Editorial comment

Non peer reviewedSubmitted Versio

Developmental signals in skin morphogenesis

Non peer reviewedFinal Accepted Versio

What role for qualitative methods in randomised experiments?

The vibrant debate on randomized experiments within international development has been slow to accept a role for qualitative methods within research designs. Whilst there are examples of how „field visits? or descriptive analyses of context can play a complementary, but secondary, role to quantitative methods, little attention has been paid to the possibility of randomized experiments that allow a primary role to qualitative methods. This paper assesses whether a range of qualitative methods compromise the internal and external validity criteria of randomized experiments. It suggests that life history interviews have advantages over other qualitative methods, and offers one alternative to the conventional survey tool

Role redesign in the National Health Service: The effects on midwives' work and professional boundaries

yesThis article examines the effects of role redesign on the work and professional boundaries of midwives employed in the National Health Service. It outlines midwives' views and experiences of attempts to change their skills and professional boundaries and, using the concept of closure, considers the implications for the midwifery profession. The findings show that role redesign is changing midwives' work and that the traditional emotional, social and caring skills associated with a midwife are being undermined by the growth in technical work. Importantly, midwives attempts to use closure have met with limited success and aspects of their work which they enjoy are being delegated to maternity support workers, while midwives' roles expand to include work traditionally performed by doctors. Midwives' concerns about the implications of work redesign for maternity care and their professional boundaries reflect the uncertainty surrounding the profession about the future role and skills of a midwife

Transient activaton of β-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours

When β-catenin signalling is disturbed from mid-gestation onwards lineage commitment is profoundly altered in postnatal mouse epidermis. We have investigated whether adult epidermis has the capacity for β-catenin-induced lineage conversion without prior embryonic priming. We fused N-terminally truncated, stabilised β-catenin to the ligand-binding domain of a mutant oestrogen receptor (ΔNβ -cateninER). ΔNβ-cateninER was expressed in the epidermis of transgenic mice under the control of the keratin 14 promoter and β -catenin activity was induced in adult epidermis by topical application of 4-hydroxytamoxifen (4OHT). Within 7 days of daily 4OHT treatment resting hair follicles were recruited into the hair growth cycle and epithelial outgrowths formed from existing hair follicles and from interfollicular epidermis. The outgrowths expressed Sonic hedgehog, Patched and markers of hair follicle differentiation, indicative of de novo follicle formation. The interfollicular epidermal differentiation program was largely unaffected but after an initial wave of sebaceous gland duplication sebocyte differentiation was inhibited. A single application of 4OHT was as effective as repeated doses in inducing new follicles and growth of existing follicles. Treatment of epidermis with 4OHT for 21 days resulted in conversion of hair follicles to benign tumours resembling trichofolliculomas. The tumours were dependent on continuous activation of β-catenin and by 28 days after removal of the drug they had largely regressed. We conclude that interfollicular epidermis and sebaceous glands retain the ability to be reprogrammed in adult life and that continuous β-catenin signalling is required to maintain hair follicle tumours.Peer reviewedFinal Published versio

Inhibition of androgen-independent prostate cancer cell growth is enhanced by combination therapy targeting Hedgehog and ErbB signalling

<p>Abstract</p> <p>Background</p> <p>Prostate cancer is a leading cause of male cancer specific mortality. When cure by radical prostatectomy is not possible the next line of prostate cancer treatment is androgen deprivation. However prolonged androgen deprivation often results in relapse and androgen-independent prostate cancer that is inevitably fatal despite optimal chemotherapy. The Hedgehog signalling pathway has recently been implicated in prostate cancer development and metastasis. EGFR or ErbB2 expression has been also correlated with androgen independence, shorter survival and metastasis.</p> <p>Results</p> <p>We determined that the Hedgehog and ErbB signalling pathways are active in circulating tumour cells isolated from androgen-independent prostate cancer patients and in the androgen-independent prostate cancer cell line LNCaP C4-2B. As a basis for synergistic chemotherapy protocols combinations of the Hedgehog specific inhibitor cyclopamine and the ErbB signalling inhibitors gefitinib or lapatinib were tested in this study. Androgen-independent prostate cancer cell growth was inhibited by a SMO inhibitor (cyclopamine) which blocks Hedgehog signalling and by ErbB inhibitors (gefitinib and lapatinib). The isobologram and combination index method of Chou and Talalay was used to evaluate drug interactions. Synergistic antiproliferation effects were observed when the Hedgehog and ErbB inhibitors were combined.</p> <p>Conclusion</p> <p>Androgen-independent prostate cancer cell proliferation was associated with activity of the Hedgehog and ErbB signalling pathways. Cyclopamine, gefitinib or lapatinib treatment significantly decreased the proliferation of androgen-independent prostate cancer cells. The Hedgehog pathway therefore represents a promising new therapeutic target in androgen-independent prostate cancer. Synergistic effects were observed when Hedgehog and ErbB inhibitors were used together. This study may have clinical implications for improving the treatment of advanced prostate cancer.</p

Developing an instrument for assessing fidelity of motivational care planning: The Aboriginal and Islander Mental health initiative adherence scale

PurposeThe aim of this study was to design and trial an Adherence Scale to measure fidelity of Motivational Care Planning (MCP) within a clinical trial. This culturally adapted therapy MCP uses a client centered holistic approach that emphasises family and culture to motivate healthy life style changes.MethodsThe Motivational Care Planning-Adherence Scale (MCP-AS) was developed through consultation with Aboriginal and Islander Mental Health Initiative (AIMhi) Indigenous and non-Indigenous trainers, and review of MCP training resources. The resultant ten-item scale incorporates a 9-Point Likert Scale with a supporting protocol manual and uses objective, behaviourally anchored criteria for each scale point. A fidelity assessor piloted the tool through analysis of four audio-recordings of MCP (conducted by Indigenous researchers within a study in remote communities in Northern Australia). File audits of the remote therapy sessions were utilised as an additional source of information. A Gold Standard Motivational Care Planning training video was also assessed using the MCP-AS.ResultsThe Motivational Care Planning-Adherence Scale contains items measuring both process and content of therapy sessions. This scale was used successfully to assess therapy through observation of audio or video-recorded sessions and review of clinical notes. Treatment fidelity measured by the MCP-AS within the pilot study indicated high fidelity ratings. Ratings were high across the three domains of rapport, motivation, and self-management with especially high ratings for positive feedback and engagement, review of stressors and goal setting.ConclusionsThe Motivational Care Planning-Adherence Scale has the potential to provide a measure of quality of delivery of Motivation Care Planning. The pilot findings suggest that despite challenges within the remote Indigenous community setting, Indigenous therapists delivered therapy that was of high fidelity. While developed as a research tool, the scale has the potential to support fidelity of delivery of Motivation Care Planning in clinical, supervision and training settings. Larger studies are needed to establish inter-rater reliability and internal and external validity

Human papillomavirus is detected in transitional cell carcinoma arising in renal transplant recipients

"This is a non-final version of an article published in final form in Pathology The Journal of the Royal College of Pathologists of Australasia 41 (3) pp.245-247"Aims: We investigated the role of human papillomavirus HPV in the development of transitional cell carcinoma TCC arising in renal transplant recipients. Methods: Genomic DNA was extracted from 10 m paraffin embedded sections of five TCCs arising in five renal transplant recipients using the QIAamp DNA mini kit according to the manufacturer's instructions. β-globin PCR was performed to test DNA adequacy. Samples were tested for the presence of HPV DNA by broad spectrum HPV PCR method using non-biotinylated SPF10 primers SPF1A, SPF1B, SPF1C, SPF1D, SPF2B, SPF2D which amplify a short 65 bp fragment. Positive bands were identified on a 3 gel. Positive samples underwent a second HPV PCR and were amplified using biotinylated SPF10 primer set, which amplifies the same 65 bp region of the L1 open reading frame. INNO-LiPA line probe assay was then performed to genotype the samples which uses a reverse hybridisation principle. Results: Four of five TCCs examined were positive for HPV. The high risk HPV16 was detected in three cases whereas in the fourth case an unclassifiable HPV genotype was present. In all DNA samples, β-globin amplification was successful. Conclusions: Our results indicate that HPV and in particular HPV16 may play an aetiological role in the development of TCC in renal transplant patients.Peer reviewedSubmitted Versio

Hedgehog Signalling in Androgen Independent Prostate Cancer

Objectives: Androgen-deprivation therapy effectively shrinks hormone-naïve prostate cancer, both in the prostate and at sites of distant metastasis. However prolonged androgen deprivation generally results in relapse and androgen-independent tumour growth, which is inevitably fatal. The molecular events that enable prostate cancer cells to proliferate in reduced androgen conditions are poorly understood. Here we investigate the role of Hedgehog signalling in androgen-independent prostate cancer (AIPC). Methods: Activity of the Hedgehog signalling pathway was analysed in cultured prostate cancer cells, and circulating prostate tumour cells were isolated from blood samples of patients with AIPC. Results: AIPC cells were derived through prolonged culture in reduced androgen conditions, modelling hormone therapy in patients, and expressed increased levels of Hedgehog signalling proteins. Exposure of cultured AIPC cells to cyclopamine, which inhibits Hedgehog signalling, resulted in inhibition of cancer cell growth. The expression of the Hedgehog receptor PTCH and the highly prostate cancer-specific gene DD3PCA3 was significantly higher in circulating prostate cancer cells isolated from patients with AIPC compared with samples prepared from normal individuals. There was an association between PTCH and DD3PCA3 expression and the length of androgen-ablation therapy. Conclusions: Our data are consistent with reports implicating overactivity of Hedgehog signalling in prostate cancer and suggest that Hedgehog signalling contributes to the androgen-independent growth of prostate cancer cells. As systemic anti-Hedgehog medicines are developed, the Hedgehog pathway will become a potential new therapeutic target in advanced prostate cancer.Peer reviewedFinal Accepted Versio

International study into the use of intermittent hormone therapy in the treatment of carcinoma of the prostate : A meta-analysis of 1446 patients

OBJECTIVE: To review pooled phase II data to identify features of different regimens of intermittent hormone therapy (IHT), developed to reduce the morbidity of treating metastatic prostate cancer, and which carries a theoretical advantage of delaying the onset of androgen-independent prostate cancer, (AIPC) that are associated with success, highlighting features which require exploration with prospective trials to establish the best strategies for using this treatment. METHODS: Individual data were collated on 1446 patients with adequate information, from 10 phase II studies with >50 cases, identified through Pubmed. RESULTS: Univariate and multivariate Cox proportional hazard models were developed to predict treatment success with a high degree of statistical success. The prostate-specific antigen (PSA) nadir, the PSA threshold to restart treatment, and medication type and duration, were important predictors of outcome. CONCLUSIONS: The duration of biochemical remission after a period of HT is a durable early indicator of how rapidly AIPC and death will occur, and will make a useful endpoint in future trials to investigate the best ways to use IHT based on the important treatment cycling variables described above. Patients spent a mean of 39% of the time off treatment. The initial PSA level and PSA nadir allow the identification of patients with prostate cancer in whom it might be possible to avoid radical therapy.Peer reviewe