An investigation into mechanisms of regeneration specificity in planarian flatworms.

Many animals have the extraordinary ability to replace lost body parts, even so we humans do not. One critical but poorly understood aspect of this phenomenon is how wounds tailor the regeneration response to the particular target structure that needs to be regrown. In my thesis work I have attempted to address this problem in the champions of regeneration, the planarian flatworms. If one of these animals is cut into tiny pieces, each of the pieces will regenerate a head at the anterior end and tail at the posterior end. For over a century investigators have searched for the intrinsic polarity cue underlying this regeneration polarity, but until now its mechanistic basis is not known. The explicit goal of my thesis work was to identify this cue. The general approach that I have taken toward identification of the intrinsic polarity is to systematically compare two different planarian species with subtle variations in the establishment of regeneration polarity, Schmidtea mediterranea and Girardia tigrina. First, I demonstrate through systematic comparison of different amputation paradigms that regeneration polarity is dependent not only on species, but also on piece length, body size and anteroposterior axis position. Second, given that these findings are consistent with a gradient- based intrinsic polarity cue as prevalent hypothesis in the field, I tested whether the recently identified tail-to-head gradient of canonical Wnt (cWnt) signalling could be mechanistic basis of regeneration polarity. As precondition for doing so, I developed new approaches to measure and manipulate cWnt signalling in planaria. The data acquired with these tools suggest that the cWnt gradient may contribute to the observed position-dependence of regeneration polarity but is overall not the (only) intrinsic polarity cue. Third, I present my initial efforts to test whether the longitudinal muscle fibres (LMFs) in which notum is exclusively activated are an intrinsic polarity cue. My results suggest that “bundles” of short, intrinsically polarised LMFs running along the AP axis may express notum when they are cut anterior to their nucleus and moreover that misregulation of such a mechanism may underlie the species-dependence of regeneration polarity. Overall, the work presented in this thesis offers new insight into the cellular and conceptual basis of planarian regeneration polarity and, in doing so, the more general question of how regenerative organisms “sense” precisely what body part is missing and therefore needs to be regrown. Furthermore, it puts forward new hypotheses that through additional experimentation may explain lead to elucidation of the underlying molecular mechanisms

Insights from ultrasound : enhancing our understanding of clinical phonetics

This is the editorial from the journal "Clinical Linguistics and Phonetics", from a Special Issue entitled "Insights from Ultrasound". \ud \ud The timing of this special issue was in part inspired by the 6th Ultrafest conference in Edinburgh in 2013, a meeting in which phoneticians, clinicians and engineers working in ultrasound tongue imaging came together. We invited contributions from these and other experts in the field working with ultrasound as a tool for investigating clinical populations; as a biofeedback device in speech therapy; or as a tool for investigating typical speech production, with a view to informing investigations of clinical populations

The changing treatment of arthritis

Reproduced with permission from Australian Prescriber The document attached has been archived with permission from the publisher/copyright holder.Leslie G. Cleland, Susanna M. Proudman, Michael J. James and Peter Penglis

Is the promise of methadone Kenya's solution to managing HIV and addiction? A mixed-method mathematical modelling and qualitative study.

BACKGROUND AND OBJECTIVES: Promoted globally as an evidence-based intervention in the prevention of HIV and treatment of heroin addiction among people who inject drugs (PWID), opioid substitution treatment (OST) can help control emerging HIV epidemics among PWID. With implementation in December 2014, Kenya is the third Sub-Saharan African country to have introduced OST. We combine dynamic mathematical modelling with qualitative sociological research to examine the 'promise of methadone' to Kenya. METHODS, SETTING AND PARTICIPANTS: We model the HIV prevention impact of OST in Nairobi, Kenya, at different levels of intervention coverage. We draw on thematic analyses of 109 qualitative interviews with PWID, and 43 with stakeholders, to chart their narratives of expectation in relation to the promise of methadone. RESULTS: The modelled impact of OST shows relatively slight reductions in HIV incidence (5-10%) and prevalence (2-4%) over 5 years at coverage levels (around 10%) anticipated in the planned roll-out of OST. However, there is a higher impact with increased coverage, with 40% coverage producing a 20% reduction in HIV incidence, even when accounting for relatively high sexual transmissions. Qualitative findings emphasise a culture of 'rationed expectation' in relation to access to care and a 'poverty of drug treatment opportunity'. In this context, the promise of methadone may be narrated as a symbol of hope-both for individuals and community-in relation to addiction recovery. CONCLUSIONS: Methadone offers HIV prevention potential, but there is a need to better model the effects of sexual HIV transmission in mediating the impact of OST among PWID in settings characterised by a combination of generalised and concentrated epidemics. We find that individual and community narratives of methadone as hope for recovery coexist with policy narratives positioning methadone primarily in relation to HIV prevention. Our analyses show the value of mixed methods approaches to investigating newly-introduced interventions

Aseptic fluid transfer system

A method and means is provided, which permits the transfer of fluids between separate detached containers, in a manner which preserves the sterility of the fluids during and after their transfer

Fish oil: what the prescriber needs to know

There is a general belief among doctors, in part grounded in experience, that patients with arthritis need nonsteroidal anti-inflammatory drugs (NSAIDs). Implicit in this view is that these patients require the symptomatic relief provided by inhibiting synthesis of nociceptive prostaglandin E(2), a downstream product of the enzyme cyclo-oxygenase (COX), which is inhibited by NSAIDs. However, the concept of 'safe' NSAIDs has collapsed following a multiplicity of observations establishing increased risk for cardiovascular events associated with NSAID use, especially but not uniquely with the new COX-2-selective NSAIDs. This mandates greater parsimony in the use of these agents. Fish oils contain a natural inhibitor of COX, reduce reliance on NSAIDs, and reduce cardiovascular risk through multiple mechanisms. Fish oil thus warrants consideration as a component of therapy for arthritis, especially rheumatoid arthritis, in which its symptomatic benefits are well established. A major barrier to the therapeutic use of fish oil in inflammatory diseases is ignorance of its mechanism, range of beneficial effects, safety profile, availability of suitable products, effective dose, latency of effects and instructions for administration. This review provides an evidence-based resource for doctors and patients who may choose to prescribe or take fish oil

Development of a human model for the study of effects of hypoxia, exercise, and sildenafil on cardiac and vascular function in chronic heart failure

Background: Pulmonary hypertension is associated with poor outcome in patients with chronic heart failure (CHF) and may be a therapeutic target. Our aims were to develop a noninvasive model for studying pulmonary vasoreactivity in CHF and characterize sildenafil's acute cardiovascular effects. Methods and Results: In a crossover study, 18 patients with CHF participated 4 times [sildenafil (2 × 20 mg)/or placebo (double-blind) while breathing air or 15% oxygen] at rest and during exercise. Oxygen saturation (SaO2) and systemic vascular resistance were recorded. Left and right ventricular (RV) function and transtricuspid systolic pressure gradient (RVTG) were measured echocardiographically. At rest, hypoxia caused SaO2 (P = 0.001) to fall and RVTG to rise (5 ± 4 mm Hg; P = 0.001). Sildenafil reduced SaO2 (−1 ± 2%; P = 0.043), systemic vascular resistance (−87 ± 156 dyn·s−1·cm−2; P = 0.034), and RVTG (−2 ± 5 mm Hg; P = 0.05). Exercise caused cardiac output (2.1 ± 1.8 L/min; P < 0.001) and RVTG (19 ± 11 mm Hg; P < 0.0001) to rise. The reduction in RVTG with sildenafil was not attenuated by hypoxia. The rise in RVTG with exercise was not substantially reduced by sildenafil. Conclusions: Sildenafil reduces SaO2 at rest while breathing air, this was not exacerbated by hypoxia, suggesting increased ventilation–perfusion mismatching due to pulmonary vasodilation in poorly ventilated lung regions. Sildenafil reduces RVTG at rest and prevents increases caused by hypoxia but not by exercise. This study shows the usefulness of this model to evaluate new therapeutics in pulmonary hypertension