Doctor of Philosophy

dissertationOfficial policy narratives in the juvenile-justice system have historically vacillated between orientations to punish and rehabilitate. Yet research suggests that despite dramatic policy changes, the primary narrative of the juvenile-justice system is one of continuity. This dissertation examines how day-to-day interactions between youth and staff in a juvenile secure-care setting express public policy in ways that account for slippage between official articulations and their implemented versions. Using policy documents along with field research that includes ethnographic observations, indepth interviews, and case file reviews, this study both investigates the local setting as a site of politics and reaches across levels of analysis to offer recommendations for juvenile-justice policy implementation and service-delivery practice. It identifies insights into how policy and practice affect conceptions of identity at personal and collective levels. In secure care, interactions between youth and staff occur in an environment that is highly disparate in terms of power and yet is still one of mutual influence. Interactions have important consequences for policy, treatment services, and identity. They affect both youth-identity formation â€" a central part of the adolescent-development project â€" and staff professional identity. The quality of interactions in secure care can affect program outcomes, including youth openness to treatment, legal socialization, and recidivism. Further, I show staff behaviors and professional identities to be at risk due to the contagious influence of youth street mentalities. Key recommendations seek to enhance developmentally-appropriate and evidence-based efforts to treat delinquency, including: 1) the fostering of a productive pluralism in secure care; 2) the incorporation of procedural-justice approaches to improve the quality of interactions at multiple organizational levels; and 3) the import of a critical consonance between what we teach youth and how we teach them

Low birth weight male guinea pig offspring display increased visceral adiposity in early adulthood.

Uteroplacental insufficiency (UPI)-induced intrauterine growth restriction (IUGR) predisposes individuals to adult visceral obesity. We postulated that low birth weight (LBW) offspring, from UPI-induced IUGR pregnancies, would display a visceral adipose lipogenic molecular signature involving altered gene expression, phosphorylation status of proteins of the lipid synthesis pathway and microRNA (miR) expression profile, occurring in association with increased visceral adiposity. Normal birth weight (NBW) and LBW (obtained by uterine artery ablation) male guinea pig pups were fed a control diet from weaning to 145 days and sacrificed. Despite being lighter at birth, LBW pups displayed body weights similar to NBW offspring at 145 days. At this age, which represents young adulthood, the relative weights of LBW epididymal white adipose tissue (EWAT) and lipid content were increased; which was consistent with adipocyte hypertrophy in the LBW offspring. Additionally, the mRNA expression of lipid synthesis-related genes including acetyl-CoA carboxylase 1 (ACC1), diglyceride acyltransferase 2 (DGAT2) and peroxisome proliferator-activated receptor gamma 1 (PPARγ1), was increased in LBW EWAT. Further, LBW EWAT displayed decreased phospho-ACC (Ser79) and phospho-PPARγ (Ser273) proteins. Moreover, the mRNA expression of hormone-sensitive lipase (HSL) and fatty acid binding protein 4 (FABP4), both involved in promoting adipose lipid storage, was increased in LBW EWAT. Finally, miR-24 and miR-103-2, miRs related to adipocyte development, were both increased in LBW EWAT. These findings indicate that, following an adverse in utero environment, lipid synthesis-related genes and miR expression, along with phosphorylation status of key regulators of lipid synthesis, appear to be chronically altered and occur in association with increased visceral adiposity in young adult IUGR male offspring

Differential and synergistic effects of low birth weight and western diet on skeletal muscle vasculature, mitochondrial lipid metabolism and insulin signaling in male guinea pigs

Low birth weight (LBW) offspring are at increased risk for developing insulin resistance, a key precursor in metabolic syndrome and type 2 diabetes mellitus. Altered skeletal muscle vasculature, extracellular matrix, amino acid and mitochondrial lipid metabolism, and insulin signaling are implicated in this pathogenesis. Using uteroplacental insufficiency (UPI) to induce intrauterine growth restriction (IUGR) and LBW in the guinea pig, we investigated the relationship between UPI-induced IUGR/LBW and later life skeletal muscle arteriole density, fibrosis, amino acid and mitochondrial lipid metabolism, markers of insulin signaling and glucose uptake, and how a postnatal high-fat, high-sugar “Western” diet (WD) modulates these changes. Muscle of 145-day-old male LBW glucose-tolerant offspring displayed diminished vessel density and altered acylcarnitine levels. Disrupted muscle insulin signaling despite maintained whole-body glucose homeostasis also occurred in both LBW and WD-fed male “lean” offspring. Additionally, postnatal WD unmasked LBW-induced impairment of mitochondrial lipid metabolism, as reflected by increased acylcarnitine accumulation. This study provides evidence that early markers of skeletal muscle metabolic dysfunction appear to be influenced by the in utero environment and interact with a high-fat/high-sugar postnatal environment to exacerbate altered mitochondrial lipid metabolism, promoting mitochondrial overload

Quantification of joint blood flow by dynamic contrast-enhanced near-infrared spectroscopy: Application to monitoring disease activity in a rat model of rheumatoid arthritis

© The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI. Significance: Current guidelines for rheumatoid arthritis (RA) management recommend early treatment with disease modifying antirheumatic drugs (DMARDs). However, DMARD treatment fails in 30% of patients and current monitoring methods can only detect failure after 3 to 6 months of therapy. Aim: We investigated whether joint blood flow (BF), quantified using dynamic contrast-enhanced time-resolved near-infrared spectroscopy, can monitor disease activity and treatment response in a rat model of RA. Approach: Ankle joint BF was measured every 5 days in eight rats with adjuvant-induced arthritis (AIA) and four healthy controls. Arthritis was allowed to progress for 20 days before rats with AIA were treated with a DMARD once every 5 days until day 40. Results: Time and group had separate significant main effects on joint BF; however, there was no significant interaction between time and group despite a notable difference in average joint BF on day 5. Comparison of individual blood flow measures between rats with AIA and control group animals did not reveal a clear response to treatment. Conclusions: Joint BF time courses could not distinguish between rats with AIA and study controls. Heterogeneous disease response and low temporal frequency of BF measurements may have been important study limitations

ANG1 treatment reduces muscle pathology and prevents a decline in perfusion in DMD mice

Vascular endothelial growth factor (VEGF) and other pro-angiogenic growth factors have been investigated to enhance muscle tissue perfusion and repair in Duchenne muscular dystrophy (DMD). Current understanding is limited by a lack of functional data following in vivo delivery of these growth factors. We previously used dynamic contrast-enhanced computed tomography to monitor disease progression in murine models of DMD, but no study to date has utilized this imaging technique to assess vascular therapy in a preclinical model of DMD. In the current study, we locally delivered VEGF and ANG1 alone or in combination to dystrophic hind limb skeletal muscle. Using functional imaging, we found the combination treatment as well as ANG1 alone prevented decline in muscle perfusion whereas VEGF alone had no effect compared to controls. These findings were validated histologically as demonstrated by increased alpha-smooth muscle actin-positive vessels in muscles that received either VEGF+ANG1 or ANG1 alone compared to the sham group. We further show that ANG1 alone slows progression of fibrosis compared to either sham or VEGF treatment. The findings from this study shed new light on the functional effects of vascular therapy and suggest that ANG1 alone may be a candidate therapy in the treatment of DMD

Blood-brain barrier permeability in survivors of immune-mediated thrombotic thrombocytopenic purpura: A pilot study

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disorder of systemic microthrombosis and organ ischemia. The etiology of chronic cerebrovascular outcomes in iTTP survivors is largely unknown. In this pilot study, we measured blood-brain barrier (BBB) permeability in patients with iTTP at the start of remission and 6 months later. This prospective pilot study included 7 adult patients with incident iTTP. Eligibility criteria included ADAMTS13 activity, 10% and detectable inhibitor at diagnosis. Patients were recruited from London Health Sciences Centre in Canada (2017-2019) within 3 days of hospital admission and followed for 6 months after remission (defined as normalization of platelet count and lactate dehydrogenase with no clinical signs or symptoms of microvascular injury for more than 30 days after the last plasma exchange). All patients had cerebral computed tomography perfusion scans with BBB permeability surface product measurements. Patients (5 women, 2 men) had a mean age of 48 years (range, 21-77 years). At diagnosis, patients had a mean platelet count of 22 (standard deviation [SD], 25) 3 109/L. At the start of remission, mean BBB permeability surface product was 0.91 (0.30) mL/min/100 g. Six months later, the mean permeability surface product was 0.56 (0.22) mL/min/100 g, with a mean difference of 20.312 mL/min/100 g (95% confidence interval: 20.4729 to 20.1510; P 5.0032). In this pilot study of patients with iTTP, pathologically increased BBB permeability was evident, and although there was some improvement, this persisted 6 months after remission. Future work will explore the chronicity of these findings and their clinical implications

Giant molecular clouds in the non-grand design spiral galaxy NGC 6946

We present high spatial resolution observations of Giant Molecular Clouds (GMCs) in the eastern part of the nearby spiral galaxy NGC 6946 obtained with the Combined Array for Research in Millimeter-wave Astronomy (CARMA). We have observed 12CO(1-0), 12CO(2-1) and 13CO(1-0), achieving spatial resolutions of 5.4" x 5.0", 2.5" x 2.0" and 5.6" x 5.4" respectively over a region of 6 x 6 kpc. This region extends from 1.5 kpc to 8 kpc galactocentric radius, thus avoiding the intense star formation in the central kpc. We have recovered short-spacing u-v components by using single dish observations from the Nobeyama 45m and IRAM 30m telescopes. Using the automated CPROPS algorithm we identified 44 CO cloud complexes in the 12CO(1-0) map and 64 GMCs in the 12CO(2-1) maps. The sizes, line widths, and luminosities of the GMCs are similar to values found in other extragalactic studies. We have classified the clouds into on-arm and inter-arm clouds based on the stellar mass density traced by the 3.6 um map. On-arm clouds present in general higher star formation rates than clouds located on inter-arm regions. Although the star formation efficiency shows no systematic trend with galactocentric radius, some on-arm clouds -- which are more luminous and more massive compared to inter-arm GMCs -- are also forming stars more efficiently than the rest of the identified GMCs. These structures appear to be located on two specific regions in the spiral arms. One of them shows a strong gradient, suggesting that this region of high star formation efficiency may be the result of gas flow convergence.Comment: 23 pages, 21 figures, 3 tables. To be published in The Astrophysical Journa

Toll-like receptor polymorphisms and cerebral malaria: <it>TLR2 </it>Δ22 polymorphism is associated with protection from cerebral malaria in a case control study

<p>Abstract</p> <p>Background</p> <p>In malaria endemic areas, host genetics influence whether a <it>Plasmodium falciparum</it>-infected child develops uncomplicated or severe malaria. TLR2 has been identified as a receptor for <it>P. falciparum</it>-derived glycosylphosphatidylinositol (GPI), and polymorphisms within the TLR2 gene may affect disease pathogenesis. There are two common polymorphisms in the 5' un-translated region (UTR) of TLR2, a 22 base pair deletion in the first unstranslated exon (Δ22), and a GT dinucleotide repeat in the second intron (GTn).</p> <p>Methods</p> <p>These polymorphisms were examined in a Ugandan case control study on children with either cerebral malaria or uncomplicated malaria. Serum cytokine levels were analysed by ELISA, according to genotype and disease status. In vitro TLR2 expression was measured according to genotype.</p> <p>Results</p> <p>Both Δ22 and GTn polymorphisms were highly frequent, but only Δ22 heterozygosity was associated with protection from cerebral malaria (OR 0.34, 95% confidence intervals 0.16, 0.73). In vitro, heterozygosity for Δ22 was associated with reduced pam3cys inducible TLR2 expression in human monocyte derived macrophages. In uncomplicated malaria patients, Δ22 homozygosity was associated with elevated serum IL-6 (<it>p </it>= 0.04), and long GT repeat alleles were associated with elevated TNF (<it>p </it>= 0.007).</p> <p>Conclusion</p> <p>Reduced inducible TLR2 expression may lead to attenuated pro-inflammatory responses, a potential mechanism of protection from cerebral malaria present in individuals heterozygous for the TLR2 Δ22 polymorphism.</p