Effects of gestational and postnatal exposure to chronic intermittent hypoxia on diaphragm muscle contractile function in the rat

Alterations to the supply of oxygen during early life presents a profound stressor to physiological systems with aberrant remodeling that is often long-lasting. Chronic intermittent hypoxia (CIH) is a feature of apnea of prematurity, chronic lung disease, and sleep apnea. CIH affects respiratory control but there is a dearth of information concerning the effects of CIH on respiratory muscles, including the diaphragm—the major pump muscle of breathing. We investigated the effects of exposure to gestational CIH (gCIH) and postnatal CIH (pCIH) on diaphragm muscle function in male and female rats. CIH consisted of exposure in environmental chambers to 90 s of hypoxia reaching 5% O2 at nadir, once every 5 min, 8 h a day. Exposure to gCIH started within 24 h of identification of a copulation plug and continued until day 20 of gestation; animals were studied on postnatal day 22 or 42. For pCIH, pups were born in normoxia and within 24 h of delivery were exposed with dams to CIH for 3 weeks; animals were studied on postnatal day 22 or 42. Sham groups were exposed to normoxia in parallel. Following gas exposures, diaphragm muscle contractile, and endurance properties were examined ex vivo. Neither gCIH nor pCIH exposure had effects on diaphragm muscle force-generating capacity or endurance in either sex. Similarly, early life exposure to CIH did not affect muscle tolerance of severe hypoxic stress determined ex vivo. The findings contrast with our recent observation of upper airway dilator muscle weakness following exposure to pCIH. Thus, the present study suggests a relative resilience to hypoxic stress in diaphragm muscle. Co-ordinated activity of thoracic pump and upper airway dilator muscles is required for optimal control of upper airway caliber. A mismatch in the force-generating capacity of the complementary muscle groups could have adverse consequences for the control of airway patency and respiratory homeostasis.

Social paranoia and absurdist fiction in Cold War America and Soviet Russia: a comparative study

This thesis explores the theme of social paranoia as depicted in the Absurdist fiction of Cold War America and Soviet Russia. The central hypothesis informing this research maintains that, despite the ideology of moral and cultural “Otherness” constructed and reinforced by both nations throughout much of twentieth century, the US and the Soviet Union more often than not functioned as mirror images of paranoia and suspicion. Much of the fiction produced in Russia from the Revolution onwards and in the US during the Cold War period highlights how these two ostensibly irreconcilable nations were consumed by similar fears and gripped by an equally pervasive paranoia. These parallel conditions of anxiety and mistrust led to a surprising congruity of literary responses, which transcended the ideological divide between capitalism and communism and, as such, underscored the homogeny of fear which lay beneath the façade of constructed difference. I contend that, because Soviet Russia and the America of the Cold War period were nations consumed by fear and suspicion, authors living in both countries became preoccupied by the mechanics of such deeply paranoid societies. Consequently, much of the fiction of the US and the Soviet Union during this period was preoccupied with the themes of paranoia, conspiracy, intensive bureaucracy and the politicisation of science, which resulted in the terror of the Nuclear Age. This thesis explores how these central themes unite apparently diverse literary texts and illustrate the uniformity of terror which transcended both the physical and ideological boundaries separating the United States and the Soviet Union. In doing so, this research focuses primarily on the multi-faceted manifestations of paranoia in selected works by Soviet authors Mikhail Bulgakov, Daniil Kharms and Yuli Daniel, and American authors Joseph Heller, Thomas Pynchon and Kurt Vonnegut. Focusing on key works by each author, this research considers these texts as products of two culturally diverse, yet equally paranoid societies and explores their preoccupation with issues of spying, infiltration and conspiracy. This thesis thus emphasises how these authors counter simplistic notions of Cold War Otherness by revealing two nations possessed by a similar sense of vulnerability and insecurity. Furthermore, this thesis examines how this social anxiety is reinforced by the way in which these authors position issues such as the mechanics of the bureaucratic system and clandestine scientific experimentation as the focal point of the paranoid imagination. Ultimately, by examining the concordance of paranoiac representation in America and the Soviet Union during this period, I demonstrate that these ostensibly divergent nations harboured similar fears and insecurities.

Diaphragm muscle adaptation to sustained hypoxia: lessons from animal models with relevance to high altitude and chronic respiratory diseases

The diaphragm is the primary inspiratory pump muscle of breathing. Notwithstanding its critical role in pulmonary ventilation, the diaphragm like other striated muscles is malleable in response to physiological and pathophysiological stressors, with potential implications for the maintenance of respiratory homeostasis. This review considers hypoxic adaptation of the diaphragm muscle, with a focus on functional, structural, and metabolic remodeling relevant to conditions such as high altitude and chronic respiratory disease. On the basis of emerging data in animal models, we posit that hypoxia is a significant driver of respiratory muscle plasticity, with evidence suggestive of both compensatory and deleterious adaptations in conditions of sustained exposure to low oxygen. Cellular strategies driving diaphragm remodeling during exposure to sustained hypoxia appear to confer hypoxic tolerance at the expense of peak force-generating capacity, a key functional parameter that correlates with patient morbidity and mortality. Changes include, but are not limited to: redox-dependent activation of hypoxia-inducible factor (HIF) and MAP kinases; time-dependent carbonylation of key metabolic and functional proteins; decreased mitochondrial respiration; activation of atrophic signaling and increased proteolysis; and altered functional performance. Diaphragm muscle weakness may be a signature effect of sustained hypoxic exposure. We discuss the putative role of reactive oxygen species as mediators of both advantageous and disadvantageous adaptations of diaphragm muscle to sustained hypoxia, and the role of antioxidants in mitigating adverse effects of chronic hypoxic stress on respiratory muscle function.