Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis E virus

Many recipients of organ transplants develop chronic hepatitis, due to infection with the hepatitis E virus (HEV). Although chronic HEV infection is generally associated with immunosuppressive therapies, little is known about how different immunosuppressants affect HEV infection.status: publishe

mTOR signaling in liver regeneration: Rapamycin combined with growth factor treatment

AIM: To investigate the effects of mammalian target of rapamycin (mTOR) inhibition on liver regeneration and autophagy in a surgical resection model. METHODS: C57BL/6 mice were subjected to a 70% partial hepatectomy (PH) and treated intraperitoneally every 24 h with a combination of the mTOR inhibitor rapamycin (2.5 mg/kg per day) and the steroid dexamethasone (2.0 mg/kg per day) in phosphate buffered saline (PBS) or with PBS alone as vehicle control. In the immunosuppressant group, part of the group was treated subcutaneously 4 h prior to and 24 h after PH with a combination of human recombinant interleukin 6 (IL-6; 500 μg/kg per day) and hepatocyte growth factor (HGF; 100 μg/kg per day) in PBS. Animals were sacrificed 2, 3 or 5 d after PH and liver tissue and blood were collected for further analysis. Immunohistochemical staining for 5-Bromo-2'-deoxyuridine (BrdU) was used to quantify hepatocyte proliferation. Western blotting was used to detect hepatic microtubule-associated protein 1 light chain 3 (LC3)-II protein expression as a marker for autophagy. Hepatic gene expression levels of proliferation-, inflammation- and angiogenesis-related genes were examined by real-time reverse transcription-polymerase chain reaction and serum bilirubin and transaminase levels were analyzed at the clinical chemical core facility of the Erasmus MC-University Medical Center. RESULTS: mTOR inhibition significantly suppressed regeneration, shown by decreased hepatocyte proliferation (2% vs 12% BrdU positive hepatocyte nuclei at day 2, P < 0.01; 0.8% vs 1.4% at day 5, P = 0.02) and liver weight reconstitution (63% vs 76% of initial total liver weight at day 3, P = 0.04), and furthermore increased serum transaminase levels (aspartate aminotransferase 641 U/L vs 185 U/L at day 2, P = 0.02). Expression of the autophagy marker LC3-II, which was reduced during normal liver regeneration, increased after mTOR inhibition (46% increase at day 2, P = 0.04). Hepatic gene expression showed an increased inflammation-related response [tumor necrosis factor (TNF)-α 3.2-fold upregulation at day 2, P = 0.03; IL-1Ra 6.0-fold upregulation at day 2 and 42.3-fold upregulation at day 5, P < 0.01] and a reduced expression of cell cycle progression and angiogenesis-related factors (HGF 40% reduction at day 2; vascular endothelial growth factor receptor 2 50% reduction at days 2 and 5; angiopoietin 1 60% reduction at day 2, all P ≤ 0.01). Treatment with the regeneration stimulating cytokine IL-6 and growth factor HGF could overcome the inhibitory effect on liver weight (75% of initial total liver weight at day 3, P = 0.02 vs immunosuppression alone and P = 0.90 vs controls) and partially reversed gene expression changes caused by rapamycin (TNF-α and IL-1Ra levels at day 2 were restored to control levels). However, no significant changes in hepatocyte proliferation, serum injury markers or autophagy were found. CONCLUSION: mTOR inhibition severely impairs liver regeneration and increases autophagy after PH. These effects are partly reversed by stimulation of the IL-6 and HGF pathways

The CHORUS honeycomb tracker and its bitstream electronics

The CHORUS experiment searches for nu(mu)nu(tau) oscillation. To aid in the momentum reconstruction of charged hadrons, a honeycomb tracker was built with three orientations of six planes each. The planes are manufactured by point-welding together two precision folded conductive polycarbonate foils, forming hexagonal tubes with 30 mu m thick anode wires in the center. The honeycomb tracker in CHORUS is read out using a bitstream principle. The amplified signal of each wire is binary sampled every 5 ns and stored in a 256 bit circular buffer, implemented in dual-port memories. This technique allows a full reconstruction of a 1.28 mu s history of each wire. Eighteen cards, each handling 72 wires, are read out over a single flat cable using a card-to-card pipeline. (C) 1998 Elsevier Science B.V. All rights reserved

Liposomal encapsulation enhances the antitumour efficacy of the vascular disrupting agent ZD6126 in murine B16.F10 melanoma

Vascular disrupting agents (VDAs) are able to affect selectively tumour endothelial cell morphology resulting in vessel occlusion and widespread tumour cell necrosis. However, single-agent antitumour activity of VDAs is typically limited, as tumour regrowth occurs rapidly following drug treatment. To improve the therapeutic effectiveness of VDAs, we investigated liposomal targeting using ZD6126 as a model VDA. ZD6126 is a phosphate-prodrug of the tubulin-binding vascular disrupting agent ZD6126 phenol. ZD6126 was encapsulated into long circulating PEG-liposomes for passive targeting and PEG-liposomes conjugated with peptide ligands containing the RGD-motif for active targeting to alpha(v)-integrins on tumour endothelial cells. ZD6126 could be stably encapsulated, and liposomes displayed minimal leakage in vitro (&lt;10% in 3 weeks). In vivo, upon intravenous injection, free ZD6126 was rapidly converted into ZD6126 phenol, which was cleared from the circulation within minutes. In contrast, ZD6126 encapsulated into either RGD-targeted or PEG liposomes showed prolonged blood circulation times (t(1/2)=10 h), and ZD6126 phenol exposure was also prolonged (t(1/2)=8 h). Both liposomal formulations displayed tumour accumulation plus hepatosplenic uptake by local macrophages. The altered pharmacokinetics and tissue distribution profiles of both liposomal ZD6126 formulations resulted both in single-dose and multiple-dose regimes, in improved therapeutic efficacy in established murine B16.F10 melanomas compared with free ZD6126. The passively and actively targeted liposomes showed equal antitumour efficacy, indicating that delivery of ZD6126 to the tumour tissue may suffice to disrupt tumour blood vessels without the need for specific targeting to the tumour endothelium

The Best Interest of the Child Self-report questionnaire (BIC-S):Results of a participatory development process

This paper provides insight into the participatory development process of a self-report questionnaire for adolescents: the Best Interest of the Child Self-report questionnaire (BIC-S). The BIC-S is based on the 'Best Interest of the Child' model. This model articulates, in line with the UN Convention on the Rights of the Child, 14 childcare conditions promoting the wellbeing and development of young people. The primary intention of the BIC-S is to give young people in care a voice regarding decisions in legal and care areas that impact their future. The development process of the BIC-S consisted of three main phases (exploration, consultation, pilot), containing a total of five different research stages. Adolescents placed in secure residential care, care professionals and university students were involved in the process. We developed a differentiated instrument that enables young people to express their own views on key aspects of their current and future living conditions. The digitized questionnaire is unique in its comprehensiveness, accessibility and attractiveness for young people, and generates an evaluative profile of care conditions from the adolescents themselves. The paper shows how a theoretically sound questionnaire can be constructed to conform to standards set by adolescents themselves. The BIC-S can serve as a productive vehicle for assessment and shared decision-making in the field of youth care - both at the micro level of individual treatment and at the meso level of evaluating group programmes. Further research into its use in practice is recommended

Cellulose-Based Matrix Microspheres of Prednisolone Inclusion Complex: Preparation and Characterization

The purpose of the present investigation was to encapsulate pure prednisolone (PRD) and PRD–hydroxypropyl-β-cyclodextrin (HPβCD) complex in cellulose-based matrix microspheres. The system simultaneously exploits complexation technique to enhance the solubility of low-solubility drug (pure PRD) and subsequent modulation of drug release from microspheres (MIC) at a predetermined time. The microspheres of various compositions were prepared by an oil-in-oil emulsion–solvent evaporation method. The effect of complexation and presence of cellulose polymers on entrapment efficiency, particle size, and drug release had been investigated. The solid-state characterization was performed by Fourier transform infrared spectroscopy, thermogravimetry, differential scanning calorimetry, and powder X-ray diffractometry. The morphology of MIC was examined by scanning electron microscopy. The in vitro drug release profiles from these microspheres showed the desired biphasic release behavior. After enhancing the solubility of prednisolone by inclusion into HPβCD, the drug release was easily modified in the microsphere formulation. It was also demonstrated that the CDs in these microspheres were able to modulate several properties such as morphology, drug loading, and release properties. The release kinetics of prednisolone from microspheres followed quasi-Fickian and first-order release mechanisms. In addition to this, the f2-metric technique was used to check the equivalency of dissolution profiles of the optimized formulation before and after stability studies, and it was found to be similar. A good outcome, matrix microspheres (coded as MIC5) containing PRD–HPβCD complex, showed sustained release of drug (95.81%) over a period of 24 h