The growth of an organism is one of the major components of homeostasis. As such, controlling growth appropriately is vital for the health of all animals. The endocrine system, through various hormones, plays a critical role in regulating when an organism needs to grow and develop. The major endocrine control centre that regulates growth is the pituitary gland, which is a pea-sized organ that lies at the base of the brain. Many genes have been identified that are known to be important in the development of the pituitary gland, and several of these are specific to the cells that make growth hormone (GH). Tumours of the pituitary gland represent the most common intracranial tumour in humans, with 1 in 6 people displaying evidence of these growths at the time of their death. Pituitary tumours, as well as other pituitary abnormalities, can cause disrupted release of many hormones, which consequently affects the quality of life of these patients. We have recently found that companion animals, such as dogs and cats, are known to be susceptible to these pituitary tumours. Growth hormone, one of the major pituitary hormones, is extremely important for the development and growth of an individual, and the release of GH is normally under tight control by the hypothalamus (part of the brain), as well as from other hormones released from tissues such as the liver. Inappropriately high or low GH release can cause a series of disorders, ranging from developmental abnormalities in infants, to dwarfism or metabolic complications in adults, and even an increased risk of certain types of colon cancer. We have recently discovered that another hormone found in the pituitary gland, C-type natriuretic peptide (CNP), is produced very early on in the development of human, mice and fish pituitaries. Our recent investigation of 30 human pituitary adenomas found that each one of these tumours expressed CNP, and the receptor that controls its effects, called GC-B. In addition, our preliminary studies have shown that treating pituitary cells with CNP can cause a dramatic increase in the amount of GH that is made. The work we propose to perform, detailed within this application, will extend our understanding of how CNP might influence the way in which the pituitary gland develops and functions normally. We shall use five different models to examine the effects of CNP; cultured pituitary cells, mice that specifically lack CNP in their pituitary glands, human and cat pituitary tumours and the highly versatile Zebrafish, in which we will silence the genes that encode CNP and establish the consequences for normal growth. In addition, our laboratory is equipped with an extremely efficient genetic analyser, that allows us to measure the amounts of up to 15 different genes in a single sample, greatly increasing our productivity from these very small amounts of tissue. These studies may reveal a role for CNP in the treatment of growth disorders, either as a way to increase GH release in individuals with impaired growth, or by developing drugs to block the effects of CNP and, therefore, reduce GH release. Such findings could lead to an improved quality of life, and a reduced susceptibility to subsequent endocrine disease.

Almost one quarter of adults currently experience some form of mental health disorder in the UK, costing the healthcare system an estimated £77 billion each year. However, there exists very little objective or real-time monitoring of sufferers of mental health issues. This pilot project will investigate the development of a novel data fusion framework that will be suitable for combining many observations of a patient's behaviour to allow accurate mental health monitoring in any environment. Recent studies have shown that certain types of physical behaviour, daily cycles (circadian rhythms) and social networking activity can be indicative of an individual's state of mental health. However, recording the necessary data to make a diagnosis is difficult, both due to the nature of the health issues and because of the instrumentation needed. Recent developments in commercially available equipment (including smart phones) mean that we now have the opportunity to cheaply and routinely record human behaviour as well as daily patterns of physiology (such as sleep and cardiac activity). By then applying advanced pattern recognition and data fusion techniques, we intend to provide daily feedback of mental well-being to both the patient and care providers. This could facilitate early interventions in deteriorating individuals, thereby lowering costs of health care and reducing the severity of the illness. We also intend to begin to answer the more fundamental question about how circadian rhythms change as mental health deteriorates. The developed of a user-friendly and user-controlled monitoring system, together with a suite of suitable algorithms, will be an important step towards a larger integration of the ever increasing multi-dimensional biometric data we are beginning to collect. This includes signals such as location, body temperature, speech patterns and social interaction behaviours. The potential to fuse data from many different sensors, and many different algorithms, will provide a platform for intelligible interpretation of the vast quantities of data that are beginning to confront researchers in biomedical applications. It will also help to improve the accuracy of monitoring systems and provide the doctor with more objective assessments of patient behaviour, which could lead to more accurate and timely diagnoses.

The use of ultrasound as a diagnostic imaging tool is well known, particularly during pregnancy where ultrasound is used to create images of the developing foetus. In recent years, a growing number of therapeutic applications of ultrasound have also been demonstrated. The goal of therapeutic ultrasound is to modify the function or structure of the tissue, rather than produce an anatomical image. This is possible because the mechanical vibrations caused by the ultrasound waves can affect tissue in different ways, for example, by causing the tissue to heat up, or by generating internal radiation forces that can agitate the cells or tissue scaffolding. These ultrasound bioeffects offer a huge potential to develop new ways to treat major diseases such as cancer, to improve the delivery of drugs while minimising side-effects, and to treat a wide spectrum of neurological and psychiatric conditions. The fundamental challenge shared by all applications of therapeutic ultrasound is that the ultrasound energy must be delivered accurately, safely, and non-invasively to the target region within the body. This is difficult because bones and other tissue interfaces can severely distort the shape of the ultrasound beam. This has a significant impact on the safety and effectiveness of therapeutic ultrasound, and presents a major hurdle for the wider clinical acceptance of these exciting technologies. In principle, any distortions to the ultrasound beam could be accounted for using advanced computer models. However, the underlying physics is complex, and the scale of the modelling problem requires extremely large amounts of computer memory. Using existing software, a single simulation running on a supercomputer can take many days to complete, which is too long to be clinically useful. The aim of this proposal is to develop more efficient computer models to accurately predict how ultrasound waves travel through the human body. This will involve implementing new approaches that efficiently divide the computational problem across large numbers of interconnected computer cores on a supercomputer. New approaches to reduce the huge quantity of output data will also be implemented, including calculating clinically important parameters while the simulation runs, and optimising how the data is stored to disk. We will also develop a professional user interface and package the code within the regulatory framework required for medical software. This will allow end-users, such as doctors, to easily use the code for applications in therapeutic ultrasound without needing to be an expert in computer science. In collaboration with our clinical partners, the computer models will then be applied to different applications of therapeutic ultrasound to allow the precise delivery of ultrasound energy to be predicted for the individual patient.

The clinical application of high intensity focused ultrasound (HIFU) to the treatment of soft tissue cancers of, for example, the liver, kidney and prostate, is a young and rapidly expanding field. To date more than 30,000 patients have been treated world wide. Successful treatment is achieved when the temperature of the tumour is raised to levels at which instantaneous cell death occurs. The focused beam ensures that only the tissue being targeted is heated, whilst surrounding tissue remains unharmed. Safe and effective use of HIFU requires that validated methods for measurement and testing of clinical devices should be made available as soon as possible. These issues have not been addressed to date in any systematic fashion. Clinical HIFU systems are currently assessed on an ad hoc basis by individual clinical departments and manufacturers, using methods, many of which are unpublished. There is, therefore, an urgent need to produce standard registration and testing equipment and methodology that allows users to characterize clinical HIFU systems for the purposes of checking safety and reproducibility of a machine's output, comparing different devices or commissioning new systems. The programme of work proposed is a mixture of adaptation and extension of existing and emerging techniques to meet the requirements of this new medical technology, and the development of novel methods specifically for this application.The overall aim of this project is to improve the efficacy, safety and range of applicability of clinical HIFU treatments by:A. providing validated methods for: * ultrasonic field characterisation using pressure field mapping and acoustic power measurement techniques; * HIFU system performance testing and quality assurance using novel thermal and cavitation mapping methods * patient exposure monitoring by means of electrical impedance measurements and real time acoustic power measurement;B. establishing a world leading HIFU characterisation facility at the Institute of Cancer Research (ICR);C. disseminating the successful methods, protocols and equipment to a wider user base through: * scientific publication; * contribution to written National and International Standards; * commercial exploitation.

The clinical application of high intensity focused ultrasound (HIFU) to the treatment of soft tissue cancers of, for example, the liver, kidney and prostate, is a young and rapidly expanding field. To date more than 30,000 patients have been treated world wide. Successful treatment is achieved when the temperature of the tumour is raised to levels at which instantaneous cell death occurs. The focused beam ensures that only the tissue being targeted is heated, whilst surrounding tissue remains unharmed. Safe and effective use of HIFU requires that validated methods for measurement and testing of clinical devices should be made available as soon as possible. These issues have not been addressed to date in any systematic fashion. Clinical HIFU systems are currently assessed on an ad hoc basis by individual clinical departments and manufacturers, using methods, many of which are unpublished. There is, therefore, an urgent need to produce standard registration and testing equipment and methodology that allows users to characterize clinical HIFU systems for the purposes of checking safety and reproducibility of a machine's output, comparing different devices or commissioning new systems. The programme of work proposed is a mixture of adaptation and extension of existing and emerging techniques to meet the requirements of this new medical technology, and the development of novel methods specifically for this application.The overall aim of this project is to improve the efficacy, safety and range of applicability of clinical HIFU treatments by:A. providing validated methods for: * ultrasonic field characterisation using pressure field mapping and acoustic power measurement techniques; * HIFU system performance testing and quality assurance using novel thermal and cavitation mapping methods * patient exposure monitoring by means of electrical impedance measurements and real time acoustic power measurement;B. establishing a world leading HIFU characterisation facility at the Institute of Cancer Research (ICR);C. disseminating the successful methods, protocols and equipment to a wider user base through: * scientific publication; * contribution to written National and International Standards; * commercial exploitation.