their role as non-aligned political brokers seriously. Mr. Berisha, in particular, was in control of party politics throughout his presidency and was one of the most polarising influences on public opinion. The excessive political polarisation in all three countries has however its own logic and power. Thus Mr. Zhelev invariably supported the emergence of a political centre in Bulgaria, but this did not succeed and the policy was as damaging to his political career as the fight with would-be centrists was to Berisha's. Political practice in all three countries seems to need a presidential figure. This adds flexibility to a situation governed by hostile and mutually suspicious parties, stuck parliaments and weak or inexperienced governments. The presidents also command considerable influence on public opinion. Public opinion in Bulgaria, for example, largely supports the idea of greater power for the president, in contrast with the opinions of constitutionalists and other law-makers in the country. Under the legacy of the past, the people have a love-hate relationship with such paternalist figures. Presidents personalise politics in the public mind, but they can also become scapegoats for political failures.

Muslim Literature in Serbo-Croat in Relation to the Serbian and Croatian Literatures

Mr. Tutnjevic set out to define the position of the Muslim community within the overall framework of literature in Serbo-Croat, particularly in terms of its relation to the Serbian and Croatian Literatures, on the basis of an extensive comparative study of primary and secondary sources relating to the most important Muslim writers in Serbo-Croat. Carried out against the background of an unprecedented civil war between these national groups, his research focused rather on the encounters between them on the historical and literary stages. He concludes that the Muslim national community was established and developed on a foundation of Slavic self-consciousness and oriental influences. The constantly changing relative weights of the influence of these two factors on the community shaped the specific nature of its literature as well as its place in the cultural environment of its neighbouring national communities, and Muslim literary traditions are inseparably linked with the total literature in Serbo-Croat. A real Muslim literature first emerged at the end of the nineteenth century and virtually all authors writing about this at the time emphasised its educational character and its importance for the process of national identification. At the same time there were visible results of the self-awareness process in which Muslim authors affiliated with Serbian or Croatian literary tradition, sometimes even substituting one with another. During the period between the two world wars Muslim literature reached maturity and while Muslim authors generally focused on their national milieu in terms of subject matter, their forms of expression and their understanding of the function of literature showed the same preoccupation as other Yugoslav authors of the period. When the ideological and class-related concept of society replaced the national character of literature after 1945, Muslim writers found themselves in the same position as writers from other ethnic groups. As in earlier times, writers sought to present themselves to as wide a market as possible and would provide grounds for consideration as Serbian or Croatian writers, sometimes even explicitly presenting themselves as such. Most of the writers of this period are described at times as Yugoslav, at others as Bosnian-Herzegovina, and at still others as Serbian, Croatian or Muslim. Mr. Tutnjevic quotes, for example, the case of Camil Sijaric, a Muslim from Sandzak who also wrote in Sarajevo and falls within the boundaries of Bosnian-Herzegovnian literature, but is also described as a Muslim, Montenegrin and Serbian writer, together with a number of other such examples. An understanding of this process provides the basis for a completely new perception of the intertwining of Serbian, Croatian and Muslim literary traditions, without the earlier visible prejudice on all three sides.

Family Anomie and Juvenile Deliquency in Post-Communist Romania

The sensitivity of crime rates to social, economic and political influences has long aroused the interest of sociologists who have attempted to explain what kind of relationships might be associated with variations in crime rates between different social groups at different times. The earliest views were put forward by Emil Durkheim, and while later writers have developed (R.K. Merton, L. Srole, A, K. Cohen, etc.) have developed some aspects of his ideas further, his basic ideas of the divorce of the individual from normative standards and the lack of social integration are still valid. Ms. Voicu-Minea looked at the theoretical background in detail but then limited it to a specific social group, the family, asking first why certain individual within vulnerable families and/or negative social influences commit offences while others do not. In modern times the family has undergone massive structural and functional changes. Its former economic function, which once endowed it with a great capacity for social inclusion, has generally vanished, while its formerly crucial role in children's education has been massively reduced. These changes, which are still not complete, can lead to dysfunction and in certain social contexts such as that in post-communist Romanian society, this risk of dysfunction is still greater as unfavourably social circumstances more easily affect such families. The number of cases of juvenile delinquency in Romania has increased sharply ever since the end of the communist system and in 1996 reached the level of 18,317 cases. The sample examined included 1012 juvenile delinquents aged between 14 and 18, taken from all areas of Bucharest. Over 80% of charges related to theft, with more serious offences being relatively rare. The children underwent a series of psychological tests, accompanied by a questionnaire relating to family situation. The results showed that juvenile delinquency in Romania is overwhelmingly male, with 91.8% of offences being committed by boys. Two thirds of the research group were under the age of 16 and only just over one third attended school, with over half having left school before the legal age. While the majority of subjects had a lower than average level of education, they did not always recognise this, with two thirds seeing their level of education as being as good as or better than average. Nearly half the children (43%) did not live with both natural parents and majority came from families with three or more children. This applied both to their original families and to the families in which they were living at the time of the survey. The overwhelming majority of families were living in or around Bucharest, but under one third originated from there. Almost 25% of parents were under-schooled and around one third were unqualified workers. At least 30% of families lived in inadequate accommodation and family incomes were generally low. Ms. Voicu-Minea does however point out that over half the minors from the sample saw their family income as satisfactory or even more than satisfactory. When factors such as bad relationships between parents, corporal punishment, alcohol consumption and criminal records of family members were taken into account, the picture was bleak, making it understandable why over 36% of subjects had run away from home at least once, and in many cases repeatedly and for longer periods. The overwhelming majority of offences (80.8%) were committed in groups of between 2 and 11 persons, usually "friends" but in about 10% of cases member's of the family. IQ tests put about 75% of the sample at slightly under average, the difference being too slight to account for the behaviour problems of the majority. Personality tests, however, showed a different picture. Over 70% of those tested manifested an acute need of tenderness and a similar number a high level of potential aggressiveness. Almost half of the minors expressed such feelings as intolerance or a desire for revenge, and Ms. Voicu-Minea found a clear weakness of the Self. Around half the sample expressed sentiments of abandonment, renunciation and solitude.

Simulated winter circulation types in the North Atlantic and European region for preindustrial and glacial conditions

[1] Winter circulation types under preindustrial and glacial conditions are investigated and used to quantify their impact on precipitation. The analysis is based on daily mean sea level pressure fields of a highly resolved atmospheric general circulation model and focuses on the North Atlantic and European region. We find that glacial circulation types are dominated by patterns with an east-west pressure gradient, which clearly differs from the predominantly zonal patterns for the recent past. This is also evident in the frequency of occurrence of circulation types when projecting preindustrial circulation types onto the glacial simulations. The elevation of the Laurentide ice sheet is identified as a major cause for these differences. In areas of strong precipitation signals in glacial times, the changes in the frequencies of occurrence of the circulation types explain up to 60% of the total difference between preindustrial and glacial simulations.