Recent advances in research on iron metabolism have revealed the identity of a number of genes, signal transduction pathways, and proteins involved in iron regulation in mammals. The emerging paradigm is a coordination of homeostasis within a network of classical iron metabolic pathways and other cellular processes such as cell differentiation, growth, inflammation, immunity, and a host of physiologic and pathologic conditions. Iron, immunity, and infection are intricately linked and their regulation is fundamental to the survival (...) of mammals. The mutual dependence on iron by the host and invading pathogenic organisms elicits competition for the element during infection. While the host maintains mechanisms to utilize iron for its own metabolism exclusively, pathogenic organisms are armed with a myriad of strategies to circumvent these measures. This review explores iron metabolism in mammalian host, defense mechanisms against pathogenic microbes and the competitive devices of microbes for access to iron. (shrink)

A high percent of oxidative energy metabolism is needed to support brain growth during infancy. Unhealthy diets and limited nutrition, as well as other environmental insults, can compromise these essential developmental processes. In particular, iron deficiency anemia has been found to undermine both normal brain growth and neurobehavioral development. Even moderate ID may affect neural maturation because when iron is limited, it is prioritized first to red blood cells over the brain. A primate model was used to investigate (...) the neural effects of a transient ID and if deficits would persist after iron treatment. The large size and postnatal growth of the monkey brain makes the findings relevant to the metabolic and iron needs of human infants, and initiating treatment upon diagnosis of anemia reflects clinical practice. Specifically, this analysis determined whether brain maturation would still be compromised at 1 year of age if an anemic infant was treated promptly once diagnosed. The hematology and iron status of 41 infant rhesus monkeys was screened at 2-month intervals. Fifteen became ID; 12 met clinical criteria for anemia and were administered iron dextran and B vitamins for 1–2 months. MRI scans were acquired at 1 year. The volumetric and diffusion tensor imaging measures from the ID infants were compared with monkeys who remained continuously iron sufficient. A prior history of ID was associated with smaller total brain volumes, driven primarily by significantly less total gray matter and smaller GM volumes in several cortical regions. At the macrostructual level, the effect on white matter volumes was not as overt. However, DTI analyses of WM microstructure indicated two later-maturating anterior tracts were negatively affected. The findings reaffirm the importance of iron for normal brain development. Given that brain differences were still evident even after iron treatment and following recovery of iron-dependent hematological indices, the results highlight the importance of early detection and preemptive supplementation to limit the neural consequences of ID. (shrink)

The concept of quality of life is the basis for a new paradigm of clinical medicine. Its assessment is considered to be an important instrument in determining disease severity and effectiveness of different treatment modalities. Our studies are devoted to the problem of diabetes complications especially anemia in patients with diabetic kidney disease. Anemia in subjects with diabetic nephropathy may result from various pathogenic factors including erythropoietin deficiency, iron deficiency, vitamin B12 and/or folate deficiencies, the effects of proinflammatory (...) cytokines etc. Diabetic patients with anemia are at increased risk of cardiovascular accidents and death. The aim of this study was to assess the influence of anemia on the quality of life of patients with early stages of diabetic nephropathy. We investigated 127 patients with type 2 diabetes mellitus and early diabetic nephropathy. Anemia was defined according to the World Health Organization criteria. Anemic patients were divided into three groups according to the stage of chronic kidney disease. Patients’ quality of life was assessed with SF-36 health survey. Anemic patients had lower scores of physical role functioning and emotional role functioning as compared to the patients with normal hemoglobin level, irrespective of the stage of chronic kidney disease. Patients with anemia and chronic kidney disease stage 3 had lower scores of general health perceptions, physical functioning, bodily pain, vitality and mental health than patients in the non-anemic group. Social role functioning was similar in anemic and non-anemic patients. The possible mechanisms and implications of the above mentioned findings are discussed with a medical and humanitarian perspective. The directions of further studies are proposed. (shrink)

Uric acid has increasingly been associated with insulin resistance, hyperinsulinemia, and type 2 diabetes mellitus. Diabetic patients who are hyperuricemic have a risk of developing diabetic complications. Pathogenesis of uric acid may decrease nitric oxide bioavailability in vascular smooth muscle, endothelial cells and direct scavenging of nitric oxide by uric acid. A decrease in endothelial nitric oxide production by uric acid has also been associated with endothelial dysfunction and insulin resistance. This study aims to determine the relationship between uric acid (...) and glucose levels in patients with type 2 diabetes mellitus. The study included 161 Libyan patients (67 males and 94 females) diagnosed with type 2 diabetes mellitus. Both levels of serum uric acid and hemoglobin A1c (HbA1c) were determined. The patients were divided into two groups. The controllable diabetic group with HbA1c of less than 06.0% and the uncontrollable diabetic group with HbA1c of more than 06.0%. Patients who are suffering from type 2 diabetes mellitus without complications were included whereas patients with smoking, alcoholism, nephrotic disease, malignancy, hepatitis, and renal failure or kidney disease were excluded. The mean and standard deviation of uric acid, HbA1c and Pearson correlation coefficient test were considered. In the controllable diabetic group, serum uric acid mean was found to be 4.807±1.39 and HbA1c was found to be 5.032±1.39. In the uncontrollable diabetic group, serum uric acid was 4.897±1.66 and HbA1c was 8.396±1.65. Uric acid level has significantly been correlated with HBA1C in controlled and uncontrolled diabetic patients (p<0.05). In addition, the uric acid level was found to be higher in the uncontrolled diabetic group than that in the controlled group (p<0.05). A possible relationship between serum uric acid and the incidence of type 2 diabetes mellitus was noted. Thus, uric acid can be used as a potential biomarker to indicate impaired glucose metabolism. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Receiving the Gift of Life: My Kidney Transplant StoryJudith W. RyanAs one of three siblings who all inherited an unfortunate gene from our mother, I was born with polycystic kidney disease (PKD). None of us knew of this, however, until later middle age, and my mother not until she was 76. I was the last sibling diagnosed at the age of 56. My brothers had been diagnosed (...) some years before and jokingly started to look at me as a universal donor. Since I had a 50-50 chance of having PKD and with a mother who was one of eight children with none of her siblings known to have the disease, I had not felt an urgency to be tested. Besides, I had no signs or symptoms. But now there was a reason. I made an appointment for a renal ultrasound and while having the procedure, I tipped the screen so that I could see the results. Although the technician was not happy with this, I was repaid with the view of my kidneys looking full of bubbles. Yes, our family was three for three in the genetic game of roulette.I knew immediately how I was going to navigate this health issue. As an adult nurse practitioner I had a very good understanding of what was to come. I knew my blood type “O” was the most common and would mean the longest wait for a deceased donor transplant, at least five years if I were lucky and only after enduring several years of progressing renal failure. In addition, I had cared for dialysis patients and watched my mother endure with difficulty both peritoneal and hemodialysis prior to her death a year before my diagnosis. Knowing I would not choose dialysis left me hoping for a miracle of a living donor or, more realistically, managing my disease as best I could until I died.The next step was managing PKD symptoms and issues as my kidneys continued to fail. One of the errors in my thinking during this time turned out to be that because I had two brothers who had the same disease and were ahead of me in their disease progression, I could follow their lead. It turned out that we manifested our disease very differently. My younger brother, who was diagnosed first, had to deal with significant pain from persistent cyst ruptures, monthly, biweekly then weekly. This continued even after his transplant until he had his native kidneys removed. The other two of us did not have to deal with cyst ruptures. Additionally, anemia was no problem for my younger brother but was for us older siblings. Significant fatigue and weariness were a problem for both of my brothers but not for me.And so it went, as we compared our blood test results, that the idea of a living donor entered the conversation. I knew this would be a problem for me because how do you ask people to consider being a donor? I had difficulty asking friends for a ride to the airport. This is where the grace and kindness of others and divine intervention enter [End Page 107] our story—word about our medical dilemma spread through the visibility of my younger brother, a minister in New England.Fortunately for me, my much beloved younger brother had dozens of people who wanted to be his donor. About 12 of these potential donors were actually tested before finding a match. One of his unmatched donors became the donor for my older brother (our first family transplant). Two years later, my other brother received his transplant. Three years later, after being told he was not a good match for my brother, this dear man came forward to be a possible donor for me. Hence, I got my transplant from an unused donor from my younger brother’s group. Overall, we had living donors from three different churches located within an hour of each other in New England. I even lucked out and acquired the minister of one of the churches as my donor. All three of us received kidneys over five years from living donors who did not know my older brother... (shrink)

Gender and public markets have long been intertwined in Peru. The vast majority of market-sellers are women, and significantly this kind of work has been intimately related to women’s empowerment and agency within a deeply patriarchal society. However, with the arrival of COVID-19 the woman-centred space of the marketplace became compromised. While once a place of female empowerment, during the pandemic the market became seen as a dangerous ‘viral vector’, with 79% of Lima market sellers testing positive for Coronavirus during (...) the first lockdown of 2020. Further still, a gender-segregated quarantine policy drove women to the markets en-masse; a policy that was withdrawn early due to its spectacular, although unsurprising, failure, causing a total inability to social distance on ‘women’s days’. As such, this paper investigates the extent to which the pandemic increased the ‘feminised burden of care’ to include deadly viral infection during the gender segregated quarantine. Applying an intersectional, post-colonial framework, the ‘feminised burden of care’ is approached as stratified along racial and class lines since markets are not spaces for all women. Furthermore, this paper will show how these intersecting structures of power that have persisted through time may become more visible and observable in times of crisis, such as through Peru’s short-lived gender segregated quarantine. With this in mind, it will be possible to suggest that the events of 2020 were more than just policymaker missteps, but a persistence and exacerbation of long-existing entangled structures of colonial and patriarchal powers. As such, it can be inferred that in an emergency, it is these power structures that were automatically adopted as the first port of call, and thereby perpetuate and strengthen them into the future. (shrink)

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)

Lymphangiogenesis is an important developmental process that is critical to regulation of fluid homeostasis, immune surveillance and response as well as pathogenesis of a number of diseases, among them cancer, inflammation, and heart failure. Specification, formation, and maturation of lymphatic blood vessels involves an interplay between a series of events orchestrated by various transcription factors that determine expression of key genes involved in lymphangiogenesis. These are traditionally thought to be under control of several key growth factors including vascular growth (...) factor‐C (VEGF‐C) and fibroblast growth factors (FGFs). Recent insights into VEGF and FGF signaling point to their role in control of endothelial metabolic processes such as glycolysis and fatty acid oxidation that, in turn, play a major role in regulation of lymphangiogenesis. These advances have significantly increased our understanding of lymphatic biology and opened new therapeutic vistas. Here we review our current understanding of metabolic controls in the lymphatic vasculature. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Difficult, Difficult, Lemon, DifficultMaggie TaylorI like to joke that my husband is a lemon—he suffers from manufacturing defects that prevent his body from functioning as intended. Illnesses other 40-somethings recover from quickly are things that land him in the hospital for weeks on end. So, it was no surprise last year that an epileptic seizure led to aspiration pneumonia, admission to the lCU, intubation, multisystem organ failure, and (...) a Helivac ride to a regional hospital for a higher level of care. I was told that his odds of survival were about fifty-fifty. At the time, I was training as a clinical ethics fellow, still relatively inexperienced but savvy enough to guess the true likelihood was probably lower. Doctors don’t usually like telling brutal truths to families.But the moral complexities of his treatment did not arise when he was on the verge of death. They came days later when he was getting better. He’d survived a major surgery, come off pressors, recovered from an acute kidney injury, did well on spontaneous breathing trials (SBTs), and tolerated sedation weaning. Ironically, this was the hardest part of the hospitalization for me. Some people tolerate endotracheal tubes. Others don’t. My husband is in the latter group. He’d even self-extubated on a prior hospitalization. This time, he was too weak to lift his arms. Instead of pulling at the tube taped to his face, he stared up at me with wild eyes that said I don’t know what’s happening but I hate it; make it stop.As his discomfort became more apparent, I pressed the intensivist, Dr. Roja1, about extubating. “He’s alert, following commands, and hit the benchmarks on his vent settings.”Dr. Roja responded by saying she didn’t feel my husband was ready. They would continue conducting SBTs and reevaluate the next day.She said the same thing the next day.And the next day. Then she suggested a trach evaluation. I rejected Dr. Roja’s proposed compromise. Forcefully.It wasn’t just that I had trouble seeing my husband in this state of confusion and discomfort, although I did. I also knew continued vent dependence was something he would not accept. Over the course of our relationship, we’ve talked a lot about what interventions my husband would tolerate under various circumstances. This makes sense, given my profession and his health problems. He doesn’t want to live no matter the costs, but only if he can do so without being a burden on those he loves or dependent on machinery long-term—which, for him, means a few weeks.This is what I told Dr. Roja. At least, this is what I think I told her. It’s doubtful I stated my reasoning [End Page 28] half that clearly, given my emotional, physical, and cognitive state. It had been two weeks since my husband was admitted, and I was depleted. I was living in a hotel across from the hospital, wasn’t eating, and had fallen back into the vice of smoking cigarettes. Exhaustion and stress had made me combative: I had to defend my husband against this doctor who refused to do the right thing and take the tube out.In what felt like a last-ditch effort to get me off her back, Dr. Roja suggested an ethics consult. It was embarrassing that the intensivist was the one to suggest ethics involvement. Consumed as I was by my job as my husband’s advocate, I had forgotten my actual job.The team was able to put together a family meeting within hours. Beforehand, the ethicist came to my husband’s room and introduced herself to me and my mother.“I work in ethics too, as a clinical ethics fellow,” I said.She responded: “Oh.”That was all. Not even a word, but a sound. I don’t know what response I wanted, but that wasn’t it. This made me suspicious of the process.My mother and I joined the ethicist, Dr. Roja, and a palliative care physician in the family room. Dr. Roja led with a summary of my husband’s clinical condition... (shrink)

Fanconi anaemia (FA) is a cancer‐prone genetic disorder that is characterised by cytogenetic instability and redox abnormalities. Although rare subtypes of FA (B, D1 and D2) have been implicated in DNA repair through links with BRCA1 and BRCA2, such a role has yet to be demonstrated for gene products of the common subtypes. Instead, these products have been strongly implicated in xenobiotic metabolism and redox homeostasis through interactions of FANCC with cytochrome P‐450 reductase and with glutathione S‐transferase, and of FANCG (...) with cytochrome P‐450 2E1, as well as redox‐dependent signalling through an interaction between FANCA and Akt kinase. We hypothesise that FA proteins act directly (via FANCC and FANCG) and indirectly (via FANCA, BRCA2 and FANCD2) with the machinery of cellular defence to modulate oxidative stress. The latter interactions may co‐ordinate the link between the response to DNA damage and oxidative stress parameters (3, 6–12). BioEssays 25:589–595, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Living donation provides important access to organ transplantation, which is the optimal therapy for patients with end-stage liver or kidney failure. Paired exchanges have facilitated thousands of kidney transplants and enable transplantation when the donor and recipient are incompatible. However, frequently willing and otherwise healthy donors have contraindications to the donation of the organ that their recipient needs. Trans-organ paired exchanges would enable a donor associated with a kidney recipient to donate a lobe of liver and (...) a donor associated with a liver recipient to donate a kidney. This article explores some of the ethical concerns that trans-organ exchange might encounter including unbalanced donor risks, the validity of informed consent, and effects on deceased organ donation. (shrink)

In this article, I argue we have collective duties to people who suffer from kidney failure and these duties are best fulfilled through a government-monopsony market in kidneys. A government-monopsony market is a model where the government is the sole buyer, and kidneys are distributed according to need, not ability to pay. The framework of collective duties enables us to respond to several of the most pressing ethical and practical objections to kidney markets, including Cécile Fabre's objection (...) that it is unjust to be paid to do one's duty, Simon Rippon's objections that it is harmful to be pressured to sell a kidney and that a market is unfair, Richard Titmuss's crowding out objection, and Ronald Dworkin's objection that body parts should not be among the goods we owe each other. (shrink)

Kidney failure is a major killer. Many lives could be saved through organ donation if people were less reluctant to part with their spare kidney. Should we incentive donation by paying people to do it?

Polycystic kidney disease (PKD) is one of the most prevalent causes of heritable renal failure. The disease is characterized by the occurrence of numerous fluid‐filled cysts within the parenchyma of kidney. The cysts are epithelial in origin and expand in size, leading to crowding of normal kidney tissue. Ultimately, there is gross enlargement of the kidneys with loss of normal functions, and death usually occurs because of complications related to renal failure. Animal models of polycystic (...) kidney disease are proving to be extremely useful for studying the molecular basis of renal cyst formation and for the isolation of genes carrying the mutations. This article describes the various animal models of polycystic kidney disease, spontaneously and experimentally derived, that have recently been identified. (shrink)

Iron uptake and storage in mammalian cells is at least partly regulated at a posttranscriptional level by the iron regulatory proteins (IRP‐1 and IRP‐2). These cytoplasmic regulators share 79% similarity in protein sequence and bind tightly to conserved mRNA stem‐loops, named iron‐responsive elements (IREs). The IRP:IRE interaction underlies the regulation of translation and stability of several mRNAs central to iron metabolism. The question of why the cell requires two such closely related regulatory proteins may be resloved (...) as we learn more about the expression and regulation of these proteins. It is evident so far that, despite similarities, the IRPs differ in several important respects. They are coordinately regulated by cellular iron, but whereas IRP‐1 is inactivated by high iron levels, IRP‐2 is rapidly degraded. Further differences arise in their expression and RNA‐binding specificity. The two proteins each recognise a large repertoire of IRE‐like sequences, including a small group of exclusive RNA targets. These findings hint that IRP‐1 and IRP‐2 may bind preferenitially to certain mRNAs in vivo, possibly extending their known functions beyond the regulation of intracellular iron homeostasis. (shrink)

This thesis examines the practice of haemodialysis and kidney transplantation, the two medical therapies available for persons with kidney failure, from a phenomenological perspective. A basic assumption made in the thesis is that contemporary biomedicine is deeply embedded in the cultural, historical, economic, and political circumstances provided by the particular local, national, and transnational contexts in which it is practiced. The aim of the thesis is twofold. On the one hand, the aim is to examine the forms (...) of person- and patienthood enacted and negotiated in haemodialysis and kidney transplantation care and in the daily lives of persons with kidney failure. On the other hand, the aim is to investigate the ways in which the enacted and negotiated forms of person- and patienthood are culturally embedded and normatively charged. In order to examine and investigate this twofold aim, an empirical material has been gathered that comprises observations and in-depth interviews with patients and caregivers at four haemodialysis units, one in Riga, Latvia, and three in Stockholm, Sweden. The theoretical approach and methodology of the study is cultural and phenomenological in character, drawing on an ethnological and anthropological understanding of culture as processual and relational, and on a phenomenological understanding of personhood as embodied and intertwined with the surrounding world. The thesis shows that patients’ encounters and attempts to deal with the diagnoses and treatments associated with kidney failure are complex and often misalign them with the normatively charged orientations enacted and recommended by medicine. The complex situation that emerges when they undergo transplantation, for example, stands in stark contrast to the widespread official view of organ transplantation as a self-evidently health-bringing and normalising therapy. Through their repeated and extensive experiences of undergoing haemodialysis and living with the disease, patients eventually become able to create a synthesis between their lived experiences of their own body and their body as a medical object – what in the thesis is called a ‘sick body’ – a synthesis that allows them to reorient themselves in life and experience a sense of direction. This process relies, to a large extent, on the temporal structure that haemodialysis affords life; it is by repeatedly undergoing the treatment that patients become able to create a sick body. Even so, many of them find this temporal structure problematic; they experience it as disruptive of their control and future-orientedness and as causing an existentially difficult-to-handle boredom. The thesis also shows that the political developments and the norms prevalent in the two national contexts studied greatly affect the orientations of the treatment practices and the participants’ lives. In both Riga and Stockholm, ideals of freedom, activity, control, and self-actualisation influence what forms of patienthood and personhood are enacted. The study indicates that persons who fall ill with a serious and chronic disease only gradually become able to understand and actively cope with their differently embodied circumstances of life. This suggests that medical professionals should not too hastily enlist their patients as experts on their own bodies, but rather provide them with the time and support necessary for making repeated attempts at creating and maintaining a life with a sick body. (shrink)

Worldwide 1.2 million people are dying from kidney failure each year, and in the USA alone, approximately 100 000 people are currently on the waiting list for a kidney transplant. One possible solution to the kidney shortage is for governments to pay donors for one of their healthy kidneys and distribute these kidneys according to need. There are, however, compelling objections to this government-monopsony model. To avoid these objections, I propose a small adjustment to the model. (...) I suggest we reward kidney sellers with both money and a ceremony that celebrates their noble act. They should, in other words, receive a prize rather than a price. (shrink)

Kidneys for transplantation are scarce, and many countries give priority to children in allocating them. This paper explains and criticizes the paediatric priority. We set out the relevant ethical principles of allocation, such as utility and severity, and the relevant facts to do with such matters as sensitization and child development. We argue that the facts and principles do not support and sometimes conflict with the priority given to children. We next consider various views on how age or the status (...) of children should affect allocation. Again, these views do not support priority to children in its current form. Since distinctions based on age ought to be positively justified, the failure of all these attempts at justification implies that the priority to children is ethically mistaken. Finally, the paper points to evidence that the paediatric priority reduces the overall supply of kidneys, at least in the United States. Paediatric priority is a real-world policy that seems discriminatory, in some places probably reduces the supply of organs, has no robust official defence, and is unsupported by mainstream ethical principles. Consequently, it should be ended. (shrink)

In his (1988), Brian Baigrie criticizes my earlier discussion of the rationality of science (Siegel 1985). In this response, I argue that (1) Baigrie misses the point of my tripartite distinction between different questions one can ask about science's rationality, (2) Baigrie's argument that the history of the development of methodological principles is crucial to philosophical discussion of the rationality of science is flawed, and (3) Baigrie's charge that my view is "anemic" rests on a failure to appreciate the (...) point of my tripartite distinction. (shrink)

This essay describes the emergence of the 9/11 attacks on the World Trade Center and Pentagon as an object of conspiratorial intrigue and imagination, offering a snapshot of the “9/11 truth movement” and its various theories as they began to reach full bloom. Theories about the attacks have come to constitute the dominant conspiratorial present – a present that looks remarkably like the mid- and late-twentieth-century past, despite significant changes in information technology and the continuing institutionalization and ironization of conspiracy (...) theory as an influential form of popular politics. In addition to the 9/11 conspiracy community, the essay considers the battle over the 9/11 Commission’s review of the government’s failure to anticipate the terrorist attacks. The Commission engaged in knowing and savvy efforts to respond to conspiracy theories and to preempt popular belief in them, offering an authoritative narrative (or, more precisely, set of narratives) to explain what occurred. Meanwhile, the 9/11 truth movement made equally knowing and savvy efforts to critique the official account, responding with its own efforts to reinterpret and re-narrate the attacks, their causes, and what they signify about the contemporary world. While the 9/11 Commission may have criticized the federal government and its intelligence services for their failures of imagination prior to the attacks, the truth movement criticized the Commission either for a failure of imagination – an explanation for the attacks that could see through the “official” account – or for a quite imaginative cover-up of the hidden truths of 9/11. By considering the clash between official authorities and an active conspiracy community, this essay considers how the movement attempted to form a collective political and scholarly community, producing a blizzard of texts offering narratives that compete with the ones told by the Commission that seek the impossible grail of conspiracy theory: the truth. The essay also considers the effects, if any, of the state’s attempt to preempt and respond to conspiracy theories. (shrink)

Hematopoiesis unfolds within the bone marrow niche where hematopoietic stem cells (HSCs) play a central role in continually replenishing blood cells. The hypoxic bone marrow environment imparts peculiar metabolic characteristics to hematopoietic processes. Here, we discuss the internal metabolism of HSCs and describe external influences exerted on HSC metabolism by the bone marrow niche environment. Importantly, we suggest that the metabolic environment and metabolic cues are intertwined with HSC cell fate, and are crucial for hematopoietic processes. Metabolic dysregulation within the (...) bone marrow niche during acute stress, inflammation, and chronic inflammatory conditions can lead to reduced HSC vitality. Additionally, we raise questions regarding metabolic stresses imposed on HSCs during implementation of stem cell protocols such as allo‐SCT and gene therapy, and the potential ramifications. Enhancing our comprehension of metabolic influences on HSCs will expand our understanding of pathophysiology in the bone marrow and improve the application of stem cell therapies. (shrink)

Kidney for Sale by Owner discusses a range of different arguments that can be offered in defence of live donor kidney markets. Although Cherry’s case for establishing such markets does not rest on consequentialist considerations, Cherry nonetheless suggests that allowing the sale of organs would have net positive consequences. He argues that both renal failure patients and people living in poverty could benefit from participating in the market, and further claims that a legal trade in organs would (...) not shape society in harmful ways. This paper argues that the likely consequences of establishing an open market in kidneys are less benign than Cherry suggests. Specifically, I argue that a live donor kidney market could plausibly harm sellers, give rise to harmful pressures to participate in the market, and reinforce unjust political and social structures. I conclude by considering the implications of these arguments for the organ market debate. (shrink)

Fanconi anemia (FA) is generally classified as a DNA repair disorder, conferring a genetic predisposition to cancer and prominent bone marrow failure (BMF) in early childhood. Corroborative human and murine studies point to a fetal origin of hematopoietic stem cell (HSC) attrition under replicative stress. Along with intriguing recent insights into non‐canonical roles and domain‐specific functions of FA proteins, these studies have raised the possibility of a DNA repair‐independent BMF etiology. However, deeper mechanistic insight is critical as current curative (...) options of allogeneic stem cell transplantation and emerging gene therapy have limited eligibility, carry significant side effects, and involve complex procedures restricted to resource‐rich environments. To develop rational and broadly accessible therapies for FA patients, the field will need more faithful disease models that overcome the scarcity of patient samples, leverage technological advances, and adopt investigational clinical trial designs tailored for rare diseases. (shrink)

For patients suffering from renal failure, cadaveric donor kidneys are a scarce and valuable good. In 1996, the Eurotransplant International Foundation implemented a new kidney allocation. system. The aim of this paper is to identify and discuss issues of distributive justice in kidney allocation, with an emphasis on the basic features of the new Eurotransplant system. Particular consideration is given to waiting time and medical success.

This book explores two public sector scandals in the UK, drawing on Max Weber's thought on 'the iron cage' to understand how these cases of patient-neglect in NHS hospitals and failures by police and social workers to address the organised sexual exploitation of young girls occurred. Through examination of the management failures and institutional vulnerabilities, and with attention to the trends of bureaucratisation and rationalisation that characterised both scandals, it reveals the explanatory power of Weber's thought, developing a theoretical (...) model that updates and extends Weber's work in light of the cases discussed. Showing that ordinary people as well as ordinary people, including professionals, are still trapped in the 'iron cage', it will appeal to scholars of sociology and social theory, as well as those providing training and working within the caring and service professions of policing, social work and nursing. (shrink)

Background Advocates for a regulated system to facilitate kidney donation between unrelated donor-recipient pairs argue that monetary compensation encourages people to donate vital organs that save the lives of patients with end-stage organ failure. Scholars support compensating donors as a form of reciprocity. This study aims to assess the compensation system for the unrelated kidney donation program in the Islamic Republic of Iran, with a particular focus on the implications of Islam on organ donation and organ sales. (...) Methods This study reviews secondary documents for philosophical argumentation and ethical analysis of human organ donation and sale for transplantation. Results and discussion According to Islamic law, organ donation is an act of _sadaqatul jariyah,_ and individuals are permitted to donate organs with the intention of saving lives. The commercialization of humans as organ sellers and buyers is contrary to the Islamic legal maxim _eethaar_, undermining donors of ‘selfless’ or ‘altruistic’ motivations. Such an act should be considered immoral, and the practice should not be introduced into other countries for the sake of protecting human dignity, integrity, solidarity, and respect. I, therefore, argue that Iran’s unrelated kidney donation program not only disregards the position of the Islamic religion with respect to the provision or receipt of monetary benefits for human kidneys for transplantation but that it also misinterprets the Islamic legal proscription of the sale of human organs. I also argue that the implementation of Iran’s unrelated kidney donor transplantation program is unethical and immoral in that potential donors and recipients engage in a bargaining process akin to that which sellers and buyers regularly face in regulated commodity exchange markets. Conversely, I suggest that a modest fixed monetary remuneration as a gift be provided to a donor as a reward for their altruistic organ donation, which is permissible by Islamic scholars. This may remove the need to bargain for increased or decreased values of payment in exchange for the organ, as well as the transactional nature of ‘buyer and seller’, ensuring the philosophy of ‘donor and recipient’ is maintained. Conclusions Offering a fixed modest monetary incentive to organ donors would serve to increase organ supply while protecting donors’ health and reducing human suffering without legalizing the human organ trade. (shrink)

Bioethical arguments conceal the coercion underlying the choice between poverty and selling ones organsIn mid-May 2006, three Palestinian prisoners detained in Israel applied to the Israeli Prison Service for permission to sell their kidneys in order to send money to their children for food. Whether truly sincere or merely propagandistic, the request was made against the background of Israel’s decision to suspend the transfer of Palestinian tax moneys to the Hamas-led Palestinian Authority, and the subsequent increasing poverty and famine in (...) the Gaza Strip.1An official decision was yet to be made when this paper was written. However, the IPS chief medical officer had already made it clear that the request is likely to be rejected. Aside from emphasising that the cost of the pertinent treatment of the prisoners could not be imposed on the IPS, especially as it would greatly exceed the sum to be obtained by the sellers , he asserted that the IPS “won’t lend a hand to endangering the prisoner”. He also reiterated the official IPS policy, according to which the prisoners’ consent to such transaction could not be valid, since they might have been threatened by people from inside or outside the prison.1This is ironic. While the IPS’ professed concerns for the welfare and best interests of the prisoners are commendable, they conceal and hence reaffirm the real coercion implicit in the dilemma the prisoners face: to sell their kidney or let their children starve. Interestingly, approval of their request would have equally concealed the coercion, this time behind concerns for either their autonomy, or the welfare of their children, or both.At present, it is unlikely that Israel will acknowledge the role of national oppression and poverty in producing this dilemma. Rather, the debate will remain focused on …. (shrink)

Isthmin‐1 (Ism1) was first described to be syn‐expressed with Fgf8 in Xenopus. However, its biological role has not been elucidated until recent years. Despite of accumulated evidence that Ism1 participates in angiogenesis, tumor invasion, macrophage apoptosis, and glucose metabolism, the cognate receptors for Ism1 remain largely unknown.Ism1deficiency in mice results in renal agenesis (RA) with a transient loss ofGdnftranscription and impaired mesenchyme condensation at E11.5. Ism1 binds to and activates Integrin α8β1 to positively regulate Gdnf/Ret signaling, thus promoting mesenchyme condensation (...) and ureteric epithelium branching morphogenesis. Here, we propose the hypothesis underlying the mechanism by which Ism1 regulates branching morphogenesis during early kidney development. (shrink)

Non‐invasive microanalytical methods have been devised to study the energy metabolism of single human preimplantation embryos. Psyruvate, which is added routinely to all media used to culture human embryos, is consumed throughout the preimplantation period, with glucose assuming an increasing role at embryo compaction and blastocyst formation. All of the glucose consumed may be accounted for by the appearance of lactate in the incubation medium. The enzyme hexokinase my be involved in regulating this aerobic glycolysis. There is cosiderable indirect evidence (...) for the utilisation of endogenous as opposed to exogenous energy substrates, the most likely candidate being protein. Information on early human embryo metabolismis likely to find application in a number of areas: these include the improvement of techniques for assisted human conception, notably in the selection of embryos for transfer following In Vitro Fertilisation; the diagnosis of gentic defects at the preimplantation stage; increased undersding of the causes of implantation failure and miscarriage, and the development of novel post‐coital contraceptives. (shrink)

Acceptance of elderly or marginal health individuals as kidney donors is debated, with practices varying between centres. Transplant recipients, live kidney donors and health-care professionals caring for patients with renal failure were surveyed regarding their views on live donor kidney transplantation (LDKT) of marginal health (diabetes, hypertension, atherosclerosis, obesity, etc.) and elderly donors. Participants were recruited within a tertiary renal and transplant centre and invited to participate in focus groups and structured interviews. They also completed an (...) anonymous questionnaire. Of 464 participants who completed the questionnaire (36% health-care professionals and 64% patients), 49% and 64%, respectively, stated that marginal and elderly donors should be accepted for LDKT. In the structured interviews, emphasis was given to presenting to donor, recipient and their respective families a calculated risk regarding the effect that either a nephrectomy or transplant has on long-term quality of life. Participants stated that an independent third party in addition to the transplant team should discuss involved risks. Issues of ‘how desperate’ the recipient's situation is should also be considered. Health-care professionals stated that regardless of the strength of will of an individual to donate a kidney (despite age, health problems or personal risk), they should always have the right to say ‘no’ if performing a specific LDKT was against their professional and ethical values. About half of those surveyed considered that marginal health and elderly donors were acceptable for LDKT. Emphasis was given to the explanation to donors and recipients of the risks involved in such transplantation. (shrink)

The human intestines are constantly under the influence of numerous pathological factors: enteropathogenic microorganisms, food antigens, physico‐chemical stress associated with digestion and bacterial metabolism, therefore it must be provided with a system of protection against adverse impact. Recent studies have shown that Paneth cells play a crucial role in maintaining homeostasis of the small intestines. Paneth cells perform many vital functions aimed at maintaining a homeostatic balance between normal microbiota, infectious pathogens and the human body, regulate the qualitative composition and (...) number of intestinal microorganisms, prevent the introduction of potentially pathogenic species, and protect stem cells from damage. Paneth cells take part in adaptive and protective‐inflammatory reactions. Paneth cells maintain dynamic balance between microbial populations, and the macroorganism, preventing the development of intestinal infections and cancer. They play a crucial role in gastrointestinal homeostasis and may be key factors in the etiopathological progression of intestinal diseases. (shrink)

Julian Koplin, drawing extensively on empirical data, has argued that vendors, even in well-regulated kidney markets, are likely to be significantly harmed. I contend that his reasoning to this conclusion is dangerously mistaken. I highlight two failures. First, Koplin is insufficiently attentive to the differences between existing markets and the regulated markets proposed by advocates. On the basis of this error, he wrongly concludes that many harms will persist even in a well-regulated system. Second, Koplin misunderstands the utilitarian assessment (...) of the market. He focuses on the costs and benefits of the transaction for the vendor. But, the relevant comparison is between an individual’s welfare across different courses of action, namely, vending and the nonvending alternative. Although Koplin’s empirically informed contribution is a welcome addition to this literature, the mistakes that pervade his interpretation of the data demand correction. (shrink)

Chronic kidney failure is a serious somatic disease. Addressing the issue of living with a chronic disease means fully considering the patients’ entourage, their families, and those close to them, especially their children and spouses.Objectives: The present paper focuses on the couple’s psychological experience when one of them suffers from a chronic disease, in this instance kidney disease. In particular, how is the spouse affected by the treatment provided? The aim is not only to see how care (...) for sick people can be improved, but also, more specifically, how relatives and especially partners can receive attention.Methodology: A qualitative approach is not only adopted, being based on the psychotherapeutic follow-up of the partners of patients with chronic kidney disease, but also of the patients themselves, addressing the matter of their life as a couple. Three couples were considered, and two case studies are presented here. The issues that cut across these different situations are examined.Results and Discussion: Some couples show considerable resourcefulness. However, over the years, that capacity for adaptation and inventiveness can also be interrupted by the periods of greater suffering and even despair, especially when the somatic pathology becomes chronic. Many spouses talk about how living with a sick partner weighs down on them, causing severe fatigue. Some aspects of the illness can also become traumatic. The disease regularly disrupts the daily life of the couple and the family. This leads to a reworking of family relations. Each couple has its own history with the condition. As it emerges, it can disrupt the bonds of filiation, especially when the illness is hereditary. Making psychological care more accessible to the partners involved constitutes a major challenge for our hospital care systems. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Reviewed by:(P)rescription Narratives: Feminist Medical Fiction and the Failure of American Censorship. by Stephanie Peebles TaveraEtta M. MaddenStephanie Peebles Tavera. (P)rescription Narratives: Feminist Medical Fiction and the Failure of American Censorship. Edinburgh: Edinburgh University Press, 2022. Hardback, xii + 220 pp. ISBN 978-1-4744-9319-2.Utopian Studies readers first saw Stephanie Peebles Tavera’s work in print in her 2018 essay on reproductive health in Charlotte Perkins Gilman’s Herland. More recently, (...) in (P)rescription Narratives, she gives readers a view of the much broader historical scope of her scholarship in literary and cultural studies. Tavera’s analysis of what she labels “feminist medical fiction” considers not only novels and short stories but also literary reviews, dramas, and documentary films, many of which will be unfamiliar to readers of utopian and dystopian literature. Yet the book contextualizes the ways in which these works capture the “utopian possibilities” of women writers who pushed for breaking the boundaries of the dystopian strictures of embodied life. The literary works “rescript” what had been prescribed by others as “normalized behavior,” from the latter-nineteenth century through the Progressive Era (5, 37). As Tavera illustrates through her detailed analysis, these women’s narratives provide “interventions that... interrupt the dissemination of false [End Page 612] narratives of the female body” and “alter the course of cultural development toward greater inclusivity” (5).To establish the temporal boundaries for the project, Tavera emphasizes the Comstock Law, established in 1873, and the death of its author Anthony Comstock in 1915. While Comstock’s work often has been understood as restricting pornography, she explains the Comstock Law as more than merely that. Comstock sought to control what he and others saw as sexual deviation, which included birth control in any form. Tavera also bookends the project with lawsuits associated with Victoria Woodhull and Margaret Sanger, both women who advocated for abortion and birth control as means of allowing women to avoid the strictures over their bodies. Additionally, she explains, Comstock’s racism caused him to completely overlook Black women, ironically allowing a space in which Black women’s feminist medical fiction especially rescripts “normalized behavior” (37)—a topic she pursues in two parts of the book.The book follows a roughly chronological path as it examines four topics related to women’s health, brilliantly organized into “(p)rescriptions,” indicated by Rx, rather than chapters with numbers. Rx1, “Crip Medicine,” illustrates how authors such as Charlotte Perkins Gilman pointed to the socially constructed status of “hysteria” in a patriarchal culture that saw women as deviant by nature. Instead, these authors advocated for a more holistic examination of women’s health, impacted by the environments in which they lived. Drawing from Lyman Tower Sargent’s widely accepted view of utopianism as dreaming of a place “considerably better than the society in which the author lived,” she underscores “the utopian impulse underlies much of the work of feminist medical fiction” (39). In particular, writers of feminist medical fiction were “driven by failure.”Perhaps most familiar to illustrate this point is Gilman’s work, such as “The Yellow Wallpaper,” which illustrated how the culture failed certain characters. The narrator of that story suffers postpartum depression and is made worse by Dr. S. Weir Mitchell’s rest cure. Consequently, Gilman proceeded to write other works, such as Moving the Mountain (1911) and then Herland (1915), which push readers to envision “alternative societies” without such destructive patriarchal medical practices (39). But Tavera also explains how Louisa May Alcott’s Eight Cousins, or the Aunt-Hill (1875) critiques contemporary culture by providing a “domestic utopia” in the female domain of Aunt-Hill, wherein the male Dr. Alec Campbell demonstrates “a better way... of caring for the female body” (55). And another key example is Rebecca Harding [End Page 613] Davis’s Kitty’s Choice: A Story of Berrytown (1875). Berrytown is described as “the Utopia in actual laths, orchards, and bushel-measures of the advance guard of the reform party in the United States” (qtd. in Tavera 55). Through its two physicians, Dr. Muller and Dr. McCall, who represent homeopathic and allopathic practitioners, readers see that the society... (shrink)

The best of the living things -- Domination -- Three incomplete prefigurations -- Metaphorical dominations -- The new Lord of creation -- Attempts and temptations -- Deployment -- The formation of the modern project -- The beginnings of the realization -- The master is there -- Moral dominion -- The duty to reign -- The iron rod -- The new meaning of humanism -- The sole Lord -- Failure -- Kingdom or wasteland? -- Man, humiliated -- The subjugated (...) subject -- Man remade -- Man surpassed and ... replaced -- Checkmate? -- Lights out. (shrink)

The objection, rightfully noted but then dismissed by Henrich et al., that the observed variation across populations is a theoretically profound and potentially constructive criticism. It parallels Donald Campbell's concern that many cultural differences reported by psychologists Ironically, Campbell's doubt is a good foundation for investigations in cultural psychology.

Japan is a country largely lacking supplies of many essential natural resources including petroleum, coal, and iron ore. As her industrial base and economy expanded during the 1920s and 1930s, Japan's dependence on imports of these resources became increasingly evident. The onset of the Depression in the 1930s further threatened Japan's lifeline, and, in an effort to become economically independent and self-sufficient in natural resources , Japan's militaristic government pursued a policy of territorial expansion. Beginning in 1937, Japan's military (...) forces swept out of Manchuria into China and then into Southeast Asia in search of strategic materials such as petroleum, coal, copper, zinc, and rubber. To achieve independence in petroleum, the Japanese developed a dual approach: they would acquire natural petroleum sources in Southeast Asia and at the same time establish a synthetic fuel industry for the conversion of coal to oil. Actually, the Japanese had begun research on synthetic fuel in the 1920s, only a few years after other countries, such as Germany and Britain, that lacked sources of natural petroleum. They did excellent laboratory research on the coal hydrogenation and Fischer-Tropsch conversion processes, but in their haste to construct large synthetic fuel plants they bypassed the intermediated pilot-plant stage and failed to make a successful transition from small- to large-scale production. Unable to synthesize liquid fuels from coal, they instead derived significant quantities from the technologically simpler coal carbonization and shale oil distillation processes. In the last year of World War II, the Japanese attempted to revive their synthetic fuel industry and entered into an agreement with IG Farben for technical assistance. Germany's defeat ended this final effort. The Japanese synthetic fuel industry presents a good case study of technological failure. It shows that high-quality basic scientific research does not necessarily translate into large-scale technological success. (shrink)

In this paper I return to one of the central points of contention in the renowned debate between John Searle and Jacques Derrida with the aim of rethinking the role of success and the place of failure in communication. What is the philosophical significance of Austin's decision to exclude from his investigation (in How to Do Things with Words) certain utterances that cannot qualify as successful? Examining the conflicting ways in which Searle and Derrida understand and respond to Austin, (...) I try to flesh out Derrida's call to grant failure (or the negative) the important place it deserves in our understanding of speech. Yet, whereas for Derrida, the call to recognize failure as an internal and positive condition ultimately leads to a structural – albeit a deconstructive – critique of language's conditions of possibility, I focus instead on the implications which this insight may have for our understanding of the actuality of language. Consequently, I argue that while Derrida's critique subverts the hegemony of success, it ironically remains, like Searle, distant from and external to the actual reverberation of spoken language. (shrink)

Obesity may be the most difficult and elusive public health problem this country has ever encountered. Unlike the classical infectious diseases and plagues that killed millions in the past, it is not caused by deadly viruses or bacteria of a kind amenable to vaccines for prevention, nor are there many promising medical treatments so far. While diabetes, heart disease, and kidney failure can be caused by obesity, it is easier to treat those conditions than one of their causes. (...) I call obesity elusive partly because of the disturbingly low success rate in treating it, but also because it requires changing the patterns, woven deeply into our social fabric, of food and beverage commerce, personal eating habits, and sedentary lifestyles. It also raises the most basic ethical and policy questions: how far can government and business go in trying to change behavior that harms health, what are the limits of market freedom for industry, and how do we look upon our bodies and judge those of others?. (shrink)

Cadaver organs should be automatically availableThe shortage of donor organs and tissue for transplantation constitutes an acute emergency which demands radical rethinking of our policies and radical measures. While estimates vary and are difficult to arrive at there is no doubt that the donor organ shortage costs literally hundreds of thousands of lives every year. “In the world as a whole there are an estimated 700 000 patients on dialysis . . .. In India alone 100 000 new patients present (...) with kidney failure each year” . Almost “three million Americans suffer from congestive heart failure . . . deaths related to this condition are estimated at 250 000 each year . . . 27 000 patients die annually from liver disease . . .. In Western Europe as a whole 40 000 patients await a kidney but only . . . 10 000 kidneys”1 become available. Nobody knows how many people fail to make it onto the waiting lists and fail to register in the statistics. “As of 24th November 2002 in the United Kingdom 667 people have donated organs, 2055 people have received transplants, and 5615 people are still awaiting transplants.”2Conscious of the terrible and unnecessary tragedy that figures like these represent I have been advocating for more than 20 years now some radical measures to stem this appalling waste of human life. The measure which is the subject of Hamer and Rivlin’s paper 3 concerns the automatic availability of all cadaver organs—a measure, which I first advocated publicly in 1983.4THE AUTOMATIC AVAILABILITY OF DONOR ORGANSWe need to begin by being clear about just what it is I propose and why. At the moment in the United Kingdom we …. (shrink)

Organ shortage is a major survival issue for millions of people worldwide. Globally 1.2 million people die each year from kidney failure. In this paper, we critically examine and find lacking extant proposals for increasing organ supply, such as opting in and opt out for deceased donor organs, and parochial altruism and paired kidney exchange for live organs. We defend two ethical solutions to the problem of organ shortage. One is to make deceased donor organs automatically available (...) for transplant without requiring consent from the donor or their relatives. The other is for society to buy nonvital organs in a strictly regulated market and provide them to people in need for free. (shrink)

continent. 1.1 : 3-13. / 0/ – Introduction I want to propose, as a trajectory into the philosophically weird, an absurd theoretical claim and pursue it, or perhaps more accurately, construct it as I point to it, collecting the ground work behind me like the Perpetual Train from China Mieville's Iron Council which puts down track as it moves reclaiming it along the way. The strange trajectory is the following: Kant's critical philosophy and much of continental philosophy which has (...) followed, has been a defense against horror and madness. Kant's prohibition on speculative metaphysics such as dogmatic metaphysics and transcendental realism, on thinking beyond the imposition of transcendental and moral constraints, has been challenged by numerous figures proceeding him. One of the more interesting critiques of Kant comes from the mad black Deleuzianism of Nick Land stating, “Kant’s critical philosophy is the most elaborate fit of panic in the history of the Earth.” And while Alain Badiou would certainly be opposed to the libidinal investments of Land's Deleuzo-Guattarian thought, he is likewise critical of Kant's normative thought-bureaucracies: Kant is the one author for whom I cannot feel any kinship. Everything in him exasperates me, above all his legalism—always asking Quid Juris? Or ‘Haven’t you crossed the limit?’—combined, as in today’s United States, with a religiosity that is all the more dismal in that it is both omnipresent and vague. The critical machinery he set up has enduringly poisoned philosophy, while giving great succour to the academy, which loves nothing more than to rap the knuckles of the overambitious [….] That is how I understand the truth of Monique David-Menard’s reflections on the properly psychotic origins of Kantianism. I am persuaded that the whole of the critical enterprise is set up to to shield against the tempting symptom represented by the seer Swedenborg, or against ‘diseases of the head’, as Kant puts it. An entire nexus of the limits of reason and philosophy are set up here, namely that the critical philosophy not only defends thought from madness, philosophy from madness, and philosophy from itself, but that philosophy following the advent of the critical enterprise philosophy becomes auto-vampiric; feeding on itself to support the academy. Following Francois Laruelle's non-philosophical indictment of philosophy, we could go one step further and say that philosophy operates on the material of what is philosophizable and not the material of the external world. [1] Beyond this, the Kantian scheme of nestling human thinking between our limited empirical powers and transcendental guarantees of categorical coherence, forms of thinking which stretch beyond either appear illegitimate, thereby liquefying both pre-critical metaphysics and the ravings of the mad in the same critical acid. In rejecting the Kantian apparatus we are left with two entities – an unsure relation of thought to reality where thought is susceptible to internal and external breakdown and a reality with an uncertain sense of stability. These two strands will be pursued, against the sane-seal of post-Kantian philosophy by engaging the work of weird fiction authors H.P. Lovecraft and Thomas Ligotti. The absolute inhumanism of the formers universe will be used to describe a Shoggothic Materialism while the dream worlds of the latter will articulate the mad speculation of a Ventriloquil Idealism. But first we must address the relation of philosophy to madness as well as philosophy to weird fiction. /1/ – Philosophy and Madness There is nothing that the madness of men invents which is not either nature made manifest or nature restored. Michel Foucault. Madness and Civilization. The moment I doubt whether an event that I recall actually took place, I bring the suspicion of madness upon myself: unless I am uncertain as to whether it was not a mere dream. Arthur Schopenhauer. The World as Will and Idea, Vol. 3. Madness is commonly thought of as moving through several well known cultural-historical shifts from madness as a demonic or otherwise theological force, to rationalization, to medicalization psychiatric and otherwise. Foucault's Madness and Civilization is well known for orientating madness as a form of exclusionary social control which operated by demarcating madness from reason. Yet Foucault points to the possibility of madness as the necessity of nature at least prior to the crushing weight of the church. Kant’s philosophy as a response to madness is grounded by his humanizing of madness itself. As Adrian Johnston points out in the early pages of Time Driven pre-Kantian madness meant humans were seized by demonic or angelic forces whereas Kantian madness became one of being too human. Madness becomes internalized, the external demonic forces become flaws of the individual mind. Foucault argues that, while madness is de-demonized it is also dehumanized during the Renaissance, as madmen become creatures neither diabolic nor totally human reduced to the zero degree of humanity. It is immediately clear why for Kant, speculative metaphysics must be curbed – with the problem of internal madness and without the external safeguards of transcendental conditions, there is nothing to formally separate the speculative capacities for metaphysical diagnosis from the mad ramblings of the insane mind – both equally fall outside the realm of practicality and quotidian experience. David-Menard's work is particularly useful in diagnosing the relation of thought and madness in Kant's texts. David-Menard argues that in Kant's relatively unknown “An Essay on the Maladies of the Mind” as well as his later discussion of the Seer of Swedenborg, that Kant formulates madness primarily in terms of sensory upheaval or other hallucinatory theaters. She writes: “madness is an organization of thought. It is made possible by the ambiguity of the normal relation between the imaginary and the perceived, whether this pertains to the order of sensation or to the relations between our ideas” Kant's fascination with the Seer forces Kant between the pincers of “aesthetic reconciliation” – namely melancholic withdrawal – and “a philosophical invention” – namely the critical project. Deleuze and Guattari's schizoanalysis is a combination and reversal of Kant's split, where an aesthetic over engagement with the world entails prolific conceptual invention. Their embrace of madness, however, is of course itself conceptual despite all their rhizomatic maneuvers. Though they move with the energy of madness, Deleuze and Guattari save the capacity of thought from the fangs of insanity by imbuing materiality itself with the capacity for thought. Or, as Ray Brassier puts it, “Deleuze insists, it is necessary to absolutize the immanence of this world in such a way as to dissolve the transcendent disjunction between things as we know them and as they are in themselves”. That is, whereas Kant relied on the faculty of judgment to divide representation from objectivity Deleuze attempts to flatten the whole economy beneath the juggernaut of ontological univocity. Speculation, as a particularly useful form of madness, might fall close to Deleuze and Guattari’s shaping of philosophy into a concept producing machine but is different in that it is potentially self destructive – less reliant on the stability of its own concepts and more adherent to exposing a particular horrifying swath of reality. Speculative madness is always a potential disaster in that it acknowledges little more than its own speculative power with the hope that the gibbering of at least a handful of hysterical brains will be useful. Pre-critical metaphysics amounts to madness, though this may be because the world itself is mad while new attempts at speculative metaphysics, at post-Kantian pre-critical metaphysics, are well aware of our own madness. Without the sobriety of the principle of sufficient reason we have a world of neon madness: “we would have to conceive what our life would be if all the movements of the earth, all the noises of the earth, all the smells, the tastes, all the light – of the earth and elsewhere, came to us in a moment, in an instant – like an atrocious screaming tumult of things”. Speculative thought may be participatory in the screaming tumult of the world or, worse yet, may produce its spectral double. Against theology or reason or simply commonsense, the speculative becomes heretical. Speculation, as the cognitive extension of the horrorific sublime should be met with melancholic detachment. Whereas Kant's theoretical invention, or productivity of thought, is self -sabotaging, since the advent of the critical project is a productivity of thought which then delimits the engine of thought at large either in dogmatic gestures or non-systematizable empirical wondrousness. The former is celebrated by the fiction of Thomas Ligotti whereas the latter is espoused by the tales of H.P. Lovecraft. /2/ – Weird Fiction and Philosophy. Supernatural horror, in all its eerie constructions, enables a reader to taste treats inconsistent with his personal welfare. Thomas Ligotti Songs of a Dead Dreamer. I choose weird stories because they suit my inclination best—one of my strongest and most persistent wishes being to achieve,momentarily, the illusion of some strange suspension or violation of the galling limitations of time, space, and natural law which forever imprison us and frustrate our curiosity about the infinite cosmic spaces beyond the radius of our sight and analysis H.P. Lovecraft. “Notes on Writing Weird Fiction” Lovecraft states that his creation of a story is to suspend natural law yet, at the same time, he indexes the tenuousness of such laws, suggesting the vast possibilities of the cosmic. The tension that Lovecraft sets up between his own fictions and the universe or nature is reproduced within his fictions in the common theme of the unreliable narrator; unreliable precisely because they are either mad or what they have witnessed questions the bounds of material reality. In “The Call of Cthulhu” Lovecraft writes: The most merciful thing in the world, I think, is the inability of the human mind to correlate all its contents. We live on a placid island of ignorance in the midst of black seas of infinity, and it was not meant that we should voyage far. The sciences, each straining in its own direction, have hitherto harmed us little; but some day the piecing together of dissociated knowledge will open up such terrifying vistas of reality, and of our frightful position therein, that we shall either go mad from the revelation or flee from the deadly light into the peace and safety of a new dark age. Despite Lovecraft's invocations of illusion, he is not claiming that his fantastic creations such as the Old Ones are supernatural but, following Joshi, are only ever supernormal. One can immediately see that instead of nullifying realism Lovecraft in fact opens up the real to an unbearable degree. In various letters and non-fictional statements Lovecraft espoused strictly materialist tenets, ones which he borrowed from Hugh Elliot namely the uniformity of law, the denial of teleology and the denial of non-material existence. Lovecraft seeks to explore the possibilities of such a universe by piling horror upon horror until the fragile brain which attempts to grasp it fractures. This may be why philosophy has largely ignored weird fiction – while Deleuze and Guattari mark the turn towards weird fiction and Lovecraft in particular, with the precursors to speculative realism as well as contemporary related thinkers have begun to view Lovecraft as making philosophical contributions. Lovecraft's own relation to philosophy is largely critical while celebrating Nietzsche and Schopenhauer. This relationship of Lovecraft to philosophy and philosophy to Lovecraft is coupled with Lovecraft's habit of mercilessly destroying the philosopher and the figure of the academic more generally in his work, a destruction which is both an epistemological destruction and an ontological destruction. Thomas Ligotti's weird fiction which he has designated as a kind of “confrontational escapism” might be best described in the following quote from one of his shortstories, “The human phenomenon is but the sum of densely coiled layers of illusion each of which winds itself on the supreme insanity. That there are persons of any kind when all there can be is mindless mirrors laughing and screaming as they parade about in an endless dream”. Whereas Lovecraft's weirdness draws predominantly from the abyssal depths of the uncharted universe, Ligotti's existential horror focuses on the awful proliferation of meaningless surfaces that is, the banal and every day function of representation. In an interview, Ligotti states: We don't even know what the world is like except through our sense organs, which are provably inadequate. It's no less the case with our brains. Our whole lives are motored along by forces we cannot know and perceptions that are faulty. We sometimes hear people say that they're not feeling themselves. Well, who or what do they feel like then? This is not to say that Ligotti sees nothing beneath the surface but that there is only darkness or blackness behind it, whether that surface is on the cosmological level or the personal. By addressing the implicit and explicit philosophical issues in Ligotti's work we will see that his nightmarish take on reality is a form of malevolent idealism, an idealism which is grounded in a real, albeit dark and obscure materiality. If Ligotti's horrors ultimately circle around mad perceptions which degrade the subject, it takes aim at the vast majority of the focus of continental philosophy. While Lovecraft's acidic materialism clearly assaults any romantic concept of being from the outside, Ligotti attacks consciousness from the inside: Just a little doubt slipped into the mind, a little trickle of suspicion in the bloodstream, and all those eyes of ours, one by one, open up to the world and see its horror [...] Not even the solar brilliance of a summer day will harbor you from horror. For horror eats the light and digests it into darkness. Clearly, the weird fiction of Lovecraft and Ligotti amount to a anti-anthrocentric onslaught against the ramparts of correlationist continental philosophy. /3/ – Shoggothic Materialism or the Formless Formless protoplasm able to mock and reflect all forms and organs and processes—viscous agglutinations of bubbling cells—rubbery fifteen-foot spheroids infinitely plastic and ductile—slaves of suggestion, builders of cities—more and more sullen, more and more intelligent, more and more amphibious, more and more imitative—Great God! What madness made even those blasphemous Old Ones willing to use and to carve such things? H.P. Lovecraft. “At the Mountains of Madness” On the other hand, affirming that the universe resembles nothing and is only formless amounts to saying that the universe is something like a spider or spit. Georges Bataille. “Formless”. The Shoggoths feature most prominently in H.P. Lovecraft's shortstory “At the Mountains of Madness” where they are described in the following manner: It was a terrible, indescribable thing vaster than any subway train – a shapeless congeries of protoplasmic bubbles, faintly self -luminous, and with myriads of temporary eyes forming and un-forming as pustules of greenish light all over the tunnel-filling front that bore down upon us, crushing the frantic penguins and slithering over the glistening floor that it and its kind had swept so evilly free of all litter. The term is a litmus test for materialism itself as the Shoggoth is an amorphous creature. The Shoggoths were living digging machines bio engineered by the Elder Things, and their protoplasmic bodies being formed into various tools by their hypnotic powers. The Shoggoths eventually became self aware and rose up against their masters in an ultimately failed rebellion. After the Elder Ones retreated into the oceans leaving the Shoggoths to roam the frozen wastes of the Antarctic. The onto-genesis of the Shoggoths and their gross materiality, index the horrifyingly deep time of the earth a concept near and dear to Lovecraft's formulation of horror as well as the fear of intelligences far beyond, and far before, the ascent of humankind on earth and elsewhere. The sickly amorphous nature of the Shoggoths invade materialism at large, where while materiality is unmistakably real ie not discursive, psychological, or otherwise overly subjectivist, it questions the relation of materialism to life. As Eugene Thacker writes: The Shoggoths or Elder Things do not even share the same reality with the human beings who encounter them—and yet this encounter takes place, though in a strange no-place that is neither quite that of the phenomenal world of the human subject or the noumenal world of an external reality. Amorphous yet definitively material beings are a constant in Lovecraft's tales. In his tale “The Dream-Quest of Unknown Kadatth” Lovecraft describes Azathoth as, “that shocking final peril which gibbers unmentionably outside the ordered universe,” that, “last amorphous blight of nethermost confusion which blashphemes and bubbles at the centre of all infinity,” who, “gnaws hungrily in inconceivable, unlighted chambers beyond time”. Azathoth's name may have multiple origins but the most striking is the alchemy term azoth which is both a cohesive agent and a acidic creation pointing back to the generative and the decayed. The indistinction of generation and degradation materially mirrors the blur between the natural and the unnatural as well as life and non-life. Lovecraft speaks of the tension between the natural and the unnatural is his short story “The Unnameable.” He writes, “if the psychic emanations of human creatures be grotesque distortions, what coherent representation could express or portray so gibbous and infamous a nebulousity as the spectre of a malign, chaotic perversion, itself a morbid blasphemy against Nature?”. Lovecraft explores exactly the tension outlined at the beginning of this chapter, between life and thought. At the end of his short tale Lovecraft compounds the problem as the unnameable is described as “a gelatin—a slime—yet it had shapes, a thousand shapes of horror beyond all memory”. Deleuze suggests that becoming-animal is operative throughout Lovecraft's work, where narrators feel themselves reeling at their becoming non-human or of being the anomalous or of becoming atomized. Following Eugene Thacker however, it may be far more accurate to say that Lovecraft's tales exhibit not a becoming-animal but a becoming-creature. Where the monstrous breaks the purportedly fixed laws of nature, the creature is far more ontologically ambiguous. The nameless thing is an altogether different horizon for thought. The creature is either less than animal or more than animal – its becoming is too strange for animal categories and indexes the slow march of thought towards the bizarre. This strangeness is, as aways, some indefinite swirling in the category of immanence and becoming. Bataille begins “The Labyrinth” with the assertion that being, to continue to be, is becoming. More becoming means more being hence the assertion that Bataille's barking dog is more than the sponge. This would mean that the Shoggotth is altogether too much being, too much material in the materialism. Bataille suggests that there is an immanence between the eater and the eaten, across the species and never within them. That is, despite the chaotic storm of immanence there must remain some capacity to distinguish the gradients of becoming without reliance upon, or at least total dependence upon, the powers of intellection to parse the universe into recognizable bits, properly digestible factoids. That is, if we undo Deleuze's aforementioned valorization of sense which, for his variation of materialism, performed the work of the transcendental, but refuse to reinstate Kant's transcendental disjunction between thing and appearance, then it must be a quality of becoming-as-being itself which can account for the discernible nature of things by sense. In an interview with Peter Gratton, Jane Bennett formulates the problem thusly: What is this strange systematicity proper to a world of Becoming? What, for example, initiates this congealing that will undo itself? Is it possible to identify phases within this formativity, plateaus of differentiation? If so, do the phases/plateaus follow a temporal sequence? Or, does the process of formation inside Becoming require us to theorize a non-chronological kind of time? I think that your student’s question: “How can we account for something like iterable structures in an assemblage theory?” is exactly the right question. Philosophy has erred too far on the side of the subject in the subject-object relation and has furthermore, lost the very weirdness of the non-human. Beyond this, the madness of thought need not override. /4/ - Ventriloquial Idealism or the Externality of Thought My aim is the opposite of Lovecraft's. He had an appreciation for natural scenery on earth and wanted to reach beyond the visible in the universe. I have no appreciation for natural scenery and want the objective universe to be a reflection of a character. Thomas Ligotti. “Devotees of Decay and Desolation.” Unless life is a dream, nothing makes sense. For as a reality, it is a rank failure [….] Horror is more real than we are. Thomas Ligotti. “Professor Nobody's Little Lectures on Supernatural Horror”. Thomas Ligotti's tales are rife with mannequins, puppets, and other brainless entities which of replace the valorized subject of philosophy – that of the free thinking human being. His tales such as “The Dream of the Manikin” aim to destroy the rootedness of consciousness. James Trafford has connected the anti-egoism of Ligotti to Thomas Metzinger – where the self is at best an illusion and we plead desperately for someone else to acknowledge that we are real. Trafford has stated it thus, “Life is played out as an inescapable puppet show, an endless dream in which the puppets are generally unaware that they are trapped within a mesmeric dance of whose mechanisms they know nothing and over which they have no control”. An absolute materialism, for Ligotti, implies an alienation of the idea which leads to a ventriloquil idealism. As Ligotti notes in an interview, “the fiasco and nightmare of existence, the particular fiasco and nightmare of human existence, the sense that people are puppets of powers they cannot comprehend, etc.” And then further elaborates that,“[a]ssuming that anything has to exist, my perfect world would be one in which everyone has experienced the annulment of his or her ego. That is, our consciousness of ourselves as unique individuals would entirely disappear”. The externality of the idea leads to the unfortunate consequence of consciousness eating at itself through horror which, for Ligotti, is more real than reality and goes beyond horror-as-affect. Beyond this, taking together with the unreality of life and the ventriloquizing of subjectivity, Ligotti's thought becomes an idealism in which thought itself is alien and ultimately horrifying. The role of human thought and the relation of non-relation of horror to thought is not completely clear in Ligotti's The Conspiracy Against the Human Race. Ligotti argues in his The Conspiracy Against the Human Race,that the advent of thought is a mistake of nature and that horror is being in the sense that horror results from knowing too much. Yet, at the same time, Ligotti seems to suggest that thought separates us from nature whereas, for Lovecraft, thought is far less privileged – mind is just another manifestation of the vital principal, it is just another materialization of energy. In his brilliant “Prospects for Post-Copernican Dogmatism” Iain Grant rallies against the negative definition of dogmatism and the transcendental, and suggests that negatively defining both over-focuses on conditions of access and subjectivism at the expense of the real or nature. With Schelling, who is Grant's champion against the subjectivist bastions of both Fichte and Kant, Ligotti's idealism could be taken as a transcendental realism following from an ontological realism. Yet the transcendental status of Ligotti's thought move towards a treatment of the transcendental which may threaten to leave beyond its realist ground. Ligotti states: Belief in the supernatural is only superstition. That said, a sense of the supernatural, as Conrad evidenced in Heart of Darkness, must be admitted if one's inclination is to go to the limits of horror. It is the sense of what should not be- the sense of being ravaged by the impossible. Phenomenally speaking, the super-natural may be regarded as the metaphysical counterpart of insanity, a transcendental correlative of a mind that has been driven mad. Again, Ligotti equates madness with thought, qualifying both as supernatural while remaining less emphatic about the metaphysical dimensions of horror. The question becomes one of how exactly the hallucinatory realm of the ideal relates to the black churning matter of Lovecraft's chaos of elementary particles. In his tale “I Have a Special Plan for This World” Ligotti formulates thus: A: There is no grand scheme of things. B: If there were a grand scheme of things, the fact – the fact – that we are not equipped to perceive it, either by natural or supernatural means, is a nightmarish obscenity. C: The very notion of a grand scheme of things is a nightmarish obscenity. Here Ligotti is not discounting metaphysics but implying that if it does exist the fact that we are phenomenologically ill-equipped to perceive that it is nightmarish. For Ligotti, nightmare and horror occur within the circuit of consciousness whereas for Lovecraft the relation between reality and mind is less productive on the side of mind. It is easier to ascertain how the Kantian philosophy is a defense against the diseases of the head as Kant armors his critical enterprise from too much of the world and too much of the mind. The weird fiction of both Lovecraft and Ligotti demonstrates that there is too much of both feeding into one another in a way that corrodes the Kantian schema throughly, breaking it down into a dead but still ontologically potentiated nigredo. The haunting, terrifying fact of Ligotti's idealism is that the transcendental motion which brought thought to matter, while throughly material and naturalized, brings with it the horror that thought cannot be undone without ending the material that bears it either locally or completely. Thought comes from an elsewhere and an elsewhen being-in-thought. The unthinkable outside thought is as maddening as the unthought engine of thought itself within thought which doesn't exist except for the mind, the rotting décor of the brain. /5/ - Hyperstitional Transcendental Paranoia or Self -Expelled Thought Weird fiction has been given some direct treatment in philosophy in the mad black Deleuzianism of Nick Land. Nick Land along with others in the 1990s created the Cyber Culture Research Unit as well as the research group Hyperstition. The now defunct hyperstitional website, an outgrowth of the Cyber Culture Research Unit, defined hyperstition in the following fourfold: 1-Element of effective culture that makes itself real. 2-Fictional quantity functional as a time-traveling device. 3-Coincidence intensifier. 4-Call to the Old Ones. The distinctively Lovecraftian character of hyperstition is hard to miss as is its Deleuzo-Guattarian roots. In the opening pages of A Thousand Plateaus Deleuze and Guattari write, “We have been criticized for over-quoting literary authors. But when one writes, the only question is which other machine the literary machine can be plugged into”. The indisinction of literature and philosophy mirrors the mess of being and knowing as post-correlationist philosophy, where philosophy tries to make itself real where literature, especially the weird, aims itself at the brain-circuit of horror. The texts of both Lovecraft and Ligotti work through horror as epistemological plasticity meeting with proximity as well as the deep time of Lovecraft and the glacially slow time of paranoia in Ligotti. Against Deleuze, and following Brassier, we cannot allow the time of consciousness, the Bergsonian time of the duree, to override natural time, but instead acknowledge that it is an unfortunate fact of existence as a thinking being. Horror-time, the time of consciousness, with all its punctuated moments and drawn out terrors, cannot compare to the deep time of non-existence both in the unreachable past and the unknown future. The crystalline cogs of Kant's account of experience as the leading light for the possibility of metaphysics must be throughly obliterated. His gloss of experience in Prolegomena to any Future Metaphysics could not be more sterile: Experience consists of intuitions, which belong to the sensibility, and of judgments, which are entirely a work of the understanding. But the judgments which the understanding makes entirely out of sensuous intuitions are far from being judgments of experience. For in the one case the judgment connects only the perceptions as they are given in sensuous intuition [....] Experience consists in the synthetic connection of appearances in consciousness, so far as this connection is necessary. Here it is difficult to dismiss the queasiness that Kant's legalism induces upon sight for both Badiou and David-Menard. Kant's thought becomes, as Foucault says when reflecting on Sade's text in relation to nature, “the savage abolition of itself”. For Badiou, Kant's philosophy simply closes off too much of the outside, freezing the world of thought in an all too limited formalism. Critical philosophy is simply the systematized quarantine on future thinking, on thinking which would threaten the formalism which artificially grants thought its own coherency in the face of madness. Even the becoming-mad of Deleuze, while escaping the rumbling ground, makes grounds for itself, mad grounds but grounds which are thinkable in their affect. The field of effects allows for Deleuze's aesthetic and radical empiricism, in which effects and/or occasions make up the material of the world to be thought as a chaosmosis of simulacra. Given a critique of an empiricism of aesthetics, of the image, it may be difficult to justify an attack on Kantian formalism with the madness of literature, which does not aim to make itself real but which we may attempt to make real. That is, how do Lovecraft's and Ligotti's materials, as materials for philosophy to work on, differ from either the operative formalisms of Kant or the implicitly formalized images of Deleuzian empiricism? It is simply that such texts do not aim to make themselves real, and make claims to the real which are more alien to us than familiar, which is why their horror is immediately more trustworthy. This is the madness which Blanchot discusses in The Infinite Conversation through Cervantes and his knight – the madness of book-life, of the perverse unity of literature and life a discussion which culminates in the discussion of one of the weird's masters, that of Kafka. The text is the knowing of madness, since madness, in its moment of becoming-more-mad, cannot be frozen in place but by the solidifications of externalizing production. This is why Foucault ends his famous study with works of art. Furthermore extilligence, the ability to export the products of our maligned brains, is the companion of the attempts to export, or discover the possibility of intelligences outside of our heads, in order for philosophy to survive the solar catastrophe. To borrow again from Deleuze, writing is inseparable from becoming. The mistake is to believe that madness is reabsorbed by extilligence, by great works, or that it could be exorcised by the expelling of thought into the inorganic or differently organic. Going out of our heads does not guarantee we will no longer mean we cannot still go out of our minds. This is simply because of the outside, of matter, or force, or energy, or thing-in-itself, or Schopenhauerian Will. In Lovecraft’s “The Music of Erich Zahn” an “impoverished student of metaphysics” becomes intrigued by strange viol music coming from above his room. After meeting the musician the student discovers that each night he plays frantic music at a window in order to keep some horridness at bay, some “impenetrable darkness with chaos and pandemonium”. The aesthetic defenses provided by the well trained brain can bear the hex of matter for so long, the specter of unalterability within it which too many minds obliterate, collapsing everything before the thought of thought as thinkable or at least noetically mutable on our own terms. Transcendental paranoia is the concurrent nightmare and promise of Paul Humphrey's work, of being literally out of our minds. It is the gothic counterpart of thinking non-conceptually but also of thinking never belonging to any instance of purportedly solid being. As Bataille stated, “At the boundary of that which escapes cohesion, he who reflects within cohesion realizes there is no longer any room for him” Thought is immaterial only to the degree that it is inhuman, it is a power that tries, always with failure, to ascertain its own genesis. Philosophy, if it can truly return to the great outdoors, if it can leave behind the dead loop of the human skull, must recognize not only the non-priority of human thought, but that thought never belongs to the brain that thinks it, thought comes from somewhere else. To return to the train image from the beginning “a locomotive rolling on the surface of the earth is the image of continuous metamorphosis” this is the problem of thought, and of thinking thought, of being no longer able to isolate thought, with only a thought-formed structure. [1] One of the central tenets of Francois Laruelle's non-philosophy is that philosophy has traditionally operated on material already presupposed as thinkable instead of trying to think the real in itself. Philosophy, according to Laruelle, remains fixated on transcendental synthesis which shatters immanence into an empirical datum and an a prori factum which are then fused by a third thing such as the ego. For a critical account of Laruelle's non-philosophy see Ray Brassier's Nihil Unbound. (shrink)

Mitochondrial bioenergetics plays a key role in multiple basic cellular processes, such as energy production, nucleotide biosynthesis, and iron metabolism. It is an essential system for animals' life and death (apoptosis) and it is required for embryo development. This, in conjunction with its being subjected to adaptive processes in multiple species and its gene products being involved in the formation of reproductive barriers in animals, raises the possibility that mitochondrial bioenergetics could be a candidate genetic mechanism of speciation. Here, (...) we discuss genetic and biochemical evidence for the possible involvement of this unique system, encoded by two genomes (the mitochondrial and nuclear genomes), that differ by an order of magnitude in their mutation rates in processes leading to speciation events. (shrink)

In this paper I shall be arguing against the claim made by Erin and Harris and others, that creating a “regulated market” in organs for transplantation taken from living vendors is both viable practically and a moral imperative. No-one can doubt that there is currently a crisis in the provision of organs for transplantation, with a massive gap between supply and demand. There are a number of reasons for this crisis. Since its development as a life-saving measure in the second (...) half of the last century, organ transplantation has expanded exponentially, both in terms of survival rates, the number of people on the waiting list for the procedure, and the range of transplantable organs. Advances in immuno-suppression and in prevention of infection have led to improvement in both the survival of the recipients and of the transplanted organs. At the same time, there has been an increase in repeat transplantations and in multiple organ transplants. The range of conditions for which transplantation is offered has widened, and transplantable organs now include: kidney, liver, pancreas, heart and lung. Brain-dead donors can provide all of these organs, while the kidney and sections of the liver and pancreas can also be obtained from living donors. Survival outcomes are better from living donors than from cadaveric donors, and, in the case of kidney failure, better from transplantation than from dialysis. [End Page 164] The relevant question, however, is whether permitting a market in human organs is morally justifiable, and, even if it were, whether it would provide a solution to the current crisis. I argue in this paper that organ trading is wrong in principle, since it commodifies the human body and inevitably exploits the poor and the socially vulnerable, and that, far from alleviating the crisis, it is likely to make it worse. First we should note that there is an uncompromising opposition to all forms of organ trading from two major international healthcare organisations. (shrink)

Ms. P. is in the ICU with respiratory failure and sepsis. She has been on a ventilator for almost a week, and now has impending kidney failure. Her children, who have been taking turns at the bedsi...

The transcription factor Nrf2 is the master regulator of cellular stress response, facilitating the expression of cytoprotective genes, including those responsible for drug detoxification, immunomodulation, and iron metabolism. FDA‐approved Nrf2 activators, Tecfidera and Skyclarys for patients with multiple sclerosis and Friedreich's ataxia, respectively, are non‐specific alkylating agents exerting side effects. Nrf2 is under feedback regulation through its target gene, transcriptional repressor Bach1. Specifically, in Parkinson's disease and other neurodegenerative diseases with Bach1 dysregulation, excessive Bach1 accumulation interferes with Nrf2 activation. (...) Bach1 is a heme sensor protein, which, upon heme binding, is targeted for proteasomal degradation, relieving the repression of Nrf2 target genes. Ideally, a combination of Nrf2 stabilization and Bach1 inhibition is necessary to achieve the full therapeutic benefits of Nrf2 activation. Here, we discuss recent advances and future perspectives in developing small molecule inhibitors of Bach1, highlighting the significance of the Bach1/Nrf2 signaling pathway as a promising neurotherapeutic strategy. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Editors’ NoteJames M. DuBois, Ana S. Iltis, and Heidi A. WalshFrom childhood, David Slakter had undergone tests and invasive procedures to monitor his nephritis. It was not a surprise when in 2015, doctors told him he needed a kidney transplant. The wife of a childhood friend was a close match and gave him one of her kidneys. Before his transplant, aerobic exercise was difficult; a few months after (...) transplant, Slakter could ride his bike, hike, and work out with a personal trainer. He no longer had to weigh food or gauge his potassium consumption, a concern for people with kidney failure. For Slakter, “life post-transplant has been a significant improvement.”Individuals or family members of those who have received an organ transplant from a living or deceased donor share their stories in this issue of Narrative Inquiry in Bioethics. The symposium is titled “Receiving the Gift of Life: Stories from Organ Transplant Recipients.” Organ transplantation can extend an individual’s life by decades. It can also greatly improve an individual’s quality of life, as was Slakter’s experience. At the same time, organ transplantation is expensive and stressful. Recipients can experience complications, including organ rejection, and there are few appealing alternatives.After her heart transplant, author Leilani R. Graham required four open-heart surgeries, ECMO, and an intra-aortic balloon pump. She experienced delirium, necrotizing pneumonia, and severe muscular atrophy that required her to re-learn how to walk. She struggled with weight gain, explosive mood swings, hair loss, and was terrified that her body would reject the new heart. For Graham, “[Transplant] was not the miracle [she] was hoping for.” Graham says she felt unprepared for and inadequately informed about what to expect after her transplant, which left her “battered, beaten, and bruised” with a 12-inch line from neck to navel and “bullet holes” up and down her torso from the chest tubes. When reflecting on her experience post-transplant, Graham says, “It wasn’t the physical trauma that hurt the most. It was that no one seemed surprised [by the aftereffects of transplant].” Seemingly no one, that is except Graham, who calls on transplant providers to “prioritize empathy.”The symposium editors are Jason T. Eberl and Tristan McIntosh. Three commentary articles, written by Macey Leigh Levan, Heather Lannon, and Vidya A. Fleetwood, Roslyn B. Mannon & Krista L. Lentine, offer important insights into the authors’ stories. The editors thank Mid-America Transplant, the UCSF Lung Transplant Program, Donor Connect, William L. Freeman, MD, MPH, MJIL, CIP, Janet Monk, and the individuals who gave anonymous donations to support the publication of this issue, an open-access VOICES edition of the symposium, and accompanying teaching guides.The research article in this issue, “‘A Shell of My Former Self’: Using Figurative Language to Promote Communication about Patient Suffering,” was written by Tyler Tate, Elizabeth Stein, and Robert A. Pearlman. The relief of suffering is a primary goal of medicine. However, the authors note that clinicians often miss or ignore suffering because they focus on the causes rather than the experience of suffering, or the subjective nature of suffering makes it difficult to discuss. The authors believe that “the key to communicating about suffering lies in finding [End Page vii] the right kind of words to describe the experience” and say that figurative language offers a promising approach. In their research, the authors performed qualitative analysis on 52 works of literature and identified 254 excerpts of figurative language with themes of non-physical or psychological suffering. The authors found 13 salient themes: brokenness, diminishment, disorientation, drowning, emptiness, imprisonment, battle, darkness, isolation, invisibility, lifelessness, punishment, and torture. The authors reiterate that developing a shared language of suffering could foster a therapeutic patient-clinician relationship and improve clinicians’ ability to recognize and address a patient’s experience of suffering.María Susana Ciruzzi wrote the first of two case studies included in this issue. “The Sword of King Solomon” addresses a tragic and difficult subject—how to navigate the situation posed by conjoined twins when “any decision will produce damage and suffering.” The case involves two infant male patients born at 37 weeks gestation as omphalo-ischiopagus conjoined twins... (shrink)