Gradual physical decline characterises the illness trajectories of care home residents.

Background: Three archetypal trajectories of physical decline have been identified: a short period of rapid decline; long-term limitations with intermittent acute periods; and a prolonged gradual decline. An understanding of illness trajectories can help clarify the evolving needs of people with progressive conditions, and inform the development of palliative care services to meet their needs. Many frail older people live and die in care homes; the present study is the first to explore the illness trajectories of residents in care home settings.

Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis.

We have recently shown that non-viral gene therapy can stabilise the decline of lung function in patients with cystic fibrosis (CF). However, the effect was modest, and more potent gene transfer agents are still required. Fuson protein (F)/Hemagglutinin/Neuraminidase protein (HN)-pseudotyped lentiviral vectors are more efficient for lung gene transfer than non-viral vectors in preclinical models.

Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial.

Background: Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis.

Methods: We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK.

Anticipatory prescribing at the end of life in Lothian care homes.

Common symptoms at the end of life include pain, breathlessness, anxiety, respiratory secretions and nausea. National end-of-life care strategies advocate anticipatory prescribing for timely management of these symptoms to enhance patient care by preventing unnecessary distress. This study investigated the extent to which residents in eight Lothian care homes had anticipatory medications prescribed prior to death.

Improving end-of-life care in nursing homes: implementation and evaluation of an intervention to sustain quality of care.

Background: Internationally, policy calls for care homes to provide reliably good end-of-life care. We undertook a 20-month project to sustain palliative care improvements achieved by a previous intervention.

Aim: To sustain a high standard of palliative care in seven UK nursing care homes using a lower level of support than employed during the original project and to evaluate the effectiveness of this intervention.

Differential global gene expression in cystic fibrosis nasal and bronchial epithelium.

Respiratory epithelium is the target of therapies, such as gene therapy, for cystic fibrosis (CF) lung disease. To determine the usefulness of the nasal epithelium as a pre-screen for lung-directed therapies, we profiled gene expression in CF and non-CF nasal and bronchial epithelium samples using Illumina HumanRef-8 Expression BeadChips. 863 genes were differentially expressed between CF and non-CF bronchial epithelium but only 15 were differentially expressed between CF and non-CF nasal epithelium (≥1.

The use of carboxymethylcellulose gel to increase non-viral gene transfer in mouse airways.

We have assessed whether viscoelastic gels known to inhibit mucociliary clearance can increase lipid-mediated gene transfer. Methylcellulose or carboxymethylcellulose (0.25-1.

Detection of CFTR transgene mRNA expression in respiratory epithelium isolated from the murine nasal cavity.

Background: When assessing the efficacy of gene transfer agents (GTAs) for cystic fibrosis (CF) gene therapy, we routinely evaluate gene transfer in the mouse nose and measure transfection efficiency by assessing transgene-specific mRNA using the real-time (TaqMan) quantitative reverse transcriptase-polymerase chain reaction. TaqMan is traditionally used to quantify expression in whole tissue homogenates, which in the nose would contain many cells types, including respiratory and olfactory epithelium. Only the respiratory epithelium is a satisfactory model for human airway epithelium and therefore CFTR gene transfer should be specifically assessed in respiratory epithelial cells (RECs).

Limitations of the murine nose in the development of nonviral airway gene transfer.

A clinical program to assess whether lipid GL67A-mediated gene transfer can ameliorate cystic fibrosis (CF) lung disease is currently being undertaken by the UK CF Gene Therapy Consortium. We have evaluated GL67A gene transfer to the murine nasal epithelium of wild-type and CF knockout mice to assess this tissue as a test site for gene transfer agents. The plasmids used were regulated by either (1) the commonly used short-acting cytomegalovirus promoter/enhancer or (2) the ubiquitin C promoter.

Tripod-like cationic lipids as novel gene carriers.

An innovative family of tridentate-cationic "single-chained lipids" designed to enhance DNA compaction and to promote endosomal escape was synthesized by coupling various lipids to a multibranched scaffold. DNA retardation assays confirmed the ability of the most members of the library to complex DNA. Classical molecular dynamics simulations performed on the lauryl derivative, bound to a short strand of DNA in aqueous solution supported these observations.