Violence is a serious public health concern. It embodies a considerable societal burden and its individual cost, in terms of both physical and mental health, is enormous, whether it pertains to victims, perpetrators or those close to them. Currently, legal, forensic and psychiatric institutions are confronted with the difficult task of determining whether a specific individual may be at risk of harming others. Violence risk assessments are conducted in order to find a way to reduce or manage that risk, either in the community or within institutions. Because the decisions made by mental health professionals during such assessments have serious consequences, it is essential that the decision-making processes be scientifically and clinically sound. The Historical/Clinical/Risk-Management-20 (HCR-20) represents one of the most researched and established instruments used to assess risk for community and institutional violence in offenders, civil psychiatric patients, forensic psychiatric patients, as well as males and females with mental illness, personality disorder or substance abuse problems. Since the development of the HCR-20 in 1997, a large body of data on its efficacy has been collected, and the authors concluded that some revisions were necessary. Diana Strub’s research involves an evaluation of a subscale of the revised HCR-20 assessment scheme in its entirety on a new sample of 150 individuals (i.e. offenders and mentally disordered offenders), about to be released into the community. Her work has implications for violence risk reduction and management for individuals with mental illness, personality disorders, correctional involvement and/or substance abuse problems. Such violence prevention strategies are expected, in turn, to considerably reduce physical and mental health concerns for those at risk, their victims and those close to them, as well as alleviate some of the burden placed on the health care system.
Program: Trainee
A cross-national evaluation of opioid dependence treatment service systems in Canada and the United States
Methadone maintenance treatment (MMT) is the most effective form of treatment for opioid dependence, a chronic, recurrent disease. However, the availability and means by which MMT is delivered varies greatly, both locally and internationally. Understandably, the resulting accessibility, quality and comprehensiveness of care provided through the various treatment practices have important public health implications, and require careful consideration. Notably, there are vast differences between the drug treatment systems in California and British Columbia. Treatment for opioid dependence remains restricted in California due to regulatory constraints on treatment settings, (i.e. registered drug treatment centres), and physician practice, (i.e. limits on the number of patients per physician). Nonetheless, treatment through drug treatment centres may offer some advantages. In comparison, access to MMT in BC has improved following administrative transfer from the federal government to provincial colleges of physicians and subsequent deregulation through the introduction of community-based treatment (i.e. office-based prescription and dispensation in community-based pharmacies). Community-based treatment may maximize access, albeit at a relatively high cost, although the economic merits of maximizing access are well-established. Building on his earlier research in this area, Mr. Nosyk is working to identify differences in patient characteristics, treatment outcomes and costs of opioid dependence treatment systems in both the countries, with a specific focus on the performance of the treatment systems in terms of effectiveness, efficiency and equity. The knowledge gained from his research can be extended to estimate the health and economic impact of introducing treatment services at the population-level, and corresponds with long-term recommendations to expand services to provide more comprehensive treatment for substance users in BC.
Seasonal plasticity in brain estrogen signaling mechanisms regulating aggression
While estradiol, a kind of estrogen, is often considered a “”female”” hormone, it is fundamentally important for both female and male brain function. It is a hormone with a wide range of effects on the brain and human behaviour. In early life, estradiol plays an important role in the growth of brain cells and in the establishment of differences between male and female brains. In adulthood, estradiol activates both male and female reproductive behaviour. Studies also implicate estradiol in the regulation of aggression, learning and memory, muscle control and the perception of pain. Furthermore, estradiol has been shown to influence depression, recovery from stroke and brain injury, Parkinson’s disease and Alzheimer’s disease. Because estradiol is involved in a vast array of brain functions, many of which are critical to human health, it is important to understand how estradiol affects brain cells. Dr. Sarah Heimovics’ research explores the degree to which there is plasticity in how estradiol affects the brain and behaviour. Specifically, she is investigating the effect of environmental factors, such as photoperiod, on estradiol signalling mechanisms the brain. Traditionally, estradiol has been understood to influence brain and behaviour genomically, via changes in gene expression over a relatively long timescale (days to weeks). However, a growing body of research suggestes that estradiol also has rapid (within 30 minutes), non-genomic effects. Dr. Heimovics will compare the role of genomic and non-genomic estradiol signalling mechanisms in the neural regulation of aggressive behaviour on short and long photoperiods. She is testing the hypothesis that non-genomic estradiol signalling is more pronounced on short photoperiod (as during the winter in BC), which may have implications relative to depression. The results of this research will contribute to the greater understanding of how estradiol acts on the brain, which is a critical issue for the health of British Columbians.
The role of microbiota in susceptibility to inflammatory bowel disease.
The cause of inflammatory bowel disease (IBD), including intestinal disorders characterized by chronic inflammation such as Crohn’s disease and ulcerative colitis, remains unclear. However, changes in the microbiota have been linked to IBD, including Crohn's disease and ulcerative colitis, as significant differences exist between the microbiota of IBD patients and healthy individuals. As western societies have developed, improvements in health and hygiene have altered human-microbe interactions through increased sanitation, antibiotic usage and vaccination. Concordantly, epidemiological studies have shown an alarming increase in the occurrence of immune mediated disorders, such as IBD. However, whether a change in microbiota composition precedes and contributes to onset of IBD or is a result of IBD remains to be determined. Marta Wlodarska and colleagues have previously shown that clinical levels of antibiotics will cause a shift in, but not complete ablation of the microbiota which results in a differential disease outcome by Salmonella Typhimurium infection. Her current research project expands on this work by investigating how antibiotic-induced fluctuations of the microbiota disrupt the homeostatic state of the intestinal immune system, potentially leading to increased susceptibility to IBD. Specifically, she is using clinical levels of antibiotics to shift the composition of the microbiota and evaluate how that affects the outcome and severity of C.rodentium-induced colitis. Additionally, her research should also provide an understanding of how changes in microbiota composition affect the homeostatic state of the mucosal immune system through intestinal epithelial cell-mediated cytokine secretion. Collectively, her work will increase the understanding of the interplay between the microbiota and immune responses as well as any associated impact on colitis. These issues are central to increasing our understanding of IBD in general, and may lead to the development of new diagnostic and therapeutic tools.
Identification and analysis of proteins required for tubulin homeostasis: impact on nervous system disorders and cancer
A cytoskeleton is a central component of all cells, and is made of protein filaments that assemble into networks. These networks allows cells to divide, change shape as needed and perform a multitude of other vital functions. Microtubules (MTs), are essential cytoskeletal components composed of an elementary protein called tubulin. To fulfill its cellular function, the activity and level of tubulin must be maintained optimally by a process known as homeostasis. This process is not well understood, but is known to be particularly important for nervous system function. In fact, disruption of tubulin homeostasis can lead to neurological problems such as Huntington’s disease. Furthermore, because MTs are important in the uncontrolled division of tumour cells, tubulin represents an important target for cancer treatment. To improve our understanding of the fundamental principles guiding tubulin homeostasis, Dr. Melissa Frederic has undertaken research to identify and characterize proteins associated with the function, organization and maintenance of tubulin, using mainly C. elegans, a tiny worm, and mammalian tissue culture cells as model systems. One protein that will be characterized at the molecular and cellular levels, termed HECTD1, has been identified in her lab as a likely factor influencing tubulin homeostasis; importantly, it has also been linked to neural tube defects in a mouse system where the protein was removed. At the same time, Dr. Frederic is doing genetic screens to identify proteins that effect tubulin homeostasis, including one that utilizes the anticancer drug taxol or benzyl isothiocyanate. Together, the characterization of HECTD1 and the discovery and subsequent characterization of additional proteins implicated in tubulin homeostasis, are expected to shed new light on nervous system disorders such as neurodegeneration and neural tube defects, the most common congenital malformation in humans, as well as cancer.
Influence of aging on candidate neuropsychiatric disease genes measured using differential coexpression
Aging and developmental change represent body wide changes in genes. Because many genes change as people age, the relationships between genes also often change, a phenomenon called differential coexpression (of RNA levels). Studying differential coexpression has uncovered changes that cause disease. However, knowledge gaps remain with respect to relationships between disease and aging in neurological diseases, for example. Many diseases have a specific age of onset, schizophrenia for example, typically strikes in early adulthood. This suggests that in multi-gene disorders, where interactions between genes play a role, rewiring may occur between susceptibility genes at the age of disease onset. Dr. Gillis’s current research project builds on his earlier work which showed that aging is associated with numerous changes in coexpression, and that genes known to be associated with specific diseases change their relationships with age in healthy individuals. His current project involves studying how the relationships between candidate genes – differential coexpression – in schizophrenia and Alzheimer’s Disease, change as a function of age. By understanding how networks of gene interactions might be rewired in diseases, we can identify candidate genes that would be missed otherwise, and beneficially influence the design of treatments and diagnostics.
Perceptual and attentional abnormalities in autism – understanding impaired discrimination of the eyes
Autism is a pervasive developmental disorder involving impairments in social interaction, verbal and non-verbal communication, a lack of imaginative play, and repetitive and restricted solitary activities. A critical goal of autism research is the identification of biological, behavioural and cognitive markers that will help researchers determine the links between genes and autism and aid in the development of effective diagnostic tools, as well as improve upon existing intervention and treatment programs. Of note, abnormal perceptual processing is currently a candidate marker of autism. There is mounting evidence to suggest that people with autism show specific perceptual abnormalities, and that these abnormalities may play a causal role in deficits in social processing. For example, research suggests that individuals with autism show abnormal perception of faces, with a reduced ability to discriminate visual changes to the eye area of a face, as compared with normal perception of changes to the nose and mouth. However, it is unclear whether these abnormalities are due to a deficit in perceiving visual information from the eyes, or a lack of attention to this visual information. Elina Birmingham’s research involves the use of eye tracking and a new methodology called the moving window technique, to measure the focus of attention in children with autism while they undertake visual face exploration. Her research will provide insight into several key questions regarding perceptual and attentional abnormalities as indicators of autism in children. The results of her study will contribute to the goal of identifying markers of autism, and as such may have important implications for treatment and intervention methods.
Developing New Non-Invasive Optical Techniques for Detecting and Diagnosing Cancer
While cancer continues to affect thousands of Canadians, when detected at an early stage patients have a better chance of survival. Therefore, the development of sensitive diagnostic tools to enable early cancer detection and diagnosis is important. Dr. Anthony Lee is focusing his research efforts on the design and development of high resolution, non-invasive, in vivo optical imaging tools that will allow clinicians to perform so called ‘optical biopsies’ to detect and diagnose lung and skin cancers while the patient is being examined. Lung cancer is the leading cause of cancer mortality. The only reliable way to definitively diagnose the disease is to perform a lung biopsy for histological inspection by a pathologist. This technique is invasive and is associated with numerous problems. Dr. Lee’s Optical Coherence Tomography (OCT), is a technique that shows promise as a non-invasive diagnostic tool for lung cancer. Part of his project will be dedicated to developing a new OCT instrument designed specifically for use in patients’ lungs. OCT is similar in principle to ultrasound except that it uses light rather than sound as the imaging signal. It has higher resolution than ultrasound and sufficient penetration into tissue to examine the lung epithelial lining, where most cancers originate. The endoscopic probe being designed can image large segments of the bronchial tree in high resolution. Additionally, Dr. Lee is developing a Multiphoton Microscopy (MPM), instrument for use in diagnosing skin cancer, the most commonly diagnosed form of cancer. MPM has microscopic resolution and will be able to create 3-dimensional volumetric images of tissue. The results of Dr. Lee’s work will provide improved diagnostic tools to replace traditional biopsies which are time and resource intensive. Moreover, if cancer diagnoses can be confirmed in situ, immediate treatment becomes a possibility and may eliminate the need for subsequent patient visits.
Developing an innovative antibody-based nanopharmaceutical for treating cancer
Rituximab is an anti-CD20 monoclonal antibody (mAb), approved for use in combination with standard chemotherapeutic agents for treatment of patients with CD20-positive B cell lymphomas. Although it provides significant benefits for lymphoma patients, it is not curative, and for several specific forms of lymphoma, rituximab offers little or no benefit. To date, the mechanism(s) underlying the anti-tumour activity of this mAb in vivo are not clear. However, one area of particular interest is in activities that involve clustering of the CD20 molecule on the cell surface. Clustering of CD20 has been shown to elicit changes in cell signalling pathways that promote cell death, while enhancing sensitivity of lymphoma cell lines to cytotoxic agents. By better understanding this mechanism of antibody-induced tumour death it will be possible to determine the clinical basis for insensitivity to rituximab. Jesse Popov’s research is exploring this mechanism of activity by comparing a novel, highly active multivalent form of rituximab that he has developed, to the activity of rituximab. The results of his research will provide for improvements on the novel mAb he has developed and may also provide a possible therapeutic alternative to rituximab. Importantly, this novel agent can be made with any therapeutic antibody, not just rituximab, which means that it has the potential to be used for treating virtually any type of cancer. Such improvements over current therapies translate directly into a higher quality of life for cancer patients.
The Relationship Between the Immune System and the Normal Gut Microflora in Salmonella Typhimurium Infection: A Two Sided Tale
Understanding the role of the microbiota in the development and progression of diseases has received a great deal of attention in recent years. The microbiota is defined as the group of microorganisms, such as bacteria, which normally inhabit the human body. These microorganisms, also known as microflora, are composed of a variety of species of bacteria, each having a different function, and there are some bacteria whose functions remain unknown. Several studies have shown that patients with inflammatory bowel diseases, such as Crohn’s Disease, have a microbiota composition that is different from healthy individuals, suggesting that certain species of bacteria might be important in causing some common gut inflammatory disorders. Dr. Navkiran Gill is investigating how the human immune system regulates the microbiota and how our microbiota may direct our immune responses to various pathogens. Specifically, she is doing a series of experiments involving antibiotic use in specially bred mice infected with Salmonella. The results will provide important information regarding the effect of antibiotics on the microflora, and allow her to correlate changes in our microflora to changes in our ability to mount an immune response against a pathogen such as Salmonella. The results of Dr. Gill’s research will provide information that may be used to design new therapeutics that take into consideration the important role of our microflora.