Prelamin A mediates myocardial inflammation in dilated and HIV-associated cardiomyopathies

Cardiomyopathies are complex heart muscle diseases that can be inherited or acquired. Dilated cardiomyopathy can result from mutations in LMNA, encoding the nuclear intermediate filament proteins lamin A/C. Some LMNA mutations lead to accumulation of the lamin A precursor, prelamin A, which is disease causing in a number of tissues, yet its impact upon the heart is unknown. Here, we discovered myocardial prelamin A accumulation occurred in a case of dilated cardiomyopathy, and we show that a potentially novel mouse model of cardiac-specific prelamin A accumulation exhibited a phenotype consistent with inflammatory cardiomyopathy, which we observed to be similar to HIV-associated cardiomyopathy, an acquired disease state. Numerous HIV protease therapies are known to inhibit ZMPSTE24, the enzyme responsible for prelamin A processing, and we confirmed that accumulation of prelamin A occurred in HIV+ patient cardiac biopsies. These findings (a) confirm a unifying pathological role for prelamin A common to genetic and acquired cardiomyopathies; (b) have implications for the management of HIV patients with cardiac disease, suggesting protease inhibitors should be replaced with alternative therapies (i.e., nonnucleoside reverse transcriptase inhibitors); and (c) suggest that targeting inflammation may be a useful treatment strategy for certain forms of inherited cardiomyopathy

Prelamin A mediates inflammation in dilated and HIV associated cardiomyopathies

Cardiomyopathies are complex heart muscle diseases that can be inherited or acquired. Dilated cardiomyopathy can result from mutations in LMNA, encoding the nuclear intermediate filament proteins lamin A/C. Some LMNA mutations lead to accumulation of the lamin A precursor, prelamin A, which is disease causing in a number of tissues yet its impact upon the heart is unknown. Here we discovered myocardial prelamin A accumulation occurred in a case of dilated cardiomyopathy and show that a novel mouse model of cardiac specific prelamin A accumulation exhibited a phenotype consistent with ‘inflammatory cardiomyopathy’ which we observed to be similar to HIV associated cardiomyopathy, an acquired disease state. Numerous HIV protease therapies are known to inhibit ZMPSTE24, the enzyme responsible for prelamin A processing, and we confirmed that accumulation of prelamin A occurred in HIV+ patient cardiac biopsies. These findings: (1) confirm a unifying pathological role for prelamin A common to genetic and acquired cardiomyopathies; (2) have implications for the management of HIV patients with cardiac disease suggesting protease inhibitors should be replaced with alternative therapies i.e. non-nucleoside reverse transcriptase inhibitors; and (3) suggest that targeting inflammation may be a useful treatment strategy for certain forms of inherited cardiomyopathy

Prelamin A mediates myocardial inflammation in dilated and HIV-Associated cardiomyopathies

Cardiomyopathies are complex heart muscle diseases that can be inherited or acquired. Dilated cardiomyopathy can result from mutations in LMNA, encoding the nuclear intermediate filament proteins lamin A/C. Some LMNA mutations lead to accumulation of the lamin A precursor, prelamin A, which is disease causing in a number of tissues, yet its impact upon the heart is unknown. Here, we discovered myocardial prelamin A accumulation occurred in a case of dilated cardiomyopathy, and we show that a potentially novel mouse model of cardiac-specific prelamin A accumulation exhibited a phenotype consistent with inflammatory cardiomyopathy, which we observed to be similar to HIV-associated cardiomyopathy, an acquired disease state. Numerous HIV protease therapies are known to inhibit ZMPSTE24, the enzyme responsible for prelamin A processing, and we confirmed that accumulation of prelamin A occurred in HIV' patient cardiac biopsies. These findings (a) confirm a unifying pathological role for prelamin A common to genetic and acquired cardiomyopathies; (b) have implications for the management of HIV patients with cardiac disease, suggesting protease inhibitors should be replaced with alternative therapies (i.e., nonnucleoside reverse transcriptase inhibitors); and (c) suggest that targeting inflammation may be a useful treatment strategy for certain forms of inherited cardiomyopathy

The cardio-respiratory effects of passive heating and the human thermoneutral zone

Abstract The thermoneutral zone (TNZ) defines the range of ambient temperatures at which resting metabolic rate (MR) is at a minimum. While the TNZ lower limit has been characterized, it is still unclear whether there is an upper limit, that is, beyond which MR during rest increases, and if so, what physiological upregulations explain this. We take the first step to fill this knowledge gap by measuring MR and multiple physiological variables in participants exposed to ambient heat stress while resting. Thirteen participants were exposed for an hour to 28℃‐50% relative humidity (RH) air, and both 40 and 50℃ each in 25% RH and humid (50% RH) conditions. Core and skin temperatures, blood pressure, sweat‐, heart‐, and breathing‐rate, minute ventilation, and movement levels were recorded throughout each condition. MR increased 35% (p = .015) during exposure to 40℃‐25% RH compared to baseline and a further 13% (p = .000) at in 50℃‐50%RH. This was not explained by increased fidgeting (p = .26), suggesting physiological upregulation. However, while greater heat stress invoked increases in heart rate (64%, p = .000), minute ventilation (78%, p = .000), and sweat rate (74%. p = .000) when comparing 50℃‐50% RH with baseline, the exact size of their relative energy cost is unclear and, therefore, so is their contribution to this increase in MR. Our study shows clear evidence that resting MR increases in humans at high temperature—there is a metabolic upper critical temperature, at least as low as 40℃. Further studies should pinpoint this value and fully explain this increased MR

Positivism and the peace/power dialectic: feminist reflections in a transnational age

Human rights have often been described as the ‘morality of the law.’ Decades of feminist critique have exposed the foundations of law as deeply biased and patriarchal. And yet the idea that almost all legal philosophers are or should be positivists continues to hold sway in some quarters. The claim of this chapter is that the positivist paradigm of law, the idea that a law is valid if it emanates from a particular recognised source, provides a de minimis standard for the basis of legal relations and a starting point for critique, but offers little more. In this reductionist sense then it may be appropriate to state that everyone who engages with law is de facto a positivist. However, in an increasingly complex, diversified and pluralistic society where the transcendence of national borders and processes of globalisation neither recognise nor sustain state specific Grundnormen, legal positivism faces challenges and realities which will not and cannot leave the fundaments of the positivist paradigm unchanged. Rather, examination of the positivist paradigm through the transnational lenses of both human rights and feminist critique demonstrates that the metaphysical austerity lauded by proponents of the positivist position as a virtue, leaves it barren and inadequate to respond to the deep structural inequalities of the law. The patriarchal assumptions of the norms constituting the positivist paradigm must be challenged. The role played by human rights in providing the positivist position with a moral conscience and an opportunity to address not yet imagined atrocities and quotidian injustices in an increasingly globalised society must be critically analysed. In carrying out such a critical examination, this chapter conceptualises and historically establishes positivism at the apex of what is introduced as the peace/power dialectic. The conclusion is that whilst positivism as a historical methodology for peace may not have been (on a generous reading) malicious in establishing the economy of exclusions that it relies on, including gender, race, social class, sexuality and ability, the maintenance of the positivist position as legal truth and the position of power might well be