Transplant surgeons in the USA have begun performing a novel organ procurement protocol in the setting of circulatory death. Unlike traditional donation after circulatory death (DCD) protocols,in situnormothermic perfusion DCD involves reperfusing organs, including the heart, while still contained in the donor body. Some commentators, including the American College of Physicians, have claimed thatin situreperfusion after circulatory death violates the widely accepted Dead Donor Rule (DDR) and conclude thatin situreperfusion is ethically impermissible. In this paper I argue that, in terms (...) of respecting the DDR,in situreperfusion cardiac transplantation does not differ from traditional DCD cardiac transplantation. I do this by introducing and defending a refined conception of circulatory death, namelyvegetative state function permanentism. I also argue against the controversial brain occlusion feature of thein situreperfusion DCD protocol, on the basis that it is ethically unnecessary and generates the problematic appearance of ethical dubiousness. (shrink)

Different housing conditions, including housing space and the physiological and social environment, may affect rodent behavior. Here, we examined the effects of different housing conditions on post-stroke angiogenesis and functional recovery to clarify the ambiguity about environmental enrichment and its components. Male rats in the model groups underwent right middle cerebral artery occlusion followed by reperfusion. The MCAO rats were divided into four groups: the physical enrichment group, the social enrichment group, the combined physical and social enrichment group and (...) the ischemia/reperfusion + standard conditioning group. The rats in the sham surgery group were housed under standard conditions. In a set of behavioral tests, including the modified Neurological Severity Score, rotarod test, and adhesive removal test, we demonstrated that the animals in the enriched condition groups exhibited significantly improved neurological functions compared to those in the standard housing group. Smaller infarction volumes were observed in the animals of the PSE group by MRI detection. The enriched conditions increased the microvessel density in the ischemic boundary zone, as revealed by CD31 immunofluorescent staining. The immunochemical and q-PCR results further showed that environmental enrichment increased the expression levels of angiogenic factors after ischemia/reperfusion injury. Our data suggest that all three enrichment conditions promoted enhanced angiogenesis and functional recovery after ischemia/reperfusion injury compared to the standard housing, while only exposure to the combination of both physical and social enrichment yielded optimal benefits. (shrink)

Normothermic Regional Perfusion, or NRP, is a method of donated organ reperfusion using cardiopulmonary bypass or a modified extracorporeal membrane oxygenation (ECMO) circuit after circulatory death while leaving organs in the dead donor’s corpse. Despite its potential, several key ethical issues remain unaddressed by this technology.

Carbon monoxide (CO), a product of organic oxidation processes, arises in vivo during cellular metabolism, most notably heme degradation. CO binds to the heme iron of most hemoproteins. Tissue hypoxia following hemoglobin saturation represents a principle cause of CO‐induced mortality in higher organisms, though cellular targets cannot be excluded. Despite extreme toxicity at high concentrations, low concentrations of CO can confer cytoprotection during ischemia/reperfusion or inflammation‐induced tissue injury. Likewise, heme oxygenase, an enzyme that produces CO, biliverdin and iron, as (...) well as a secondary increase in ferritin synthesis, from the oxidation of heme, can confer protection in vivo and in vitro. CO has been shown to affect several intracellular signaling pathways, including guanylate cyclase, which generates guanosine 3′:5′ cyclic monophosphate and the mitogen‐activated protein kinases (MAPK). Such pathways mediate, in part, the known vasoregulatory, anti‐inflammatory, anti‐apoptotic and anti‐proliferative effects of this gas. Exogenous CO delivered at low concentrations is showing therapeutic potential as an anti‐inflammatory agent and as such can modulate numerous pathophysiological states. This review will delve into the biological significance and medical applications of this gas molecule. BioEssays 26:270–280, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Back to the Future:Obtaining Organs from Non-Heart-Beating CadaversRobert M. Arnold (bio) and Stuart J. Youngner (bio)Organ Transplantation requires viable donor organs. This simple fact has become the Achilles' heel of transplantation programs. Progress in immunology and transplant surgery has outstripped the supply of available organs. Between 1988 and 1991, for example, the number of transplant candidates on waiting lists increased by about 55 percent, while the number of donors (...) increased only about 16 percent.1 By the end of March 1993, more than 30,000 potential recipients awaited transplantation (United Network for Organ Sharing Database (UNOS) 1993). Every day six of these patients die prior to receiving a heart or liver transplant, while patients needing kidney transplants must tolerate a lower quality of life on dialysis (Grenvik 1992; Evans, Orians, and Ascher 1992).This scarcity is likely to get worse. As transplantation becomes more successful, it is being offered to sicker and older patients. Attempts to transplant other solid organs, such as small bowel and pancreas, will only fuel the demand for donors. However, the current source of organs is unlikely to grow. Most organs come from patients who have been declared dead by neurologic criteria (commonly referred to as "brain dead" or heart-beating cadaver donors (HBCDs) because their hearts are beating at the time of procurement). Estimates of the potential pool of HBCDs have been revised downward from 20,000-27,000 to roughly 10,000-12,000 (Nathan et al. 1991). Improvements in automobile safety and handgun legislation will likely lead to further reductions. Moreover, the rate of procurement from HBCDs has remained relatively flat despite extensive public awareness campaigns and legislation requiring hospitals to routinely request donation from families of dead patients (Caplan et al. 1992).If organ transplantation is going to continue to flourish, alternative [End Page 103] sources of organs must be found. Recently the University of Pittsburgh Medical Center (UPMC) proposed procuring organs from patients who have been declared dead by traditional cardiopulmonary rather than brain-oriented criteria after they or their families have decided to forgo life-sustaining treatment—hereafter referred to as the Pittsburgh protocol (UPMC Policy 1993). These patients are typically referred to as non-heart-beating cadaver donors (NHBCDs) because their hearts are no longer beating at the time of organ procurement.Although NHBCDs were a major source of transplantable kidneys prior to the institution of death by neurologic criteria, their usefulness was limited by "warm ischemia time." This term refers to the injury to tissues that occurs when the blood supply is interrupted and before the organs are cooled and reperfused. Under the Pittsburgh protocol, therapy is withdrawn in the operating room where a waiting surgical team removes organs immediately after death is declared. By controlling the place and time of death, it has been possible to minimize warm ischemia time and thus solve the technical problems previously associated with procurement from NHBCDs.The potential contribution of NHBCD organs is significant. Nathan (1992), using data from Delaware Valley Transplant Program, concludes that the use of severely brain injured, but not "brain dead" patients, would increase the donor pool by 20-25 percent. Moreover, unpublished data from the Pittsburgh organ procurement organization, the Center for Organ Recovery and Education (CORE), suggests that these organs, particularly kidneys, function as well as those procured from HBCDs (Broznick 1993).This volume is devoted to the ethical, psychosocial, and public policy implications of procuring organs from non-heart-beating cadaver donors after a discussion to forgo life-sustaining treatment. The genesis of this volume was a project in which we invited leading experts in transplantation, ethics, and public policy to use the Pittsburgh protocol as a starting point for exploring a broad range of issues associated with attempts to procure organs from NHBCDs. The issues raised by NHBCDs turned out to have important implications about the fundamental conceptual and moral assumptions underlying organ procurement.Although each of the papers in this volume can be read separately, we intend the volume to be read as a whole. Many of the latter pieces on the ethical implications of the policy are best understood in light of the earlier background papers... (shrink)

Mammalian hibernation is characterized by profound reductions in metabolism, oxygen consumption and heart rate. As a result, the animal enters a state of suspended animation where core body temperatures can plummet as low as −2.9°C. Not only can hibernating mammals survive these physiological extremes, but they also return to a normothermic state of activity without reperfusion injury or other ill effects. This review examines recent findings on the genes, proteins and small molecules that control the induction and maintenance of (...) hibernation in mammals. The molecular events involved with remodeling metabolism, inducing hypothermia and maintaining organ function are discussed and considered with respect to analogous processes in non‐hibernating mammals such as mice and humans. The advent of sequenced genomes from three distantly related hibernators, a bat, hedgehog and ground squirrel, provides additional opportunities for molecular biologists to explore the mechanistic aspects of this biological adaptation in greater detail. BioEssays 29:431–440, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

In eukaryotes, small amounts of nitrite confer cytoprotection against ischemia/reperfusion‐related tissue damage in vivo, possibly via reduction to nitric oxide (NO) and inhibition of mitochondrial function. Several hemeproteins are involved in this protective mechanism, starting with deoxyhemoglobin, which is capable of reducing nitrite. In facultative aerobic bacteria, such as Pseudomonas aeruginosa, nitrite is reduced to NO by specialized heme‐containing enzymes called cd1 nitrite reductases. The details of their catalytic mechanism are summarized below, together with a hypothesis on the biological (...) role of the unusual d1‐heme, which, in the reduced state, shows unique properties (very high affinity for nitrite and exceptionally fast dissociation of NO). Our results support the idea that the nitrite‐based reactions of contemporary eukaryotes are a vestige of earlier bacterial biochemical pathways. The evidence that nitrite reductase activities of enzymes with different cellular roles and biochemical features still exist today highlights the importance of nitrite in cellular homeostasis. (shrink)

Understanding the mechanisms and the time and spatial evolution of penumbra following an ischemic stroke is crucially important for developing therapeutics aimed at preventing this area from evolving towards infarction. To help in integrating the available data, we decided to build a formal model. We first collected and categorised the major available evidence from animal models and human observations and summarized this knowledge in a flow-chart with the potential key components of an evolving stroke. Components were grouped in ten sub-models (...) that could be modelled and tested independently: the sub-models of tissue reactions, ionic movements, oedema development, glutamate excitotoxicity, spreading depression, NO synthesis, inflammation, necrosis, apoptosis, and reperfusion. Then, we figured out markers, identified mediators and chose the level of complexity to model these sub-models. We first applied this integrative approach to build a model based on cytotoxic oedema development following a stroke. Although this model includes only three sub-models and would need to integrate more mechanisms in each of these sub-models, the characteristics and the time and spatial evolution of penumbra obtained by simulation are qualitatively and, to some extent, quantitatively consistent with those observed using medical imaging after a permanent occlusion or after an occlusion followed by a reperfusion. (shrink)

Ischemic stroke involves numerous and complex pathophysiological mechanisms including blood flow reduction, ionic exchanges, spreading depressions and cell death through necrosis or apoptosis. We used a mathematical model based on these phenomena to study the influences of intensity and duration of ischemia on the final size of the infarcted area. This model relies on a set of ordinary and partial differential equations. After a sensibility study, the model was used to carry out in silico experiments in various ischemic conditions. The (...) simulation results show that the proportion of apoptotic cells increases when the intensity of ischemia decreases, which contributes to the model validation. The simulation results also show that the influence of ischemia duration on the infarct size is more complicated. They suggest that reperfusion is beneficial when performed in the early stroke but may be either inefficacious or even deleterious when performed later after the stroke onset. This aggravation could be explained by the depolarisation waves which might continue to spread ischemic damage and by the speeding up of the apoptotic process leading to cell death. The effect of reperfusion on cell death through these two phenomena needs to be further studied in order to develop new therapeutic strategies for stroke patients. (shrink)