A loss of sarcolemmal dystrophin was observed by immuno-fluorescence studies in rabbit hearts subjected to in situ myocardial ischemia and by immuno-blotting of the Triton soluble membrane fraction of isolated rabbit cardiomyocytes subjected to in vitro ischemia. This ischemic loss of dystrophin was a specific event in that no ischemic loss of sarcolemmal α-sarcoglycan, γ-sarcoglycan, αDG, or βDG was observed. The maintenance of sarcolemmal βDG (43 Kd) during ischemia was interesting in that dystrophin binds to the C-terminus of βDG. However, during late in vitro ischemia, a 30 Kd band was observed that was immuno-reactive for βDG. Additionally, this 30 Kd-βDG band was observed in rabbit myocardium subjected to autolysis. Finally, the 30 Kd-βDG was observed in the purified sarcolemmal fraction of rabbit cardiomyocytes subjected to a prolonged period of in vitro ischemia, confirming the sarcolemmal localization of this band. The potential patho-physiologic significance of this band was indicated by the appearance of this band at 120-180 min of in vitro ischemia, directly correlating with the onset of irreversible injury, as manifested by osmotic fragility. Additionally the appearance of this band was significantly reduced by the endogenous cardioprotective mechanism, in vitro ischemic preconditioning, which delays the onset of osmotic fragility. In addition to dystrophin, βDG binds caveolin-3 and Grb-2 at its C-terminus. The presence of Grb-2 and caveolin-3 in the membrane fractions of oxygenated and ischemic cardiomyocytes was determined by Western blotting. An increase in the level of membrane Grb-2 and caveolin-3 was observed following ischemic preconditioning as compared to control cells. The formation of this 30 Kd-βDG degradation product is potentially related to the transition from the reversible to the irreversible phase of myocardial ischemic cell injury and a decrease in 30 Kd-βDG might mediate the cardioprotection provided by ischemic preconditioning.

Isolated systolic hypertension (ISH) is a growing health concern in the United States (US) black population. The stratified prevalence of untreated ISH has not been fully investigated in non-Hispanic blacks. Cross-sectional data on 4625 non-Hispanic blacks aged ≥18 years were collected from the National Health and Nutrition Examination Survey 1999-2010, representing a probability sample of the US civilian noninstitutionalized black population. The 6-year prevalence of ISH and 95% confidence intervals (CIs) were estimated by conducting weighted frequency and logistic procedures. The prevalence of untreated ISH was 11.2% among non-Hispanic black adults in 1999-2010. Individuals who received lower education (high school or below) had higher prevalence of untreated ISH than those with higher education (12.8% (95% CI: 11.3-14.2%) vs. 9.0% (95% CI: 7.5-10.6%)). The prevalence of untreated ISH was higher in young men than in young women (4.3% (95% CI: 3.3-5.4%) vs. 1.8% (95% CI: 0.9-2.7%)), and higher in middle-aged adults with lower education than in middle-aged adults with higher education (14.1% (95% CI: 11.4-16.7%) vs. 7.7% (95% CI: 5.5-9.8%)). Compared with 1999-2004, the prevalence of untreated ISH in 2005-2010 decreased for old individuals (27.7% vs. 40.8%), old men (24.4% vs. 40.0%) and old individuals who received higher education (21.4% vs. 40.7%). Untreated ISH is more prevalent in old blacks, and significant reduction of the prevalence in this group suggests that public health interventions, lifestyle modifications or health awareness are in the right direction.

Many older patients are not being aggressively managed for hypertension. Healthcare providers are often hesitant to start or even aggressively titrate antihypertensive medication, especially in the aged. Multiple studies have demonstrated that morbidity and mortality can be significantly reduced by appropriate intervention in all age groups. There are some clinical situations, however, where the provider must approach cautiously, such as in patients with a wide pulse pressure or those with a propensity toward adverse reactions. The data are clear that in the United States, undertreatment, rather than overtreatment, appears to be the issue. This article reviews studies that support the aggressive treatment of hypertension. The nuances of aging, which often influence the healthcare provider's treatment decisions, are also discussed. Suggestions for reasonable approaches to these difficult cases will be considered.

To clarify the role of charge in protein movement across the pulmonary endothelial barrier, we simultaneously measured the permeability-surface area product (PS) for native [isoelectric point (pI) 4.4-5.1] and cationic (pI 7.2-8.0) albumin in isolated rabbit lungs perfused with and without protamine sulfate. We focused our measurement on the initial (endothelial) barrier by using a technique that is based on the very rapid (3 min) uptake of tracer. This allowed us to distinguish the charge properties of the endothelium separate from other barriers. In control studies, PS was greater for cationic than for native albumin (8.67 ± 0.93 vs. 2.55 ± 0.20 x 10-2 ml · min-1 · g dry lung-1). In the presence of 1 mg/ml protamine sulfate, cationic albumin permeability was not different from control (7.34 ± 0.49 x 10-2 ml · min-1 · g dry lung-1), whereas PS for anionic albumin increased to 8.82 ± 1.32 x 10-2 ml · min-1 · g dry lung-1. Thus the protamine sulfate eliminated the difference between native and cationic albumin PS. This selective increase in anionic albumin permeability is presumably due to the cation, protamine sulfate, binding to the anionic charges on the endothelium and reducing the anionic charge-charge repulsion. If protamine sulfate had produced a general endothelial injury, the PS for both albumins would have increased. Our results suggest that the normal pulmonary endothelium is an anionic charge barrier restricting the transcapillary movement of negatively charged molecules.

Although adenosine receptors have been implicated in the induction of preconditioning in a variety of experimental models, there is controversy concerning the specific adenosine receptor subtypes mediating this effect. Concentration-protection relationships for adenosine and adenosine agonists in rabbit cardiomyocytes were used to characterize the role of adenosine receptor subtypes in preconditioning. Isolated cells were ischemically preconditioned or pre-incubated for 10 min with increasing concentrations of adenosine, CCPA (2-chloro-N6-cyclopentyladenosine) APNEA (N6-2-(4-aminophenyl)ethyladenosine), or BNECA (N6-benzyl-5'-N-ethyl-carboxamidoadenosine) in the presence or absence of 1 or 10 μM of the selective A1-adenosine antagonist DPCPX (8-Cyclopentyl-1,3-dipropylxanthine). Following a 30-min post-incubation period, cells were pelleted, layered with oil and ischemically incubated for 180 min. Injury was assessed by osmotic swelling and trypan blue exclusion of sequential samples, and determination of the areas beneath the mortality curves. Adenosine produced a broad concentration-protection curve which was displaced to the right by DPCPX. The curve for A1-selective agonist CCPA was biphasic, with an initial response below 1 nM and a second above 1 μM. DPCPX abolished the early response leaving a steep monophasic curve between 0.1 and 10 μM CCPA. The APNEA curve appeared monophasic, the major slope occurring between 1-100 nM; DPCPX (1 μM) shifted the concentration-response curve ≃ 30-fold and decreased the slope. Adenosine receptor agonist BNECA produced preconditioning characterized by a shallow monophasic concentration-protection curve with a maximal effect of 49% and an EC50 of ≃ 5 nM; DPCPX shifted the BNECA concentration-protection relationship ≃ 40-fold with only a modest increase in slope. Analysis of the data suggests that induction of preconditioning results from interaction of agonists with the A1 receptor and a second adenosine receptor having properties consistent with the A3 receptor. Adenosine, CCPA, APNEA, BNECA and DPCPX each appear to be selective for the A1 adenosine receptor subtype in isolated rabbit cardiomyocytes.

The hypothesis that calcium influxes from the extracellular space play an important role in the pathogenesis of irreversible anoxic injury was tested using isolated adult rat myocytes. Myocytes treated with 6 mm amytal and 3 mm iodoacetate and subsequently incubated in either calcium-containing (1.12 mm) or calcium-free media (with or without 1 mm EGTA) developed rigor contracture (cell squaring) and cell death (trypan blue permeability) at the same rate. The rates of cell death in both calcium-containing and calcium-free media were increased by incubation in hypotonic media even though the rates of contracture development remained unaltered. Cells developed osmotic fragility prior to membrane permeability increases. The calcium ionophore, A23187 (10 μm), induced rapid rounding of rod-shaped cells subjected only to mitochondrial inhibition in calcium containing media, confirming its ability to cause an increase in cellular permeability to calcium. However, A23187 did not alter the rates of cell death of totally metabolically inhibited myocytes in either calcium-containing or calcium-free media with EGTA. The results indicate that influxes of calcium are not necessary for the development of irreversible injury in metabolically inhibited, isolated myocytes.

This dissertation examines the ways in which abandoned and sparsely populated spaces can begin to offer up their hidden, alternative histories through the process of ethnographic inquiry. My research explains how it is possible to engage with peripheral and often marginalized North American cultures through the anthropological study of affect, space and materiality. Here, I have endeavoured to construct a rich narrative of space, place and human geography that sees the ghost towns of the North American prairies and the isolated fishing communities of Grand Bruit, Newfoundland and Matinicus, Maine as dynamic texts that can be read as both alternative historical inscriptions and as anthropological phenomena that describe a unique aspect of unseen culture. Far from being empty spaces, these locations present deeply engaging deposits of local history and alternate world views. However, if left undocumented, I believe that these spaces will soon be erased from the dominant narratives of culture and historicity, swept away by the winds of resource depletion and rural-to-urban migration. In what follows, I present an opportunity for the reader to join me in unpacking and analysing these rarely understood and oft-neglected histories that are intrinsic to contemporary North American culture and identity. / Thesis / Doctor of Philosophy (PhD)

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Yes / Despite evidence inferring muscle and contractile mode-specific effects of high-fat diet (HFD), no study has yet considered the impact of HFD directly on eccentric muscle function. The present work uniquely examined the effect of 20-week HFD on the isometric, concentric and eccentric muscle function of isolated mouse soleus (SOL) and extensor digitorum longus (EDL) muscles. CD-1 female mice were randomly split into a control (n = 16) or HFD (n = 17) group and for 20 weeks consumed standard lab chow or HFD. Following this period, SOL and EDL muscles were isolated and assessments of maximal isometric force and concentric work loop (WL) power were performed. Each muscle was then subjected to either multiple concentric or eccentric WL activations. Post-fatigue recovery, as an indicator of incurred damage, was measured via assessment of concentric WL power. In the EDL, absolute concentric power and concentric power normalised to muscle mass were reduced in the HFD group (P < 0.038). HFD resulted in faster concentric fatigue and reduced eccentric activity-induced muscle damage (P < 0.05). For the SOL, maximal isometric force was increased, and maximal eccentric power normalised to muscle mass and concentric fatigue were reduced in the HFD group (P < 0.05). HFD effects on eccentric muscle function are muscle-specific and have little relationship with changes in isometric or concentric function. HFD has the potential to negatively affect the intrinsic concentric and eccentric power-producing capacity of skeletal muscle, but a lack of a within-muscle uniform response indicates disparate mechanisms of action which require further investigation.