Quantitative Three-Dimensional Assessment of Bone and Cartilage in Osteoarthritic and Normal Knees Using Novel Imaging Methods and Mechanical Indentation Testing

Osteoarthritis (OA) is a painful, debilitating disease affecting approximately three million Canadians, most commonly at the knee. In addition to joint cartilage damage, the disease is also marked by changes in the underlying bone. It has been suggested that changes in bone stiffness, thickness and density influence and accelerate the breakdown of cartilage and the development of OA. In order to verify this (i.e. understand when during the disease process these changes occur and assess their impact on the timing and extent of damage to the bone or cartilage) there is an urgent need to develop a tool that can reliably assess bone and cartilage simultaneously. The aim of James Johnston’s research is to understand early onset and progression of osteoarthritis and to develop diagnostic tools for its early detection. Johnston has already developed a novel method of matching bone to cartilage that can be used to assess cartilage and underlying bone simultaneously in any joint. He is now working on a method to investigate relationships between bone (thickness, density) and cartilage (thickness, biochemistry) using magnetic resonance imaging (MRI), computed tomography (CT) and three-dimensional assessments. He will then link information gained through these imaging methods with physical stiffness measures to determine how these properties are affected at early and late stages of OA, compared to healthy subjects. This research will improve understanding of how OA develops, and contribute to the development of methods for the early detection and treatment of the disease.

Neuropsychological predictors of medication adherence and employment status following kidney transplantation

For her Master’s research, supported by a 2005 MSFHR Trainee Award, Shannon Gelb researched whether cognitive difficulties (brain functions such as memory and reasoning) exist following a kidney transplant. The research revealed that adult recipients of kidney transplants tend to perform worse than healthy individuals without transplants in tests of verbal memory (the ability to recall verbal information after a delay period) and executive functioning (activities such as multi-tasking and problem-solving). However, the impact of these results on daily life is unclear. Building on this research, Gelb is examining the relationship between cognition and two functional outcomes for kidney transplant recipients: adhering to prescribed medications and maintaining employment. Not taking medication properly, which is associated with increased risk of the body rejecting the transplanted kidney, is a significant problem among kidney transplant recipients. Employment rates among kidney transplant recipients are also poor – 59 to 83 per cent of kidney transplant recipients never return to work following kidney transplantation. The research may help clarify the potential need for increased education and patient support following kidney transplantation.

Defining the role of FOXP3 in human CD4+ T cells

In recent years, new immunosuppressive drugs have made considerable improvements to the success of transplantation procedure and the treatment of autoimmune diseases. Despite these successes, the side effects of long-term drug treatment invariably decrease patients’ quality of life and cause generalized suppression of the immune system. To develop a more direct approach for these therapies, efforts are now focused on a particular aspect of the immune system that controls the response. T regulatory (Tr) cells are a subset of white blood cells that have the ability to suppress undesired immune responses, while leaving other aspects of the normal immune system intact. A gene named FoxP3 has been identified as the master controller for development of a subset of Tr cells that can provide protection against some types of autoimmune diseases and promote acceptance of foreign tissue in a transplant setting. FoxP3 plays an essential role in maintaining normal immune function, but the exact mechanisms by which this gene operates in Tr cells are not known. Due to the high potential for using Tr cells for immunomodulatory therapies, Sarah Allan is investigating the role of FoxP3 in human cells. Her research will increase our understanding of how Tr cells arise naturally, the mechanisms by which they suppress immune responses and how they differ from other types of T cells at the molecular and genetic level. This work will contribute to the development of novel therapies for autoimmune diseases, transplantation, and other pathologies of the immune system.

T regulatory cells and T helper 17 cells: interactions between two distinct T cell subsets important for immune homeostasis

The immune system tries to maintain an optimal balance between immune responses to control infection and tumour growth, and reciprocal responses that prevent inflammation and autoimmune diseases. Impaired immune responses, such as those that occur with autoimmune disorders (multiple sclerosis, type 1 diabetes) and organ transplant rejection, result when a person’s immune system mistakenly attacks normal cells. Currently, patients afflicted with this condition must follow a strict regime of immunosuppressive drugs for the rest of their lives. However, these treatments seriously compromise the body’s ability to fight infection and also increase the risk of developing cancer. Sarah Crome is studying the role of a newly discovered class of cells, called T regulatory (Treg) cells in immune system response. She is studying how Treg cells suppress other immune cells and essentially act as a “brake” for the immune system. She is also examining how a subset of T cells, called T helper 17 cells, cause harmful immune responses that result in the rejection of transplanted tissues. A better understanding of these cells and the interactions and factors that regulate their differentiation and function, may lead to more effective treatments for organ transplantation and autoimmune diseases without compromising normal immune function.

Health Innovation Design and Evaluation (HeIDE)

In the last decade, the Canadian government has invested billions of dollars in development of a Canadian health information infrastructure. Health information technology goals are varied but they usually include faster, more efficient delivery of care based on shared information through electronic health records. However, despite the investment to develop an information technology infrastructure, the potential gains for the health system have been slow to materialize. Dr. Ellen Balka’s research focuses on the challenges associated with realizing Canada’s vision of an information technology-rich health care sector. She is working with stakeholders in actual health care settings, including technology developers, health system decision makers and health care providers, to assess design shortcomings, usability, implementation challenges, and issues related to governance of information technology within organizations. Dr. Balka’s studies will contribute to a more comprehensive understanding of how complex it is to introduce new information-based technologies into the health sector, and will lead to development of strategies that improve the rate of success for these initiatives within the health system. This will ensure that the potential benefits of these systems and technologies (administrative efficiencies, improved patient care and development of health data for research purposes) can be achieved.

Optimizing functional ability in stroke rehabilitation

Each year, approximately 50,000 Canadians suffer a stroke—the number one cause of neurological disability leading to impaired balance and mobility. Almost 90 per cent of stroke survivors have difficulties with everyday tasks, a reduced tolerance for physical activity, a sedentary lifestyle and multiple secondary complications. Many of these complications can be reduced with rehabilitation.

As a MSFHR-funded scholar, Dr. Janice Eng researched the effectiveness of a specific exercise program in improving balance and mobility in people with stroke. Now, Dr. Eng is working to optimize the functional abilities of people with stroke through innovative and effective rehabilitation interventions. One of these treatments includes a novel, cost-effective therapy where the patient manages their own amount of therapy for the arm and hand using a self-guided program. Dr. Eng will conduct a series of clinical studies aimed at improving arm and leg function in people living with stroke. People with stroke will be invited to participate in these studies and measurements of their abilities will be evaluated before and after the treatment. Changes in their abilities will then be analyzed and compared to individuals with stroke who receive what is considered standard therapy.

The development of effective rehabilitation interventions will improve the functional abilities of people with stroke, enable participation in social roles and physical activities, reduce secondary complications, and enhance quality of life. Novel interventions can also serve as a model for rehabilitation interventions in populations with other chronic health conditions.

The Drainage of Cerebrospinal Fluid and Development of Inflammatory Biomarkers in Acute Spinal Cord Injury

Approximately 1,050 new spinal cord injuries occur every year in Canada, primarily in young people. There are currently approximately 40,000 Canadians living with a spinal cord injury (SCI). As a physician and neuroscientist, Dr. Brian Kwon is actively involved in discovering new ways to improve the prognosis of those with SCI. Experimental treatments that have shown tremendous benefits in animal models of spinal cord injury have not translated in human clinical trials. This discrepancy suggests important differences in the biological responses to spinal cord injury between humans and animals. Within minutes of a spinal cord injury occurring, the spinal cord swells at the injury site. This swelling reduces blood flow and oxygen to the spinal cord tissue and can subsequently result in further secondary damage. Dr. Kwon is researching whether draining some of the cerebrospinal fluid (CSF) that surrounds the spinal cord will reduce the pressure on the cord, restoring blood flow and minimizing the risk for secondary damage. In a clinical trial of patients enrolled at Vancouver General Hospital within 48 hours of their SCI, CSF samples will be taken and measured for proteins that regulate inflammation. This biochemical evaluation will offer the first human description of how these inflammatory proteins are expressed following injury, leading to new biomarkers or indicators of injury severity to assist with further research. The expression proteins will be compared with the expression of proteins in animal models to determine differences in response between humans and animals. Ultimately, these insights will assist researchers in developing therapies to improve the lives of patients with spinal cord injuries.

Genetics of alopecia areata

Alopecia areata (AA) is a common autoimmune disease leading to extensive hair loss in men, women and children. About 640,000 Canadians (one out of 50) will develop AA. There is no cure, and treatment options are minimal. While, in general, the condition is not life threatening, hair loss can be psychologically devastating, particularly for women and children. Using a rat model, Dr. McElwee has identified several areas on chromosomes where genes coding for AA susceptibility are present. Now further work is required to determine the specific genes involved and what they do. Once these genes are identified in the rat model, the next step is a large scale study to identify corresponding genes in AA-affected humans. A more comprehensive understanding of the structure and function of these genes in comparison to corresponding genes in non-affected individuals will lead to a better understanding of how AA develops. In the long run, the goal is to explore the development of treatments which specifically target and ameliorate the affects of underlying genetic flaws that give rise to the disorder.

Novel strategies for treatment of PTEN deficient prostate cancer

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men of the Westernized world. While early stage disease is frequently curable with surgery or radiotherapy, limited treatment options are currently available for approximately one-third of patients who clinically present with locally advanced or metastatic disease resulting in a poor prognosis for patients with advanced disease. One treatment option that is currently being used for advanced PCa is a medical procedures designed to block androgenic steroids to induce death of prostate cancer since prostate cancer cells typically require these hormones for their growth and integrity. While this treatment is often effective with a response rate of up to 80%, within 1-3 years the tumours inevitably recur as hormone-refractory variants, a condition for which there is no current effective therapy. Thus if we are to have an impact on survival rates of patients with PCa, new therapeutic strategies are required for treating advanced disease. Up to 50% of advanced prostate cancers have acquired mutations in a gene called PTEN that essentially inactivated it. Inactivation of PTEN in prostate cancer is correlated with a poor prognosis. Loss or inactivation of this gene makes prostate cancer cells more resistant to different forms of therapy including chemo-, radiation and hormone-therapy. The development and progression of cancer is dependent on the deregulation of the intricate balance in the rates of cell growth and death. The proposed project addresses how loss of the PTEN gene confers cell with a survival advantage and resistance to therapies. Under ordinary conditions, PTEN keeps growth of normal cells in check by serving as a brake to inhibit cell growth. When PTEN is mutated in cancer, the brakes fail and this confers uncontrolled growth and increased resistance of the cancer cells to chemotherapy and hormone ablation therapy. My lab is actively working on how loss of PTEN protects prostate cancer cells from death signals and we are looking for different ways to block the effects of inactivating PTEN. Results of this study will be directly relevant to development of new therapies aimed at treating the subset of advanced prostate cancers that have lost PTEN.

Early diagnosis of compartment syndrome following tibial fractures using Intra-Compartmental Pressure Monitoring, near infra-red spectroscopy and plasma ischemic markers

Fractures of the main bone in the lower leg, known as the tibia, cause local bleeding, and tissue swelling within the compartments of the leg. In some patients, pressure within the compartments rises sufficiently high to prevent blood flow and cuts of the oxygen supply to intracompartmental muscles, nerves and other tissues. This condition is known as acute compartment syndrome. It is a surgical emergency and requires immediate identification and surgical treatment to save the function and viability of the lower leg. Delay in diagnosing this condition exposes the patient to increased risk of local muscle loss and a wide range of severe complications which requires multiple surgical procedures, prolonged hospitalization and even amputation of the affected limb. At the present time, diagnosis of acute compartment syndrome is mainly based on the clinical observation which is not always reliable and early. Measurement of intra-compartmental pressure can help to confirm the diagnosis but requires an invasive procedure which has some drawbacks. It is believed that direct monitoring of muscle oxygenation may provide early and precise diagnosis of this condition. Near infrared spectroscopy (NIRS) is a noninvasive and continuous method for monitoring tissue oxygenation. Babak Shadgan, a sport medicine researcher, is studying whether careful monitoring of lower leg muscle oxygenation in fractured leg patients who are in a higher risk of acute compartment syndrome may allow for an early diagnosis of this critical condition. If effective, this new method would improve speed and accuracy of diagnosis, leading to improved care for patients and substantial health care cost-savings.