Toward more effective gene delivery

A report on the symposium 'In vivo barriers to gene delivery', Cold Spring Harbor, USA, 26-29 November 2007

Hospital‐Level Variation in the Use of Intensive Care

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93706/1/hesr1402.pd

The experiences of veterans with mental health problems participating in an occupational therapy and resilience workshop intervention: an exploratory study

Introduction Occupational therapy has long had a strong presence in military mental healthcare. Today’s veterans have complex needs and can face challenges reintegrating into civilian life. This exploratory study investigated whether veterans receiving mental health treatment who participated in a bespoke occupational therapy and resilience workshop intervention improved their perceived participation in everyday life. Method An interpretivist hermeneutic phenomenological approach was used to explore veterans’ perspectives. Ten participants took part in two semistructured focus groups. Thematic analysis was used to identify and analyse patterns within the data. Findings Most participants developed occupational goals and started to make lifestyle changes; participants developed an appreciation of the value of occupation; participants developed insight into their recovery journeys; and value was placed on the ‘healing power’ of the group. Conclusion This exploratory study provides preliminary evidence to suggest occupational therapy was influential in helping participants understand the impact of occupation on health and start making lifestyle changes. Participants also reflected on their recovery journeys. The benefits of doing this within a group environment appear to have been particularly therapeutic. Original occupational therapy research in this specialism is sparse. This novel study provides insight that can further discussion and enhance understanding about what the profession can offer this client group

Investigating predictive coding in younger and older children using MEG and a multi-feature auditory oddball paradigm

There is mounting evidence for predictive coding theory from computational, neuroimaging, and psychological research. However, there remains a lack of research exploring how predictive brain function develops across childhood. To address this gap, we used pediatric magnetoencephalography to record the evoked magnetic fields of 18 younger children (M = 4.1 years) and 19 older children (M = 6.2 years) as they listened to a 12-min auditory oddball paradigm. For each child, we computed a mismatch field "MMF": an electrophysiological component that is widely interpreted as a neural signature of predictive coding. At the sensor level, the older children showed significantly larger MMF amplitudes relative to the younger children. At the source level, the older children showed a significantly larger MMF amplitude in the right inferior frontal gyrus relative to the younger children, P < 0.05. No differences were found in 2 other key regions (right primary auditory cortex and right superior temporal gyrus) thought to be involved in mismatch generation. These findings support the idea that predictive brain function develops during childhood, with increasing involvement of the frontal cortex in response to prediction errors. These findings contribute to a deeper understanding of the brain function underpinning child cognitive development

Studying Brain Function in Children Using Magnetoencephalography

Magnetoencephalography (MEG) is a non-invasive neuroimaging technique which directly measures magnetic fields produced by the electrical activity of the human brain. MEG is quiet and less likely to induce claustrophobia compared with magnetic resonance imaging (MRI). It is therefore a promising tool for investigating brain function in young children. However, analysis of MEG data from pediatric populations is often complicated by head movement artefacts which arise as a consequence of the requirement for a spatially-fixed sensor array that is not affixed to the child's head. Minimizing head movements during MEG sessions can be particularly challenging as young children are often unable to remain still during experimental tasks. The protocol presented here aims to reduce head movement artefacts during pediatric MEG scanning. Prior to visiting the MEG laboratory, families are provided with resources that explain the MEG system and the experimental procedures in simple, accessible language. An MEG familiarization session is conducted during which children are acquainted with both the researchers and the MEG procedures. They are then trained to keep their head still whilst lying inside an MEG simulator. To help children feel at ease in the novel MEG environment, all of the procedures are explained through the narrative of a space mission. To minimize head movement due to restlessness, children are trained and assessed using fun and engaging experimental paradigms. In addition, children's residual head movement artefacts are compensated for during the data acquisition session using a real-time head movement tracking system. Implementing these child-friendly procedures is important for improving data quality, minimizing participant attrition rates in longitudinal studies, and ensuring that families have a positive research experience

Temporal spatial and metabolic measures of walking in highly functional individuals with lower limb amputations

OBJECTIVE: The aim of this descriptive exploratory study is to record the temporal spatial parameters and metabolic energy expenditure during walking of individuals with amputation, walking with advanced prostheses and following completion of comprehensive rehabilitation, to able-bodied controls. DESIGN: Cross-sectional SETTING: Multi-disciplinary comprehensive rehabilitation centre PARTICIPANTS: Thirty severely injured United Kingdom military personnel with amputation and subsequent completion of their rehabilitation programme (10 unilateral trans-tibial, 10 unilateral trans-femoral, and 10 bilateral trans-femoral) were compared to (and of similar age, height and mass (p &lt; 0.537) as) 10 able-bodied controls. INTERVENTIONS: Not applicable Main Outcomes and Measures: Temporal spatial and metabolic energy expenditure data were captured during walking on level ground at self-selected speed. RESULTS: The individuals with amputation were all male, with a mean age 29 years (SD = 4) and mean New Injury Severity Score of 31 (SD = 16). Walking speed, stride length, step length and cadence of individuals with a unilateral trans-tibial or trans-femoral amputation was comparable to controls, and only for individuals with a bilateral trans-femoral amputation was walking speed significantly slower (1·12m/s, p = 0.025) and cadence reduced (96 steps/min, p = 0.026). Oxygen cost for individuals with a unilateral trans-tibial amputation (0·15 ml/kg/m) was the same as for controls (0·15 ml/kg/m), and significantly increased by 20% (0·18ml/kg/m, p = 0.023) for unilateral trans-femoral and by 60% (0·24 ml/kg/m, p &lt; 0.001) for bilateral trans-femoral individuals with amputation. CONCLUSION: The scientific literature reports a wide range of gait and metabolic energy expenditure across individuals with amputation. The results of this study indicate that the individuals with amputation have a gait pattern which is highly functional and efficient. This is comparable to a small number of studies reporting similar outcomes for individuals with a unilateral trans-tibial amputation, but the results from this study are better than those on individuals with trans-femoral amputations reported elsewhere, despite comparison with populations wearing similar prosthetic componentry. Those studies that do report similar outcomes have included individuals who have been provided with a comprehensive rehabilitation programme. This suggests that such a programme may be as important as, or even more important than, prosthetic component selection in improving metabolic energy expenditure. The data are made available as a benchmark for what is achievable in the rehabilitation of some individuals with amputations, but agreeably may not be possible for all amputees to achieve

Active Adenoviral Vascular Penetration by Targeted Formation of Heterocellular Endothelial–epithelial Syncytia

The endothelium imposes a structural barrier to the extravasation of systemically delivered oncolytic adenovirus (Ad). Here, we introduced a transendothelial route of delivery in order to increase tumor accumulation of virus particles (vp) beyond that resulting from convection-dependent extravasation alone. This was achieved by engineering an Ad encoding a syncytium-forming protein, gibbon ape leukemia virus (GALV) fusogenic membrane glycoprotein (FMG). The expression of GALV was regulated by a hybrid viral enhancer-human promoter construct comprising the human cytomegalovirus (CMV) immediate-early enhancer and the minimal human endothelial receptor tyrosine kinase promoter (“eTie1”). Endothelial cell-selectivity of the resulting Ad-eTie1-GALV vector was demonstrated by measuring GALV mRNA transcript levels. Furthermore, Ad-eTie1-GALV selectively induced fusion between infected endothelial cells and uninfected epithelial cells in vitro and in vivo, allowing transendothelial virus penetration. Heterofusion of infected endothelium to human embryonic kidney 293 (HEK 293) cells, in mixed in vitro cultures or in murine xenograft models, permitted fusion-dependent transactivation of the replication-deficient Ad-eTie1-GALV, due to enabled access to viral E1 proteins derived from the HEK 293 cytoplasm. These data provide evidence to support our proposed use of GALV to promote Ad penetration through tumor-associated vasculature, an approach that may substantially improve the efficiency of systemic delivery of oncolytic viruses to disseminated tumors

Use of Tissue-Specific MicroRNA to Control Pathology of Wild-Type Adenovirus without Attenuation of Its Ability to Kill Cancer Cells

Replicating viruses have broad applications in biomedicine, notably in cancer virotherapy and in the design of attenuated vaccines; however, uncontrolled virus replication in vulnerable tissues can give pathology and often restricts the use of potent strains. Increased knowledge of tissue-selective microRNA expression now affords the possibility of engineering replicating viruses that are attenuated at the RNA level in sites of potential pathology, but retain wild-type replication activity at sites not expressing the relevant microRNA. To assess the usefulness of this approach for the DNA virus adenovirus, we have engineered a hepatocyte-safe wild-type adenovirus 5 (Ad5), which normally mediates significant toxicity and is potentially lethal in mice. To do this, we have included binding sites for hepatocyte-selective microRNA mir-122 within the 39 UTR of the E1A transcription cassette. Imaging versions of these viruses, produced by fusing E1A with luciferase, showed that inclusion of mir-122 binding sites caused up to 80-fold decreased hepatic expression of E1A following intravenous delivery to mice. Animals administered a ten-times lethal dose of wild-type Ad5 (5610 10 viral particles/mouse) showed substantial hepatic genome replication and extensive liver pathology, while inclusion of 4 microRNA binding sites decreased replication 50-fold and virtually abrogated liver toxicity. This modified wild-type virus retained full activity within cancer cells and provided a potent, liver-safe oncolytic virus. In addition to providing many potent new viruses for cancer virotherapy, microRNA control of virus replication should provide a new strategy for designing safe attenuated vaccines applied across a broad range of viral disease