This article focusses upon defining those factors which may contribute to the pathogenesis of cancer. The molecular basis of tumour etiology is discussed with reference to cancer predisposing syndromes, and in particular to the human inherited disease, Bloom's sysdrome. In Bloom's syndrome, patients are predisposed to a wide variety of malignant disease. We propose a model in which overexpression of the ubiquitous c‐myc proto‐oncogene contributes to this process.

Plasminogen activator inhibitor‐1 (PAI‐1) is a physiological inhibitor of urokinase (uPA), a serine protease known to promote cell migration and invasion. Intuitively, increased levels of PAI‐1 should be beneficial in downregulating uPA activity, particularly in cancer. By contrast, in vivo, increased levels of PAI‐1 are associated with a poor prognosis in breast cancer. This phenomenon is termed the “PAI‐1 paradox”. Many factors are responsible for the upregulation of PAI‐1 in the tumor microenvironment. We hypothesize that there is a (...) breast cancer predisposition to a more aggressive stage when PAI‐1 is upregulated as a consequence of Metabolic Syndrome (MetS). MetS exerts a detrimental effect on the breast tumor microenvironment that supports cancer invasion. People with MetS have an increased risk of coronary heart disease, stroke, peripheral vascular disease and hyperinsulinemia. Recently, MetS has also been identified as a risk factor for breast cancer. We hypothesize the existence of the “PAI‐1 cycle”. Sustained by MetS, adipocytokines alter PAI‐1 expression to promote angiogenesis, tumor‐cell migration and procoagulant microparticle formation from endothelial cells, which generates thrombin and further propagates PAI‐1 synthesis. All of these factors culminate in a chemotherapy‐resistant breast tumor microenvironment. The PAI‐1 cycle may partly explain the PAI‐1 paradox. In this hypothesis paper, we will discuss further how MetS upregulates PAI‐1 and how an increased level of PAI‐1 can be linked to a poor prognosis. BioEssays 29:1029–1038, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

As the spread of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) continues to surge worldwide, our knowledge of coronavirus disease 2019 (COVID‐19) is rapidly expanding. Although most COVID‐19 patients recover within weeks of symptom onset, some experience lingering symptoms that last for months (“long COVID‐19”). Early reports of COVID‐19 sequelae, including cardiovascular, pulmonary, and neurological conditions, have raised concerns about the long‐term effects of COVID‐19, especially in hard‐hit communities. It is becoming increasingly evident that cancer patients are more susceptible (...) to SARS‐CoV‐2 infection and are at a higher risk of severe COVID‐19 than the general population. Nevertheless, whether long COVID‐19 increases the risk of cancer in those with no prior malignancies, remains unclear. Given, the disproportionate impact of the disease on the African American community, yet another unanswered question is whether racial disparities are to be expected in COVID‐19 sequelae. Herein, we propose that long COVID‐19 may predispose recovered patients to cancer development and accelerate cancer progression. This hypothesis is based on growing evidence of the ability of SARS‐CoV‐2 to modulate oncogenic pathways, promote chronic low‐grade inflammation, and cause tissue damage. Comprehensive studies are urgently required to elucidate the effects of long COVID‐19 on cancer susceptibility. (shrink)

Résumé Cet article rend compte d’une recherche sur le vécu des couples confrontés au cancer. La qualité de vie du patient et de son entourage devient de plus en plus cruciale au fur et à mesure que s’accroît l’espérance de vie des personnes atteintes. Le couple constitue une entité psychique spécifique qui résulte de la dynamique intersubjective entre conjoints. Cette entité peut être atteinte en cas de maladie grave. L’étude servant d’appui à cet article porte sur l’annonce de la (...) maladie, la période des traitements et la rémission. Il est ainsi mis en évidence que le « syndrome de Lazare » ne concerne pas que la personne malade, mais également le conjoint et que l’homéostasie du couple est perturbée bien au-delà de l’annonce de la rémission. (shrink)

Résumé Cet article rend compte d’une recherche sur le vécu des couples confrontés au cancer. La qualité de vie du patient et de son entourage devient de plus en plus cruciale au fur et à mesure que s’accroît l’espérance de vie des personnes atteintes. Le couple constitue une entité psychique spécifique qui résulte de la dynamique intersubjective entre conjoints. Cette entité peut être atteinte en cas de maladie grave. L’étude servant d’appui à cet article porte sur l’annonce de la (...) maladie, la période des traitements et la rémission. Il est ainsi mis en évidence que le « syndrome de Lazare » ne concerne pas que la personne malade, mais également le conjoint et que l’homéostasie du couple est perturbée bien au-delà de l’annonce de la rémission. (shrink)

Tick bite induced α‐gal syndrome (AGS) following consumption of mammalian meat is a recently described intriguing disease occurring worldwide. Here we argue that AGS and delayed allergy in general is an adaptive defence method against cancer. Our hypothesis synthesizes two lines of supporting evidence. First, allergy has been shown to have direct anti‐cancer effects with unknown mechanism. Second, eating processed meat was shown to be linked to developing cancer. Humans lost their genes encoding molecules α‐gal 30 MYA (...) and Neu5Gc 2 MYA, the latter co‐occurring with the start of using fire. These molecules are acquired from external sources, as tick bite for α‐gal and mammalian meat for Neu5Gc, the latter accumulating in tumors. The resulting specific delayed allergic response is a molecular adaptation to fight cancer. By further testing and applying our hypothesis, new avenues in cancer research and therapy will open that might save lives and decrease human suffering. (shrink)

Mutations in enhancer‐associated chromatin‐modifying components and genomic alterations in non‐coding regions of the genome occur frequently in cancer, and other diseases pointing to the importance of enhancer fidelity to ensure proper tissue homeostasis. In this review, I will use specific examples to discuss how mutations in chromatin‐modifying factors might affect enhancer activity of disease‐relevant genes. I will then consider direct evidence from single nucleotide polymorphisms, small insertions, or deletions but also larger genomic rearrangements such as duplications, deletions, translocations, and (...) inversions of specific enhancers to demonstrate how they have the ability to impact enhancer activity of disease genes including oncogenes and tumor suppressor genes. Considering that the scientific community only fairly recently has begun to focus its attention on “enhancer malfunction” in disease, I propose that multiple new enhancer‐regulated and disease‐relevant processes will be uncovered in the near future that will constitute the mechanistic basis for novel therapeutic avenues. (shrink)

Mutations in enhancer‐associated chromatin‐modifying components and genomic alterations in non‐coding regions of the genome occur frequently in cancer, and other diseases pointing to the importance of enhancer fidelity to ensure proper tissue homeostasis. In this review, I will use specific examples to discuss how mutations in chromatin‐modifying factors might affect enhancer activity of disease‐relevant genes. I will then consider direct evidence from single nucleotide polymorphisms, small insertions, or deletions but also larger genomic rearrangements such as duplications, deletions, translocations, and (...) inversions of specific enhancers to demonstrate how they have the ability to impact enhancer activity of disease genes including oncogenes and tumor suppressor genes. Considering that the scientific community only fairly recently has begun to focus its attention on “enhancer malfunction” in disease, I propose that multiple new enhancer‐regulated and disease‐relevant processes will be uncovered in the near future that will constitute the mechanistic basis for novel therapeutic avenues. (shrink)

The autosomal recessive genetic disorder, Nijmegen Breakage Syndrome, is characterised by an excessively high risk for the development of lymphatic tumours and an extreme sensitivity towards ionising radiation. The most likely explanation for these characteristics, a deficiency in the repair of DNA lesions, has been greatly substantiated by the recent cloning of the gene mutated in Nijmegen Breakage Syndrome patients and the analysis of its protein product, nibrin. The direct involvement of this protein in the processing of DNA double strand (...) breaks caused by ionising radiation and those also necessary for normal DNA metabolism can be correlated with many of the cellular and clinical aspects of the disease, including the cancer predisposition of patients and their heterozygous relatives. BioEssays 21:649–656, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Hereditary breast and ovarian cancers are frequently attributed to germline mutations in the tumor suppressor genes BRCA1 and BRCA2. BRCA1/2 act to repair double‐strand breaks (DSBs) and suppress the demise of unstable replication forks. Our work elucidated a dynamic interplay between BRCA2 and the WRN DNA helicase/exonuclease defective in the premature aging disorder Werner syndrome. WRN and BRCA2 participate in complementary pathways to stabilize replication forks in cancer cells, allowing them to proliferate. Whether the functional overlap of WRN and (...) BRCA2 is relevant to replication at gaps between newly synthesized DNA fragments, protection of telomeres, and/or metabolism of secondary DNA structures remain to be determined. Advances in understanding the mechanisms elicited during replication stress have prompted the community to reconsider avenues for cancer therapy. Insights from studies of PARP or topoisomerase inhibitors provide working models for the investigation of WRN's mechanism of action. We discuss these topics, focusing on the implications of the WRN‐BRCA2 genetic interaction under conditions of replication stress. (shrink)

Despite huge efforts towards understanding the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pathogenesis, little is known about the long‐term consequences of the disease. Here, we critically review existing literature about oncogenesis as a potential long‐term effect of SARS‐CoV‐2 infection. Like other viral infections, SARS‐CoV‐2 may promote cancer onset by inhibiting tumor suppressor genes. We conclude that, although unlikely, such hypothesis cannot be excluded a priori and we delineate an experimental approach to address it. Also see the video abstract (...) here: https://youtu.be/TBUTDSLR7vY. (shrink)

Genetic cancer predisposition testing in the paediatric population poses unique ethical dilemmas. Using the hypothetical example of a teenager with cancer with a high probability of having an underlying cancer predisposition syndrome, we discuss the ethical considerations that affect the decision-making process. Because legally these decisions are made by parents, genetic testing in paediatrics can remove a child’s autonomy to preserve his or her own ‘open future’. However, knowledge of results confirming a predisposition syndrome can potentially be (...) beneficial in modifying treatment and surveillance plans and enabling at-risk family members to obtain cascade testing for themselves. Considering virtue ethics to envision the best characters of the patient, parents and healthcare providers can guide them to the better choice to test or not to test, with the ultimate goal of achieving the best outcome for survival andeudaimonia, human flourishing reliably sought out. (shrink)

Familial clustering of a disease is defined as the occurrence of the disease within some families in excess of what would be expected from the occurrence in the population. It has been demonstrated for several cancer types, ranging from rare cancers as the adenomatosis-coli-associated colon cancer or the Li-Fraumeni syndrome to more common cancers as breast cancer and colon cancer. Familial clustering, however, is merely an epidemiological pattern, and it does not tell whether genetic or environmental (...) causes or both in combination are responsible for the familial clustering. Familial clustering may be due to genetic predisposition to the disease, but exposure to environmental factors — shared by members of some families, but not by members of other families — may also cause familial clustering and hence mimic genetic inheritance in the study of nuclear families. Based on assumptions regarding the individual steps in the biological process starting with exposure to carcinogens and ending with death from disseminated cancer we suggest that genetic and environmental factors may both be involved in most of these steps. The present paper focuses on research methodologies necessary to discriminate between the effect of genes and family environment in the development of cancer. (shrink)

The rapidly changing field of genetics affects society through advances in health-care and through implications of genetic research. This study addresses the impacts of new genetic discoveries and technologies on different segments of today's society. The book begins with a chapter on genetic complexity, and subsequent chapters discuss moral and ethical questions arising from today's genetics from the perspectives of health care professionals, the media, the general public, special interest groups and commercial interests.

This paper examines the legal and ethical aspects of traceback testing, a process in which patients who have been previously diagnosed with ovarian cancer are identified and offered genetic testing so that their family members can be informed of their genetic risk and can also choose to undergo testing. Specifically, this analysis examines the ethical and legal limits in implementing traceback testing in cases when the patient is deceased and can no longer consent to genetic testing.

Hirschsprung disease and the multiple endocrine neoplasia type 2 syndromes are hereditary disorders related to the abnormal migration, proliferation or survival of neural crest cells and their derivatives. Hirschsprung disease is a frequent disorder of the enteric nervous system, resulting in intestinal obstruction. The multiple endocrine neoplasia type 2 syndromes predispose to cancers of neural crest derivatives. Both diseases are associated with heterozygous mutations in the RET proto‐oncogene. RET encodes a transmembrane receptor tyrosine kinase expressed in neural crest (...) lineages and whose ligand, glial‐cell‐line‐derived neurotrophic factor, has been very recently identified. In vitro expression studies demonstrate that while Hirschsprung disease mutations result in loss of function of the mutant RET tyrosine kinase, multiple endocrine neoplasia type 2 mutations lead to its constitutive activation. Thus, the two ‘faces’ of RET, gain of function and loss of function, each lead to a different syndrome, respectively: multiple endocrine neoplasia type 2, a cancer syndrome, or Hirschsprung disease, a developmental defect. (shrink)

The article examines the relationship between a trait’s effect on survival and reproduction and the notion of functional efficiency underlying the biostatistical theory of health. BST faces the problem of how to measure a trait’s joint effect on survival and reproduction in its account of function. If one measures the joint effect by means of the biological notion of fitness, examples such as the hereditary breast and ovarian cancer syndrome do not count as a disorder. If one does not (...) invoke biological fitness, it is unclear how to measure the joint effect while keeping to BST’s naturalist credentials. (shrink)

Recent evidence from studies on DNA repair systems that are implicated in accelerated aging syndromes, have revealed a mechanism through which low levels of persistent damage might exert beneficial effects for both cancer prevention and longevity assurance. Beneficial effects of adaptive responses to low doses of insults that in higher concentrations show adverse effects are generally referred to as hormesis. There are numerous examples of hormetic effects ranging from mild stresses of irradiation to heat stress, hypergravity, pro‐oxidants, or (...) food restriction. Although the notion of hormesis is supported by many observations in various organisms, at least two major caveats have thus far prevented the application of hormesis for disease prevention in humans. First, the very nature of hormesis using toxins as a treatment regimen harbors the inherent danger of detrimental consequences. Second, the molecular mechanisms through which insults might exert beneficial effects have thus far remained elusive. Here, I discuss a mechanistic basis for hormesis and its implications for cancer prevention and healthy aging. (shrink)

When positionally cloned in late 1989, it was anticipated that mutations within the Wilms' tumour suppressor gene (WT1) would prove responsible for this common solid kidney cancer of childhood. Characterisation of the WT1 expression pattern and of the structure of the encoded protein isoforms and their mode of action has now spanned almost a decade. WT1 proteins act as nucleic acid-binding zinc finger-containing transcription factors involved in both transactivation and repression. These activities are facilitated and constrained by interactions with (...) other proteins. Expression analyses and knockout mice indicate that WT1 protein plays a critical role in normal kidney and gonad development. Specific constitutional WT1 mutations results in several urogenital anomaly syndromes. While only 10% of sporadic Wilms' tumours do display WT1 mutation, WT1 is mutated in other cancers, including acute myeloid leukaemia. Much is still to be determined in WT1 biology. The next decade will see at least three streams of attention. The first two, elucidation of the role of WT1 in RNA metabolism and the characterisation of further protein partners, may together explain the distinct tissue-specific functions of WT1. Finally, further research into the role of WT1 in haematopoiesis will improve our understanding of WT1 in leukaemia. BioEssays 21:191-202, 1999. (C) 1999 John Wiley & Sons, Inc. (shrink)

C/D box snoRNAs (SNORDs) are an abundantly expressed class of short, non‐coding RNAs that have been long known to perform 2′‐O‐methylation of rRNAs. However, approximately half of human SNORDs have no predictable rRNA targets, and numerous SNORDs have been associated with diseases that show no defects in rRNAs, among them Prader‐Willi syndrome, Duplication 15q syndrome and cancer. This apparent discrepancy has been addressed by recent studies showing that SNORDs can act to regulate pre‐mRNA alternative splicing, mRNA abundance, activate enzymes, (...) and be processed into shorter ncRNAs resembling miRNAs and piRNAs. Furthermore, recent biochemical studies have shown that a given SNORD can form both methylating and non‐methylating ribonucleoprotein complexes, providing an indication of the likely physical basis for such diverse new functions. Thus, SNORDs are more structurally and functionally diverse than previously thought, and their role in gene expression is under‐appreciated. The action of SNORDs in non‐methylating complexes can be substituted with oligonucleotides, allowing devising therapies for diseases like Prader‐Willi syndrome. (shrink)

Globalizing Feminist Bioethics is a collection of new essays on the topic of international bioethics that developed out of the Third World Congress of the International Association of Bioethics in 1996. Rosemarie Tong is the primary editor of this collection, in which she, Gwen Anderson, and Aida Santos look at such international issues as female genital cutting, fatal daughter syndrome, use of reproductive technologies, male responsibility, pediatrics, breast cancer, pregnancy, and drug testing.

In At the Will of the Body , Arthur Frank told the story of his own illnesses, heart attack and cancer. That book ended by describing the existence of a "remission society," whose members all live with some form of illness or disability. The Wounded Storyteller is their collective portrait. Ill people are more than victims of disease or patients of medicine they are wounded storytellers. People tell stories to make sense of their suffering when they turn their diseases (...) into stories, they find healing. Drawing on the work of authors such as Oliver Sacks, Anatole Broyard, Norman Cousins, and Audre Lorde, as well as from people he met during the years he spent among different illness groups, Frank recounts a stirring collection of illness stories, ranging from the well-known--Gilda Radner's battle with ovarian cancer--to the private testimonials of people with cancer, chronic fatigue syndrome, and disabilties. Their stories are more than accounts of personal suffering: they abound with moral choices and point to a social ethic. Frank identifies three basic narratives of illness in restitution, chaos, and quest. Restitution narratives anticipate getting well again and give prominence to the technology of cure. In chaos narratives, illness seems to stretch on forever, with no respite or redeeming insights. Quest narratives are about finding that insight as illness is transformed into a means for the ill person to become someone new. (shrink)

The skin‐cancer‐prone hereditary disease xeroderma pigmentosum is typically characterized by defective nucleotide excision repair (NER) of DNA. However, since all subunits of the core basal transcription factor TFIIH are required for both RNA polymerase II basal transcription and NER, some mutations affecting genes that encode TFIIH subunits can result in clinical phenotypes associated with defective basal transcription. Among these is a syndrome called trichothiodystrophy (TTD) in which the prominent features are brittle hair and nails, and dry scaly skin. A (...) recent study provides dramatic support for the so‐called transcription hypothesis of TTD.(1) Specifically, several patients have been shown to carry a mutation in the XPD gene, which encodes a thermolabile form of XPD protein, resulting in loss of hair during febrile episodes. BioEssays 23:671–673, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Since the birth of the first test-tube baby, Louise Brown, in 1977, we have seen truly remarkable advances in biotechnology. We can now screen the fetus for Down Syndrome, Spina Bifida, and a wide range of genetic disorders. We can rearrange genes in DNA chains and redirect the evolution of species. We can record an individual's genetic fingerprint. And we can potentially insert genes into human DNA that will produce physical warning signs of cancer, allowing early detection. In fact, (...) biotechnology has progressed to such a point that virtually any kind of genetic manipulation, if not already possible, is just around the corner. But these breakthroughs also raise serious ethical and moral dilemmas that we are only now beginning to confront. In Wonderwoman and Superman, noted medical ethicist John Harris offers the first thorough analysis of the moral dilemmas created by the revolution in molecular biology. Covering a wide array of recent innovations, Harris discusses, for example, the moral decisions involved and the consequences of creating egg and embryo banks. Who should be allowed to use such resources? Should recipients be screened? Should such banks be open for public or private use? And does it cheapen life to make embryos available for sale? In another chapter, Harris examines the question of conceiving children chiefly for organ donation, focusing on the recent case of a woman who wanted to have a second child to provide a bone marrow donor for her first child sick with leukemia (she intended to abort the fetus if its bone marrow did not genetically match that of her living child). In this case, the medical staff had to decide whether they should perform in-vitro fertilization, knowing that the mother did not satisfy the clinic's criteria (there was no father), and also knowing the potential for abortion. Discussing the ethics of the mother's choice and the clinic's choice, Harris asks whether it is morally correct to create a child as an organ donor, whether the future child would suffer, whether it is worth any suffering to be born, and who has the right to weigh the various factors (both moral and physiological) involved in making these decisions. Delving into a multitude of issues such as when life begins, when suffering is needless, and whether we should play God, Wonderwoman and Superman provides not only a thought-provoking inquiry into the potential and actual ethical dilemmas created by the many advances in biotechnology, but challenges us to learn to choose responsibly and to face the moral implications of the choices that confront us. (shrink)

Recent studies have explored the effectiveness of open-label placebos for a variety of conditions, including chronic pain, cancer-related fatigue and irritable bowel syndrome. OLPs are thought to sidestep traditional ethical worries about placebos because they do not involve deception: with an OLP, patients or subjects are told outright that they are not given an active substance. As deception is framed as the primary hurdle to ethical placebo use, the door is ostensibly opened to ethical studies of OLPs. In this (...) article, I suggest that even though OLPs seemingly do not involve deception, there are other ethical considerations in their clinical investigation and subsequent use. Research ethics often focusses on informed consent—of which, deception and honesty are a piece—as a means to justify research practices with human subjects. Yet, it is but one of the ethical considerations that should be taken into account. With research into placebo effects in particular, I argue that the history of clinical placebo use grounds special considerations for OLP research that go beyond respect for the autonomy of individual patients through informed consent and encompass structural concerns about the type of patient for whom a placebo has historically been thought appropriate. (shrink)

The sources, extent and margins of parental obligations in taking decisions regarding their children’s medical care are subjects of ongoing debates. Balancing children’s immediate welfare with keeping their future open is a delicate task. In this paper, we briefly present two examples of situations in which parents may be confronted with the choice of whether to authorise or demand non-therapeutic interventions on their children for the purpose of fertility preservation. The first example is that of children facing cancer treatment, (...) and the second of children with Klinefelter syndrome. We argue that, whereas decisions of whether to preserve fertility may be prima facie within the limits of parental discretion, the right to an open future does not straightforwardly put parents under an obligation to take actions that would detect or relieve future infertility in their children—and indeed in some cases taking such actions is problematic. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Invisible HarmKimberly ZieselmanI’m a 48–year–old intersex woman born with Androgen Insensitivity Syndrome (AIS) writing to share my personal experience as a patient affected by a Difference of Sex Development (DSD). Although I appear to be a DSD patient “success story”, in fact, I have suffered and am unsatisfied with the way I was treated as a young patient in the 1980’s, and the continued lack of appropriate care for (...) intersex people even today.As the Executive Director of the advocacy organization Advocates for Informed Choice and a board member of the AIS–DSD Support Group since 2012, I have heard doctors reference the “silent happy majority” of DSD patients all too often. They speak [End Page 122] of patients who were treated in childhood and went on to live (seemingly) contented lives. It appears however that doctors have drawn this conclusion from the fact that most of their patients have not returned to complain about their treatment. While there is little evidence to support the success doctors claim, there is quite a bit of evidence that suggests my suffering is the norm rather than the exception.Medical professionals would likely include me in that “silent majority,” only seeing a woman who identifies and appears typically female, graduated law school, married for over twenty years, with adopted children and a successful career. And while I have been fortunate in many ways, I no longer want my voice to be presumed buried within that silent majority. Instead, I am speaking out today to tell my story.My StoryAt age 15 I was diagnosed with amenorrhea and referred to a reproductive oncologist who told my parents I had a partially developed uterus and ovaries that would likely soon become cancerous. We were told my vagina was abnormally short and might require surgery in order to have heterosexual intercourse.Neither my parents nor I was ever told I had AIS and XY chromosomes, or that the gonads being removed were testes, not ovaries. I was told I needed a “full hysterectomy” to prevent cancer and hormone replacement therapy. That summer I spent my 16th birthday recuperating from surgery. I spent the next 25 years living a lie.A lie that has had a profound and harmful impact on me.At some level, I knew I was not being told the whole truth. My parents’ and the doctors’ actions signaled to me something more might be going on. But I was afraid to ask questions; my parents were distressed and I didn’t want to cause them any more pain. Over the years I have wondered just how much my parents knew but withheld from me (albeit with good intentions). I sensed something awful was being hidden from me, and I didn’t know whom I could trust.When I asked my doctor if I could meet someone else with my condition, I was told I was different, that there was “nobody” with my medical condition in the world, that my situation was “very rare.” I was told to get on with my life and not talk about my surgery because it wasn’t important; I was healthy and could adopt if I wanted to become a parent. I was told I must take a hormone pill each day for the rest of my life to stay healthy.But what I heard was, “you are not a real woman: you are a damaged freak, so go out and fake the rest of your life and be sure nobody knows your secret.” So that’s what I did. I was a “good girl” and took my pills, didn’t ask questions and did what the men in white coats asked me to do. There was no support provided for either my parents or me. No social workers, no therapists. Perhaps most shockingly, there was no true informed consent.A few years ago I was diagnosed with post-traumatic stress syndrome caused by anxiety I had been harboring for over two decades about my past surgery and fear of getting cancer. I decided to obtain my medical records from the hospital and discover the truth.Covering several pages of... (shrink)

Experiential evidence shows that pain is associated with common meanings. These include a meaning of threat or danger, which is experienced as immediately distressing or unpleasant; cognitive meanings, which are focused on the long-term consequences of having chronic pain; and existential meanings such as hopelessness, which are more about the person with chronic pain than the pain itself. This interdisciplinary book - the second in the three-volume Meanings of Pain series edited by Dr Simon van Rysewyk - aims to better (...) understand pain by describing experiences of pain and the meanings these experiences hold for the people living through them. The lived experiences of pain described here involve various types of chronic pain, including spinal pain, labour pain, rheumatic pain, diabetic peripheral neuropathic pain, fibromyalgia, complex regional pain syndrome, endometriosis-associated pain, and cancer-related pain. Two chapters provide narrative descriptions of pain, recounted and interpreted by people with pain. Language is important to understanding the meaning of pain since it is the primary tool human beings use to manipulate meaning. As discussed in the book, linguistic meaning may hold clues to understanding some pain-related experiences, including the stigmatisation of people with pain, the dynamics of patient-clinician communication, and other issues, such as relationships between pain, public policy and the law, and attempts to develop a taxonomy of pain that is meaningful for patients. Clinical implications are described in each chapter. This book is intended for people with pain, their family members or caregivers, clinicians, researchers, advocates, and policy makers. (shrink)

In vitro fertilization using donated oocytes has proven to be an effective treatment option for many prospective parents struggling with infertility, and the usage of donated oocytes in assisted reproduction has increased markedly since the technique was first successfully used in 1984. Data published by the Centers for Disease Control and Prevention on the use of assisted reproductive technologies in the United States indicate that approximately 12% of all ART cycles in the country now use donated oocytes. The increased use (...) of oocyte donation in the United States has prompted discussion regarding risks associated with the process and how best to ensure the safety of oocyte donors.Physical risks associated with oocyte donation include bleeding, infection, ovarian hyperstimulation syndrome and a potential, although unconfirmed, increased risk of developing various forms of cancer, such as uterine, colon, breast, ovarian, and endometrial cancers. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Standing UpEmily QuinnA 10–year old and her mother walk into a male gynecologist’s office. That sounds like the beginning of a sick joke, right? Imagine how it must have felt to actually be that 10–year–old. I walked into the Salt Lake City ob–gyn office, terrified out of my mind. It was the year 1999 and due to the recent accessibility of the Internet, there was a surprising amount of (...) information about complete androgen insensitivity syndrome (CAIS) available. There was also an active and prominent support group for women with CAIS and other similar conditions. Despite all of this, I was standing in the office of a doctor who knew nothing about my body. He did not direct me to any actual support, and for the next twelve years I went from doctor to doctor, none of them really knowing what to do with me. For as much as I was in and out of the doctor’s office, I never seemed to receive any “care.”It was really difficult to have doctors who knew nothing about my condition. It was scary to be a kid with hundreds of questions but without an adult who had the answers. So many doctors were excited to look at me, to talk to me, to get the chance to meet me. As a child it made me feel like a freak. I felt alone, and scared, like I was on parade for all of these people who didn’t know anything about me except that I was “special.”I was savvy enough to turn to the Internet for help, but searching for “sex disorders” online was a terrifying thing to do back then. Even now, it’s not a safe space for a pre–teen looking for answers. I was so scared and ashamed of my body, and I desperately wanted someone to talk to about it. I found articles about celebrities who were rumored to be like me, and I saw the word “hermaphrodite” thrown around as carelessly as it had been used in my doctor’s office. I wished desperately that one of those celebrities would admit to having a body like mine. Because if any of them were like me, maybe I wouldn’t be the freak that the adults made me feel like I was. Maybe then I wouldn’t be so alone.As hard as all of this was, in a way my doctor’s lack of knowledge turned out to be both a blessing and a curse. I felt cursed and ashamed of this different, “broken” body that couldn’t be “fixed.” I felt like a problem that nobody had the solution to. I was told so many lies—that I would definitely get cancer, that I could never have sex, that I needed surgery immediately. Not once was I ever told the truth—that there were hundreds of others out there I could talk to, that I didn’t do anything wrong, that I was going to be okay. My doctors didn’t point me in the direction of a support group or a therapist who could help me work through what it all meant. In Utah, the most important thing a woman can do is to have children, and it was devastating to learn I would not to be able to conceive. I wish any of my doctors had pointed me in the direction of a professional I could talk to about it.It wasn’t until I was older that I discovered the blessing amongst all of this pain. As it turns out, my doctors were so entirely ignorant about my condition that they didn’t know how to remove or even find my internal testes. I’ve managed to make it 25 years without surgery. Now, when I speak to medical students, many of them balk at this idea that surgery is something I’ve “escaped.” But I know how many affected individuals see it as I do. It’s incredibly lucky that somebody with CAIS is surgically untouched, and I fully believe that rarity to be the saddest thing. It shouldn’t be the norm to... (shrink)

In lieu of an abstract, here is a brief excerpt of the content:“Normalizing” Intersex Didn’t Feel Normal or Honest to Me.Karen A. WalshI am an intersex woman with Complete Androgen Insensitivity Syndrome (CAIS). My 57–year history with this has its own trajectory—mostly driven by medical events, and how I and my parents reacted. Most of my treatment by physicians has not been positive. It didn’t make me “normal” at all. I was born normal and didn’t require medical interventions. And by (...) the way, I’ve never been confused about who or what I am.Truthful disclosure didn’t come to me about my biology and what was done to me as an infant until I was 33, when I forced the issue by removing my medical records from my endocrinologist’s office. I learned that there was never full disclosure to my [End Page 119] parents either, and therefore there was no informed consent for the “corrective” surgeries performed on me as an infant. My parents were only told that their little girl would get cancer and would not have a normal development as a girl unless her “deformed ovaries” were removed, and that they should never discuss these problems with me. Thus, after having presented with an inguinal hernia and having exploratory surgery at age 16 months, my intra–abdominal testes were removed in a second surgery two months later. I was pronounced a “male pseudohermaphrodite,” a diagnosis that was shared neither with my parents nor with me.Years later, I discovered an article my surgeon published in 1960 in the Delaware Medical Journal about me and another intersex person he operated on (whom he labeled a “true hermaphrodite”). The article gives a very detailed pathology report of my gonads, but only two sentences regarding my welfare and the rationale for performing those surgeries. Dr. J. F. Kustrup wrote in this article, “These [two cases] emphasize the need for early diagnosis and treatment in order to avoid the possibility of malignant change and to permit these individuals to follow a normal psychosexual pattern.” And: “Hermaphroditism and pseudohermaphroditism are conditions in which early diagnosis and treatment are essential to avoid malignant degeneration and to allow the child some chance toward normal pyschic [sic] development.” I was grateful to find this article because it revealed the unfounded assumptions underpinning the recommendations for treatment, much of which continues today. Worse even than the sort of social prejudice that shapes treatment is the absence of evidence for what doctors treat as “necessary” interventions. For my syndrome, CAIS, there never was—and still is not—data to support the cancer scare, or the opinion that I’d be confused and not have a normal life.From about the age of four, I can remember being different and being stonewalled by my doctor and prevented by my parents from talking about it. The feelings and fears I tried to express were shushed away, and I could tell that my questions were upsetting everyone. Even if I had wanted to be complicit with their lame diversions and nonsensical explanations, the massive abdominal scars were there as a daily reminder and hinted at a very different story.The Road to Hell is Paved with Good IntentionsGrowing up, I was treated like a fascinoma and a lab rat at a major teaching hospital on the East Coast. All I learned from those doctors as a young kid was what it feels like to be ogled, photographed and probed by a roomful of white–coated male doctors. Dissociation made itself my friend, and helped me to cope through the annual genital and anal exams and probing. I thought I was a freak and I felt completely powerless to protect myself from them and their “care”.At my annual appointment at age 12, with my mom present, three doctors told me I was infertile. Learning that I couldn’t have kids really saddened and shocked me, but there was no opportunity to talk about my feelings—either that day, or any time afterward. I was told to stop crying. I remember them telling me that there was no one else like me and that this was a random genetic anomaly, thereby reinforcing the freakishness... (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Philosophy and Rhetoric 35.3 (2002) 208-222 [Access article in PDF] Writing, Illness and Affirmation Jeremiah Dyehouse My formula for greatness in a human being is amor fati: that one wants nothing to be different, not forward, not backward, not in all eternity. Not merely to bear what is necessary, still less conceal it—all idealism is mendaciousness in the face of what is necessary—but love it. —Friedrich Nietzsche In her (...) widely circulated book On Death and Dying, Elisabeth Kübler-Ross, M.D., addresses herself to a changed historical context for work in medicine. In societies with increasingly effective medical care, she argues, doctors and nurses find themselves working with patients whose health problems range from imperceptible yet terminal sicknesses to psychosomatic ailments. Today, especially, it is easy to see the reality of her description of this situation: forms of terminal cancer can be detected earlier and earlier in a patient's life, rendering the disconcerting reality of a terminal illness with few or no symptoms. Equally strange for doctors and patients today are forms of environmental illness like chronic fatigue syndrome, a condition suffered by many but still disputed by doctors and researchers. To this situation of medical risk, personal suffering, and therapeutic care, Kübler-Ross prescribes a communicative engagement with the dying. This engagement, she argues, not only teaches doctors about death and dying, but it also provides respite for those who must experience these events.The problem of communicating with the dying, the main focus of Kübler-Ross's book, is nevertheless eclipsed by the other, more notable aspect of On Death and Dying. For out of this book emerged the now very popular understanding of the stages of death, the normal sequence of an individual's emotional reconciliation to dying: the processes of denial and isolation, anger, bargaining, depression—the whole series of intrapsychic processes leading up to a final acceptance of death and dying. Now we live amongst a whole panoply of staged progresses towards the acceptance of trauma: trauma associated not only with death and dying but also with substance abuse, catastrophe, and forms of violence. It is perhaps worth recalling, however, that the most famous of these stage models, the five stages [End Page 208] of death, emerged out of Kübler-Ross's attempt to learn what the dying can teach the living about communication.In what follows, I assume that writing about illness is another, more popular form of Kübler-Ross's descriptive and communicative project. To write pathography, as Anne Hunsaker Hawkins calls narratives of illness and dying in her survey of these texts, Reconstructing Illness: Studies in Pathography, is to engage with what sickness and dying teach about life and writing. As might be guessed, most pathographies orbit familiar centers of gravity: agency for the dying, reconciliation for the living, the whole leaden project of acceptance. Even so, pathography is not always and everywhere engaged in such projects. Pathography, as Hawkins demonstrates, is a highly variable project. Literary pathography is quite different from popular pathography, and texts within these categories differ with respect to the purpose of their writing. Pathography is conceived as a communicative engagement with sickness and dying, with the sick and the dying, but is hardly unified in its aims or its functions. It is a form of writing that not just potentially but actually admits a diversity of purposes and produces a variety of effects.It is my purpose here to propose a typology for pathographies. Although pathography as a genre of writing takes a bewildering variety of forms, these writings can be grouped according to their effects. I divide pathography into three types, according to the kind of response they offer to sickness and dying, to the sick and the dying. First, I treat pathography as a process of passive acceptance, the bearing of a burden proposed by the necessities of illness and death. Next, I characterize pathographies that approach the writing of illness or dying as a process of active acceptance. This type of pathography uses writing about illness and dying as a process for the... (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Psychiatric Comorbidity:More Than a Kuhnian AnomalyPeter Zachar (bio)Keywordscomorbidity, classification, epidemiology, differential diagnosis, personality disorderDr. Aragona's article in this issue of Philosophy, Psychiatry, & Psychology makes some important points regarding the relationship between comorbidity rates and the classification system currently used in psychiatry. Particularly persuasive is his claim that observed patterns of comorbidity are, in important respects, consequences of the structure of the classification system. I am not convinced, however, (...) that comorbidity is best conceptualized as an artifact of the taxonic structure of the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD). Instead, I suggest that the use of dichotomies such as true versus artifactual should be used with caution when psychiatric classification is being discussed.In contrast with the artifact hypothesis, I argue that the phenomena covered by the term "comorbidity" are real, expectable features of the psychiatric domain. They are not the phlogiston and luminiferous ether of psychiatry. I am skeptical of the notion that high comorbidity rates as a whole can be understood as Kuhnian anomalies, or that there is a crisis, or that after a period of revolutionary science a new paradigm would eliminate these 'anomalies.' In short, high rates of comorbidity in psychiatry will not simply disappear once scientists develop a better nosological paradigm. High levels of comorbidity can, however, be both lowered and provided a better, evidence-based conceptual framework.Many Conditions, One OrganIn general medicine, comorbidity conventionally refers to the simultaneous occurrence of two independent disease processes or distinct clinical entities, such as heart disease and liver cancer (Feinstein, 1970; Jablensky 2004). The presence of one disease is supposed to affect the other in such a way that the co-occurrence of the two has implications for prognosis and treatment.Comorbidity in psychiatry is a broader concept, referring to a variety of conditions that overlap in multiple ways. The different kinds of overlap are amenable to detailed empirical analysis (e. g., Klein and Riso 1993; Neale and Kendler 1995). Depressive reactions to primary disorders, attention deficit symptoms associated with mania, panic attacks in the context of severe borderline personality disorder, substance abuse disorders among psychopaths, histrionic dynamics combined [End Page 13] with narcissistic personality traits, and emergent conditions such as schizoaffective disorder are all distinct types of comorbidity. The kinds of overlapping conditions just listed are sometimes termed psychiatric comorbidity. Also important is comorbidity between psychiatric disorders and general medical conditions as is studied in behavioral medicine and health psychology. The crisis, if there is one, is a crisis of comorbidities.The heart disease and liver cancer type of comorbidity as independent organ systems being affected is ruled out a priori in psychiatric comorbidity proper. In psychiatry, "psychopathological disease processes" can all be expected to affect a single organ, namely the brain or, more likely, affect the different systems that are tightly integrated in the brain. The tight integration can make putative comorbid psychiatric disorders difficult to disentangle.It is a widely held consensus that causes, not organ systems, are what matter in comorbidity. In this tradition, Dr. Aragona claims that in general medicine shared symptoms between two diseases (such as fever and fatigue) are not a problem because the diseases are differentiated with respect to etiology; in psychiatry, however, where syndromes are differentiated by a description of symptoms only, symptomatic overlap is a problem.Is descriptive psychopathology, therefore, a root cause of the "crisis of comorbidity" and should it be abandoned in favor of etiological classification? Unfortunately, forcing psychiatric nosology to conform to an etiological paradigm is unlikely to resolve the problem of psychiatric comorbidity. As noted, the problem is one of distinguishing between the different etiological disease processes that are affecting tightly integrated systems in the brain. The brain as a whole is a multilevel, dynamic, and open system, which has an ecology (Zachar 2000). As argued by Kendler (2005) and Schaffner (2002, 2008), it has not thus far, and may never be fully possible to segregate causes and their associated psychiatric disorders into parsimonious etiological packages. In the ecology of neuroscience, causes and effects tend to merge in a continuous series of common pathways.It would be foolish... (shrink)

Experiential evidence shows that pain is associated with common meanings. These include a meaning of threat or danger, which is experienced as immediately distressing or unpleasant; cognitive meanings, which are focused on the long-term consequences of having chronic pain; and existential meanings such as hopelessness, which are more about the person with chronic pain than the pain itself. This interdisciplinary book - the second in the three-volume Meanings of Pain series edited by Dr Simon van Rysewyk - aims to better (...) understand pain by describing experiences of pain and the meanings these experiences hold for the people living through them. The lived experiences of pain described here involve various types of chronic pain, including spinal pain, labour pain, rheumatic pain, diabetic peripheral neuropathic pain, fibromyalgia, complex regional pain syndrome, endometriosis-associated pain, and cancer-related pain. Two chapters provide narrative descriptions of pain, recounted and interpreted by people with pain. Language is important to understanding the meaning of pain since it is the primary tool human beings use to manipulate meaning. As discussed in the book, linguistic meaning may hold clues to understanding some pain-related experiences, including the stigmatisation of people with pain, the dynamics of patient-clinician communication, and other issues, such as relationships between pain, public policy and the law, and attempts to develop a taxonomy of pain that is meaningful for patients. Clinical implications are described in each chapter. This book is intended for people with pain, their family members or caregivers, clinicians, researchers, advocates, and policy makers. (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)

In lieu of an abstract, here is a brief excerpt of the content:Nuclear Power after Fukushima 2011:Buddhist and Promethean PerspectivesGraham ParkesDuring 2010 many environmentalists previously opposed to nuclear power were deciding, in the face of anthropogenic climate change from burning fossil fuels, that the only way to prevent runaway global warming would be to build more nuclear power plants after all.1 There are risks involved—though fewer than with carbon-based sources of energy.2 When one compares the detrimental effects of nuclear power (...) with those of burning fossil fuel, it is clear that the human injury and death toll (not to mention environmental devastation) resulting from the former have been nothing compared to the damage caused by the extraction and consumption of fossil fuels, owing to mining accidents, oil spills, and so forth—not to mention the massive carbon dioxide emissions.On the other hand, the problem of how and where to store the growing amount of radioactive waste from nuclear power plants, which remains deadly for many thousands of years, has yet to be solved. Costly security measures have to be taken to guard against terrorist attacks and theft of materials usable for nuclear devices. When full safety features are included, nuclear power plants become ever more expensive to build, and the costs of insuring them against accidents are so prohibitive that governments have to subsidize them, which they are increasingly unwilling to do.Not long after the explosions and meltdowns at the Fukushima Daiichi nuclear power station in March 2011, two dismal world records were announced: in 2010 we discharged a record amount of carbon dioxide (more than 30 gigatons) into the atmosphere, mainly by burning fossil fuels, and, as a direct consequence, carbon dioxide levels in the atmosphere (as measured at the Earth Systems Research Laboratory in Hawai'i) reached a record level of 395 parts per million. These figures suggest that we are continuing to generate a rise in global average temperatures that is already destroying the livelihoods of millions and will soon jeopardize the lives of hundreds of millions more.As a consequence of the 2011 Fukushima disaster, Japan—long a leading promoter of nuclear power—has begun to enforce some widely neglected safety regulations and is seriously reconsidering its reliance on nuclear energy. China has put construction of [End Page 89] new power plants on hold. Other nations (such as Germany, Italy, Switzerland, Thailand, and Malaysia) have decided to phase out or cancel plans to build more nuclear power stations. Yet the primary motivations remain unclear, since people's attitudes toward the dangers of nuclear radiation are anything but rational—as evidenced by the mass departure of foreigners from Japan after the catastrophe at Fukushima, when health dangers beyond the vicinity of the power station were minimal.In Europe, the reaction to the Fukushima disaster has clearly been aggravated by memories of the catastrophe at Chernobyl in 1986. While Chernobyl was a more widely destructive event than Fukushima, releasing a much greater amount of radioactivity, its effects on human health continue to generate disagreement. According to the third report on the effects of the Chernobyl catastrophe issued by the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), among the 134 plant staff and emergency workers who suffered acute radiation syndrome (ARS), the condition proved fatal for twenty-eight of them. By 2006 another nineteen ARS survivors died, although their deaths were not directly attributable to the effects of ionizing radiation. Although the report attributes "a substantial fraction" of the six thousand cases of thyroid cancer in people who were children at the time of the accident to their consumption of milk contaminated with iodine-131, only fifteen cases had proved fatal by 2005, some twenty years later.3 The death toll, then, was fewer than fifty.By contrast, a study by a group of scientists from Belarus, Russia, and the Ukraine, Chernobyl: Consequences of the Catastrophe for People and the Environment, estimates the number of deaths attributable to the meltdown at around 980,000—almost twenty thousand times greater than the estimate by the UN scientific committee.4 What are we to make of this vast discrepancy, especially since the UNSCEAR report "was prepared in close cooperation with... (shrink)

Based on genetic and biochemical advances on the molecular mechanism of circadian rhythms, a computational model for the mammalian circadian clock is used to examine the dynamical bases of circadian‐clock‐related physiological disorders in humans. Entrainment by the light–dark cycle with a phase advance or a phase delay is associated with the Familial advanced sleep phase syndrome (FASPS) or the Delayed sleep phase syndrome (DSPS), respectively. Lack of entrainment corresponding to the occurrence of quasiperiodic oscillations with or without phase jump can (...) be associated with the non‐24 h sleep–wake syndrome. In the close vicinity of the entrainment domain, the model uncovers the possibility of infradian oscillations of very long period. Perturbation in the form of chronic jet lag, as used in mice, prevents entrainment of the circadian clock and results in chaotic or quasiperiodic oscillations. It is important to clarify the conditions for entrainment and for its failure because dysfunctions of the circadian clock may lead to physiological disorders, which pertain not only to the sleep–wake cycle but also to mood and cancer. BioEssays 30:590–600, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The ubiquitin–proteasome system (UPS) is the major proteolytic pathway that degrades intracellular proteins in a regulated manner. Deregulation of the UPS has been implicated in the pathogenesis of many neurodegenerative disorders like Alzheimer's disease, Parkinson's diseases, Huntington disease, Prion‐like lethal disorders, in the pathogenesis of several genetic diseases including cystic fibrosis, Angelman's syndrome and Liddle syndrome and in many cancers. Multiple lines of evidence have already proved that UPS has the potential to be an exciting novel therapeutic target for the (...) treatment of these diseases. Here I review how aberrant functions of various genes have implicated UPS in many human disorders including neurodegeneration and cancers. I also discuss the finding that some proteasome inhibitors possess a therapeutic potential as drugs against many such diseases. BioEssays 30:1172–1184, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:From Impatience to EmpathyStephanie Pierce and Kavita Shah AroraWe gave J.H. a label the first time we met her, as many often do—“Uncooperative.” She was a patient with autism and intellectual delay who had presented to the emergency department (ED) with vaginal bleeding. After receiving the gynecology consult request from the emergency medicine physicians, we were already mentally formulating our recommendations based on the information they told us over (...) the phone. “Does not cooperate with exam,” “no acute surgical intervention is currently warranted,” and “recommend outpatient follow–up.”When we arrived in her room, she was sitting in the hospital bed surrounded by a protective shield of caregivers from her group home. We introduced ourselves as the gynecology team but it was obvious that J.H. could not communicate verbally. Upon speaking with her caregivers we learned that she had Cowden syndrome, a genetic disease that confers significantly increased risks for several types of cancer including endometrial, thyroid, and breast cancers. J.H. had also been having heavy vaginal bleeding, which was difficult for her caregivers to manage, and this was the reason she was brought into the emergency department. After attempting to gain as much information as we could from the caregivers, we started to perform an abdominal exam, which made J.H. extremely agitated. We quickly stopped the exam and the caregivers helped to calm J.H. We remember our mixture of emotions—bewilderment at the agitation and commotion in the exam room full of people, frustration at not being able to complete our exam fully, and annoyance that this “difficult patient” was taking up our limited time between surgical cases. Thankfully, these knee–jerk reactions were quickly replaced by feelings of concern for the patient and the realization of how frightening an experience this must be for her—being in a strange place with white walls and unfamiliar people, unable to communicate her thoughts.J.H.’s mother, her surrogate decision–maker, was not at the hospital that day but the caregivers told us that she had expressed a strong desire for her daughter to have a prophylactic hysterectomy due to her lifetime risk for developing uterine cancer as well as a permanent solution to the bleeding concerns. What had initially started as a simple ED consult was now turning into a complex question. The ethical and legal dilemma was obvious—whether to perform a major surgery that would irreversibly sterilize a patient who could not consent on her own behalf in order to minimize the potential risk of cancer later in life. While medical management could improve the bleeding and potentially reduce the risk of cancer, frequent exams would be necessary [End Page 19] to ensure that the medication was working and that premalignant changes were not occurring in J.H.’s uterus. However, based on our experience in the emergency department, J.H. would need anesthesia for such exams and it was doubtful the medications would completely normalize her elevated risk of uterine malignancy. We knew that in order to address this question, we would need to see J.H. again along with her mother to have a frank discussion about the risks and benefits of such a decision, and so we made plans to see her in our outpatient clinic.Several days later, J.H., her mother, and the group home caregivers arrived in the office. Anticipating a complex discussion, we had requested a representative from the hospital ethics committee to join us at the visit. We didn’t know what to expect meeting J.H.’s mother for the first time but as we sat in the room talking, it was obvious that she was truly trying to act in her daughter’s best interest. Similarly, it was touching to watch the faces of the caregivers from the group home as they nodded in solidarity with J.H.’s mother, also clearly wanting what was best for her and supporting her mother in this difficult decision. J.H., meanwhile, seemed content to sit silently with us during the discussion, surrounded as she was by people who cared deeply for her well–being.After extensive partnership with the ethics consultants... (shrink)

Dysregulation of genes that control cell‐cycle progression and DNA repair is a hallmark of tumorigenesis. It is becoming increasingly apparent, however, that these defects also contribute to degeneration of post‐mitotic neurons under certain conditions. The gene for ataxia‐telangiectasia mutated (ATM) is a prototype for this dual mechanism of action, with loss‐of‐function mutations causing not only selective degeneration of cerebellar neurons but also increased susceptibility to breast cancer and hematologic malignancy. Increased dosage of amyloid precursor protein in Down syndrome (trisomy (...) 21) predisposes to dementia of Alzheimer type and may also contribute to acute leukemia and transient myeloproliferative disorder. The gene parkin, loss‐of‐function mutations in which account for about half of cases of early‐onset Parkinson disease, has been identified as a candidate tumor suppressor gene by several groups. Parkin is deleted or downregulated in several tumor types, and its re‐expression sensitizes derivative cell lines to inhibitors of cell‐cycle progression. The overlap of molecular pathways implicated in cancer and neurodegeneration challenges long‐held notions about differentiated cellular states and may open the door to novel therapeutic approaches to both groups of disorders. BioEssays 30:719–727, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The clinical relevance of whole-exome sequencing is unquestionable. In the prenatal setting, the standard testing process of reflexing from karyotype to microarray to single-gene disorders may take several weeks, leaving a family in prolonged turmoil and often without answers in time to make a decision about the pregnancy. WES provides a powerful amount of data more quickly and with a higher yield of diagnostic results, allowing a timelier plan for medical management and decision-making. However, while results that pertain specifically to (...) the testing indication can be isolated, the potential for incidental findings or results that are unrelated to the original testing indication is significant. In 2013, ACMG published recommendations for reporting incidental or secondary findings, providing a list of 57 clinically actionable genes for which reporting should be obligatory. These recommendations were updated in 2015 to include the option to opt out of receiving all secondary findings. The list includes childhood-onset conditions, for which medical management would be immediately impacted. However, the list also includes adult-onset conditions such as hereditary breast and ovarian cancer and Lynch syndrome. Historically, decisions regarding genetic testing for these conditions have been left up to the individual until they reach the age of consent. While the 2015 recommendations are an improvement over the 2013 recommendations insofar as they allow an option to opt out of receiving secondary findings, the recommendations continue to have potentially troubling ethical consequences. (shrink)

Aneuploidy, an aberrant number of chromosomes in a cell, is a feature of several syndromes associated with cognitive and developmental defects. In addition, aneuploidy is considered a hallmark of cancer cells and has been suggested to play a role in neurodegenerative disease. To better understand the relationship between aneuploidy and disease, various methods to measure the chromosome numbers in cells have been developed, each with their own advantages and limitations. While some methods rely on dividing cells and thus (...) bias aneuploidy rates to that population, other, more unbiased methods can only detect the average aneuploidy rates in a cell population, cloaking cell‐to‐cell heterogeneity. Furthermore, some techniques are more prone to technical artefacts, which can result in over‐ or underestimation of aneuploidy rates. In this review, we provide an overview of several “traditional” karyotyping methods as well as the latest high throughput next generation sequencing karyotyping protocols with their respective advantages and disadvantages. (shrink)

Aldehyde dehydrogenase 2 (ALDH2) deficiency constitutes one of the most common hereditary enzyme deficiencies, affecting 35% to 40% of East Asians and 8% of the world population. It causes the well-known Asian Alcohol Flush Syndrome, characterized by facial flushing, palpitation, tachycardia, nausea, and other unpleasant feelings when alcohol is consumed. It is also associated with a marked increase in the risk of a variety of serious disorders, including esophageal cancer and osteoporosis. Our recent studies with murine models have demonstrated (...) that a one-time administration of an adeno-associated virus (AAV) gene transfer vector expressing the human ALDH2 coding sequence (AAVrh.10hALDH2) will correct the deficiency state and prevent alcohol-induced abnormalities of the esophagus and bone. If successful in humans, such strategy would reduce the increased risk-associated disorders such as esophageal cancer and osteoporosis, but also prevent the Asian Alcohol Flush Syndrome. This treatment thus raises ethical concerns: although it would potentially prevent fatal disease, it could also allow affected individuals to drink alcohol without suffering the Asian Alcohol Flush Syndrome and, hence, potentially enable personal destructive behavior. Here we explore the ethical arguments against the development of a gene therapy for ALDH2 deficiency and we find them wanting. We contend that development of such treatments is ethically appropriate and should be part and parcel of the solutions offered against the condition. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:FDA Releases Draft Guidance on Regulation of Genetically Engineered AnimalsJohn P. Gluck (bio) and Mark T. Holdsworth (bio)On 18 September 2008, the U.S. Food and Drug Administration (FDA) issued a draft set of guidelines for those involved in developing genetically engineered animals with heritable recombinant DNA (rDNA) constructs and is requesting comment from industry and the public about their content. The document does not impose new regulations but details (...) how existing laws and regulations apply to genetically engineered (GE) animals and offers advice to developers on how to negotiate the laws in the most efficient and productive manner. The draft guidance document is not legally enforceable at this juncture, but the guidelines are recommendations reflecting the FDA's "current thinking on a topic."The modification of GE animals being developed for commercialization, which are the focus of the document, fall into six categories: modifications intended to (1) enhance food quality—e.g., faster growing fish and meats with better nutritional profiles; (2) improve animal health via increased resistance to disease—e.g., mastitis in dairy cattle and Bovine Spongiform Encephalopathy (BSE); (3) create so-called "biopharm" animals capable of producing therapeutic products such as insulin, clotting factors, and tissues for human transplantation; (4) reduce the barriers to human animal interaction—e.g., hypoallergenic pets; (5) develop valid animal models of human disease—e.g., Parkinson's disease, Lesh-Nyhan's syndrome, and cancer; and (6) improve production of industrial or consumer products such as fiber. The timing of the guidelines coincides with the FDA's belief in an expected boon in the number of GE animals approaching the stage of commercialization.The FDA's involvement in the approval process emerges from the new animal drug provisions of the Federal Food Drug and Cosmetic Act and the definition of what constitutes a drug. The Act defines a new animal drug as "an article (other than food) intended to affect the structure or any function of the body of... animals." A rDNA construct intended to affect the structure or function of an animal meets the definition of a new animal drug, regardless of whether the resulting GE animals are intended for human food or the production of pharmaceuticals or any other substances. [End Page 393]Before proceeding to a review of the draft guidelines, it is important briefly to set the controversies around GE animals in historical and ethical context.The Ethical DebateFrom its inception, the intentional genetic modification or genetic engineering of molecules, plants, and animals by the techniques of gene splicing has consistently elicited strong responses from both the scientific community and the public. There are some data to suggest that although the concerns of scientists fall primarily into the category of possible biohazards, those of the public also reflect great concern about the intrinsic moral issues, such as whether there is something fundamentally wrong with this line of work, making it a form of forbidden knowledge (see, e.g., Gaskell 1997). When news of Paul Berg's attempts in 1970 to graft the primate tumor virus (SV 40) onto the intestinal tract bacteria Escherichia coli for the purpose of studying how normal cells may be transformed into cancerous cells was shared with colleagues, he was strongly encouraged to reflect on the potential public health risks if somehow the altered bacteria broke containment and entered the environment. Thanks to Berg's leadership, these concerns soon resulted in conferences held in Asilomar, California, and New Hampton, New Hampshire, where the ethical responsibilities of microbiologists involved in this research were discussed. These initial discussions resulted in what has come to be known as "The Moratorium Letter" (Shattuck 1996) published in the journal Science in 1974. This letter, signed by 11 leaders in the field, actually recommended restrictions on several types of experiments that were considered to be particularly risky and stated "that adherence to our major recommendations will entail postponement or possibly abandonment of certain types of scientifically worthwhile experiments" (Berg 1974). An international conference on the issues came to similar conclusions about the need for a research moratorium for the sake of public safety. Recommendations arising from conference participants led to the formation of the National Institutes... (shrink)