Biomedical Physiology and Kinesiology, Department of

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Genetic Polymorphisms at TIMP3 Are Associated with Survival of Adenocarcinoma of the Gastroesophageal Junction

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2013
Abstract: 

The poor survival of adenocarcinomas of the gastroesophageal junction (GEJ) makes them clinically important. Discovery of host genetic factors that affect outcome may guide more individualized treatment. This study tests whether constitutional genetic variants in matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) genes are associated with outcome of GEJ adenocarcinoma. Single nucleotide polymorphisms (SNPs) at four TIMP (TIMP1-4) and three MMP genes (MMP2, MMP7 and MMP9) were genotyped in DNA samples from a prospective cohort of patients with primary adenocarcinoma of the GEJ admitted to the British Columbia Cancer Agency. Cox proportional hazards regression, with adjustment for patient, disease and treatment variables, was used to estimate the association of SNPs with survival. Genotypes for 85 samples and 48 SNPs were analyzed. Four SNPs across TIMP3, (rs130274, rs715572, rs1962223 and rs5754312) were associated with survival. Interaction analyses revealed that the survival associations with rs715572 and rs5754312 are specific and significant for 5FU+cisplatin treated patients. Sanger sequencing of the TIMP3 coding and promoter regions revealed an additional SNP, rs9862, also associated with survival. TIMP3 genetic variants are associated with survival and may be potentially useful in optimizing treatment strategies for individual patients.

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Article
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Non-Hodgkin Lymphoma Risk and Variants in Genes Controlling Lymphocyte Development

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2013
Abstract: 

Non-Hodgkin lymphomas (NHL) are a heterogeneous group of solid tumours of lymphoid cell origin. Three important aspects of lymphocyte development include immunity and inflammation, DNA repair, and programmed cell death. We have used a previously established case-control study of NHL to ask whether genetic variation in genes involved in these three important processes influences risk of this cancer. 118 genes in these three categories were tagged with single nucleotide polymorphisms (SNPs), which were tested for association with NHL and its subtypes. The main analysis used logistic regression (additive model) to estimate odds ratios in European-ancestry cases and controls. 599 SNPs and 1116 samples (569 cases and 547 controls) passed quality control measures and were included in analyses. Following multiple-testing correction, one SNP in MSH3, a mismatch repair gene, showed an association with diffuse large B-cell lymphoma (OR: 1.91; 95% CI: 1.41–2.59; uncorrected p = 0.00003; corrected p = 0.010). This association was not replicated in an independent European-ancestry sample set of 251 diffuse large B-cell lymphoma cases and 737 controls, indicating this result was likely a false positive. It is likely that moderate sample size, inter-subtype and other genetic heterogeneity, and small true effect sizes account for the lack of replicable findings.

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Article
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Myelosuppressive Conditioning Using Busulfan Enables Bone Marrow Cell Accumulation in the Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2013
Abstract: 

Myeloablative preconditioning using irradiation is the most commonly used technique to generate rodents having chimeric bone marrow, employed for the study of bone marrow-derived cell accumulation in the healthy and diseased central nervous system. However, irradiation has been shown to alter the blood-brain barrier, potentially creating confounding artefacts. To better study the potential of bone marrow-derived cells to function as treatment vehicles for neurodegenerative diseases alternative preconditioning regimens must be developed. We treated transgenic mice that over-express human mutant superoxide dismutase 1, a model of amyotrophic lateral sclerosis, with busulfan to determine whether this commonly used chemotherapeutic leads to stable chimerism and promotes the entry of bone marrow-derived cells into spinal cord. Intraperitoneal treatment with busulfan at 60 mg/kg or 80 mg/kg followed by intravenous injection of green fluorescent protein-expressing bone marrow resulted in sustained levels of chimerism (~80%). Bone marrow-derived cells accumulated in the lumbar spinal cord of diseased mice at advanced stages of pathology at both doses, with limited numbers of bone marrow derived cells observed in the spinal cords of similarly treated, age-matched controls; the majority of bone marrow-derived cells in spinal cord immunolabelled for macrophage antigens. Comparatively, significantly greater numbers of bone marrow-derived cells were observed in lumbar spinal cord following irradiative myeloablation. These results demonstrate bone marrow-derived cell accumulation in diseased spinal cord is possible without irradiative preconditioning.

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Article
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Familial Hypertrophic Cardiomyopathy Related Cardiac Troponin C L29Q Mutation Alters Length-Dependent Activation and Functional Effects of Phosphomimetic Troponin I*

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2013
Abstract: 

The Ca2+ binding properties of the FHC-associated cardiac troponin C (cTnC) mutation L29Q were examined in isolated cTnC, troponin complexes, reconstituted thin filament preparations, and skinned cardiomyocytes. While higher Ca2+ binding affinity was apparent for the L29Q mutant in isolated cTnC, this phenomenon was not observed in the cTn complex. At the level of the thin filament in the presence of phosphomimetic TnI, L29Q cTnC further reduced the Ca2+ affinity by 27% in the steady-state measurement and increased the Ca2+ dissociation rate by 20% in the kinetic studies. Molecular dynamics simulations suggest that L29Q destabilizes the conformation of cNTnC in the presence of phosphomimetic cTnI and potentially modulates the Ca2+ sensitivity due to the changes of the opening/closing equilibrium of cNTnC. In the skinned cardiomyocyte preparation, L29Q cTnC increased Ca2+ sensitivity in a highly sarcomere length (SL)-dependent manner. The well-established reduction of Ca2+ sensitivity by phosphomimetic cTnI was diminished by 68% in the presence of the mutation and it also depressed the SL-dependent increase in myofilament Ca2+ sensitivity. This might result from its modified interaction with cTnI which altered the feedback effects of cross-bridges on the L29Q cTnC-cTnI-Tm complex. This study demonstrates that the L29Q mutation alters the contractility and the functional effects of the phosphomimetic cTnI in both thin filament and single skinned cardiomyocytes and importantly that this effect is highly sarcomere length dependent.

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Article
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Development and Validation of a Questionnaire for Analyzing Real-Life Falls in Long-Term Care Captured On Video

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2013
Abstract: 

Background

Falls are the number one cause of injuries in older adults, and are particularly common in long-term care (LTC). Lack of objective evidence on the mechanisms of falls in this setting is a major barrier to prevention. Video capture of real-life falls can help to address this barrier, if valid tools are available for data analysis. To address this need, we developed a 24-item fall video analysis questionnaire (FVAQ) to probe key biomechanical, behavioural, situational, and environmental aspects of the initiation, descent, and impact stages of falls. We then tested the reliability of this tool using video footage of falls collected in LTC.

Methods

Over three years, we video-captured 221 falls experienced by 130 individuals in common areas (e.g., dining rooms, hallways, and lounges) of two LTC facilities. The FVAQ was developed through literature review and an iterative process to ensure our responses captured the most common behaviours observed in preliminary review of fall videos. Inter-rater reliability was assessed by comparing responses from two teams, each having three members, who reviewed 15 randomly-selected videos. Intra-rater reliability was measured by comparing responses from one team at baseline and 12 months later.

Results

In 17 of the 24 questions, the percentage of inter- and intra-rater agreement was over 80% and the Cohen's Kappa was greater than 0.60, reflecting good reliability. These included questions on the cause of imbalance, activity at the time of the fall, fall direction, stepping responses, and impact to specific body sites. Poorer agreement was observed for footwear, contribution of clutter, reach-to-grasp responses, and perceived site of injury risk.

Conclusions

Our results provide strong evidence of the reliability of the FVAQ for classifying biomechanical, behavioural, situational, and environmental aspects of falls captured on video in common areas in LTC. Application of this tool should reveal new and important strategies for the prevention and treatment of falls and fall-related injuries in this setting.

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Article
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Total and High Molecular Weight Adiponectin and Ethnic-Specific Differences in Adiposity and Insulin Resistance: A Cross-Sectional Study

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2013
Abstract: 

Background

Ethnic-specific differences in insulin resistance (IR) are well described but the underlying mechanisms are unknown. Adiponectin is an insulin sensitizing adipocytokine that circulates as multiple isoforms, with high molecular weight (HMW) adiponectin associated with greatest insulin sensitivity. The objective of this study is to determine if plasma total and HMW adiponectin concentrations underlie ethnic-specific differences in IR.

Methods

Healthy Canadian Aboriginal, Chinese, European, and South Asian adults (N = 634) were assessed for sociodemographics; lifestyle; fasting plasma insulin, glucose, and total and HMW adiponectin; and adiposity measures [BMI, waist circumference, waist-to-hip ratio, percent body fat, and subcutaneous and visceral adipose tissue (quantified by computed tomography)]. The homeostasis model assessment-insulin resistance (HOMA-IR) assessed IR.

Results

South Asians had the greatest HOMA-IR, followed by Aboriginals, Chinese, and Europeans (P < 0.001). Plasma total and HMW adiponectin concentrations were lower in Chinese and South Asians than Aboriginal and Europeans (P < 0.05). Total and HMW adiponectin were inversely associated with HOMA-IR (P < 0.001). Ethnicity modified the relationship between HMW adiponectin and HOMA-IR with stronger effects observed in Aboriginals (P = 0.001), Chinese (P = 0.002), and South Asians (P = 0.040) compared to Europeans. This was not observed for total adiponectin (P = 0.431). At mean total adiponectin concentrations South Asians had higher HOMA-IR than Europeans (P < 0.001).

Conclusions

For each given decrease in HMW adiponectin concentrations a greater increase in HOMA-IR is observed in Aboriginals, Chinese, and South Asians than Europeans. Ethnic-specific differences in HMW adiponectin may account for differences in IR.

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Article
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The Perspectives of Educators, Regulators And Funders Of Massage Therapy On The State Of The Profession In British Columbia, Canada

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2013
Abstract: 

Background

Registered Massage Therapists (RMTs) are valuable members of the healthcare team who assist in health promotion, disease prevention, treatment, rehabilitation and palliation. RMT visits have increased across Canada over the past decade with the highest increase in British Columbia (BC). Currently, RMTs are private practitioners of healthcare operating within a largely publicly funded system, positioning them outside of the dominant system of healthcare and making them an important case study in private healthcare. In another paper we examined the perspectives of RMTs themselves. Here, we offer perspectives of regulators, educators and funders of Massage Therapy (MT) on advancement of the profession.

Methods

We interviewed 28 stakeholders of MT in BC – including members of the MT regulatory board, representatives from MT colleges in BC and public and private health insurers.

Results

All three groups identified research, particularly on efficacy of MT, as playing a vital role in enhancing the professional credibility of MT. However, participants noted that presently research is not a large feature of the current MT curricula and we analyze why this may be and how it can improve. Finally, conferral of baccalaureate degree status could assist RMTs in gaining recognition with the general public and other healthcare professionals.

Conclusion

RMTs have potential to ameliorate population health in a cost-effective manner. Their role in British Columbia’s healthcare landscape could be expanded if they produce more research and earn degree status.

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Article
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Association Of Supermarket Characteristics With The Body Mass Index Of Their Shoppers

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2013
Abstract: 

Background

Research on the built food environment and weight status has mostly focused on the presence/absence of food outlets while ignoring their internal features or where residents actually shop. We explored associations of distance travelled to supermarkets and supermarket characteristics with shoppers’ body mass index (BMI).

Methods

Shoppers (n=555) of five supermarkets situated in different income areas in the city were surveyed for food shopping habits, demographics, home postal code, height and weight. Associations of minimum distance to a supermarket (along road network, objectively measured using ArcGIS), its size, food variety and food basket price with shoppers’ BMI were investigated. The ‘food basket’ was defined as the mixture of several food items commonly consumed by residents and available in all supermarkets.

Results

Supermarkets ranged in total floor space (7500–135 000 square feet) and had similar varieties of fruits, vegetables and cereals. The majority of participants shopped at the surveyed supermarket more than once per week (mean range 1.2 ± 0.8 to 2.3 ± 2.1 times per week across the five supermarkets, p < 0.001), and identified it as their primary store for food (52% overall). Mean participant BMI of the five supermarkets ranged from 23.7 ± 4.3 kg/m2 to 27.1 ± 4.3 kg/m2 (p < 0.001). Median minimum distance from the shoppers’ residence to the supermarket they shopped at ranged from 0.96 (0.57, 2.31) km to 4.30 (2.83, 5.75) km (p < 0.001). A negative association was found between food basket price and BMI. There were no associations between BMI and minimum distance to the supermarket, or other supermarket characteristics. After adjusting for age, sex, dissemination area median individual income and car ownership, BMI of individuals who shopped at Store 1 and Store 2, the supermarkets with lowest price of the ‘food basket’, was 3.66 kg/m2 and 3.73 kg/m2 higher compared to their counterparts who shopped at the supermarket where the ‘food basket’ price was highest (p < 0.001).

Conclusions

The food basket price in supermarkets was inversely associated with BMI of their shoppers. Our results suggest that careful manipulation of food prices may be used as an intervention for decreasing BMI.

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Article
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Statistical Validation Of Wavelet Transform Coherence Method To Assess The Transfer Of Calf Muscle Activation To Blood Pressure During Quiet Standing

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2013
Abstract: 

Background

Continuous and discrete wavelet transforms have been established as valid tools to analyze non-stationary and transient signals over Fourier domain methods. Additionally, Fourier transform based coherence methods provide aggregate results but do not provide insights into the changes in coherent behavior over time, hence limiting their utility.

Methods

Statistical validation of the wavelet transform coherence (WTC) was conducted with simulated data sets. Time frequency maps of signal coherence between calf muscle electromyography (EMG) and blood pressure (BP) were obtained by WTC to provide further insight into their interdependent time-varying behavior via the skeletal muscle pump during quiet stance. Data were collected from healthy young males (n = 5, 19–28 years) during a quiet stance on a balance platform. Waveforms for EMG and BP were acquired and processed for further analysis.

Results

Low values of bias and standard deviation (< 0.1) were observed and the use of both simulated and real data demonstrated that the WTC method was able to identify time points of significant coherence (> Threshold) and objectively detect existence of interdependent activity between the calf muscle EMG and blood pressure.

Conclusions

The WTC method effectively identified the presence of linear coupling between the EMG and BP signals during quiet standing. Future studies with more human data are needed to establish the exact characteristics of the identified relationship.

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Article
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Inherited Common Variants In Mitochondrial DNA And Invasive Serous Epithelial Ovarian Cancer Risk

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2013
Abstract: 

Background

Mitochondria are the site of oxidative phosphorylation, a process which generates reactive oxygen species (ROS). Elevated ROS levels can lead to oxidative stress, a cellular state implicated in carcinogenesis. It is hypothesized that alternations in mitochondrial (MT) DNA, including heritable MT single nucleotide polymorphisms (MT-SNPs), have the potential to change the capacity of MT function, leading to increased oxidative stress and cancer risk. We investigated if common MT-SNPs and/or haplogroups and are associated with invasive serous ovarian cancer (OvCa) risk.

Methods

A panel of 64 MT-SNPs designed to tag all common variation in the European MT genome (minor allele frequency (MAF) >1%, r^2 >0.8) was genotyped in study participants of European descent using the Sequenom MassARRAY iPlex Gold® system (Sequenom Inc, CA, USA). Invasive serous OvCa cases (n = 405) and frequency age-matched controls (n = 445) were drawn from a population-based case-control study of OvCa in western Canada. Binary logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (C.I.) for carriage of the minor versus major allele by case-control status. MitoTool was used to test the relationship between European haplogroup status and case-control status using Fisher’s exact test.

Results

The most significant disease-SNP association was for rs2857285, a synonymous MT-SNP in ND4 (OR = 4.84, 95% CI: 1.03–22.68, P = 0.045). After adjustment for multiple testing using a Bonferroni correction of the Type 1 error this MT-SNP was not significant. No other MT-SNP had a P-value < 0.05. European haplogroup status was not associated with case status. Most MT-SNPs (73%) genotyped had a MAF <5%.

Conclusion

Common European MT-SNPs (MAF > 5%) and haplogroups were not associated with invasive serous OvCa risk in this study; however, most European MT-SNPs have a low MAF (<5%), which we were underpowered to adequately assess. Larger studies are needed to clarify the role of low MAF MT-SNPs (MAF < 5%) in invasive serous OvCa risk.

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Article
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