Erythropoietin (EPO), long appreciated as the chief endocrine regulator of red blood cell formation, is now recognized to exert many additional functions outside the bone marrow. Thus, the quest is on to define the full range of EPO functions in the physiology and pathology of non‐hematopoietic tissues. Two recent studies in man and mice have highlighted the importance of the mammalian skin as one peripheral tissue with a previously unsuspected role in EPO biology; both, as a target and as (...) a source of EPO. In addition, the skin has been proposed to function as an oxygen sensor. The present hypothesis essay critically reviews the currently available evidence for this and provides a unifying theoretical scenario for intracutaneous EPO functions and for a potential role of the skin in the control of EPO production. Mainly, we propose that the skin itself directly contributes to the up‐regulation of EPO plasma levels in response to hypoxia. (shrink)

2007 will be remembered as the year in which the Tour de France died. Race leader and likely eventual winner, Michael Rasmussen, was eliminated near the end on an allegation of doping. Since the 1960s, the idealistic drug crusaders have been on a mission to reverse the course of history, and eliminate drugs from the sport. But this “zero tolerance” strategy to drugs has failed, as 2007's Tour spectacularly showed. Only around 10–15% of professional athletes are drug tested. Currently, it (...) is illegal to use erythropoietin (EPO) or blood doping to move your haematocrit from 48 to 49% even though some people will have a normal level of 49%. A regulated permissive policy would paradoxically reduce risk to athletes. The present system creates an environment of risk to the athlete. A rational policy on doping would allow safe performance‐enhancing interventions which are consistent with the spirit of a particular sport. (shrink)

David DeGrazia1 offers, to my mind, a decisive response to the bioconservative suggestion that moral bioenhancement threatens human freedom or undermines its value. In this brief commentary, I take issue with DeGrazia's way of defining MB. A different concept of MB exposes a danger missed by his analysis.Two ways to define MBDeGrazia presents MB as a form of enhancement directed at moral capacities. There are, in the philosophical literature, two broad approaches to defining human enhancement. Simplifying somewhat, one account identifies (...) enhancement with improvement. DeGrazia joins other advocates of MB in preferring this type of account, defining a human enhancement as ‘any deliberate intervention that aims to improve an existing capacity, select for a desired capacity, or create a new capacity in a human being.’1An alternative approach relativises enhancement to human norms.2 ,3 In this view, improvements up to levels of functioning properly considered normal for humans are therapy, not enhancement. Improvements beyond those levels are enhancements. The injection of synthetic erythropoietin by someone suffering from anaemia is therapy. When healthy Tour de France competitors inject EPO, it is enhancement.We can minimise philosophical disputes about word meanings by endorsing a conceptual pluralism that acknowledges the need for more than one concept of human enhancement to address the hugely varied ways in which technology may alter humans. In the debate about biomedical moral improvements there would be enhancement as improvement and enhancement beyond human norms.DeGrazia effectively deploys the concept of enhancement as improvement to …. (shrink)

This paper will review the strategies and learning trajectories followed to tap the opportunities opened by the successive waves of biotechnologies: early imitators followed by late imitators in the first generation of biosimilars (erythropoietin, insulins, interferons), and then sequential entry and skipping stages during the second generation (monoclonal antibodies).

The formation of the World Anti-Doping Agency in 1999 was spurred by the 1998 revelation of widespread use in professional cycling of erythropoietin. The drug was supposedly a real danger. The long-term consequences were unknown, but rumor said it made athletes’ blood thick as jam with clots and other circulatory fatalities likely consequences. Today the fear of EPO has dampened. However, new scientific avenues such as ‘neuro-doping’ have replaced EPO as emergent and imagined threats to athletes and to the (...) integrity of sport. In this paper, we analyze the alleged threat from ‘neuro-doping’ in the following steps: First, we outline an understanding of ‘neuro-doping’ in a narrow sense, which we then put into context by looking at the phenomenon in a broader sense. Second, we highlight examples of societal perceptions of sport and science in order to shed light on where the concern for ‘neuro-doping’ comes from. Third, we address the more general fear of technology as a root for this concern. Fourth, we examine the evidence for the performance enhancing capacities of ‘neuro-doping’, where after we look at the obstacles for a ban on this technology. We conclude the analysis by stating that at present ‘neuro-doping’ cannot be considered a threat to the integrity of sport. Finally, however, we put this conclusion into perspective by examining what the most reasonable response would be if in the future neuro-stimulation techniques becomes an effective performance-enhancing mean in sport. (shrink)

To resort to hypoxic air machines—would that be to cheat? This clearly depends on whether such machines are prohibited or not. So the important question is this: Should sport authorities prohibit them or not?One way of approaching this question may be to argue casuistically. Erythropoietin is prohibited. Blood doping is prohibited. Training at high altitude is allowed. Does the hypoxic air machine bear more resemblance to training at high altitude than to the use of EPO? If that is the (...) case it should not be prohibited. If, on the other hand, it bears more resemblance to the use of EPO, then it should be prohibited.However, to argue casuistically is not entirely satisfactory. Even if, through such reasoning, we reach an answer, we do not obtain a principled explanation of the answer. We may get a hint at what to do , but not at why we should do so.1 So the question need to be posed at a more principled level: If rules against doping in sport are to be …. (shrink)

Included in the acute response of lowlanders exposed to reduced oxygen availability is an elevated red blood cell count due to increased erythropoietin (Epo) synthesis. According to current thinking, hypoxia is “sensed” by hydroxylases that permit Hypoxia Inducible Factor 1α (HIF‐1α) to complex with HIF‐1β to form a transcriptional activator (HIF‐1) that drives expression of hypoxia‐sensitive genes (such as EPO) under hypoxic conditions. In altitude‐adapted Andean natives, the Epo hypoxic response may be blunted; however, our data indicate that the (...) DNA sequences of the genes encoding Epo (including the 3′ regulatory region) and HIF‐1α appear to be conserved. Hence, adaptive changes in the Andean hypoxic response are not a consequence of changes in the primary sequence of these proteins or of known transcriptional regulatory domains of EPO. These results suggest that the altered erthropoietic response in Andean natives reflects adaptations in hypoxia sensing, rather than hypoxia response, mechanisms. BioEssays 25:515–519, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

This paper shows how critical realism can be used to integrate empirical data and philosophical analysis within ‘empirical bioethics’. The term empirical bioethics, whilst appearing oxymoronic, simply refers to an interdisciplinary approach to the resolution of practical ethical issues within the biological and life sciences, integrating social scientific, empirical data with philosophical analysis. It seeks to achieve a balanced form of ethical deliberation that is both logically rigorous and sensitive to context, to generate normative conclusions that are practically applicable to (...) the problem, challenge, or dilemma. Since it incorporates both philosophical and social scientific components, empirical bioethics is a field that is consistent with the use of critical realism as a research methodology. The integration of philosophical and social scientific approaches to ethics has been beset with difficulties, not least because of the irreducibly normative, rather than descriptive, nature of ethical analysis and the contested relation between fact and value. However, given that facts about states of affairs inform potential courses of action and their consequences, there is a need to overcome these difficulties and successfully integrate data with theory. Previous approaches have been formulated to overcome obstacles in combining philosophical and social scientific perspectives in bioethical analysis; however each has shortcomings. As a mature interdisciplinary approach critical realism is well suited to empirical bioethics, although it has hitherto not been widely used. Here I show how it can be applied to this kind of research and explain how it represents an improvement on previous approaches. (shrink)

The current ban on certain performance enhancing substances in sport such as erythropoietin faces a line-drawing problem: what is the moral difference between taking an EPO injection to incre...

Johanna Knapstein,1 Daniel Grimm,1 Marcus A Wörns,1 Peter R Galle,1 Hauke Lang,2 Tim Zimmermann111st Department of Internal Medicine, Johannes Gutenberg-University, Mainz, Germany; 2Department of General, Visceral and Transplantation Surgery, Johannes Gutenberg-University, Mainz, GermanyIntroduction: Hepatitis C virus reinfection occurs universally after liver transplantation, with accelerated cirrhosis rates of up to 30% within 5 years after liver transplantation. Dual antiviral therapy with pegylated interferon-2a and ribavirin only reaches sustained virological response rates of ~30% after liver transplantation. With the approval of viral NS3/4A (...) protease inhibitors telaprevir, boceprevir, and simeprevir and the NS5B polymerase inhibitor sofosbuvir, combination therapy offers new therapeutic options for HCV-infected patients, resulting in considerably higher sustained virological response rates in the nontransplant setting. Case presentation: We report three cases of TVR-based triple antiviral therapy in HCV genotype 1 reinfected patients after liver transplantation, of whom a 57-year-old Caucasian female and a 43-year-old Caucasian male were therapy naïve, and a 49-year-old Caucasian male patient was pretreated ineffectively. After 4 weeks of therapy, viral load decreased one to three log10 and became negative in weeks 6 to 8 in the therapy naïve patients. The pretreated patient showed a negative viral load in week 4. TVR was administered over 12 weeks, 750 mg thrice daily. Doses of immunosuppression with cyclosporine were reduced four to six fold. Initial peg-IFN and RBV doses ranged from 135–180 µg/week and 800–1,200 mg/day, according to the patient's body weight. Doses of peg-IFN and RBV were adapted to 90–135 µg/week and 400–800 mg/day after 2 to 12 weeks of protease inhibitor therapy. Dual therapy was continued for 36 weeks with total treatment duration of 48 weeks in the therapy naïve patients leading to a sustained virological response 12 weeks after the end of therapy. In the pretreated patient a breakthrough was detected in week 24 and therapy was discontinued. Overall, antiviral therapy was well tolerated. Side effects included dysgeusia and anemia leading to erythropoietin application and blood transfusions. Conclusion: This case series emphasizes that triple therapy with TVR is an efficient treatment for therapy naïve HCV genotype 1 reinfected patients after liver transplantation. But therapeutic options for pretreated patients require improvement. Keyword: cyclosporine, interferon, ribavirin, hepatitis C, protease inhibitor. (shrink)

Los métodos productivos de enseñanza preparan a los estudiantes para resolver problemas semejantes a los que se enfrentarán en el ejercicio laboral. Este trabajo tiene como objetivo fundamentar la pertinencia de la utilización del caso clínico como herramienta didáctica para la enseñanza en las ciencias básicas biomédicas, mediante un sistema de tareas para abordar los contenidos del tema Fisiología de la sangre de la asignatura Sangre y Sistema Inmune de la carrera de medicina. El caso clínico permite la vinculación de (...) las ciencias básicas biomédicas con las ciencias clínicas. Su utilización contribuye a la aproximación del estudiante de las ciencias básicas al estudio de estas durante su formación médica. El aprendizaje se logra a lo largo del proceso de resolución del mismo, se estimula la incorporación de conceptos necesarios para resolver el problema y se aprende un método para abordar situaciones en la práctica. Se elaboró un sistema de tareas y preguntas derivadas del problema profesional síndrome anémico. El problema docente se basó en un artículo médico que expone un caso de lesiones por empalamiento que produjo un gran sangramiento en un individuo. Se elaboraron preguntas problémicas relacionadas con la fisiología de la sangre y el tratamiento que recibió el paciente con eritropoyetina, factores de la coagulación y soluciones cristaloides en sustitución de la sangre. Se incluyó una pregunta que aborda un conflicto ético para sistematizar los conocimientos adquiridos en la asignatura Sociedad y Salud II. Productive teaching methods train students to solve problems similar to those they will face in their work life. The objective of the paper is to argue pertinence in the use of the clinical case as a didactic tool in biomedical basic sciences teaching by means of a task system that deals with the contents of the Blood Physiology subject in the Blood and Immune System subject matter of the medicine degree. Clinical cases enable the link between biomedical basic sciences and clinical sciences. Their use contributes to basic sciences students' approach to the study of the latter during their medical training. Learning is achieved through its solving process; the introduction of necessary problem-solving concepts is encouraged and a method to deal with in-practice situations is learned. A task and questions system derived from the anemic syndrome professional problem was made. The teaching problem was based on a medical article which presents a case of an individual who suffered impaling injuries which caused a great bleeding. Problem questions related to blood physiology and to the erythropoietin-based treatment the patient received, coagulation factors and crystalloid fluids used as blood substitutes, were prepared. It was included a question that deals with an ethical conflict in order to systematize the knowledge acquired in the Society and Health II subject matter. (shrink)

Consider four elite female runners who trained hard for a 1500‐meter race. Runner 1 took extra‐strength aspirin before the race. Runner 2 has a genetic condition that results in greater levels of testosterone in her body than the typical range for a woman. Runner 3 has been on a carefully scheduled regimen of the hormone erythropoietin (EPO), which has increased her red blood cell count. Runner 4 has a team of diet, sleep, and exercise experts who ensured that she (...) coordinated the exactly right balance of carbs and protein with her rest and workouts. Which of them cheated? Thomas Murray's Good Sport: Why Our Games Matter—and How Doping Undermines Them does not answer this question, but it provides tools to figure it out, and it argues that trying to answer is important. (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)