Using interpretative phenomenological analysis to inform physiotherapy practice: An introduction with reference to the lived experience of cerebellar ataxia

The attached file is a pre-published version of the full and final paper which can be found at the link below.This article has been made available through the Brunel Open Access Publishing Fund.Qualitative research methods that focus on the lived experience of people with health conditions are relatively underutilised in physiotherapy research. This article aims to introduce interpretative phenomenological analysis (IPA), a research methodology oriented toward exploring and understanding the experience of a particular phenomenon (e.g., living with spinal cord injury or chronic pain, or being the carer of someone with a particular health condition). Researchers using IPA try to find out how people make sense of their experiences and the meanings they attach to them. The findings from IPA research are highly nuanced and offer a fine grained understanding that can be used to contextualise existing quantitative research, to inform understanding of novel or underresearched topics or, in their own right, to provoke a reappraisal of what is considered known about a specified phenomenon. We advocate IPA as a useful and accessible approach to qualitative research that can be used in the clinical setting to inform physiotherapy practice and the development of services from the perspective of individuals with particular health conditions.This article is available through the Brunel Open Access Publishing Fund

Increased Matrix Metalloproteinase (MMPs) Levels Do Not Predict Disease Severity or Progression in Emphysema

Rationale: Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema. Methods: Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period. Main Results: Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline. Conclusions: MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease. © 2013 D'Armiento et al

A High Throughput Amenable Arabidopsis-P. aeruginosa System Reveals a Rewired Regulatory Module and the Utility to Identify Potent Anti-Infectives

We previously demonstrated that in a metasystem consisting of Arabidopsis seedlings growing in liquid medium (in 96 well plates) even microbes considered to be innocuous such as laboratory strains of E. coli and B. subtilis can cause potent damage to the host. We further posited that such environment-induced adaptations are brought about by ‘system status changes’ (rewiring of pre-existing cellular signaling networks and components) of the host and the microbe, and that prolongation of such a situation could lead to the emergence of pathogenic states in real-life. Here, using this infection model, we show that the master regulator GacA of the human opportunistic pathogen P. aeruginosa (strain PA14) is dispensable for pathogenesis, as evidenced by three independent read-outs. The gene expression profile of the host after infection with wild type PA14 or the gacA mutant are also identical. GacA normally acts upstream of the quorum sensing regulatory circuit (that includes the regulator LasR) that controls a subset of virulence factors. Double mutants in gacA and lasR behave similar to the lasR mutant, as seen by abrogation of a characteristic cell type specific host cell damage caused by PA14 or the gacA mutant. This indicates that a previously unrecognized regulatory mechanism is operative under these conditions upstream of LasR. In addition, the detrimental effect of PA14 on Arabidopsis seedlings is resistant to high concentrations of the aminoglycoside antibiotic gentamicin. These data suggest that the Arabidopsis seedling infection system could be used to identify anti-infectives with potentially novel modes of action

Performance deficits of NK1 receptor knockout mice in the 5 choice serial reaction time task: effects of d Amphetamine, stress and time of day.

Background The neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by d-amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon. Methods and Results The 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without, d-amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater omissions (inattentiveness), perseveration and premature responses (impulsivity) in the 5-CSRTT. In NK1R-/- mice, perseveration in the LITI was increased by injection-stress but reduced by d-amphetamine. Omissions by NK1R-/- mice in the VITI were unaffected by d-amphetamine, but premature responses were exacerbated by this psychostimulant. Omissions in the VITI were higher, overall, in the morning than the afternoon but, in the LITI, premature responses of NK1R-/- mice were higher in the afternoon than the morning. Conclusion In addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because d-amphetamine reduced perseveration in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of omissions and premature responses in NK1R-/- mice given d-amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies

The bashful and the boastful : prestigious leaders and social change in Mesolithic Societies

The creation and maintenance of influential leaders and authorities is one of the key themes of archaeological and historical enquiry. However the social dynamics of authorities and leaders in the Mesolithic remains a largely unexplored area of study. The role and influence of authorities can be remarkably different in different situations yet they exist in all societies and in almost all social contexts from playgrounds to parliaments. Here we explore the literature on the dynamics of authority creation, maintenance and contestation in egalitarian societies, and discuss the implications for our interpretation and understanding of the formation of authorities and leaders and changing social relationships within the Mesolithic

Treatment of atypical central neurocytoma in a child with high dose chemotherapy and autologous stem cell rescue

The authors describe a 9 month old female with recurrent atypical central neurocytoma and leptomeningeal spread treated with high dose chemotherapy, autologous stem cell rescue, and adjuvant therapy. She had a complete response to therapy and was disease free at 4 years of age until a recurrence 6 months later. The use of intensive chemotherapy followed by autologous stem cell rescue for atypical neurocytoma may be considered as an adjunct to surgical therapy in young patients with atypical neurocytoma not amenable to radiation therapy

Rab-GTPase binding effector protein 2 (RABEP2) is a primed substrate for Glycogen Synthase kinase-3 (GSK3)

Glycogen synthase kinase-3 (GSK3) regulates many physiological processes through phosphorylation of a diverse array of substrates. Inhibitors of GSK3 have been generated as potential therapies in several diseases, however the vital role GSK3 plays in cell biology makes the clinical use of GSK3 inhibitors potentially problematic. A clearer understanding of true physiological and pathophysiological substrates of GSK3 should provide opportunities for more selective, disease specific, manipulation of GSK3. To identify kinetically favourable substrates we performed a GSK3 substrate screen in heart tissue. Rab-GTPase binding effector protein 2 (RABEP2) was identified as a novel GSK3 substrate and GSK3 phosphorylation of RABEP2 at Ser200 was enhanced by prior phosphorylation at Ser204, fitting the known consensus sequence for GSK3 substrates. Both residues are phosphorylated in cells while only Ser200 phosphorylation is reduced following inhibition of GSK3. RABEP2 function was originally identified as a Rab5 binding protein. We did not observe co-localisation of RABEP2 and Rab5 in cells, while ectopic expression of RABEP2 had no effect on endosomal recycling. The work presented identifies RABEP2 as a novel primed substrate of GSK3, and thus a potential biomarker for GSK3 activity, but understanding how phosphorylation regulates RABEP2 function requires more information on physiological roles of RABEP2

A Pilot study of the Sharing Risk Information Tool (ShaRIT) for Families with Hereditary Breast and Ovarian Cancer Syndrome

<p>Abstract</p> <p>Background</p> <p>Individuals who carry deleterious BRCA mutations face significantly elevated risks of breast, ovarian, and other cancers. These individuals are also responsible for informing relatives of their increased risk for carrying the family BRCA mutation. Few interventions have been developed to facilitate this family communication process.</p> <p>Methods</p> <p>We developed the Sharing Risk Information Tool (ShaRIT), a personalized educational intervention, to support BRCA carriers as they discuss BRCA positive results and their implications with relatives. We conducted a pilot study of 19 BRCA carriers identified through the University of California San Francisco Cancer Risk Program. Our study had two aims: 1) to assess the feasibility and acceptability of ShaRIT, and 2) describe characteristics associated with increased family communication and BRCA testing. Participants in our study were divided into two groups: those who had not received ShaRIT as part of their genetic counseling protocol (control group, n = 10) and those who received ShaRIT (n = 9).</p> <p>Results</p> <p>All 9 women who received ShaRIT reported that it was a useful resource. Characteristics associated with increased sharing and testing included: female gender, degree of relationship, and frequency of communication. Increased pedigree knowledge showed a trend toward higher rates of sharing.</p> <p>Conclusions</p> <p>Both participants and genetic counselors considered ShaRIT a well-received, comprehensive tool for disseminating individual risk information and clinical care guidelines to Hereditary Breast and Ovarian Cancer Syndrome families. Because of this, ShaRIT has been incorporated as standard of care at our institution. In the future we hope to evaluate the effects of ShaRIT on family communication and family testing in larger populations of BRCA positive families.</p

An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M. tuberculosis), is a major cause of morbidity and mortality worldwide and efforts to control TB are hampered by difficulties with diagnosis, prevention and treatment 1,2. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease, but current tests cannot identify which individuals will develop disease 3. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines 4,5. We identified a whole blood 393 transcript signature for active TB in intermediate and high burden settings, correlating with radiological extent of disease and reverting to that of healthy controls following treatment. A subset of latent TB patients had signatures similar to those in active TB patients. We also identified a specific 86-transcript signature that discriminated active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-γ and Type I IFNαβ signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis, suggest that this TB signature reflects both changes in cellular composition and altered gene expression. Although an IFN signature was also observed in whole blood of patients with Systemic Lupus Erythematosus (SLE), their complete modular signature differed from TB with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto under-appreciated role of Type I IFNαβ signalling in TB pathogenesis, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic