The Treatment of Neonatal Seizures: A Critical Review of the Evidence

In a critical review of the literature to assess the efficacy of monotherapy and subsequent combinant anticonvulsant therapy in the treatment of neonatal seizures, four studies were examined; three randomised control trials and one retrospective cohort study. Each study used phenobarbital for monotherapy with doses reaching a maximum of 40mg/kg. Anticonvulsant drugs used in conjunction with phenobarbitone for combinant therapy included midazolam, clonazepam, lorazepam, phenytoin and lignocaine. Each study used an electroencephalograph for seizure diagnosis and neonatal monitoring when determining therapy efficacy and final outcome assessments. Collectively the studies suggest neither monotherapy nor combinant therapy are entirely effective in seizure control. Monotherapy demonstrated a 29% - 50% success rate for complete seizure control whereas combinant therapy administered after the failure of monotherapy demonstrated a success rate of 43% - 100%. When these trials were combined the overall success for monotherapy was 44% (n = 34/78) and for combinant therapy 72% ( n = 56/78). Though the evidence was inconclusive, it would appear that combinant therapy is of greater benefit to infants unresponsive to monotherapy. Further research such as multi-site randomised controlled trials using standardised criteria and data collection are required within this specialised area.

Shoot growth dynamics and photosynthetic response to increased nitrogen availability in the alpine willow salix-glauca

Plants subjected to increases in the supply of resource(s) limiting growth may allocate more of those resources to existing leaves, increasing photosynthetic capacity, and/or to production of more leaves, increasing whole-plant photosynthesis. The responses of three populations of the alpine willow, Salix glauca, growing along an alpine topographic sequence representing a gradient in soil moisture and organic matter, and thus potential N supply, to N amendments, were measured over two growing seasons, to elucidate patterns of leaf versus shoot photosynthetic responses. Leaf-(foliar N, photosynthesis rates, photosynthetic N-use efficiency) and shoot-(leaf area per shoot, number of leaves per shoot, stem weight, N resorption efficiency) level measurements were made to examine the spatial and temporal variation in these potential responses to increased N availability. The predominant response of the willows to N fertilization was at the shoot-level, by production of greater leaf area per shoot. Greater leaf area occurred due to production of larger leaves in both years of the experiment and to production of more leaves during the second year of fertilization treatment. Significant leaf-level photosynthetic response occurred only during the first year of treatment, and only in the dry meadow population. Variation in photosynthesis rates was related more to variation in stomatal conductance than to foliar N concentration. Stomatal conductance in turn was significantly related to N fertilization. Differences among the populations in photosynthesis, foliar N, leaf production, and responses to N fertilization indicate N availability may be lowest in the dry meadow population, and highest in the ridge population. This result is contrary to the hypothesis that a gradient of plant available N corresponds with a snowpack/topographic gradient.

Does the p38 MAP kinase inhibitor pamapimod have potential for the treatment of rheumatoid arthritis?

Background: Methotrexate alone or in combination with other agents is the standard treatment for moderate-to-severe rheumatoid arthritis. As the biological agents are expensive, they are not usually used until methotrexate has failed to give a good response. Thus, there is scope for the development of cheaper drugs that can be used instead of methotrexate or in addition to methotrexate. Objectives/methods: Pamapimod is a p38α inhibitor being developed for use in the treatment of rheumatoid arthritis. The objective was to evaluate the recent clinical trials of pamapimod in subjects with rheumatoid arthritis. Results: There is no clear cut evidence that pamapimod alone or in the presence of methotrexate is efficacious in subjects with rheumatoid arthritis, but it does cause adverse effects. Conclusion: It is unlikely that pamapimod will be useful in the treatment of rheumatoid arthritis.

Tyrosine monitoring in children with early and continuously treated phenylketonuria: Results of an international practice survey

Investigations into the biochemical markers associated with executive function (EF) impairment in children with early and continuously treated phenylketonuria (ECT-PKU) remain largely phenylalanine-only focused, despite experimental data showing that a high phenylalanine:tyrosine (phe:tyr) ratio is more strongly associated with EF deficit than phe alone. A high phe:tyr ratio is hypothesized to lead to a reduction in dopamine synthesis within the brain, which in turn results in the development of EF impairment. This paper provides a snapshot of current practice in the monitoring and/or treatment of tyrosine levels in children with PKU, across 12 countries from Australasia, North America and Europe. Tyrosine monitoring in this population has increased over the last 5 years, with over 80% of clinics surveyed reporting routine monitoring of tyrosine levels in infancy alongside phe levels. Twenty-five percent of clinics surveyed reported actively treating/managing tyrosine levels (with supplemental tyrosine above that contained in PKU formulas) to ensure tyrosine levels remain within normal ranges. Anecdotally, supplemental tyrosine has been reported to ameliorate symptoms of both attention deficit hyperactivity disorder and depression in this population. EF assessment of children with ECT-PKU was likewise highly variable, with 50% of clinics surveyed reporting routine assessments of intellectual function. However when function was assessed, test instruments chosen tended towards global measures of IQ prior to school entry, rather than specific assessment of EF development. Further investigation of the role of tyrosine and its relationship with phe and EF development is needed to establish whether routine tyrosine monitoring and increased supplementation is recommended.

Beyond sanctions : is there a need to treat first-time offenders?

Aims: Driving Under the Influence (DUI) enforcement can be a broad screening mechanism for alcohol and other drug problems. The current response to DUI is focused on using mechanical means to prevent inebriated persons from driving, with little attention the underlying substance abuse problems. ---------- Methods: This is a secondary analysis of an administrative dataset of over 345,000 individuals who entered Texas substance abuse treatment between 2005 and 2008. Of these, 36,372 were either on DUI probation, referred to treatment by probation, or had a DUI arrest in the past year. The DUI offenders were compared on demographic characteristics, substance use patterns, and levels of impairment with those who were not DUI offenders and first DUI offenders were compared with those with more than one past-year offense. T tests and chi square tests were used to determine significance. ---------- Results: DUI offenders were more likely to be employed, to have a problem with alcohol, to report more past-year arrests for any offense, to be older, and to have used alcohol and drugs longer than the non-DUI clients who reported higher ASI scores and were more likely to use daily. Those with one past-year DUI arrest were more likely to have problems with drugs other than alcohol and were less impaired than those with two or more arrests based on their ASI scores and daily use. Non-DUI clients reported higher levels of mood disorders than DUIs but there was no difference in their diagnosis of anxiety. Similar findings were found between those with one or multiple DUI arrests. ----------Conclusion: Although first-time DUIs were not as impaired as non-DUI clients, their levels of impairment were sufficient to cause treatment. Screening and brief intervention at arrest for all DUI offenders and treatment in combination with abstinence monitoring could decrease future recidivism.

A criminological analysis : using real-time monitoring to gather data on online predators

The Internet presents a constantly evolving frontier for criminology and policing, especially in relation to online predators – paedophiles operating within the Internet for safer access to children, child pornography and networking opportunities with other online predators. The goals of this qualitative study are to undertake behavioural research – identify personality types and archetypes of online predators and compare and contrast them with behavioural profiles and other psychological research on offline paedophiles and sex offenders. It is also an endeavour to gather intelligence on the technological utilisation of online predators and conduct observational research on the social structures of online predator communities. These goals were achieved through the covert monitoring and logging of public activity within four Internet Relay Chat(rooms) (IRC) themed around child sexual abuse and which were located on the Undernet network. Five days of monitoring was conducted on these four chatrooms between Wednesday 1 to Sunday 5 April 2009; this raw data was collated and analysed. The analysis identified four personality types – the gentleman predator, the sadist, the businessman and the pretender – and eight archetypes consisting of the groomers, dealers, negotiators, roleplayers, networkers, chat requestors, posters and travellers. The characteristics and traits of these personality types and archetypes, which were extracted from the literature dealing with offline paedophiles and sex offenders, are detailed and contrasted against the online sexual predators identified within the chatrooms, revealing many similarities and interesting differences particularly with the businessman and pretender personality types. These personality types and archetypes were illustrated by selecting users who displayed the appropriate characteristics and tracking them through the four chatrooms, revealing intelligence data on the use of proxies servers – especially via the Tor software – and other security strategies such as Undernet’s host masking service. Name and age changes, which is used as a potential sexual grooming tactic was also revealed through the use of Analyst’s Notebook software and information on ISP information revealed the likelihood that many online predators were not using any safety mechanism and relying on the anonymity of the Internet. The activities of these online predators were analysed, especially in regards to child sexual grooming and the ‘posting’ of child pornography, which revealed a few of the methods in which online predators utilised new Internet technologies to sexually groom and abuse children – using technologies such as instant messengers, webcams and microphones – as well as store and disseminate illegal materials on image sharing websites and peer-to-peer software such as Gigatribe. Analysis of the social structures of the chatrooms was also carried out and the community functions and characteristics of each chatroom explored. The findings of this research have indicated several opportunities for further research. As a result of this research, recommendations are given on policy, prevention and response strategies with regards to online predators.

Clinical indicators of quality for Australian residential aged care facilities : establishing reliability, validity, and quality thresholds

Background: In response to the need for more comprehensive quality assessment within Australian residential aged care facilities, the Clinical Care Indicator (CCI) Tool was developed to collect outcome data as a means of making inferences about quality. A national trial of its effectiveness and a Brisbane-based trial of its use within the quality improvement context determined the CCI Tool represented a potentially valuable addition to the Australian aged care system. This document describes the next phase in the CCI Tool.s development; the aims of which were to establish validity and reliability of the CCI Tool, and to develop quality indicator thresholds (benchmarks) for use in Australia. The CCI Tool is now known as the ResCareQA (Residential Care Quality Assessment). Methods: The study aims were achieved through a combination of quantitative data analysis, and expert panel consultations using modified Delphi process. The expert panel consisted of experienced aged care clinicians, managers, and academics; they were initially consulted to determine face and content validity of the ResCareQA, and later to develop thresholds of quality. To analyse its psychometric properties, ResCareQA forms were completed for all residents (N=498) of nine aged care facilities throughout Queensland. Kappa statistics were used to assess inter-rater and test-retest reliability, and Cronbach.s alpha coefficient calculated to determine internal consistency. For concurrent validity, equivalent items on the ResCareQA and the Resident Classification Scales (RCS) were compared using Spearman.s rank order correlations, while discriminative validity was assessed using known-groups technique, comparing ResCareQA results between groups with differing care needs, as well as between male and female residents. Rank-ordered facility results for each clinical care indicator (CCI) were circulated to the panel; upper and lower thresholds for each CCI were nominated by panel members and refined through a Delphi process. These thresholds indicate excellent care at one extreme and questionable care at the other. Results: Minor modifications were made to the assessment, and it was renamed the ResCareQA. Agreement on its content was reached after two Delphi rounds; the final version contains 24 questions across four domains, enabling generation of 36 CCIs. Both test-retest and inter-rater reliability were sound with median kappa values of 0.74 (test-retest) and 0.91 (inter-rater); internal consistency was not as strong, with a Chronbach.s alpha of 0.46. Because the ResCareQA does not provide a single combined score, comparisons for concurrent validity were made with the RCS on an item by item basis, with most resultant correlations being quite low. Discriminative validity analyses, however, revealed highly significant differences in total number of CCIs between high care and low care groups (t199=10.77, p=0.000), while the differences between male and female residents were not significant (t414=0.56, p=0.58). Clinical outcomes varied both within and between facilities; agreed upper and lower thresholds were finalised after three Delphi rounds. Conclusions: The ResCareQA provides a comprehensive, easily administered means of monitoring quality in residential aged care facilities that can be reliably used on multiple occasions. The relatively modest internal consistency score was likely due to the multi-factorial nature of quality, and the absence of an aggregate result for the assessment. Measurement of concurrent validity proved difficult in the absence of a gold standard, but the sound discriminative validity results suggest that the ResCareQA has acceptable validity and could be confidently used as an indication of care quality within Australian residential aged care facilities. The thresholds, while preliminary due to small sample size, enable users to make judgements about quality within and between facilities. Thus it is recommended the ResCareQA be adopted for wider use.

Response to "a step in the right direction : commentary on expected values for pedometer-determined physical activity in youth"

The figure Beets took exception to displays sex‐ and age‐specific median values of aggregated published expected values for pedometer determined physical activity.

The molecular mechanisms utilised by mesenchymal stem cells in migration to acute myocardial infarction

Heart damage caused by acute myocardial infarction (AMI) is a leading cause of death and disability in Australia. Novel therapies are still required for the treatment of this condition due to the poor reparative ability of the heart. As such, cellular therapies that assist in the recovery of heart muscle are of great current interest. Culture expanded mesenchymal stem cells (MSC) represent a stem and progenitor cell population that has been shown to promote tissue recovery in pre-clinical studies of AMI. For MSC-based therapies in the clinic, an intravenous route of administration would ideally be used due to the low cost, ease of delivery and relative safety. The study of MSC migration is therefore clinically relevant for a minimally invasive cell therapy to promote regeneration of damaged tissue. C57BL/6, UBI-GFP-BL/6 and CD44-/-/GFP+/+ mice were utilised to investigate mMSC migration. To assist in murine models of MSC migration, a novel method was used for the isolation of murine MSC (mMSC). These mMSC were then expanded in culture and putative mMSC were positive for Sca-1, CD90.2, and CD44 and were negative for CD45 and CD11b. Furthermore, mMSC from C57BL/6 and UBI-GFP-BL/6 mice were shown to differentiate into cells of the mesodermal lineage. Cells from CD44-/-/GFP+/+ mice were positive for Sca-1 and CD90.2, and negative for CD44, CD45 and CD11b however, these cells were unable to differentiate into adipocytes and chondrocytes and express lineage specific genes, PLIN and ACAN. Analysis of mMSC chemokine receptor (CR) expression showed that although mMSC do express chemokine receptors, (including those specific for chemokines released after AMI), these were low or undetectable by mRNA. However, protein expression could be detected, which was predominantly cytoplasmic. It was further shown that in both healthy (unperturbed) and inflamed tissues, mMSC had very little specific migration and engraftment after intravenous injection. To determine if poor mMSC migration was due to the inability of mMSC to respond to chemotactic stimuli, chemokine expression in bone marrow, skin injury and hearts (healthy and after AMI) was analysed at various time points by quantitative real-time PCR (qRT PCR). Many chemokines were up-regulated after skin biopsy and AMI, but the highest acute levels were found for CXCL12 and CCL7. Due to their high expression in infarcted hearts, the chemokines CXCL12 and CCL7 were tested for their effect on mMSC migration. Despite CR expression at both protein and mRNA levels, migration in response to CXCL12 and CCL7 was low in mMSC cultured on Nunclon plastic. A novel tissue culture plastic technology (UpCellTM) was then used that allowed gentle non-enzymatic dissociation of mMSC, thus preserving surface expression of the CRs. Despite this the in vitro data indicated that CXCL12 fails to induce significant migration ability of mMSC, while CCL7 induces significant, but low-level migration. We speculated this may be because of low levels of surface expression of chemokine receptors. In a strategy to increase cell surface expression of mMSC chemokine receptors and enhance their in vitro and in vivo migration capacity, mMSC were pre-treated with pro-inflammatory cytokines. Increased levels of both mRNA and surface protein expression were found for CRs by pre-treating mMSC with pro-inflammatory cytokines including TNF-á, IFN-ã, IL-1á and IL-6. Furthermore, the chemotactic response of mMSC to CXCL12 and CCL7 was significantly higher with these pretreated cells. Finally, the effectiveness of this type of cell manipulation was demonstrated in vivo, where mMSC pre-treated with TNF-á and IFN-ã showed significantly increased migration in skin injury and AMI models. Therefore this thesis has demonstrated, using in vitro and in vivo models, the potential for prior manipulation of MSC as a possible means for increasing the utility of intravenously delivery for MSC-based cellular therapies.

CFD Simulation of turbulence promoters in a water treatment reactor

A new immobilized flat plate photocatalytic reactor for wastewater treatment has been proposed in this study to avoid subsequent catalyst removal from the treated water. The reactor consists of an inlet, reactive section where catalyst is coated and an outlet parts. In order to optimize the fluid mixing and reactor design, this study aims to investigate the influence of baffles and its arrangement on the flat plate reactor hydrodynamics using computational fluid dynamics (CFD) simulation. For simulation, an array of baffles acting as turbulence promoters is inserted in the reactive zone of the reactor. In this regard, results obtained from the simulation of a baffled- flat plate photoreactor hydrodynamics for different baffle positions, heights and intervals are presented utilizing RNG k-ε turbulence model. Under the conditions simulated, the qualitative flow features, such as the development and separation of boundary layers, vortex formation, the presence of high shear regions and recirculation zones, and the underlying mechanism are examined. The influence of various baffle sizes on the distribution of pollutant concentration is also highlighted. The results presented here indicate that the spanning of recirculation increases the degree of interfacial distortion with a larger interfacial area between fluids which results in substantial enhancement in fluid mixing. The simulation results suggest that the qualitative and quantitative properties of fluid dynamics in a baffled reactor can be obtained which provides valuable insight to fully understand the effect of baffles and its arrangements on the flow pattern, behaviour, and feature.

Evaluation of financial incentives as a quality improvement strategy in the public hospital context : clinician attitudes, design variables, and economic costs

In 2008, a three-year pilot ‘pay for performance’ (P4P) program, known as ‘Clinical Practice Improvement Payment’ (CPIP) was introduced into Queensland Health (QHealth). QHealth is a large public health sector provider of acute, community, and public health services in Queensland, Australia. The organisation has recently embarked on a significant reform agenda including a review of existing funding arrangements (Duckett et al., 2008). Partly in response to this reform agenda, a casemix funding model has been implemented to reconnect health care funding with outcomes. CPIP was conceptualised as a performance-based scheme that rewarded quality with financial incentives. This is the first time such a scheme has been implemented into the public health sector in Australia with a focus on rewarding quality, and it is unique in that it has a large state-wide focus and includes 15 Districts. CPIP initially targeted five acute and community clinical areas including Mental Health, Discharge Medication, Emergency Department, Chronic Obstructive Pulmonary Disease, and Stroke. The CPIP scheme was designed around key concepts including the identification of clinical indicators that met the set criteria of: high disease burden, a well defined single diagnostic group or intervention, significant variations in clinical outcomes and/or practices, a good evidence, and clinician control and support (Ward, Daniels, Walker & Duckett, 2007). This evaluative research targeted Phase One of implementation of the CPIP scheme from January 2008 to March 2009. A formative evaluation utilising a mixed methodology and complementarity analysis was undertaken. The research involved three research questions and aimed to determine the knowledge, understanding, and attitudes of clinicians; identify improvements to the design, administration, and monitoring of CPIP; and determine the financial and economic costs of the scheme. Three key studies were undertaken to ascertain responses to the key research questions. Firstly, a survey of clinicians was undertaken to examine levels of knowledge and understanding and their attitudes to the scheme. Secondly, the study sought to apply Statistical Process Control (SPC) to the process indicators to assess if this enhanced the scheme and a third study examined a simple economic cost analysis. The CPIP Survey of clinicians elicited 192 clinician respondents. Over 70% of these respondents were supportive of the continuation of the CPIP scheme. This finding was also supported by the results of a quantitative altitude survey that identified positive attitudes in 6 of the 7 domains-including impact, awareness and understanding and clinical relevance, all being scored positive across the combined respondent group. SPC as a trending tool may play an important role in the early identification of indicator weakness for the CPIP scheme. This evaluative research study supports a previously identified need in the literature for a phased introduction of Pay for Performance (P4P) type programs. It further highlights the value of undertaking a formal risk assessment of clinician, management, and systemic levels of literacy and competency with measurement and monitoring of quality prior to a phased implementation. This phasing can then be guided by a P4P Design Variable Matrix which provides a selection of program design options such as indicator target and payment mechanisms. It became evident that a clear process is required to standardise how clinical indicators evolve over time and direct movement towards more rigorous ‘pay for performance’ targets and the development of an optimal funding model. Use of this matrix will enable the scheme to mature and build the literacy and competency of clinicians and the organisation as implementation progresses. Furthermore, the research identified that CPIP created a spotlight on clinical indicators and incentive payments of over five million from a potential ten million was secured across the five clinical areas in the first 15 months of the scheme. This indicates that quality was rewarded in the new QHealth funding model, and despite issues being identified with the payment mechanism, funding was distributed. The economic model used identified a relative low cost of reporting (under $8,000) as opposed to funds secured of over $300,000 for mental health as an example. Movement to a full cost effectiveness study of CPIP is supported. Overall the introduction of the CPIP scheme into QHealth has been a positive and effective strategy for engaging clinicians in quality and has been the catalyst for the identification and monitoring of valuable clinical process indicators. This research has highlighted that clinicians are supportive of the scheme in general; however, there are some significant risks that include the functioning of the CPIP payment mechanism. Given clinician support for the use of a pay–for-performance methodology in QHealth, the CPIP scheme has the potential to be a powerful addition to a multi-faceted suite of quality improvement initiatives within QHealth.

Self-management of cancer treatment-related fatigue, nausea, vomiting and oral mucositis in Chinese cancer patients

Background: Treatment-related symptoms continue to place a significant burden on many cancer patients. Many side effects require patients to engage in a range of self-management actions. While some studies have explored self-management of treatment-related side effects in Western settings, very few studies were identified that described the self-management practices of cancer patients in China. Objective: The purposes of this study are to: (1) Investigate Chinese cancer patients. self-management behaviours in dealing with the fatigue, nausea/vomiting and oral mucositis that result from treatment, as well as the perceived effectiveness of these behaviours and related self-efficacy in performing them. (2) Explore factors influencing symptom self-management behaviours using the Cancer Symptom Self-management Framework based on Grey, Knafl and McCorkle.s (2006) self-management framework as a guide. Methods: This study was divided into two phases. Phase One consisted of the translation and modification of two instruments. The adaptation of these instruments to ensure applicability in the Chinese context was achieved through semi-structured interviews with six cancer patients, and content evaluation with eight experienced oncology nurses. A pilot study was conducted with nine cancer patients to trial the questionnaire set in the Chinese context. Based on the results of Phase One, Phase Two involved a cross-sectional survey of Chinese cancer patients undergoing cancer treatment using these instruments. A total of 277 chemotherapy patients with fatigue and/or nausea and vomiting, and 100 radiotherapy patients with oral mucositis were surveyed. Results: Participants in this study reported a variety of self-management behaviours to cope with fatigue, nausea, vomiting and oral mucositis. There are some consistencies as well disparities between strategies that are frequently used and those rated as effective. For fatigue self-management, participants were more likely to use strategies related to rest and sleep, while activity enhancement strategies were rated as achieving higher relief. For nausea and vomiting self-management, dietary modification and taking medication were most frequently used and rated as moderately effective. Psychological strategies were used by more than a third of participants and were rated as mildly effective. Some other infrequently used strategies, such as distraction by keeping busy and acupressure, were rated as moderately effective. For oral mucositis self-management, having soft, bland food and keeping the mouth moisturised were most frequently reported and they were rated as achieving moderate relief. A prescribed mouthwash was used by most but not all participants and brought moderate relief. In general, patients had low-to-moderate self-efficacy in nausea and vomiting self-management behaviours, moderate self-efficacy in fatigue self-management behaviours, and low-to-moderate self-efficacy in oral mucositis self-management behaviours. In terms of the factors influencing symptom self-management, different predictors were identified affecting engagement in fatigue, nausea/vomiting and oral mucositis self-management behaviours. Self-efficacy scores of different behaviours were consistently found to be a positive predictor of the relief level from corresponding behaviours, after controlling for other variables. Perceived social support from health care professionals was identified as an important factor influencing nausea and vomiting self-management behaviours, while neighbourhood support was important for fatigue self-management. In addition, symptom distress was identified as an important factor influencing nausea and vomiting self-management. Conclusion: Similar to reports from overseas, Chinese cancer patients initiate a wide range of self-management behaviours in response to treatment-related side effects. While some behaviours were reported to provide relief, many did not. Given these results, this study has a number of practical implications for health care professionals, particularly in relation to developing tailored self-management programs for fatigue, nausea, vomiting and oral mucositis. Additionally, this study suggests a number of theoretical implications and directions for future research. It is envisaged that these recommendations may pave the way for further studies understanding and promoting cancer symptom self-management in Chinese people affected by cancer.

A Bayesian model predicts the response of axons to molecular gradients

Axon guidance by molecular gradients plays a crucial role in wiring up the nervous system. However, the mechanisms axons use to detect gradients are largely unknown. We first develop a Bayesian “ideal observer” analysis of gradient detection by axons, based on the hypothesis that a principal constraint on gradient detection is intrinsic receptor binding noise. Second, from this model, we derive an equation predicting how the degree of response of an axon to a gradient should vary with gradient steepness and absolute concentration. Third, we confirm this prediction quantitatively by performing the first systematic experimental analysis of how axonal response varies with both these quantities. These experiments demonstrate a degree of sensitivity much higher than previously reported for any chemotacting system. Together, these results reveal both the quantitative constraints that must be satisfied for effective axonal guidance and the computational principles that may be used by the underlying signal transduction pathways, and allow predictions for the degree of response of axons to gradients in a wide variety of in vivo and in vitro settings.

The acute adaptations of normal and pathological human Achilles tendons to eccentric and concentric exercise

Eccentric exercise is the conservative treatment of choice for mid-portion Achilles tendinopathy. While there is a growing body of evidence supporting the medium to long term efficacy of eccentric exercise in Achilles tendinopathy treatment, very few studies have investigated the short term response of the tendon to eccentric exercise. Moreover, the mechanisms through which tendinopathy symptom resolution occurs remain to be established. The primary purpose of this thesis was to investigate the acute adaptations of the Achilles tendon to, and the biomechanical characteristics of, the eccentric exercise protocol used for Achilles tendinopathy rehabilitation and a concentric equivalent. The research was conducted with an orientation towards exploring potential mechanisms through which eccentric exercise may bring about a resolution of tendinopathy symptoms. Specifically, the morphology of tendinopathic and normal Achilles tendons was monitored using high resolution sonography prior to and following eccentric and concentric exercise, to facilitate comparison between the treatment of choice and a similar alternative. To date, the only proposed mechanism through which eccentric exercise is thought to result in symptom resolution is the increased variability in motor output force observed during eccentric exercise. This thesis expanded upon prior work by investigating the variability in motor output force recorded during eccentric and concentric exercises, when performed at two different knee joint angles, by limbs with and without symptomatic tendinopathy. The methodological phase of the research focused on establishing the reliability of measures of tendon thickness, tendon echogenicity, electromyography (EMG) of the Triceps Surae and the standard deviation (SD) and power spectral density (PSD) of the vertical ground reaction force (VGRF). These analyses facilitated comparison between the error in the measurements and experimental differences identified as statistically significant, so that the importance and meaning of the experimental differences could be established. One potential limitation of monitoring the morphological response of the Achilles tendon to exercise loading is that the Achilles tendon is continually exposed to additional loading as participants complete the walking required to carry out their necessary daily tasks. The specific purpose of the last experiment in the methodological phase was to evaluate the effect of incidental walking activity on Achilles tendon morphology. The results of this study indicated that walking activity could decrease Achilles tendon thickness (negative diametral strain) and that the decrease in thickness was dependent on both the amount of walking completed and the proximity of walking activity to the sonographic examination. Thus, incidental walking activity was identified as a potentially confounding factor for future experiments which endeavoured to monitor changes in tendon thickness with exercise loading. In the experimental phase of this thesis the thickness of Achilles tendons was monitored prior to and following isolated eccentric and concentric exercise. The initial pilot study demonstrated that eccentric exercise resulted in a greater acute decrease in Achilles tendon thickness (greater diametral strain) compared to an equivalent concentric exercise, in participants with no history of Achilles tendon pain. This experiment was then expanded to incorporate participants with unilateral Achilles tendinopathy. The major finding of this experiment was that the acute decrease in Achilles tendon thickness observed following eccentric exercise was modified by the presence of tendinopathy, with a smaller decrease (less diametral strain) noted for tendinopathic compared to healthy control tendon. Based on in vitro evidence a decrease in tendon thickness is believed to reflect extrusion of fluid from the tendon with loading. This process would appear to be limited by the presence of pathology and is hypothesised to be a result of the changes in tendon structure associated with tendinopathy. Load induced fluid movement may be important to the maintenance of tendon homeostasis and structure as it has the potential to enhance molecular movement and stimulate tendon remodelling. On this basis eccentric exercise may be more beneficial to the tendon than concentric exercise. Finally, EMG and motor output force variability (SD and PSD of VGRF) were investigated while participants with and without tendinopathy performed the eccentric and concentric exercises. Although between condition differences were identified as statistically significant for a number of force variability parameters, the differences were not greater than the limits of agreement for repeated measures. Consequently the meaning and importance of these findings were questioned. Interestingly, the EMG amplitude of all three Triceps Surae muscles did not vary with knee joint angle during the performance of eccentric exercise. This raises questions pertaining to the functional importance of performing the eccentric exercise protocol at each of the two knee joint angles as it is currently prescribed. EMG amplitude was significantly greater during concentric compared to eccentric muscle actions. Differences in the muscle activation patterns may result in different stress distributions within the tendon and be related to the different diametral strain responses observed for eccentric and concentric muscle actions.