Prevention of peritoneal adhesions:A promising role for gene therapy

Adhesions are the most frequent complication of abdominopelvic surgery,yet the extent of the problem,and its serious consequences,has not been adequately recognized.Adhesions evolved as a life-saving mecha-nism to limit the spread of intraperitoneal inflammatory conditions.Three different pathophysiological mechanisms can independently trigger adhesion formation.Mesothelial cell injury and loss during operations,tissue hypoxia and inflammation each promotes adhesion formation separately,and potentiate the effect of each other.Studies have repeatedly demonstrated that interruption of a single pathway does not completely prevent adhesion formation.This review summarizes the pathogenesis of adhesion formation and the results of single gene therapy interventions.It explores the prom-ising role of combinatorial gene therapy and vector modif ications for the prevention of adhesion formation in order to stimulate new ideas and encourage rapid advancements in this field.

Protein phosphatase 2A,a key player in Alzheimer’s disease

Protein phosphatase 2A(PP2A)is the pre-dominant serine/threonine phosphatase in eukaryotic cells.In the brains of patients with Alzheimer’s disease(AD),decreased PP2A activities were observed,which is suggested to be involved in neurofibrillary tangle(NFT)formation,disturbed amyloid precursor protein(APP)secretion and neurodegeneration in AD brain.Based on our research and other previousfindings,decreased PP2Ac level,decreased PP2A holoenzyme composition,increased level of PP2A inhibitors,increased PP2Ac Leu309 demethylation and Tyr307 phosphorylation underlie PP2A inactivation in AD.β-amyloid(Aβ)over-production,estrogen deficiency and impaired homocys-teine metabolism are the possible up-stream factors that inactivate PP2A in AD neurons.Further studies are required to disclose the role of PP2A in Alzheimer’s disease.

Pseudovirus-based neuraminidase inhibition assays reveal potential H5N1 drug-resistant mutations

The use of antiviral drugs such as influenza neuraminidase (NA) inhibitors is a critical strategy to prevent and control flu pandemic, but this strategy faces the challenge of emerging drug-resistant strains. For a highly pathogenic avian influenza (HPAI) H5N1 virus, biosafety restrictions have significantly limited the efforts to monitor its drug responses and mechanisms involved. In this study, a rapid and biosafe assay based on NA pseudovirus was developed to study the resistance of HPAI H5N1 virus to NA inhibitor drugs. The H5N1 NA pseudovirus was comprehensively tested using oseltamivir-sensitive strains and their resistant mutants. Results were consistent with those in previous studies, in which live H5N1 viruses were used. Several oseltamivir-resistant mutations reported in human H1N1 were also identified to cause decreased oseltamivir sensitivity in H5N1 NA by using the H5N1 NA pseudovirus. Thus, H5N1 NA pseudoviruses could be used to monitor HPAI H5N1 drug resistance rapidly and safely.

Calcineurin Inhibitors in the Treatment of Adult Autoimmune Hepatitis:A Systematic Review

Background and Aims:A considerable number of au-toimmune hepatitis(AIH)patients completely or partially fail on first-line treatment.Several studies on the use of calcineurin inhibitors(CNIs)in the treatment of AIH have been published without focusing on indication.The aim was to assess the efficacy of CNIs in the treatment of adult AIH patients,specifically focusing on indication:first-line intolerant and with first-line insufficient response(failure to achieve or maintain remission),and with second versus third-line treatment.Methods:A literature search included studies on the use of CNIs in adult AIH.Patients with past or present use of CNIs from the Dutch AIH group cohort were added.The primary endpoint was biochemical remission while using CNIs.Secondary endpoints were biochemical response,treatment failure,and adverse effects.Results:Twenty studies from the literature and nine Dutch patients were included describing the use of cyclosporine in 59 and tacrolimus in 219 adult AIH patients.The CNI remission rate was 53%in patients with insufficient response to first-line treatment and 67%in patients intolerant to first-line treat-ment.CNIs were used as second-line treatment in 73%with a remission rate of 52%and as third-line treatment in 22%with a remission rate of 26%.Cyclosporine was discontin-ued in 13%and tacrolimus in 11%of patients because of adverse events.Conclusions:CNIs as rescue treatment in adult AIH patients are reasonably effective and safe both with insufficient response or intolerance to previous treat-ment.Prospective studies are needed.