Prenatal exposures to PBDEs and PFCs: Sources of exposure, thyroid effects, and neurodevelopmental effects in children

Polybrominated diphenyl ethers (PBDEs) and perfluorocarbons (PFC) are chemicals that are used as flame retardants and surfactants in a wide variety of consumer products. In animal studies, both chemical groups have been shown to have toxic effects on the thyroid and have the potential to affect fetal brain development. A small but growing body of evidence suggests similar thyroid effects may occur in humans; however, the links between these chemicals and thyroid disruption in early pregnancy, the most critical window of exposure, are still unclear. The specific effects of prenatal PBDE and PFC exposures on neurodevelopment in humans are largely unknown. Disturbingly, both chemicals are present in the blood of the entire Canadian population, including children and newborns, and the most important sources of these chemicals are poorly understood. The post-doctoral research of Dr. Glenys Webster will help fill these gaps by 1) identifying the main sources of PBDEs in maternal blood, 2) exploring whether maternal PBDE levels are associated with maternal thyroid hormone levels in early pregnancy, a time when thyroid hormones play a critical role in fetal brain development, and 3) examining the relationships between maternal PBDE and PFC levels and neurodevelopmental outcomes in one- to three-year-old children, as measured by cognition, motor function and behavior. Dr. Webster’s work will use data from two existing pregnancy cohorts in Vancouver and Cincinnati, and will link the sources of chemical exposure to chemical levels in blood to maternal thyroid effects to child neurodevelopmental effects, all within the same study populations. Understanding the public health implications of population-wide exposures to PBDEs and PFCs will provide key information for ongoing risk assessment and risk management strategies in Canada and will support the development of effective chemical regulation policies to protect public health.

Studies Towards the Total Synthesis of Eleutherobin and Designed Analogues for Cancer Therapy

Cancer is one of the leading causes of death among Canadians, and therefore the identification of new cancer therapies is of great importance. To that end, researchers have found that the structurally diverse defence chemicals provided by sessile marine organisms offer great potential in the fight against cancer. In fact, in the past decade more than 30 natural products isolated from marine sources have entered preclinical and clinical trials as potential treatments for cancer. However, it is rarely ecologically or economically feasible to obtain the active ingredient by harvesting the natural source. Fortunately, synthetic organic chemistry – where molecules are fabricated in the laboratory through a series of chemical transformations – can serve as an alternative source of these compounds. Eleutherobin was originally isolated from a rare soft coral located of the coast of Western Australia in 1997, and in preliminary tests it has shown many promising anti-cancer properties. In fact, taxol, a member of the same class of agents, has already been used to treat more than one million patients suffering from advanced breast and ovarian cancers. Over the past two years, Jeffrey Mowat has spearheaded research centered on the development of a concise synthesis of eleutherobin and analogues of this substance as candidates for cancer treatment. However, so far, eleutherobin's preclinical evaluation has been hampered by lack of material from the natural source or chemical synthesis. Mr. Mowat's current research project addresses this situation through the development of a synthetic strategy that would significantly reduce the number of steps required to access eleutherobin and facilitate its preclinical evaluation. His research also provides a venue for the construction of analogues of eleutherobin, the biological evaluation of which may well lead to the discovery of new, improved antimitotic drugs for cancer therapy.

An Examination of the Risks and Health Needs of Adolescents and Young Adults with FASD in the Criminal Justice System.

Fetal alcohol spectrum disorder (FASD) is an umbrella term referring to a range of permanent deficits that occur in a developing fetus as a result of exposure to alcohol during pregnancy. FASD is the leading cause of developmental disability among Canadian children and is identified as a major public health concern in Canada. Individuals with FASD experience high rates of health related problems, including serious mental illness and substance use, homelessness, violence and victimization. In BC, the government has committed to the important goal of providing individuals living with FASD the support needed to reach their full potential in healthy and safe communities. To assist in achieving this goal, the province has called for more research to inform treatment efforts in general health and justice settings. Kaitlyn McLachlan’s research speaks to that need by providing a knowledge base specific to the risks and health needs of youth diagnosed with FASD in the justice system. The overall purpose of this study is to improve health outcomes for justice-involved youth with FASD, in part, by developing a knowledge-base about offending patterns and salient risk indicators in youth with FASD. The project will be based in BC and parallel data collection efforts will be made in additional provinces so that reliable conclusions can be made about this population. The information from this study can be used to inform the targets and timing of interventions and improve clinicians’ recommendations about risk, risk management and interventions. The knowledge gathered about mental health and substance use problems will also be crucial in determining the types of community-based services youth with FASD require outside the justice system in order to maintain good health.

Function of clathrin-based endocytic proteins during infections by extracellular bacterial pathogens

Most E. coli bacteria live within the intestines of humans and other animals where they help with normal digestion. However, certain types of E. coli cause disease and represent serious global health concerns. For example, diseases mediated by these pathogenic E. coli often lead to gastro-intestinal infections, resulting in severe and persistent watery or bloody diarrhea. These diseases affect a significant population, especially infants, in many developing countries and the associated mortality rates can exceed 30 percent. Previous research by Ann Lin and others has shown that clathrin, a protein that involves endocytosis, plays a key role in generating E. coli-based diarrhea in humans. Expanding on this research, Ms. Lin is now focusing on the identification of clathrin-associated endocytic components necessary for the development of enteropathogenic E. coli infections, using both in vitro and in vivo approaches. Because other bacteria and viruses (such as influenza), also control clathrin-based internalization mechanisms as part of their infection, Ms. Lin’s’s research will not only provide valuable insight into the mechanism of E. coli-based disease, but will also generate new avenues for the development of novel therapeutics to eradicate other infectious diseases.

Assessing Protective Factors for Self-harm: Development of the Barriers to Self-harm Inventory

Deliberate self-harm (DSH) is the deliberate, direct destruction of body tissue without suicidal intent. Common forms of DSH include cutting, burning or hitting oneself and, not surprisingly, it is associated with a variety of negative health outcomes. DSH often begins in adolescence. Without treatment it can persist for several years and decades. Although promising treatments exist, studies indicate that many individuals in treatment fail to reduce their DHS behaviours. To date, few studies have examined factors that directly prevent someone from engaging in DSH, either over the short- or long-term. Brianna Turner’s research is focusing on factors that directly prevent DSH, as well as the development of a novel psychometric measure that can be used easily within busy health care settings to assess protective barriers against DSH and predict future DSH. These are novel research directions that fit within two larger investigational projects underway that looking at the emotional, individual and environmental factors that predict changes related to self harm. Additionally, and importantly, the results of this study have the potential to improve the quality of care and health outcomes for individuals who engage in deliberate self-harm.

The Next Generation of Multifunctional Nanoparticles for Cancer Imaging and Therapy

In photodynamic therapy (PDT), a nano particle (NP), is placed within the body and is illuminated with light from outside the body. Normally, the light that gets absorbed by the NP can produce high energy oxygen molecules which will chemically react with and destroy most organic molecules that are next to them, like tumours. This type of light therapy can also be employed to release small drug molecules from the surface of the NP. PDT can be far less expensive than radiotherapy or surgical operation and post operative care. Furthermore, PDT recovery typically requires hours or days rather than weeks, and does not leave a toxic trail of reactive molecules throughout the body as is the case with chemotherapy. This is because the light is targeted at the precise location of the NPs. PDT therefore, is potentially a non-invasive procedure for treatment of diseases, growths and tumours. Additionally, NPs with multiphoton upconversion properties are useful for the diagnosis and treatment of cancer and hold great promise for biosensing and bioimaging. Dr. John-Christopher Boyer is involved in designing the next generation of multifunctional NPs capable of both imaging and selectively targeting cancer cells using photodynamic therapy based on molecular switches. The ultimate goal of his project is to develop nanoparticles with photon upconversion properties, and apply them in sensitive cancer detection. Consequently, a focus of his current research project is to evaluate the performance of the upconverting NPs when applied to sensitive detection and treatment of prostate cancer. Dr. Boyer’s research could significantly enhance Canada’s position in nanomedicine, and developments in this area may well revolutionise medical practice in cancer detection and treatment over the coming years.

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.

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.

Social Attention and Visual Exploration in Children with Autism Spectrum Disorders

Autism is a severe neurological developmental disorder characterized, in part, by social impairment. A key social impairment present early in the development of children with autism is abnormal gaze following. Children with autism often do not follow the eye-gaze of others towards objects or events in the environment, which hampers their development of language and social skills. It may be that the seemingly abnormal gaze following evident in children with autism results from abnormal basic attentional responses to gaze cues. Clinical reports suggest that when in object-rich environments, these children demonstrate a diminished ability to focus on socially meaningful stimuli. Therefore, further research focusing on the ability to orient to gaze cues within complex visual environments such as classrooms, is critical. Adrienne Rombough has developed a computer task that examines orienting responses to gaze cues within complex visual scenes. In her current research she is using this program to examine the ability of children with autism to detect changes in complex visual scenes with or without the presence of gaze cues. Her study is designed to compare the performance of school-aged children with autism to that of mental age-matched, typically developing children. Her short term objective is to address the question of whether (and to what extent), the attention orienting response to gaze cues is abnormal in autism. This is the first known study to use an alternative, indirect measure of attention (i.e. change detection), to investigate gaze cueing within complex visual scenes. Over the longer term, Ms. Rombough’s findings could potentially improve the present understanding of how children with autism use social cues to explore their visual environments and how this skill set is potentially related to social impairment. The project is part of a larger research program designed to characterize the cognitive underpinnings of social impairments in autism.

Predictors of Medication Adherence in Renal Transplant Patients: Self-Efficacy, Depressive Symptomology, and Neuropsychological abilities.

Chronic Kidney disease (CKD), is relatively common among middle-aged and older adults and the incidence is increasing. For example, 119 million Canadians had CKD in 1996, while by 2004 that number had reached roughly 154 million. Furthermore, just under 1,000 people received kidney transplants in Canada in 2005, while three times that many remained on wait lists that year alone. Needless to say, the successful clinical management of CKD is dependent on a number of factors. Recently, Ms. Theone Paterson and colleagues have determined that cognitive abilities are impaired in patients with CKD following successful kidney transplant, in a similar way to that seen in patients with CKD prior to kidney failure. Importantly, they also recently found that difficulties completing both traditional and everyday cognitive problems are predictive of decreased medication adherence among renal transplant patients, and that depressive symptoms partially mediate the relationship between traditional cognitive performance and medication adherence. Therefore, the extent to which real world functional issues such as adherence is predicted by traditional and everyday problem solving, depression and self-efficacy is an important issue in renal transplant, for patients, their healthcare providers, and their caregivers. In her current research program, Ms. Paterson is focusing on the relationships among traditional and everyday measures of cognitive performance, general and medication adherence-specific self-efficacy, self-reported depressive symptoms and medication adherence in people who have undergone successful renal transplantation. The results of this work will aid not only in understanding difficulties faced by transplant patients, but also in the development of interventions designed to improve adherence and consequently, real-world functioning for these patients. Additionally, the results of this research will be used to develop sensitive and valid measures to assess real-world function in patients with CKD and ultimately improve their quality of life.