A novel family of L-amino acid-based biodegradable polymer-lipid conjugates for the development of long-circulating liposomes with effective drug-targeting capacity.

The objective of this study was to develop biodegradable polypeptide-lipid conjugates for the design of polymer-coated long-circulating liposomes (LCL). Lipid conjugates of poly(hydroxyalkyl L-asparagine/L-glutamine) were synthesized and incorporated into 0.15 microm dipalmitoyl phosphatidylcholine (DPPC)-cholesterol liposomes.

Intravenous liposomal prednisolone downregulates in situ TNF-alpha production by T-cells in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) relapses are treated with high-dose IV glucocorticosteroids. Here we investigated mechanisms of long-circulating polyethylene glycol-coated liposomes encapsulating prednisolone (PL) in adoptive transfer experimental autoimmune encephalomyelitis. Rats received IV 10 mg/kg PL 6, 18, or 42 hr before sacrifice at disease maximum.

Complete remission of experimental arthritis by joint targeting of glucocorticoids with long-circulating liposomes.

Objective: To increase the therapeutic activity of glucocorticoids in experimental arthritis by encapsulation in long-circulating polyethylene glycol liposomes, which have shown the ability to preferentially accumulate in inflamed joints after intravenous administration.

Methods: Rats with adjuvant-induced arthritis (AIA) were treated intravenously with liposomal and free prednisolone phosphate (PLP) a few days after the first signs of disease. The effect on paw inflammation scores during the weeks after treatment was evaluated.

Inflammatory bowel disease and liver transplantation for primary sclerosing cholangitis.

Objectives: To compare the outcome of liver transplantation in primary sclerosing cholangitis (PSC) patients with and without inflammatory bowel disease (IBD), and to analyse the influence of the transplantation on the course of IBD.

Methods: Retrospective analysis of the data regarding PSC, IBD, and liver transplantation in all patients transplanted for PSC.

Setting: Single university transplantation centre.

Successful liver transplantation in a patient with sickle-cell anaemia.

Liver transplantation in the setting of sickle-cell anaemia poses several new challenges to the transplant team. Hypoxaemia, acidosis and a decrease in body temperature are common occurrences that can cause sickling in the peri-operative period, putting the patient at risk of sickle-cell crises or graft dysfunction. We describe a patient with sickle-cell anaemia who successfully underwent transplantation, and we discuss the rationale of various precautions that had to be taken.

Drug targeting by long-circulating liposomal glucocorticosteroids increases therapeutic efficacy in a model of multiple sclerosis.

High-dose glucocorticosteroid hormones are a mainstay in the treatment of relapses in multiple sclerosis. We searched for a way to deliver ultra high doses of glucocorticosteroids to the CNS of rats with experimental autoimmune encephalomyelitis (EAE) using a novel formulation of polyethylene glycol (PEG)-coated long-circulating liposomes encapsulating prednisolone (predni solone liposomes, PL). 3H-labelled PL showed selective targeting to the inflamed CNS, where up to 4.

Blockade of intragraft IL-2 receptor-alpha by basiliximab is insufficient to prevent activation of liver graft infiltrating cells.

Treatment with basiliximab, a CD25 (Interleukin-2 receptor-alpha; IL-2Ralpha)-blocking human-murine chimeric antibody, reduces the incidence of acute rejections after organ transplantation, but rejection is not completely prevented. We investigated whether rejections during basiliximab treatment were due to insufficient exposure to the antibody or to incomplete blockade of intragraft CD25, and whether CD25-blockade affected activation of liver transplant infiltrating cells. Twenty-seven basiliximab-treated liver transplant recipients and seven patients not treated with basiliximab, from which post-transplant liver biopsies were available, were retrospectively selected for this study.

Mycophenolic acid is a potent inhibitor of the expression of tumour necrosis factor- and tumour necrosis factor-receptor superfamily costimulatory molecules.

The tumour necrosis factor (TNF) ligands CD154, CD70 and TNF receptors CD134 and CD137 are all involved in allograft rejection. Because these molecules are not present on resting T cells, we investigated whether immunosuppressive drugs could inhibit their induction. Expression was induced in vitro on T cells by phorbol 12-myristate 13-acetate and ionomycin or by allogeneic dendritic cells in the presence or absence of cyclosporin A (CsA), tacrolimus (TAC), rapamycin derivative (SDZ RAD), or mycophenolic acid (MPA), and determined by flow cytometry.

Expression of CD80 on Kupffer cells is enhanced in cadaveric liver transplants.

In experimental animals inhibition of T cell co-stimulation immediately after organ transplantation effectively prevents rejection. We investigated whether the expression of co-stimulatory molecules is enhanced in cadaveric liver transplants, whether their expression is influenced by the transplantation procedure, and whether variation in expression between liver transplants is related to the occurrence of acute rejection. Expression of CD80, CD86 and the macrophage marker CD68 were determined by immunohistochemistry in biopsies from 40 clinical liver transplants obtained at different time-points during the transplantation procedure, and in normal liver tissue obtained from 10 human livers.

Basiliximab interferes with the detection of soluble IL-2 receptor by the Immulite Immunoassay system.

The use of the Immulite Automated Immunoassay system is becoming an increasingly popular method for accurate and fast measurement of sIL-2R in serum. Here, we report that detection of sIL-2R using the Immulite Immunoassay system in serum samples of patients who are treated with basiliximab, a monoclonal antibody against the alpha-chain of the IL-2 receptor, may lead to false measurements.

Role of complement activation in hypersensitivity reactions to doxil and hynic PEG liposomes: experimental and clinical studies.

Pegylated liposomal doxorubicin (Doxil) and 99mTc-HYNIC PEG liposomes (HPL) were reported earlier to cause hypersensitivity reactions (HSRs) in a substantial percentage of patients treated i.v. with these formulations.

Portal flow diversion is essential for graft survival in canine auxiliary partial orthotopic liver transplantation.

After auxiliary partial orthotopic liver transplantation for inborn errors of metabolism, finding a balance in portal blood flow distribution between native liver and graft is complicated. We investigated the correction of hypoallantoinuria in the Dalmatian dog with a reduced-size Beagle orthotopic auxiliary liver graft, depending on intra-operative intervention in the portal flow. There were three groups: a ligation group, where the host portal vein was tied off, a free-flow group with random flow to both livers and a banding group, where the host portal vein was banded with an adjustable strapband.

Are cytokine gene polymorphisms related to in vitro cytokine production profiles?

Currently, there is much interest in the genetic basis for diseases or disease manifestations and, in particular, in whether they are related to cytokine gene polymorphisms. It has become accepted to denote such single-nucleotide polymorphisms of cytokine genes by their presumed association with high or low in vitro cytokine production. In this article, we analyze the relationship between cytokine gene polymorphisms and in vitro tumor necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), and interleukin (IL)-10 and IL-13 production, both in liver transplant recipients and in healthy volunteers.

Early differentiation between rejection and infection in liver transplant patients by serum and biliary cytokine patterns.

Background: Differentiation between acute liver graft rejection and infection remains a clinical challenge during the early posttransplantation period. Although cytokines play a pivotal role in mediating allograft rejection, previous studies demonstrate that most cytokines are not specific for liver graft rejection or infections. However, other studies suggest that adhesion molecules and cytokines in bile reflect the immunologic activity within the liver more closely.

Liposomes for intravenous drug targeting: design and applications.

Drug targeting with liposomes has been studied for over 25 years and has demonstrated its value in clinical practice. This mini review offers an overview of the design and application of liposomes for i.v.

Granzyme expression in fine-needle aspirates from liver allografts is increased during acute rejection.

We investigated whether determination in fine-needle aspiration biopsy (FNAB) specimens of cells expressing granzymes (Grs) and Fas ligand would provide a reliable, easy, and quantitative measure of rejection activity in the transplanted liver. Retrospectively, 13 FNAB specimens obtained during clinical acute rejection, 10 FNAB specimens obtained during subclinical rejection, 12 FNAB specimens obtained during cytomegalovirus (CMV) infection, and 26 FNAB specimens obtained in the absence of rejection or infection were included on the study. Cytospin preparations of FNAB and peripheral-blood specimens were immunocytochemically stained for Fas-ligand and Gr, and increments in the liver were calculated by subtracting frequencies of positive cells in blood from those in FNAB specimens.

[The pregnant patient with acute liver disease].

Acute liver disease was diagnosed in three pregnant patients: two 30-year-old women had a 'haemolysis, elevated liver enzymes, low platelets' (HELLP) syndrome and acute fatty liver of pregnancy, respectively, and a 20-year-old woman had acute liver failure due to acute hepatitis B. The first two patients had a caesarean section, the third one delivered her child, which died spontaneously shortly after birth at a gestational age of 23 weeks. She was then treated by liver transplantation.

Cytokine gene polymorphisms and acute human liver graft rejection.

Interindividual differences exist in the capacity to produce cytokines. It has been reported that levels of in vitro cytokine production measured after stimulated cell culture are associated with polymorphisms in cytokine genes. Moreover, a correlation between heart, kidney, liver, and lung graft rejection or survival with cytokine gene polymorphisms has been described.

Selective decontamination of the digestive tract to prevent postoperative infection: a randomized placebo-controlled trial in liver transplant patients.

Objective: To determine the efficacy of selective decontamination of the digestive tract (SDD) in patients undergoing elective transplantation of the liver.

Design: Randomized, double-blind, placebo-controlled study.

Setting: Two academic teaching hospitals.

Pseudo-Budd-Chiari Syndrome: decompensated alcoholic liver disease mimicking hepatic venous outflow obstruction.

Three patients with rapid onset decompensated liver disease who were referred to our hospital with presumed Budd-Chiari syndrome are described. This diagnosis was based on marked hepatomegaly, caudate lobe hypertrophy and failure to visualize hepatic veins by Doppler-ultrasound examination. Detailed history, biochemistry, and histology were, however, highly suggestive of alcoholic liver cirrhosis with steatohepatitis-induced hepatomegaly.