Biomedical Physiology and Kinesiology - Theses, Dissertations, and other Required Graduate Degree Essays

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Using an activator of hERG (RPR-260245) in a model of acquired and inherited Long QT syndrome type 2

Author: 
Date created: 
2017-07-17
Abstract: 

The human ether-a-go-go related gene (hERG) channel is the molecular correlate of the rapid delayed rectifier current (IKr); its dysfunction causes Long QT syndrome type II (LQT II). RPR-260245 (RPR) is an activator of hERG that increases hERG current by slowing deactivation. Thus, it represents a potential treatment strategy for LQT. However, only few studies have addressed its impact on cardiac physiology. We used electrophysiology techniques in Xenopus Laevis oocytes and optical mapping in induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) to test the effects of RPR on hERG and on the cardiac action potential. We show that RPR has little effect on the cardiac AP in WT iPSC-CMs but demonstrate a partial rescue in our model of acquired LQT (aLQT) under dofetilide block and a partial rescue in our model of LQT II. Finally, RPR significantly increases protective hERG current, especially in instances of the R56Q mutation.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Glen Tibbits
Thomas Claydon
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

Atypical Neuronal Oscillatory Synchrony of the Auditory Steady State Response in Down Syndrome

Author: 
Date created: 
2017-08-18
Abstract: 

The mechanisms by which the brain coordinates a constant flood of information to provide a unified perception of reality remains poorly understood. Mounting evidence suggests that information integration is closely related to oscillatory activity in the gamma frequency band. Individuals with Down Syndrome (DS) reportedly struggle with higher cognitive processes, but existing knowledge representing the neuronal oscillatory dynamics of the DS brain remains limited. Cortical circuit dysfunction can be probed by the examination of phase coherence of the Auditory Steady State Response (ASSR). Using a measure of phase coherence to assess oscillatory synchrony in the auditory cortices, results show evidence of reduced inter-hemispheric phase locking in the gamma band at the group level (N=12) for DS individuals (p < 0.01) compared to control participants. These findings indicate the DS brain does not integrate information as effectively as non-DS individuals do, contributing to a deeper understanding of the neurophysiological correlates of DS symptomology.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Sam Doesburg
Teresa Cheung
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

A pilot randomized controlled trial of exercise to improve walking energetics among older adults with mobility limitation: The HealthySteps Study

Date created: 
2017-07-11
Abstract: 

Mobility is a fundamental component of healthy aging; however, mobility limitation is a prevalent, energetically costly problem among older adults. We conducted a pilot randomized controlled trial to compare the effects of two, 12-week exercise interventions (timing and coordination, TC; aerobic walking, AW) to an active control (stretching and relaxation; SR) on outcomes related to mobility among community-dwelling older adults with mobility limitation (n=72). At 12 weeks, TC reduced mean energy cost of walking by 13-15% versus SR. Among those with high baseline cost, TC reduced mean energy cost by 20-26% versus SR. Reductions were maintained at 24-week follow-up. AW had no effect at 12 or 24 weeks. Fatigability, daily physical activity, endurance, physical function, and life-space mobility did not change with TC or AW versus SR at 12 or 24 weeks. In summary, 12 weeks of TC, but not AW, improved walking economy among older adults with mobility limitation.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Dawn Mackey
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

Mechanistic Insight into Human ether-a-go-go-related Gene (hERG) K+ Channel Activation and Deactivation gating

Author: 
Date created: 
2017-06-15
Abstract: 

hERG encodes the pore-forming α-subunit of the voltage-gated potassium channel that underlies the rapid delayed rectifier current, IKr, in the heart, which is essential for normal cardiac electrical activity and rhythm. Inherited mutations in, or pharmacological blockade of, hERG channels deplete the cardiac repolarization reserve, increasing the risk of life-threatening arrhythmias. The molecular bases of hERG gating events and drug binding are poorly understood. hERG channels display unique gating characteristics critical for their physiological function. They activate and deactivate slowly, yet inactivate and recover from inactivation rapidly. In addition, the promiscuous nature of drug interactions with hERG channels presents a therapeutic challenge for drug design and development. My thesis provides novel mechanistic and structural characterization of the unusual activation and deactivation gating processes of hERG. In my first study, I used a proline scan approach to define the activation gate region in hERG channels. Proximal substitutions (I655P-Q664P) impeded gate closure, trapping channels in the open state, while distal substitutions (R665P-Y667P) preserved normal gating, suggesting that Q664 marks the position of the activation gate in hERG. This is more than one helical turn lower than in related channels, which may allow for drug docking. Using two different approaches to measure voltage sensor gating in trapped open channels, I then demonstrated that slow activation is an intrinsic property of the voltage-sensing unit of hERG. In my second study, I showed that voltage-sensor stabilization slows hERG channel deactivation gating. I characterized the temporal sequence of events leading to voltage-sensor stabilization upon membrane depolarization. I showed that this occurs via two separable mechanisms, one derived from pore-gate-opening and the other from the voltage-sensing unit itself. In addition, I show that voltage sensor return in hERG channels is less energetically favourable than pore closure during repolarization and thus is what limits deactivation. Finally, I characterize the use of voltage clamp fluorimetry as a technique to track conformational rearrangements of the hERG voltage sensor associated with gating. These findings provide novel and in depth understanding regarding how hERG channels function and foundational knowledge relevant to finding targets for the treatment and management of cardiac arrhythmias.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Thomas Claydon
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Dissertation) Ph.D.

Compliant flooring for fall injury prevention in long-term care

Date created: 
2017-03-06
Abstract: 

A promising strategy for reducing the incidence and severity of fall-related injuries in long-term care (LTC) is to decrease the ground surface stiffness, and the subsequent forces applied to the body parts at impact, through installation of compliant flooring. Evidence about the feasibility of compliant flooring in LTC is extremely limited. My PhD research addresses this gap by conducting a comprehensive, multimethod evaluation of compliant flooring. Specifically, I investigate the feasibility of compliant flooring for fall injury prevention in LTC by synthesizing the available evidence (study 1), determining the effects of compliant flooring on external hand forces exerted by LTC staff when pushing wheeled equipment (study 2), and examining the barriers to and facilitators of implementing compliant flooring as perceived by key stakeholders (studies 3 and 4). In my first study, I conducted a scoping review to describe the extent, range, and nature of research activity on compliant flooring, and to identify research gaps and directions for future research. I found compliant flooring is a promising strategy for preventing fall-related injuries from a biomechanical perspective. Additional research is required, however, to determine whether compliant flooring prevents fall-related injuries in real-world settings, is a cost-effective intervention strategy, and can be installed without negatively affecting workplace safety. My second study compared the effects of flooring system and resident weight on the forces required by LTC staff to push floor-based lifts used to transfer residents. Compared to the conventional lift, the motor-driven lift substantially reduced forces in all experimental conditions and thus may help to address risk of work-related musculoskeletal injury. My third study examined the feasibility of compliant flooring from the perspective of organizational-level LTC stakeholders. My interview findings provide new evidence about facilitators and barriers that stakeholders consider in deciding to install compliant flooring in LTC, such as staff’s openness (or resistance) to change and flooring performance. My fourth study sought input about compliant flooring from additional stakeholders through a symposium. My findings suggest that while stakeholders perceive compliant flooring to add value to the LTC setting, there also remain significant informational and financial barriers to the uptake of compliant flooring. Overall, my thesis should inform planners and architects in the development of safer environments for vulnerable older adults, and improve policies and programs for fall injury prevention in LTC.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Dawn Mackey
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Dissertation) Ph.D.

A social ecological model of adherence to hip protectors in long-term care

Date created: 
2017-01-30
Abstract: 

Hip fractures among older adults living in long-term care (LTC) are debilitating and costly, and are nearly always caused by falls. If worn at the time of falling, specific types of hip protectors reduce fracture risk by 80%. However, the clinical value of hip protectors is compromised by poor user adherence in the wearing of these devices. My thesis provides insight into the factors governing adherence with hip protectors in LTC. In my first study, I conducted a systematic review of extant literature. A total of 1086 articles were identified, and of these, 28 met our inclusion criteria. Barriers and facilitators were grouped into four taxonomies: (i) system-related; (ii) caregiver-related; (iii) resident-related; (iv) hip protector-related. My second study involved the development and validation of the C-HiP index to measure commitment to hip protectors amongst paid care providers in LTC. Exploratory factor analysis yielded a factor structure consisting of two lower-order factors and a single higher-order factor. Expert evaluation by LTC clinicians provided evidence of content validity. Internal consistency was high (Cronbach’s alpha=0.96). My third study identified social ecological determinants of commitment to hip protectors by means of a cross-sectional survey (n=529). Mean (SD) commitment was 4.15 (0.71) out of 5.00. Commitment was associated with race/ethnicity, occupation, organizational tenure, awareness of a padded hip fracture, familiarity of hip protectors, perceptions of transformational leadership, communication, resident-provider relationship quality, and the existence of a champion of hip protectors within the home. Finally, I conducted a 12-month retrospective cohort study in fourteen publically subsidized LTC homes to identify factors governing adherence with hip protectors, and to examine the clinical value of hip protectors to prevent hip fractures. The percentage of residents who wore hip protectors during at least one fall was negatively correlated with regional socioeconomic deprivation (ρ=-0.630) and the percentage of residents with depression (ρ=-0.538), and was positively correlated with the percentage of residents paying for care privately (ρ=0.539) and who fractured their hip in the past 180 days (ρ=0.677). The relative risk of hip fracture was 0.36 (95% CI 0.14–0.90) in falls with hip protectors compared to falls without hip protectors.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Stephen Robinovitch
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Dissertation) Ph.D.

Thermal perception and physiological responses in males and females during mild cold exposures in different clothing ensembles

Author: 
Date created: 
2016-06-13
Abstract: 

In the first study of this thesis 10 males and 10 females walked on a treadmill with a ~10 km/h wind and an ambient temperature of -8°C. The hypotheses tested included: 1) females will have lower skin temperature and surface heat flux while all other physiological responses are similar when compared to male, 2) within each sex, an elasticized (E) coat versus a non-elasticized (NE) coat would give a diminished physiological strain and 3) that within each sex, the E coat versus the NE coat would give a better thermal comfort. Results in this first study showed some differences in physiological responses between the sexes, that males had higher thermal comfort ratings in an E versus a NE coat during exercise (p<0.05). In the second study, it was hypothesized that females would have greater sensitivity to skin temperature changes than males on the hand, back and chest. The results showed females versus males were less sensitive to temperature changes only on the chest (p <0.05). In conclusion, in the first study some physiological responses differed between the sexes, the E compared to the NE coat provided no beneficial physiological responses within each sex and finally the E versus the NE coat provided greater thermal comfort in males. In the second study females were less sensitive to cold stimuli on the chest compared to males.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Matthew White
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

Investigation and management of sudden unexpected death in the young in Canada

Author: 
Date created: 
2016-12-20
Abstract: 

Sudden unexpected death in the young, SUDY, is devastating for families, their communities and health care professionals. When no cause of death is identified after a thorough autopsy and other ancillary tests, “autopsy-negative” SUDY, it leaves families without answers as to why their loved one died. At least one third of autopsy-negative SUDY cases are attributed to an inherited cardiac disorder. Therefore, surviving relatives may be at risk of another tragic death if they are not referred for expert clinical assessment. The main focus of this dissertation was to explore the investigation and management of SUDY and SUDY-affected families in Canada with the end goal of developing guidelines for coroners and medical examiners to standardize their investigative practices. To achieve this goal, three studies were conducted. The first study determined the current practices of SUDY investigation by coroners and medical examiners by surveying Canadian death investigation agencies and cardiac electrophysiologists – clinicians with expertise in inherited cardiac disorders that can predispose individuals to SUDY. The findings revealed heterogeneous practices, particularly around post mortem tissue retention at autopsy and molecular genetic testing, supporting the need for SUDY investigation protocols, tissue retention, cause/manner of death classification and written recommendations for SUDY-affected relatives to undergo clinical assessment. The second study involved genetic testing of post mortem tissue retained from autopsy from a child SUD cohort in collaboration with the Manitoba Medical Examiner’s Office. We successfully identified variants that may assist in the diagnosis of 15% of autopsy-negative child SUD cases. We reported our findings to the medical examiner who informed the families of our cohort and recommended that they be clinically assessed to reduce the risk of future SUDY. In the final study, the findings from the first two studies, both limitations and successes, were combined with a systematic scoping review of published and grey literature on SUDY investigation guidelines. Seven recommendations were developed for Canadian death investigation agencies to standardize their approaches to SUDY investigation.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Glen Tibbits
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Dissertation) Ph.D.

The mechanics of the gastrocnemii-Achilles tendon complex during human cycling: Experimental and modelling approaches to predict in vivo forces

Date created: 
2016-08-30
Abstract: 

Skeletal muscle is the engine that produces force to power movement in humans and animals alike. To date the invasive nature of obtaining muscle-tendon forces in humans has limited our understanding of muscle function during coordinated locomotor tasks. Phenomenological, Hill-type models of skeletal muscle are often used, providing estimates of a muscle’s force as a function of its activation state, force-length, and force-velocity properties. However, few studies have examined the accuracy of whole muscle-tendon forces obtained from such models during in vivo motor tasks. The goal of my thesis was to develop, test, and refine methods to better quantify muscle mechanical output in humans, using ultrasound and electromyographic recordings, together with advanced Hill-type models. My first study developed techniques to non-invasively estimate in vivo Achilles tendon forces. I used ultrasound-based measures of tendon length and tendon mechanical properties to determine forces during cycling. In my second study, I compared gastrocnemii forces, predicted from a traditional Hill-type model with one contractile element, to force estimates derived from ultrasound-based tendon length changes. Because the traditional Hill-type model fails to account for variable activation states of different fibre types, I additionally tested a two-element model that includes both slow and fast contractile elements. I found that Hill-type models predicted 31-85% of the cyclists’ gastrocnemii forces across a range of conditions elicited, producing results comparable to those reported in animal models. Further, at higher cadences, the two-element model better estimated forces because it accounted for the increased recruitment of fast fibres. Traditional Hill-type models also neglect dynamic shape changes in contracting muscles, which may be important in modulating the velocities at which fascicles operate. My third study compared predictions of muscle architecture (fascicle lengths and pennation angles) generated from a 1D Hill-type model and additionally from 2D and 3D geometric models that allowed dynamic shape changes to occur. I found that the 1D model provided predictions of muscle architecture that were similar to the predictions of 2D and 3D models and that muscle shape changes and fascicle velocities were more closely linked to force than activation. Taken together, this research provides a non-invasive approach for studying in vivo muscle-tendon mechanics and testing the predictions of Hill-type models.

Document type: 
Thesis
File(s): 
Senior supervisor: 
James Wakeling
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Dissertation) Ph.D.

Psycho-Social Support for Patients with Cardiovascular Disease (CVD): Barriers to a Cardiac Rehabilitation Program (CRP)

Author: 
Date created: 
2016-07-28
Abstract: 

Cardiac Rehabilitation Programs (CRP) are effective behavioural interventions that reduce morbidity and mortality in patients with cardiovascular disease. Despite the myriad of benefits, participation remains sub-optimal with drop-out rates as high as 60%. Patients who discontinue CRP are under-treated and consequently, are at greater risk for further cardiac events. It is imperative to find alternative strategies to support to this high-risk population. The objectives of the present thesis were three fold: i) to identify baseline characteristics of participants who previously dropped-out of a CRP (chapter 2); ii) to assess self-efficacy among patients who complete a CRP versus those who drop-out (chapter 3); iii) to test the feasibility of an Internet-mediated VC intervention to provide ongoing psycho-social support among patients who previously dropped-out of a CRP (chapter 4).

Document type: 
Thesis
File(s): 
Senior supervisor: 
Scott Lear
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.