Polysubstance use: psychosocial functions of combined use of alcohol and psychostimulants

Much of the research that informs current understandings of drug and alcohol use and addictive behaviour is based on studies that concentrate on a single substance type. This narrow focus is in distinct contrast to actual patterns of use and related harms: most Canadians with substance use problems use more than one substance (polysubstance use), often on the same occasion, and their behaviours and health outcomes may be strongly shaped by this combination. Health policies and programs are usually developed, implemented and evaluated one substance or behaviour at a time, without consideration of possible consequences for other substance use and addiction outcomes. In the current research literature there is a lack of information regarding polysubstance use. This includes when, in what order, and in what quantities people use substances, why they choose to use simultaneously, and the risk behaviours (e.g. sexual behaviour, spending behaviours) associated with simultaneous polysubstance use. Kristina Brache is exploring the patterns of use, the settings and the motivations associated with combined use of alcohol and psychostimulants (cocaine, amphetamines). She is conducting a series of in-depth interviews and self-administered surveys of 150-200 substance-using individuals in a treatment setting. Understanding the use of multiple substances can inform prevention and intervention strategies to reduce harm or risk to individuals using multiple substances. Ultimately, this research could improve health and health delivery systems by informing policy, programs and treatment about combined drug use in this population of interest.

Social Determinants of Rural and Northern Community Health

Research has increasingly linked the health of individuals to the integrity of a community’s social fabric, the extent to which residents in a community trust each other and participate in community activities, and on the networks of communication and exchange between community members. However, little research on this “”social capital”” has been conducted in British Columbia. Yet, communities in British Columbia are facing an accelerated pace of structural change due to the effects of globalization, changes over the past 15 years in health and welfare systems, and industrial restructuring. It is imperative, particularly in the Central and Northern Interior of the province, where an unprecedented eco-economic crisis is unfolding due to the pine-beetle infestation, that the impacts of these changes in community structure and functioning and, in turn, their impacts on social capital and the health and the health and educational status of children and adolescents are investigated in a way that may lead to amelioration. Building on the foundation of over a decade of work on the social determinants of workplace and community health and a recently awarded New Emerging Team grant to investigate the social determinants of community health in British Columbia, this program of research will further methodological developments in community health research while strengthening the base for community health research at the University of Victoria, in BC, nationally, and internationally. Given that many other communities in Canada, as well as in other nations, similar challenges, the knowledge, conclusions, and recommendations arising from this program of research will be applicable in other jurisdictions.

Timely Access to End-of-life Care for Patients with Life-threatening Illness

The goal of this study is to ensure patients with cancer and other fatal illnesses receive the right kind of end-of-life care at the right time and in the right place. For this to be possible, it is essential to improve the ability of clinicians to accurately assess how long these patients will live because their expected length of survival is a key factor in determining the types of care they will receive. In a research project involving one palliative care program in BC and two in Alberta, this team is assessing the extent to which health data that is collected routinely during initial and follow-up assessments can improve the accuracy of survival estimates.

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Carbohydrate recognition and metabolism in streptococcus pneumoniae: Structural and functional dissection of unique virulence factors

Pneumonia is an acute respiratory disease, the major cause of which is the bacterium Streptococcus pneumoniae. This bacterium is the leading cause of death from infectious disease in North America and a leading cause of death worldwide, particularly in children and the elderly. This bacterium can also cause meningitis, septicemia, and otitis media (middle ear infection). Reports indicate that 40 per cent of pneumonia cases caused by S. pneumoniae are resistant to penicillin and new multidrug resistant strains are beginning to emerge. To reduce increasing rates of antibiotic resistance and augment judicious use of the pneumococcal vaccine, alternative methods for treating S. pneumoniae infections must be found. Several proteins have been found in S. pneumoniae that are believed to contribute to its virulence. It is suspected some of these proteins destroy sugars such as glycogen in specific lung cells that normally serve to protect the lungs against infection. These damaging proteins are potential targets for preventing or slowing the infection. Dr. Alisdair Boraston will focus on two aspects of these S. pneumoniae proteins: if and how these proteins are destroying sugars and how to inhibit this activity. Biochemical studies will provide understanding about how these enzymes degrade sugars and whether any inhibitor molecules can interfere with this. Structural studies using X-ray crystallography will show structural features of the proteins that contribute to their activity and aid in the design of new inhibitors. Taken together, this information will lead to new approaches and agents to target pneumonia caused by S. pneumoniae.

MeCP2 and chromatin: An alternative to the global binding hypothesis

Rett syndrome is a severe neurodevelopmental disease that affects approximately one in 10,000 girls. Progressive symptoms begin at a very young age and worsen through childhood. These include loss of speech, purposeful hand use, ability to walk, and the development of seizures. In 85 per cent of cases, the cause of Rett syndrome has been traced to mutations of a protein known as MeCP2. Dr. Toyotaka Ishibashi is studying the relationship at the cell level among the MeCP2 protein, DNA and chromatin (a complex of DNA and protein that regulates the binding of the MeCP2 protein to DNA). Despite some research carried out in recent years, details of the interaction of MeCP2 with chromatin remain largely unknown. Toyotaka is investigating how MeCP2 works in normal cells, which is critical for later study of how gene mutations interfere with the normal function of the protein to cause the symptoms of Rett syndrome. Ultimately, Toyotaka hopes to clarify the role of the MeCP2’s nucleosome — the most elementary structure involved in regulating the protein’s activity — to provide potential cellular targets for drug targeting and new prospects for the development of clinical therapies.

Defining the structural basis of surface antigen glycoprotein mediated virulence in Toxoplasma gondii

Toxoplasmosis is a serious human pathogen carried by about one-third of the population. People develop toxoplasmosis either after ingesting undercooked meat that contains T. gondii cysts, or by coming into contact with cat feces from an infected animal. Once infected, healthy adults initially show a range of temporary flu-like symptoms; however, while these symptoms pass, the parasite Toxoplasma gondii remains in the body for life, with limited drug treatment available. Infection during pregnancy can cause miscarriage, neonatal death and a variety of fetal abnormalities, including developmental delays. It is also harmful to those whose immune systems are compromised, such as those with HIV/AIDS, cancer or who have had an organ transplant. Very little is known about how T. gondii causes disease. Dr. Martin Boulanger is studying the structure of host-pathogen interactions to determine the activities that allow T. gondii to attach to and invade human cells. With this information, treatments can be developed to prevent or manage Toxoplasmosis. This work will also apply to better understanding of other parasite-caused disease such as malaria and cryptosporidiosis.

Exploring and exploiting the protein psoriasin as a new target for breast cancer therapies

Ductal carcinoma in situ (DCIS) is a precursor to invasive breast cancer, and the protein psoriasin is one of the most highly expressed genes in DCIS. Psoriasin is present at abnormally high levels in many pre-invasive breast cancer cells and in a smaller subgroup of invasive breast cancer cells. Recent research has shown that the interaction of psoriasin with the signaling protein Jab1 may be a keystone of the signal network of the breast cancer cell, and that psoriasin binding can cause Jab1 to stimulate the development of invasive and metastatic breast cancer cells. Inhibiting protein-protein interactions is an exciting new approach in the search for targeted cancer therapeutics, and the psoriasin-Jab1 interaction is a promising new target for the treatment of breast cancer. Dr. Fraser Hof’s work deals with fundamental questions about the interactions of proteins and small molecules and with the applied design of small molecule therapeutics. His proposal is to design and develop novel drug molecules to block this psoriasin-Jab1 interaction, first to validate the target and then to guide subsequent drug development. A drug that inhibits this interaction may offer a novel therapy to directly target pre-invasive breast cancer and prevent the development of invasive breast cancer. This therapy may also hold promise as a new approach to target the small subgroup of invasive breast cancers where psoriasin is also present, as this subgroup is typically not eligible for current targeted therapies such as tamoxifen and herceptin.

Dopamine mechanisms of reward learning and cognitive control in children with attention deficit hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is the most frequently encountered childhood onset disorder in primary care settings. ADHD is characterized by certain behaviours, most commonly: inattention, hyperactivity, and impulsiveness. Although preliminary research indicates that the biological roots of ADHD may involve certain areas of the brain, the link between the cognitive and behavioral manifestations of ADHD and its neural basis is poorly understood. Research shows that the midbrain’s dopamine system — a neural system associated with reward learning and reward-related behavior (reinforcement learning) — is abnormal in children with ADHD. To date, however, there has been little research regarding exactly how the disturbance of the dopamine system leads to this impaired reinforcement learning. Dr. Clay Holroyd is interested in the neurobiological mechanisms that underlie cognitive control — how people regulate their attention, thoughts, and actions in accord with high-level goals and intentions. Specifically, he is focusing on how people detect and correct their errors and, and how they learn from the consequences of their actions. Currently, ADHD research is an important component of his ongoing research program. Dr. Holroyd is investigating impaired cognitive control, error processing, and reinforcement learning in children with ADHD. Using behavioural experiments and computational modeling, he is researching whether the cognitive and behavioral impairments associated with ADHD are the result of the transmission of abnormal reinforcement learning (RL) signals from the midbrain dopamine (DA) system to the frontal areas of the brain involved in cognitive control. Developing a greater understanding of the link between the neural impairment in ADHD and learning and behavior is an important step towards creating a common and accepted model of ADHD; one that spans multiple levels of analysis, including biology, behavior and cognition. This research will provide a greater understanding of the neurobiological mechanisms that underlie cognitive and could lead to the development of new therapeutic treatments for children with ADHD.

Developmental Neuroscience Research Team for Behavioural Self Regulation

This award supports the development of a team of clinicians and researchers addressing gaps of understanding about the causes of developmental disorders including Fetal Alcohol Spectrum Disorder, Attention Deficit Hyperactive Disorder and Conduct Disorder. These gaps include the electrophysiological processes underlying problems in social development, such as self-regulation, that affect children diagnosed with these disorders.