Human severe combined immune deficiency (SCID) is the most serious inherited immunological deficit. Recent work has revealed defects in the predominant pathway for double‐strand break repair called nonhomologous DNA end joining, or NHEJ. Progress in the biochemistry and genetics of NHEJ and of human SCID has proven to be synergistic between these two fields in a manner that covers the range from biochemical etiology to considerations about possible gene therapy for the B− SCID patients. BioEssays 25:1061–1070, (...) 2003. © 2003 Wiley Periodicals, Inc. (shrink)

In response to adverse events in retroviral gene therapy clinical trials conducted in France to correct for X-linked severe combined immune deficiency disorder (X-SCID), an advisory committee of the Food and Drug Administration convened in October 2002, February 2003, and March 2005, to deliberate and provide recommendations for similarly sponsored research in the United States. A similar National Institutes of Health committee met in February 2003. In this article, I review the transcripts and/or minutes of these (...) meetings to evaluate the extent to which the ethical dimension of the research was engaged even as the molecular and clinical evidence was reviewed. I then provide representative ethical arguments to demonstrate the sort of ethical reasoning that should be included as part of the agenda of such committee meetings. (shrink)

Relatively little has been written about the ethics of conducting early phase clinical trials involving subjects from the developing world. Below, I analyze ethical issues surrounding one of gene transfer’s most widely praised studies conducted to date: in this study, Italian investigators recruited two subjects from the developing world who were ineligible for standard of care because of economic considerations. Though the study seems to have rendered a cure in these two subjects, it does not appear to have complied with (...) various international guidelines that require that clinical trials conducted in the developing world be responsive to their populations’ health needs. Nevertheless, policies devised to address large scale, late stage trials, such as the AZT short‐course placebo trials, map somewhat awkwardly to early phase studies. I argue that interest in conducting translational research in the developing world, particularly in the context of hemophilia trials, should motivate more rigorous ethical thinking around clinical trials involving economically disadvantaged populations. (shrink)

ABSTRACTRelatively little has been written about the ethics of conducting early phase clinical trials involving subjects from the developing world. Below, I analyze ethical issues surrounding one of gene transfer’s most widely praised studies conducted to date: in this study, Italian investigators recruited two subjects from the developing world who were ineligible for standard of care because of economic considerations. Though the study seems to have rendered a cure in these two subjects, it does not appear to have complied with (...) various international guidelines that require that clinical trials conducted in the developing world be responsive to their populations’ health needs. Nevertheless, policies devised to address large scale, late stage trials, such as the AZT short‐course placebo trials, map somewhat awkwardly to early phase studies. I argue that interest in conducting translational research in the developing world, particularly in the context of hemophilia trials, should motivate more rigorous ethical thinking around clinical trials involving economically disadvantaged populations. (shrink)

A pathogenic connection between autoreactive T cells, fungal infection, and carcinogenesis has been demonstrated in studies of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy as well as in a mouse model in which kinase-dead Ikkα knock-in mice develop impaired central tolerance, autoreactive T cell–mediated autoimmunity, chronic fungal infection, and esophageal squamous cell carcinoma, which recapitulates APECED. IκB kinase α is one subunit of the IKK complex required for NF-κB activation. IKK/NF-κB is essential for central tolerance establishment by regulating the development of medullary thymic (...) epithelial cells that facilitate the deletion of autoreactive T cells in the thymus. In this review, we extensively discuss the pathogenic roles of inborn errors in the IKK/NF-κB loci in the phenotypically related diseases APECED, immune deficiency syndrome, and severe combined immunodeficiency; differentiate how IKK/NF-κB components, through mTEC, T cells/leukocytes, or epithelial cells, contribute to the pathogenesis of infectious diseases, autoimmunity, and cancer; and highlight the medical significance of IKK/NF-κB in these diseases. IKK/NF-κB regulates the expression of many genes that encode proteins involved in many crucial biological functions, such as immunity, tissue homeostasis, and fungal/bacterial/viral infections. Also, IKKα plays anti-tumor activities in many organs independently of NF-κB pathways. Thus, an inborn error in one of these gene loci can cause severe human diseases through these complicated mechanisms. (shrink)

Introduction: Congenital myasthenic syndromes refer to a heterogenic group of neuromuscular transmission disorders. CMS-subtypes are diverse regarding exercise intolerance and muscular weakness, varying from mild symptoms to life-limiting forms with neonatal onset. Long-term follow-up studies on disease progression and treatment-response in pediatric patients are rare.Patients and Methods: We analyzed retrospective clinical and medication data in a cohort of 32 CMS-patients including the application of a standardized, not yet validated test to examine muscular strength and endurance in 21 patients at the (...) last follow-up. Findings obtained in our cohort were compared with long-term follow-up studies of CMS-cohorts from the literature by considering the underlying molecular mechanisms. Outcomes of CMS-ST were compared to results of normal clinical assessment.Results: Thirty-two pediatric patients with defects in eight different CMS-genes were followed by a median time of 12.8 years. Fifty-nine percentage of patients manifested with first symptoms as neonates, 35% as infants. While 53% of patients presented a reduced walking distance, 34% were wheelchair-bound. Even under adequate therapy with pyridostigmine and 3,4-diaminopyridine, CHAT-mutations led to the progression of muscular weakness partly in combination with persistent respiratory and bulbar symptoms. RAPSN, CHRND, and CHRNB1 patients with neonatal manifestation, early respiratory problems, and bulbar symptoms showed a good and maintained treatment response. CHAT and CHRNE patients required higher PS dosages, whereas RAPSN patients needed a lower mean dosage at the last follow-up. The benefits of short-term medication and long-term progression of symptoms were highly dependent on the specific genetic defect. CMS-ST was carried out in 17/21 patients, determined affected muscle groups including bulbar and ocular symptoms, some of which were not reported by the patients.Conclusions: Our findings and comparison with the literature- suggest a better treatment-response and less severe progression of symptoms present in patients suffering from mutations in CMS-genes directly associated with receptor deficiency, while patients with defects leading to synaptopathy and presynaptic defects tend to have worse outcomes. Assessment of affected muscular groups and clinical symptoms by CMS-ST may be a useful tool for optimal therapeutic management of the patients, especially for future clinical studies. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Human Gene TherapyMary Carrington Coutts (bio)On September 14, 1990, researchers at the U.S. National Institutes of Health (NIH) performed the first approved gene therapy procedure on a four-year-old girl named Ashanti DeSilva. Born with a rare genetic disease, severe combined immune deficiency (SCID), Ashanti lacked a healthy immune system and was extremely vulnerable to infection. Children with SCID usually develop overwhelming infections and rarely (...) survive to adulthood; even a common childhood illness like chicken pox is life-threatening. Ashanti led a cloistered existence, avoiding contact with people outside her family, remaining in the sterile environment of her home, and battling frequent illnesses with massive amounts of antibiotics.In Ashanti's gene therapy procedure, her own white blood cells were genetically modified and then infused back into her bloodstream. Laboratory tests show that the therapy has strengthened Ashanti's immune system. She no longer has recurrent colds, has been allowed to attend school, and has been immunized against whooping cough. This gene therapy procedure is not a cure, however. The genetically-treated white blood cells only survive for a few months and must then be replaced, but Ashanti's future is much brighter because of the new therapy (VI, Thompson [The First] 1993).Although this simplified description of Ashanti's gene therapy procedure sounds like a happy ending, it is little more than an optimistic chapter in a long story. The road to the first approved gene therapy procedure was rocky and fraught with controversy. The biology of human gene therapy is very complex, and there are still many techniques that need to be developed and diseases that need to be understood more fully before gene therapy is well established. The public policy debate surrounding the possible use of genetically engineered material in human subjects is equally complex. Major participants in the debate come from the fields of biology, government, law, medicine, philosophy, politics, and religion, each bringing different views to the discussion.In studying the ethics of gene therapy, one should draw a distinction between [End Page 63] therapy on somatic (non-reproductive) cells and germ (reproductive) cells. Only the germ cells carry the genes that will be passed on to the next generation. Reactions to gene therapy have varied widely. Some commentators on gene therapy object to any form of genetic manipulation, no matter how well-intentioned (VI, Rifkin 1983). Another reaction is to allow the use of somatic-cell therapy, but not to approve the use of germ-line therapy, which could have unforeseeable effects on future generations. A different stance is that, with proper regulation and safeguards, germ-line gene therapy is a logical extension of the progress made to date and that it is an ethically acceptable procedure.TechniquesTo date, 43 research protocols have been approved for somatic-cell gene therapy in the United States. The techniques employed in each protocol vary, but in general a virus is used as a "vector" to insert the desired gene into the DNA of the patient's cells, in order to compensate for a defective gene. For Ashanti's gene therapy, this technique involved obtaining white blood cells and introducing properly functioning genes into as many of the cells as possible. The normal genes were delivered through the use of a specially-engineered virus.Although similar techniques are used in germ-line gene therapy, the procedure is more difficult. There are two basic ways to perform germ-line gene therapy: (1) to treat a preimplantation embryo that carries a serious genetic defect before its implantation in the mother, which necessitates the use of in vitro fertilization techniques; or (2) to treat the germ cells (sperm or egg cells) of afflicted adults so that the genetic defects would not be passed on to their offspring, which requires the technical expertise to delete the defective gene and insert a properly functioning replacement. Because of the complexity of the procedures involved and the attendant ethical controversy, germ-line therapy is not currently performed.Candidate Diseases for Gene TherapyAt present, gene therapy is likely to be most successful in treating diseases that are caused by single-gene defects and has been approved for treating diseases such... (shrink)

The HIV/AIDS epidemic in Haiti has often been referred to as a “mystery,” and “striking similarities” between patterns of disease in Haiti and in sub-Saharan Africa are often underlined. The occurrence of AIDS in Haitians has also led to the postulation of a number of theories positing a Haitian origin for AIDS and linking the syndrome in Haitians to voodoo. A review of the epidemiological data gathered and published in the early years of the pandemic suggests that these “exotic” (...) theories are not necessary to explain the Haitian epidemic, which is clearly linked not to Africa but to the United States. Patterns of risk identified among many of the first Haitians with AIDS are similar to risk factors identified in North America and Europe (same-sex contact with an HIV-infected individual and blood transfusion). The Haitian epidemicsubsequently came to resemble patterns seen in sub-Saharan Africa, where AIDS is predominantly a heterosexually transmitted disease. Similarly shifting patterns are described for several other Caribbean nations, underlining the importance of a historical analysis of the Caribbean pandemic as well as the necessity to link analysis of local epidemiology of AIDS/HIV to larger considerations of political economy. (shrink)

Current research into the molecular biology of blood‐clotting factors suggests that the basis of inherited bleeding disorders may soon be understood. In addition, the expression of cloned genes for the factors in mammalian cell lines provides the hope of pure factors being available for replacement therapy, uncontaminated with the causative agents for Hepatitis and Acquired Immune Deficiency Syndrome (AIDS), identified in the blood products at present available. The recent findings on the molecular biology of several of the (...) key blood clotting genes are described here. (shrink)

Theories of distributive justice are often criticised for either excluding people with disabilities from the domain of justice altogether, or casting them as deficient in personal attributes. I argue that the capabilities approach to justice is largely immune to these flaws. It has the conceptual resources to locate most of the causes of disadvantage in the interaction between a person and her environment and in doing so can characterise the disadvantages of disability in a way that avoids the imputation (...) of natural deficiency. However, I also argue that the capabilities approach cannot accommodate some of the stronger claims advanced by some disability scholars. No plausible capabilities approach can guarantee that social change will always be the just or fair remedy for disadvantage, and there is a small number of severe cases of disability where capability shortfalls will be attributed to the person’s ‘deficient’ physical and mental impairments. (shrink)

Some embodied theories of concepts state that concepts are represented in a sensorimotor manner, typically via simulation in sensorimotor cortices. Fred Adams (2010) has advanced an empirical argument against embodied concepts reasoning as follows. If concepts are embodied, then patients with certain sensorimotor impairments should perform worse on categorization tasks involving those concepts. Adams cites a study with Moebius Syndrome patients that shows typical categorization performance in face-based emotion recognition. Adams concludes that their typical performance shows that embodiment is (...) false. Moebius patients must draw on amodal (non-embodied) emotion concepts. In this paper, I review face-based emotion recognition studies with Moebius patients yielding conflicting results and diagnose these conflicts as a difference in experimental design. When emotion labels are provided, patients have typical performance, but when labels are not provided patients are severely deficient. I then show how an embodied, psychological constructionist view of emotions predicts and explains these performance differences. The upshot is that embodied theories of concepts are vindicated. (shrink)

Acquired Immune Deficiency Syndrome (AIDS) is an emotive subject, particularly in southern Africa. Among those who have been directly affected by the disease, or who perceive themselves to be personally at risk, talking about AIDS inevitably arouses strong emotions - amongst them fear, distress, loss and anger. Conventionally, human geography research has avoided engagement with such emotions. Although the ideal of the detached observer has been roundly critiqued, the emphasis in methodological literature on 'doing no harm' has (...) led even qualitative researchers to avoid difficult emotional encounters. Nonetheless, research is inevitably shaped by emotions, not least those of the researchers themselves. In this paper, we examine the role of emotions in the research process through our experiences of researching the lives of young AIDS migrants in Malawi and Lesotho. We explore how the context of the research gave rise to the production of particular emotions, and how, in response, we shaped the research, presenting a research agenda focused more on migration than AIDS. This example reveals a tension between universalised ethics expressed through ethical research guidelines that demand informed consent, and ethics of care, sensitive to emotional context. It also demonstrates how dualistic distinctions between reason and emotion, justice and care, global and local are unhelpful in interpreting the ethics of research practice. (shrink)

The emergent Coronavirus Disease 2019 caused by the Severe Acute Respiratory Syndrome Coronavirus 2 could produce a maternal immune activation via the inflammatory response during gestation that may impair fetal neurodevelopment and lead to postnatal and adulthood mental illness and behavioral dysfunctions. However, so far, limited evidence exists regarding long-term physiological, immunological, and neurodevelopmental modifications produced by the SARS-CoV-2 in the human maternal-fetal binomial and, particularly, in the offspring. Relevant findings derived from epidemiological and preclinical models show (...) that a MIA is indeed linked to an increased risk of neurodevelopmental disorders in the offspring. We hypothesize that a gestational infection triggered by SARS-CoV-2 increases the risks leading to neurodevelopmental disorders of the newborn, which can affect childhood and the long-term quality of life. In particular, disruption of either the maternal or the fetal cholinergic anti-inflammatory pathway could cause or exacerbate the severity of COVID-19 in the maternal-fetal binomial. From a translational perspective, in this paper, we discuss the possible manifestation of a MIA by SARS-CoV-2 and the subsequent neurodevelopmental disorders considering the role of the fetal-maternal cytokine cross-talk and the CAP. Specifically, we highlight the urgent need of preclinical studies as well as multicenter and international databanks of maternal-fetal psychophysiological data obtained pre-, during, and post-infection by SARS-CoV-2 from pregnant women and their offspring. (shrink)

Many functional glycoproteins are expressed on the lymphocyte cell surface. Some of them carry O-linked oligosaccharides (O-glycans), which are conjugated through serine or threonine residues. During various biological processes, including T-cell activation, a tetrasaccharide on the T-cell surface is dramatically converted to a branched hexasaccharide, called core2 O-glycan. The same structural change in O-glycans is also found on the lymphocytes from patients with immunodeficiency conditions such as Wiskott-Aldrich syndrome and AIDS. Several studies revealing the roles of core2 O-glycans in (...) immune responses show that this is a biologically significant change. In particular, core2 O-glycans expressed on the cell surface reduce cell–cell interactions, thereby regulating immune responses. Furthermore, core2 O-glycan is a key backbone structure in forming selectin ligands. Thus, O-linked oligosaccharides, in particular those containing core2 branches, play vital roles in immune responses and may play dual roles in certain situations. This review will summarize the results obtained from various studies investigating the roles of O-glycans in immunological processes. BioEssays 23:46–53, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Many functional glycoproteins are expressed on the lymphocyte cell surface. Some of them carry O-linked oligosaccharides (O-glycans), which are conjugated through serine or threonine residues. During various biological processes, including T-cell activation, a tetrasaccharide on the T-cell surface is dramatically converted to a branched hexasaccharide, called core2 O-glycan. The same structural change in O-glycans is also found on the lymphocytes from patients with immunodeficiency conditions such as Wiskott-Aldrich syndrome and AIDS. Several studies revealing the roles of core2 O-glycans in (...) immune responses show that this is a biologically significant change. In particular, core2 O-glycans expressed on the cell surface reduce cell–cell interactions, thereby regulating immune responses. Furthermore, core2 O-glycan is a key backbone structure in forming selectin ligands. Thus, O-linked oligosaccharides, in particular those containing core2 branches, play vital roles in immune responses and may play dual roles in certain situations. This review will summarize the results obtained from various studies investigating the roles of O-glycans in immunological processes. BioEssays 23:46–53, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Two essential periods may be identified in the early stages of the history of vitamin D-resistant rickets. The first was the period during which a very well known deficiency disease, rickets, acquired a scientific status: this required the development of unifying principles to confer upon the newly developing science of pathology a doctrine without which it would have been condemned to remain a collection of unrelated facts with very little practical application. One first such unifying principle was provided by (...) the notion of hygiene; while the blanket explanations provided by this notion alone were much too general to enable rickets to achieve scientific status, it did point out the need to look for specific external causes for the disease and to examine the life-style and dietary habits of the patients. The second phase of the conceptualization of the disease was the assumption of a specific cause — that is, using concepts developed in the area of infectious diseases. This was made possible by fundamental similarities between deficiency and infectious diseases, in spite of their apparent differences. Both types of illness have some of the characteristics of what Georges Canguilhem calls the ontological representation of disease as opposed to dysharmonic representations, which primarily concern the endocrine diseases. It is precisely this shift from one to the other manner of perceiving ill health that enabled the identification of the vitamin D-resistant rickets. Conceptualization of the notion of vitamin D resistancy required that the conditions causing the disease be looked for within the organism rather than outside it; this was thus the first time that endocrine concepts were applied to studying the physiology of vitamin D.The history of resistant rickets therefore represents an interesting model for understanding the growth of biomedical knowledge. It allows the development of a number of more general ideas on the question of the relationship between biology and medicine and on the thorny problem of specificity in medical thinking. As far as this topic is concerned it can be seen that there was an ongoing exchange between medical and biological thinking during the initial period up until 1937, and that one could deny any such specificity in medical thinking during this same period. Albright, for example, used human diseases as spontaneously produced models for experimental biology. It was also more feasible for an experimental biologist to administer toxic doses than for a clinician to do so.What, then, if any, is the place of the specificity of medical thinking in this history? The fact that medicine is characterized not only by it ccognitive content78 but also by its final aim, which is to restore health, makes it necessary to take factors other than objective knowledge into consideration. This is particularly evident in two aspects of medicine, therapeutics and nosology, and in approaching the notion of pathological individuality.Therapeutic activity has a largely empirical approach. Many drugs, such as cod-liver oil, were discovered empirically. Treatment often in the past, and still now, has proceeded by trial and error, upon no established theoretical basis. At this level the relationship between biology and medicine is roughly comparable to that between science and technology79 \3- that is, it is impossible to reduce either therapeutics or technical activities to the simple application of basic science. In this sense, the application of vitamin D to vitamin-resistant rickets is quite typical. Further-more, in the case studied here, the therapeutic activity heralds a definite breaking away from the medicatrix naturae of conventional medicine dating back to ancient times, and it embodies a new concept of the organism and of disease: no longer can the diseased organism be thought of as merely having a perturbed equilibrium requiring restoration by means of a natural style of medicine. On the contrary, vitamin D resistance is an obstacle that indicates profound biological dysfunction, to be rectified only by means of an extremely aggressive and therefore dangerous therapy. The therapy thus serves to reveal the severity of the dysfunction, thereby leading inevitably to conceptual innovation. This sheds light on the theoretical innovations of which the therapeutic activity is capable.Therapeutic activity is also influenced by notions of health and illness, normal and pathological states, none of which may be determined entirely objectively. For example, the term healing as used by Albright in the case of resistant rickets that he described may be discussed in this light.Nosology, or the classification of diseases, depends largely on the description of clinical syndromes, which are themselves mainly based on subjective elements (discomfort, disability, or the extent of a patient's suffering). The advent of pathological anatomy at the beginning of the nineteenth century disrupted classification by introducing the concept of localized anatomical lesions81-and, hence, an element of material objectivity \3- into nosology. Radiological examination further complicated matters by enabling the equivalent of an autopsy on living matter. Lastly, biological examination complicated nosology by showing that biological anomalies may exist in human beings without necessarily leading to a pathological condition. Medical thinking can choose to combine all these elements to describe a disease, but can also separate them and retain only a few, or a single one, according to requirements - as did Albright.The notion of biological and pathological individuality is fundamental to the development of medical thinking. Whatever its theoretical origin, medical thinking has since ancient times incorporated the idea that each individual reacts differently to the same treatment and his own specific pathological tendencies. I mentioned earlier that in the history of vitamin D-resistant rickets the notion of rachitic tendency reflected this type of thinking. After 1937, this history progressed by successively separating new individual entities, affecting smaller and smaller groups of individuals in each case. In other words, the need to understand and to define individual illness more closely required the development of new concepts and the construction of new individual categories of disease linking these concepts to older clinical, radiological, and biochemical elements. (shrink)

AIDS is a debilitating and fatal disease that was first identified as an infectious disease syndrome in the 1970s. The discovery of a nearly universally fatal infectious and rapidly spreading disease in the post–antibiotics era created apprehension in the medical community and alarm in the general population. Questions about how patients should be handled in medical and nonmedical settings resulted in the ostracizing of many AIDS patients and inappropriate patient management. Scientific investigation into modes of disease transmission and control (...) helped to shape the management of AIDS patient care in such a way that ethical and protective practices could be developed. In this article I discuss some of the ethical questions that were addressed by appropriate scientific inquiry. (shrink)

This article focuses on the ways that sexual risk behaviors are related to race, class, and gender among low-income, culturally diverse women in South Florida. Data concerning sexual risk and gender are presented in terms of race and class variations. Results indicate that, in general, these women have a high degree of knowledge about acquired immune deficiency syndrome, a quite contemporary awareness of women's gendered subordination, and a lack of trust in heterosexual relationships. Attitudes, beliefs, and knowledge, (...) however, are not translated into sexual behaviors with men partners that would reduce their vulnerability to infection with the human immunodeficiency virus. The data indicate that race is a major factor that places women into an underclass position. Consequently, without socioeconomic resources, gendered behaviors have a direct influence on sexual risk. Multivariate analyses indicate that those women who are sex workers are significantly more likely to negotiate safe sex with clients than with main partners. The research not only challenges mainstream thinking about race, class, and gender but also provides overdue information on the vulnerability of women to HIV infection. (shrink)

Despite increased general awareness of suicide in U.S. adult correctional facilities as well as the availability of research and correctional standards that advocate increased attention and services to potentially suicidal inmates, prevention efforts within correctional facilities remain piecemeal and inmate suicide continues to be a serious public health problem. A robotic state of mind excuse, that inmate suicide is not preventable, impedes prevention efforts. In the following discussion, the key ingredients to comprehensive suicide prevention programming are offered to dispel these (...) obstacles.Suicide is a leading cause of death in jails across the United States, with well over 400 inmates taking their lives each year. In some urban jail facilities, deaths related to acquired immune deficiency syndrome slightly outnumber deaths by suicide. The rate of suicide in county jails is estimated to be approximately nine times greater than that of the general population. Overall, most jail suicide victims are young white males who have been arrested for nonviolent offenses and were intoxicated when arrested. (shrink)

Despite increased general awareness of suicide in U.S. adult correctional facilities as well as the availability of research and correctional standards that advocate increased attention and services to potentially suicidal inmates, prevention efforts within correctional facilities remain piecemeal and inmate suicide continues to be a serious public health problem. A robotic state of mind excuse, that inmate suicide is not preventable, impedes prevention efforts. In the following discussion, the key ingredients to comprehensive suicide prevention programming are offered to dispel these (...) obstacles.Suicide is a leading cause of death in jails across the United States, with well over 400 inmates taking their lives each year. In some urban jail facilities, deaths related to acquired immune deficiency syndrome slightly outnumber deaths by suicide. The rate of suicide in county jails is estimated to be approximately nine times greater than that of the general population. Overall, most jail suicide victims are young white males who have been arrested for nonviolent offenses and were intoxicated when arrested. (shrink)

Arthur Ashe's public admission to being a victim of acquired immune deficiency syndrome (AIDS) once again raises the question of media exposure of private facts. This study compares journalist and public responses to questions about how far the media should go, finding differences between the two groups, as the public is more tolerant of information bearing on official duties.

In a White House ceremony on May 16, 1997, President Clinton issued an apology on behalf of the nation for the Tuskegee Syphilis Study, a forty-year research project in which African-American men were deceived and denied treatment in order to document the natural course of syphilis. Reflection on this occasion can give us pause to take pride in the progress made toward more ethical research with humans. The President's apology is perhaps the most public of a number of recent events (...) representing a renewed attention to ethics in research with human participants. Alongside it stand the efforts of treatment activists for people with acquired immune deficiency syndrome and the revelations of the human radiation experiments. In 1995, President Clinton called for the creation of the National Bioethics Advisory Commission, which was charged with a host of projects aimed at investigating the organization and function of the federal system for overseeing human subjects research in the United States, and giving guidance on specific forms of research. (shrink)

In a White House ceremony on May 16, 1997, President Clinton issued an apology on behalf of the nation for the Tuskegee Syphilis Study, a forty-year research project in which African-American men were deceived and denied treatment in order to document the natural course of syphilis. Reflection on this occasion can give us pause to take pride in the progress made toward more ethical research with humans. The President's apology is perhaps the most public of a number of recent events (...) representing a renewed attention to ethics in research with human participants. Alongside it stand the efforts of treatment activists for people with acquired immune deficiency syndrome and the revelations of the human radiation experiments. In 1995, President Clinton called for the creation of the National Bioethics Advisory Commission, which was charged with a host of projects aimed at investigating the organization and function of the federal system for overseeing human subjects research in the United States, and giving guidance on specific forms of research. (shrink)

Brazil has occupied a central role in the access to medicines movement, especially with respect to drugs used to treat those with the human immunodeficiency virus that causes the acquired immune deficiency syndrome. Contrary to previous literature centered on the role of the domestic pharmaceutical industry, politicians seeking electoral gains, and civil society activists, I argue that the state, especially the National AIDS Program, led the struggle in contesting a corporate-driven international intellectual property regime. After reviewing the (...) origins of Brazil’s treatment policies and patent reforms, I trace the actions and relationships between the state, civil society, transnational corporations, and local industry in three instances when Brazilian officials used compulsory licenses to reduce the price of medicines. Coalition-building and “naming and shaming” tactics contributed to Brazil’s success, while changing pharmaceutical capabilities limited more aggressive actions. (shrink)

The rapid spread of the Acquired Immune Deficiency Syndrome (AIDS) and its causative agent, the Human Immunodeficiency Virus (HIV), has posed people with difficult ethical questions. Philosophically, one of the most interesting problems is whether or not there is a right to remain in ignorance about one's own HIV infection.Being informed about a positive HIV test result has caused many people anguish and led some to suicidal thoughts. On these grounds a prima facte right not to know (...) could be constructed. Paternalistic arguments have been put forward to refute the alleged right, but these arguments are invalid, as is shown in the paper.However, by a utilitarian argument it can be shown that the prima facie right to remain in ignorance is overridden by other people's rights not to be infected. With certain qualifications, even a non-voluntary testing programme for HIV is justifiable. (shrink)

The rapid spread of the Acquired Immune Deficiency Syndrome (AIDS) and its causative agent, the Human Immunodeficiency Virus (HIV), has posed people with difficult ethical questions. Philosophically, one of the most interesting problems is whether or not there is a right to remain in ignorance about one's own HIV infection.Being informed about a positive HIV test result has caused many people anguish and led some to suicidal thoughts. On these grounds a prima facte right not to know (...) could be constructed. Paternalistic arguments have been put forward to refute the alleged right, but these arguments are invalid, as is shown in the paper.However, by a utilitarian argument it can be shown that the prima facie right to remain in ignorance is overridden by other people's rights not to be infected. With certain qualifications, even a non-voluntary testing programme for HIV is justifiable. (shrink)

The thymus gland, which plays a key role in the maturation and functioning of the lymphoid system, is implicated in the acquired immune deficiency syndrome (AIDS). The observation that the thymic hormone, thymosin α1, is elevated in individuals at risk for AIDS (as opposed to being depressed in other immunodeficient states) has provided the first direct evidence that the thymus is malfunctioning early in the course of this deadly disease. These observations have been valuable in screening for (...) the syndrome with a rapid radioimmunoassay and in the initiation of the first clinical trials with thymosin in high risk homosexuals and hemophiliacs. If the progressive immune paralysis in AIDS is due to a dying thymus, the early identification of asymptomatic carriers of AIDS or individuals with modest AIDS‐related dysfunction may lead to therapy with thymosin or other thymomimetic agents that can restore immune function and prevent the onset of frank AIDS. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:The National Commission on AIDSDonald S. Goldman (bio) and Jeff Stryker (bio)A decade after the first cases were recognized in the United States, AIDS continues to vex policymakers and fascinate the public. It has been said that AIDS acts as a prism, refracting a spectrum of controversial topics. For bioethicists, these topics include: equity in the allocation of resources for treatment and research; forgoing life-sustaining care and proxy decision (...) making; informed consent in the context of HIV testing and screening; the ethical duties of health care workers to provide care for persons with HIV disease; and competing obligations of health care professionals to patients and to third parties who may be put at risk.The Role of CommissionsIf AIDS is the quintessential case study for bioethicists, it is a potential quagmire for politicians. The association of HIV disease with drug use and sexual behavior makes it a topic that all but the most courageous (or the most homophobic) politicians shy away from. A frequent political response is to form a commission.Alexander Capron, who was executive director of the President's Commission for the Study of Ethical Problems in Medicine, has described some roles commissions play: a watchdog, overseeing the work of particular government agencies; a crucible, providing a means for "publicly hammering out conclusions on controversial issues when consensus, both in the public and in the relevant disciplines, is not yet apparent"; and "a lightning rod for public concern—or viewed less charitably, dumping ground for an issue that is too difficult for the ordinary political process to handle" (Capron 1983, p. 9).Nearly every state has created a gubernatorial-level task force or commission on AIDS. The National Commission on AIDS was established under the Health Omnibus Program Extension (HOPE) Act of 1988, which was signed by President Reagan on November 4, 1988. The official charter of the commission was approved August 2, 1989 and its original two-year term was extended for a third year. The mission statement crafted by the commission to reflect its Congressional mandate reads: [End Page 339]The National Commission on Acquired Immune Deficiency Syndrome is an independent body of 15 members created to advise the President and Congress. The Commission seeks to build a broad public understanding on the magnitude, scope and urgency of the HIV/AIDS epidemic; provide and inspire leadership at all levels of both the public and private sectors; empower individuals and communities; and advocate for effective, cooperative and non-discriminatory resources required for prevention, comprehensive care, and the research necessary to halt the epidemic.As the mission statement implies, the National Commission on AIDS has viewed itself from the outset not only as a crucible for policy analysis, but also as a forum for those affected by HIV disease. In site visits and hearings the commissioners have met with hundreds of people living with HIV disease, and with caregivers on the front lines. This odyssey has taken the commission on visits to homeless shelters in New York City; to "shooting galleries" where intravenous drug users congregate in Seattle; to Native American communities in four states; to private homes in rural Georgia; and to hospitals, HIV antibody testing centers, drug treatment clinics, and hemophilia treatment centers throughout the nation. It quickly became clear during the commission's travels that HIV disease cannot be understood outside the context of the racism, homophobia, poverty and unemployment that provide the medium that fosters its spread. It also became apparent that issues of HIV prevention, care and treatment, and clinical research are inextricably intertwined and must be dealt with as such.Early InitiativesUnder the leadership of Chairperson June Osborn and Vice-chairperson David Rogers, the commission decided that the problems it saw in its first few meetings were too urgent to await a full-length annual report. Hence the commission entered the fray with a series of brief interim reports on particular aspects of AIDS. These reports enabled the commission to draw attention to urgent problems of limitations in access to health care and to underscore the plight of people with HIV disease who might otherwise garner little media attention, such as prisoners and drug users (National Commission... (shrink)

Application of evolutionary principles to epidemiological problems indicates that cultural characteristics influence the evolution of parasite virulence by influencing the success of disease transmission from immobilized, infected hosts. This hypothesis is supported by positive correlations between virulence and transmission by biological vectors, water, and institutional attendants. The general evolutionary argument is then applied to the causes and consequences of increased virulence for three diseases: cholera, influenza and AIDS.

In this paper, we apply the perspective of intra-organismal ecology by investigating a family of ecological models suitable to describe a gene therapy to a particular metabolic disorder, the adenosine deaminase deficiency (ADA-SCID). The gene therapy is modeled as the prospective ecological invasion of an organ (here, bone marrow) by genetically modified stem cells, which then operate niche construction in the cellular environment by releasing an enzyme they synthesize. We show that depending on the chosen order (a choice that (...) cannot be made on \textit{a priori} assumptions), different kinds of dynamics are expected, possibly leading to different therapeutic strategies. This drives us to discuss several features of the extension of ecology to intra-organismal ecology. (shrink)

Now widely adopted, SCID newborn screening has proven effective for early identification and treatment of SCID. In addition, screening has improved our understanding of SCID and related disorders, which are more diverse than originally believed. Newborn screening for SCID illustrates how adding new disorders to newborn screening panels can be enormously beneficial if evidence‐based guidelines are adhered to and if mechanisms are in place to track outcomes and learn along the way. These lessons should guide all additions to newborn screening, (...) including those involving sequencing. (shrink)

Eyal et al have recently argued that researchers should consider conducting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human challenge studies to hasten vaccine development. We have conducted (J. L.) and overseen (L. D.) human challenge studies and agree that they can be useful in developing anti-infective agents. We also agree that adults can autonomously choose to undergo risks with no prospect of direct benefit to themselves. However, we disagree that SARS-CoV-2 challenge studies are ethically appropriate at this (...) time, for 3 reasons: (1) current scientific knowledge of SARS-CoV-2 infection is insufficient to manage risks; (2) autonomous decision making, while necessary, does not override concerns about risk; and (3) undertaking challenge studies now would imperil confidence in the research enterprise, potentially undermining the global response to the coronavirus disease 2019 (COVID-19) pandemic. (shrink)

A journal editor recently apologised for publishing a 2010 paper in which authors designated an enzyme as New Delhi metallo-β-lactamase-1 (NDM-1) and its related gene bla_NDM-1 after a city, New Delhi. This name had raised an outcry in India, with health authorities, media and medical practitioners demanding New Delhi be dropped from the name. The name was actually first given in another 2009 paper, whose corresponding author remains the same as the 2010 paper. There is a tradition of eponymous names (...) in science. But those found derogatory to races, groups, cities, and countries have been changed. For example, Mongolism was changed to Down's syndrome; Australia antigen to HBsAg; Mexican Swine flu to H1N1; GRID (Gay Related Immune Deficiency) and 4H-Disease (Haitians, Homosexuals, Haemophiliacs and Heroin Users Disease) to AIDS. It is necessary that NDM-1 also be changed to a name based on scientific characteristics. NDM-1 must be changed to PCM (plasmid-encoding carbapenem-resistant metallo-β-lactamase). It is also necessary to review the tradition of naming organisms, diseases, genes, etc. after cities, countries and races. Often, such names giving amounts to names calling. It needs to be discarded by scientists in all new names giving from now on. Geographical and racial names giving must be replaced by scientific names giving. Journal editors must ensure that such scientific names giving is laid down as standard guideline in paper submissions. All such names still in currency need to be phased out by replacing them with names based on scientific characteristics, or in honour of their pioneering scientist/s or institutions. The lead author of the above 2010 paper has said he was not consulted about the final draft and did not agree with the conclusions of the paper. To ensure that corresponding authors do not ride roughshod over co-authors, and lead and other authors do not backtrack on papers, editors must ensure written concurrence of all authors, especially the lead author, to the final draft of a paper and include this in their guidelines for paper submissions. (shrink)

Ayurveda is the science of living being. With the aim of health and procurement of disease it almost covers all facets of life. It includes health of an individual at physical, mental, spiritual, social level. Ayurvedic classics includes brihatrayee samhita like Charak, Sushruta and Ashtanga Hridaya. A review based study of music (geet, sangeet) was done in these classics to explore whether these classics includes any form of music as therapy or not. Based on review of these classics it was (...) found that music in form of geet (vocal or instrument) has been given in contexts like vajikara(aphrodisiac), vata/pitta prakriti (basic consititutional make up), gandharva sattva, madyapana (intake of alcohol), therapy for rajyakshma (immune deficiency diseases), sanyasa (syncope/coma), jivadan (haemetemesis) etc. various swara have been correlated with their pacifying power of three sharirikadoshas viz. vata, pitta and kapha. Also a relationship between various raga of indian classical music have been said to be based on time of its singing which may be used as a therapy to pacify the dearrangement of prevalent doshas. several articles have shown music as therapy in sleep disorder, psychiatric disorders, schizophrenia, cardiovascular, cancer etc. with this paper a perspective of Ayurveda have been explored in music therapeutics. (shrink)

Drosophila responds to a septic injury by the rapid synthesis of antimicrobial peptides. These molecules are predominantly produced by the fat body, a functional equivalent of mammalian liver, and are secreted into the hemolymph where their concentrations can reach up to 100 μM. Six distinct antibacterial peptides (plus isoforms) and one antifungal peptide have been characterized in Drosophila and their genes cloned. The induction of the gene encoding the antifungal peptide relies on the spätzle/Toll/cactus gene cassette, which is involved in (...) the control of dorsoventral patterning in the embryo, and shows interesting structural and functional similarities with cytokine‐induced activation of NF‐ϰB in mammalian cells. An additional pathway, dependent on the as yet unidentified imd (for immune‐deficiency) gene, is required for the full induction of the antibacterial peptide genes. Mutants deficient for the Toll and imd pathways exhibit a severely reduced survival to fungal and bacterial infections, respectively. Recent data on the molecular mechanisms underlying recognition of non‐self are also discussed in this review. (shrink)

This paper examines the few, but important legal and coronial cases concerning withdrawing or withholding life-sustaining treatment from severely disabled or critically impaired infants in Australia. Although sparse in number, the judgements should influence common clinical practices based on assessment of “best interests” but these have not yet been adopted. In particular, although courts have discounted assessment of “quality of life” as a legitimate component of determination of “best interests,” this remains a prominent component of clinical guidelines. In addition, this (...) paper highlights the lack of uniform clinical guidelines available to medical professionals and parents in Australia when making end-of-life decisions for severely ill infants. Thus, it is argued here that there is a need for an overarching prescriptive uniform framework or set of guidelines in end-of-life decision-making for impaired infants. This would encourage greater transparency, consistency, and some degree of objectivity in an area that often appears subjective. (shrink)

All organisms possess mechanisms to repair double strand breaks (dsbs) generated in their DNA by damaging agents. Site‐specific dsbs are also introduced during V(D)J recombination. Four complementation groups of radiosensitive rodent mutants are defective in the repair of dsbs, and are unable to carry out V(D)J recombination effectively. The immune defect in Severe Combined Immunodeficient (scid) mice also results from an inability to undergo effective V(D)J recombination, and scid cell lines display a repair defect and belong to (...) one of these complementation groups. These findings indicate a mechanistic overlap between the processes of DNA repair and V(D)J recombination. Recently, two of the genes defined by these complementation groups have been identified and shown to encode components of DNA‐dependent protein kinase (DNA‐PK). We review here the three fields which have become linked by these findings, and discuss the involvement of DNA‐PK in dsb rejoining and in V(D)J recombination. (shrink)

Psychological stress reactions to the COVID-19 pandemic are complex and multifaceted. Research provides evidence of a COVID Stress Syndrome, consisting of worry about the dangerousness of getting infected with SARSCoV2 and coming into contact with infected surfaces, worry concerning the personal socioeconomic consequences of COVID-19, xenophobic fears that SARSCOV2 is being spread by foreigners, COVID-19-related traumatic stress symptoms, and compulsive checking and reassurance-seeking about COVID-19. Little is known about how these symptoms are related to vulnerability and protective personality factors. (...) Based on data from 1,976 US and Canadian adults, we conducted a prospective network analysis in which personality factors were initially assessed at Time 1 and then symptoms of the CSS were assessed at Time 2, 2.5 months later. Results indicated that trait optimism and trait resilience were negatively associated with negative emotionality, suggesting a modulatory influence. Negative emotionality was positively linked to the narrower traits of intolerance of uncertainty and health anxiety proneness. These narrower traits, in turn, were prospectively linked to symptoms of the CSS. Results suggest that the effects of broad personality traits on symptoms of the CSS were mediated by narrower traits such as the intolerance of uncertainty. Treatment implications are discussed. (shrink)

Several philosophers have argued recently that semantic properties do play a causal role. 1 It is our view that none of these arguments are satisfactory. Our aim is to reveal some of the deficiencies of these arguments, and to reassess the question in our own way. In section 1, we shall explain in more detail what is involved in the pretheoretical idea of a causally efficacious property and so provide a fuller sense of the issue. In section 2 we shall (...) discuss Fodor's and Kim's arguments that the semantic properties of mental events are causally efficacious. Their tactic is to articulate sufficient conditions for the causal efficacy of a property, and then apply these conditions to the psychological properties under consideration. We shall show that both formulations are inadequate. However, each account can remedy some of the defects of the other. We shall argue that by putting the two together, and modifying this combined account in certain ways, we can arrive at something that might just pass as a general sufficient condition for causal efficacy. We believe that the question of causal efficacy of content is best approached as a question in the philosophy of science. If one wants to know whether a given species of property is efficacious, the most productive strategy is to find a science that investigates the properties and examine the role they are assigned. In keeping with this attitude we shall restrict our discussion to the notion of content deployed within cognitive science. In section 3 we examine the role of content in cognitive science and discuss whether this role suits content to the conditions on efficacy articulated in section two. Our conclusion will be conditional and hedged: on certain views of cognitive science, content will meet the sufficient condition for efficacy. If other views are correct, the question remains open. (shrink)

SARS and monkeypox have given the public health community a unique opportunity to examine the use of quarantine measures. Until recently, the word “quarantine”was not used in polite conversation, and evoked unsavory images. The recent SARS epidemic illustrated the important role of quarantine and isolation as a public health response to communicable disease.As public health officials in Toronto began to take control of the SARS epidemic, a second wave of the disease emerged. In the first SARS epidemic, approximately 8,200 individuals (...) were isolated. There were approximately 82 probable cases, 66 suspect cases, and 24 deaths. On May 22, 2003, SARS II emerged. In total, approximately 13,000 people were quarantined. SARS II saw the onset of difficult questions being asked about the control and spread of SARS.The province of Ontario establishes the public health policies and legislative framework for the entire province. (shrink)