Novel technological developments mean that gene editing – making deliberately targeted alterations in specific genes – is now a clinical reality. The inherited metabolic disorders, a group of clinically significant, monogenic disorders, provide a useful paradigm to explore some of the many ethical issues that arise from this technological capability. Fundamental questions about the significance of the genome, and of manipulating it by selection or editing, are reviewed, and a particular focus on the legislative process that has permitted (...) the development of mitochondrial donation techniques is considered. Ultimately, decisions about what we should do with gene editing must be determined by reference to other non-genomic texts that determine what it is to be human – rather than simply to undertake gene editing because it can be done. (shrink)

Mitochondrial function is key for maintaining cellular health, while mitochondrial failure is associated with various pathologies, including inherited metabolic disorders and age‐related diseases. In order to maintain mitochondrial quality, several pathways of mitochondrial quality control have evolved. These systems monitor mitochondrial integrity through antioxidants, DNA repair systems, and chaperones and proteases involved in the mitochondrial unfolded protein response. Additional regulation of mitochondrial function involves dynamic exchange of components through mitochondrial fusion and fission. Sustained stress induces a selective autophagy (...) – termed mitophagy – and ultimately leads to apoptosis. Together, these systems form a network that acts on the molecular, organellar, and cellular level. In this review, we highlight how these systems are regulated in an integrated context‐ and time‐dependent network of mitochondrial quality control that is implicated in healthy aging. (shrink)

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)

Many inherited metabolic diseases may lead to varying degrees of brain damage and thus also to intellectual disability. Bone marrow transplantation (BMT) has been used for over two decades as a form of secondary prevention to stop or reverse the progress of the disease process in some of these conditions. At the population level the impact of BMT on the prevalence of intellectual disability is minute, but at the individual level its impact on the prognosis of the disease (...) and the well-being of the patient can be substantial. The dark side of BMT use is the burden of side effects, complications and transplantation-related mortality in less successful cases. The ethical issues involved in this therapy are discussed in this review. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Philosophy, Psychiatry, & Psychology 10.1 (2003) 63-66 [Access article in PDF] The Pragmatics of Psychiatry and the Psychiatry of Cross-Cultural Suffering Jennifer Radden I AM IN SUBSTANTIAL AGREEMENT with many of the conclusions David Brendel draws in his thoughtful discussion. Misleading language aside, I particularly applaud his use of my plea for ontological descriptivism to support clinical practice, which respects, as he puts it, the subjectively "melancholic" person living (...) behind the objectively "depressed" clinical presentation.Brendel offers two main critiques of my discussion about the relationship between today's depression and melancholia of past eras. First, he asserts that I neglect the relevance of causal reasoning in my preference for a descriptivist over a causal ontology. Second, arguing that pragmatic considerations ought to be, as he says, front and center when philosophers and psychiatrists "grapple with the complexities of psychiatric explanation," (Brendel 2003, 54) he questions what he sees as my too ready dismissal of pragmatism in this discussion. Allegiance to pragmatism seems to me to sit strangely with support for a causal ontology, as I shall try to demonstrate. But first let me comment on these two sides of Brendel's commentary.The case of Van Gogh's alleged melancholia is particularly well chosen because there has been continuing debate about Van Gogh's condition, including scholarly work attributing it to an inherited metabolic disorder (Arnold 1992). Brendel's suggestion that a causal ontology might allow us to use historical evidence to throw light on the relation between depression and melancholia is an interesting and fruitful one that I had overlooked. Brendel also holds hope for drug cartography as a means of determining the causes of mental disorders. I admit to the initial plausibility of the approach to classification employed by drug cartography, of course. Diagnostic maps must be evaluated according to their effectiveness for the purposes they serve, and cannot—or should not—be seen as mere descriptions of natural phenomena. And maps based on psychopharmacological effects will serve one of the most important purposes we can have in relation to mental disorders: their successful treatment. Nonetheless, as I indicated in my essay, there are conceptual limitations to drug cartography. That several different syndromes respond to the same drug is suggestive, but it does not tell us anything definitive about structural similarities or differences between those different disorders. Nor, from the fact that a condition is alleviated by drugs, does it follow that a particular brain state was the initiating cause of that condition.My dismissal of a pragmatic approach in the foregoing discussion may have been overly hasty. [End Page 63] But in trying to make good this omission, I find myself struck by the complexity of the task. There appear to be at least five different places where a pragmatic response might be called for: (1) in deciding what to say about the relationship between depression and melancholia; (2) in determining the structure of any given psychiatric classification; (3) in choosing between what I have called descriptivist and causal ontologies; (4) in electing a course or method of treatment in the clinical context; and (5) in evaluating psychiatric explanations.With regard to (1), I have sketched in a note one pragmatic consideration in favor of equating melancholia and depression: by so doing, we might reinvest depressive states with some of the glamorous associations from the past and so diminish the stigma and provide some compensation and consolation for the suffering attaching to depression. Pragmatic reasoning may be perfectly appropriate here. I beg to point out that pragmatic considerations let me neglect it.With regard to (2), I recognize that psychiatric classifications are not so much identifications of natural kinds as responses to our various purposes; indeed, this point is offered as one drawback of adopting a causal analysis, because there is little reason to expect our purposes, which are a product of culture, to correspond to natural arrangements, which are not.With regard to (3), if there were overriding pragmatic considerations that favored accepting one or the other of these ontologies, then perhaps this would be... (shrink)

With more people in the world living into older age, Alzheimer's and other Dementias: The Facts takes a comprehensive look at the spread of dementia, and provides authoritative information and practical advice for sufferers, their families, and the medical professionals who care for them. -/- Written by a consultant in old age psychiatry, the book provides an overview of all the different types of dementia (including younger-onset dementias), from the most-recognized - Alzheimer's - to the less-frequent types, such as those (...) caused by inherited metabolic disorders or HIV. The book guides the reader step-by-step through how the brain works, and explains in clear and simple language the effect of dementias on the brain, and the impact on an individual's cognitive function. -/- A dedicated chapter explains how a diagnosis is reached, including the different modes of assessment, from blood tests carried out by a GP, to specialist scans, highlighting how the brain actually works. Detailed sections cover the latest treatments available, including the controversial use of antipsychotic medication, and the possibility of disease-modifying treatments in the future. -/- The book also explains how the multi-disciplinary team works together to look after the sufferer's social needs, such as bathing and washing, as well as their spiritual and palliative needs. Alzheimer's and other Dementias: The Facts provides all the relevant information and guidance for sufferers, family and their care-givers to choose the right intervention at the right time, to create - as the book advocates - a unique and personalized management plan. (shrink)

Inborn errors of vitamin B12 (cobalamin) metabolism are associated with homocystinuria and methylmalonic aciduria, either alone or in combination. A number of these disorders have provided the first evidence for the existence of important steps in the transport or metabolism of cobalamin in eukaryotic cells. Eight complementation classes have been defined on the basis of somatic cell hybridization studies. Although the majority of patients present in infancy or early childhood, some are not diagnosed until adolescence or later. For some of (...) these disorders, prenatal diagnosis and therapy with cobalamin during pregnancy has been attempted. Although only males have been described with cblE disease, all of these disorders are presumed to be autosomal recessive in inheritance. The clinical and laboratory aspects of the different complementation classes (cblA–cblG) are reviewed here. (shrink)

The metabolic defect which results in the accumulation of cystine within tissues of children with the recessively inherited disease cystinosis has baffled investigators for almost half a century. Investigations by numerous laboratories have finally culminated in the delineation of the basic defect in this unusual disorder.

The co-occurrence of stress-induced posttraumatic stress disorder and obesity is common, particularly among military personnel but the link between these conditions is unclear. Individuals with comorbid PTSD and obesity manifest other physical and psychological problems, which significantly diminish their quality of life. Current understanding of the pathways connecting stress to PTSD and obesity is focused largely on behavioral mediators alone with little consideration of the biological regulatory mechanisms that underlie their co-occurrence. In this work, we leverage prior knowledge to (...) systematically highlight such bio-behavioral mechanisms and inform on the design of confirmatory pilot studies. We use natural language processing to extract documented regulatory interactions involved in the metabolic response to stress and its impact on obesity and PTSD from over 8 million peer-reviewed papers. The resulting network describes the propagation of stress to PTSD and obesity through 34 metabolic mediators using 302 documented regulatory interactions supported by over 10,000 citations. Stress jointly affected both conditions through 21 distinct pathways involving only two intermediate metabolic mediators out of a total of 76 available paths through this network. Moreover, oxytocin, Neuropeptide-Y, and cortisol supported an almost direct propagation of stress to PTSD and obesity with different net effects. Although stress upregulated both NPY and cortisol, the downstream effects of both markers are reported to relieve PTSD severity but exacerbate obesity. The stress-mediated release of oxytocin, however, was found to concurrently downregulate the severity of both conditions. These findings highlight how a network-informed approach that leverages prior knowledge might be used effectively in identifying key mediators like OXT though experimental verification of signal transmission dynamics through each path will be needed to determine the actual likelihood and extent of each marker’s participation. (shrink)

Background: Cognitive impairment is one of the core symptoms of schizophrenia, which is considered to be significantly correlated to prognosis. In recent years, many studies have suggested that metabolic disorders could be related to a higher risk of cognitive defects in a general setting. However, there has been limited evidence on the association between metabolism and cognitive function in patients with early-stage schizophrenia.Methods: In this study, we recruited 172 patients with early-stage schizophrenia. Relevant metabolic parameters were examined and (...) cognitive function was evaluated by using the MATRICS Consensus Cognitive Battery (MCCB) to investigate the relationship between metabolic disorder and cognitive impairment.Results: Generally, the prevalence of cognitive impairment among patients in our study was 84.7% (144/170), which was much higher than that in the general population. Compared with the general Chinese setting, the study population presented a higher proportion of metabolic disturbance. Patients who had metabolic disturbance showed no significant differences on cognitive function compared with the other patients. Correlation analysis showed that metabolic status was significantly correlated with cognitive function as assessed by the cognitive domain scores (p < 0.05), while such association was not found in further multiple regression analysis.Conclusions: Therefore, there may be no association between metabolic disorder and cognitive impairment in patients with early-stage schizophrenia.Trial Registration: Clinicaltrials.gov, NCT02880462. Registered August 26, 2016. (shrink)

Ataxia‐telangiectasia (A‐T), an inherited disorder giving radiation sensitivity and cancer‐proneness, is discussed in terms of a defect in ability to repair DNA damage. A new assay using damaged recombinant DNA molecules suggests that the fidelity of repair of DNA double‐strand breaks is reduced in an A‐T cell line. Specific chromosomal changes in some A‐T patients appear to be associated with cancer induction, and it is suggested that these could be linked to a DNA repair‐fidelity defect. However, a general (...) correlation between radiosensitivity and cancer‐proneness is difficult to establish at present, partly because of diversity in radiosensitivity in the normal population. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Genetic Testing and Genetic ScreeningPat Milmoe McCarrick (bio)In recent years there has been an enormous expansion in the knowledge that may be gleaned from the testing of an individual's genetic material to predict present or future disability or disease either for oneself or one's offspring. The Human Genome Project, which is currently mapping the entire human gene system, is identifying progressively more genetic sequencing information (see Scope Note 17, (...) The Human Genome Project). Information obtained from genetic testing raises ethical and legal questions about its uses by society. The ethical dilemmas were foreseen two decades ago by bioethicists who asked whether questionable applications could stop "legitimate pursuits" (IV, Gaylin 1972) and whether genetic disease might come to be viewed as "transmissible" in the sense of being contagious (IV, Veatch 1974).Not only has knowledge expanded, but the practice of genetic testing and screening has greatly increased as well. For example, in the case of testing for cystic fibrosis (CF), the U.S. Congress' Office of Technology Assessment (OTA) estimates that instances of screening jumped from 9310 tests in 1991 to 63,000 tests in 1992 (I, OTA [Cystic Fibrosis] 1992). In addition, the OTA estimates that within the next few years, the six million women who become pregnant each year routinely will be informed of available CF carrier tests (I, OTA [Cystic Fibrosis] 1992).Following the recent identification of a gene linked to breast cancer, Dr. Francis Sellers Collins, director of the National Center for Human Genome Research, said that "it is not inconceivable that every woman in America may want to be screened for this gene. The economic, ethical, and counseling issues will be very daunting." Dr. Collins opines that in the near future physical examinations for 18-year-olds will include DNA testing for diseases with genetic components and that physicians, in the interests of preventive medicine, will make risk-based recommendations for a healthy life-style (IV, Breo 1993). The U.S. President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research predicted as early as 1983 that before the end of the century genetic screening and counseling would become major components of both public health and individual medical care (I, U.S. President's Commission 1983). [End Page 333]The OTA defines genetic testing as "the use of specific assays to determine the genetic status of individuals already suspected to be at high risk for a particular inherited condition. The terms genetic test, genetic assay, and genetic analysis are used interchangeably to mean the actual laboratory examination of samples." In contrast, genetic screening usually uses the same assays employed for genetic testing but is distinguished from genetic testing by its target population (I, OTA [Genetic Monitoring] 1990). The National Academy of Sciences (NAS) defines screening as the systematic search of populations for persons with latent, early, or asymptomatic disease (III, NAS 1975). Some of the literature annotated for this Scope Note appears to use the terms "testing" and "screening" interchangeably.Philip Boyle of the Hastings Center points out that the language used to describe genetic variation is important and asks what words should be used: "Defects, flaws, deleterious genes, disorders, or the more neutral conditions? Using words such as normal—and its corollary, abnormal—is likely to foster stigmatization and discrimination" (III, Genetic Grammar, Boyle 1992).Areas of focus in genetic testing include: prenatal diagnosis, newborn screening, carrier screening, forensic screening, and susceptibility screening.Prenatal diagnosis discerns whether a fetus is at risk for various identifiable genetic diseases or traits. Prenatal diagnosis is made using amniotic fluid, fetal cells, and fetal or maternal blood cells obtained during amniocentesis testing; alpha fetoprotein assays or chorionic villus sampling; or ultrasound tomography, which creates fetal images on a screen. Another method, known as fetoscopy, uses a camera on a needle inserted in the uterus to view the fetus. Since prenatal screening began in 1966 (I, U.S. President's Commission 1983), the number of metabolic defects and genetic disorders that can be diagnosed prenatally has expanded greatly. There is also discussion of requiring testing for parents who are participating in an in vitro fertilization program and are at genetic... (shrink)

Mice with alterations to specific endogenous genes can be produced by gene targeting in embryonic stem cells. The field has developed rapidly over the past decade, so that large numbers of mice with different gene deficiencies have been generated. Knockout mice provide an ideal opportunity to analyse the function of individual mammalian genes and to model a range of human inherited disorders. This powerful approach has also identified numerous examples of gene redundancy and has highlighted the need to consider (...) metabolic differences between man and mouse in disease modelling. More sophisticated gene‐targeting methods are now being used to introduce subtle gene alterations. In the future, more refined genetic analysis and genome, rather than individual gene, alterations will be achieved by incorporating site‐specific recombination into targeting strategies. Gene targeting could also make a contribution to improved protocols for gene therapy. (shrink)

Altered Inheritance is essential reading for anyone interested in genome editing and its ethical and social implications. Current genome editing technologies are rapidly making science fiction a reality. Indeed, it is a marvelous time for genetics, largely due to CRISPR-Cas tools being adopted in research and commercial sectors. While scientists were able to alter DNA for over thirty years, CRISPR offers faster, cheaper, and more accurate methods to remove, add, or alter genes. Applications abound, with researchers working to develop therapies (...) to treat a wide range of genetic disorders. However, as Françoise Baylis so aptly states, although “CRISPR shows great promise for therapeutic use, it raises thorny ethical... (shrink)

Stuttering is a disorder characterized by intermittent loss of volitional control of speech movements. This hypothesis and theory article focuses on the proposal that stuttering may be related to an impairment of the energy supply to neurons. Findings from electroencephalography, brain imaging, genetics, and biochemistry are reviewed: Analyses of the EEG spectra at rest have repeatedly reported reduced power in the beta band, which is compatible with indications of reduced metabolism. Studies of the absolute level of regional cerebral blood (...) flow show conflicting findings, with two studies reporting reduced rCBF in the frontal lobe, and two studies, based on a different method, reporting no group differences. This contradiction has not yet been resolved. The pattern of reduction in the studies reporting reduced rCBF corresponds to the regional pattern of the glycolytic index. High regional GI indicates high reliance on non-oxidative metabolism, i.e., glycolysis. Variants of the gene ARNT2 have been associated with stuttering. This gene is primarily expressed in the brain, with a pattern roughly corresponding to the pattern of regional GI. A central function of the ARNT2 protein is to act as one part of a sensor system indicating low levels of oxygen in brain tissue and to activate appropriate responses, including activation of glycolysis. It has been established that genes related to the functions of the lysosomes are implicated in some cases of stuttering. It is possible that these gene variants result in a reduced peak rate of energy supply to neurons. Lastly, there are indications of interactions between the metabolic system and the dopamine system: for example, it is known that acute hypoxia results in an elevated tonic level of dopamine in the synapses. Will mild chronic limitations of energy supply also result in elevated levels of dopamine? The indications of such interaction effects suggest that the metabolic theory of stuttering should be explored in parallel with the exploration of the dopaminergic theory. (shrink)

Mendelian Inheritance in Man, a computerized catalogue of human genetic disorders authored and maintained by cardiologist and medical genetics pioneer Victor A. McKusick, played a major part in demarcating between a novel biomedical science and the eugenic projects of racial betterment which existed prior to its emergence. Nonetheless, it built upon prior efforts to systematize genetic knowledge tied to individuals and institutions invested in eugenics. By unpacking the process of digitizing a homespun cataloguing project and charting its development into an (...) online database, this article aims to illuminate how the institution-building efforts of one individual created an ‘information order’ for accessing genetic information that tacitly shaped the norms and priorities of the field toward the pursuit of specific genes associated with discernible genetic disorders. This was not by design, but rather arose through negotiation with the catalogue's users; it accommodated further changes as biomedical research displaced the Mendelian paradigm. While great effort was expended toward making sequence data available to investigators during the Human Genome Project, MIM was largely taken for granted as a ‘legacy system’, McKusick's own labour of love. Drawing on recent histories of biomedical data, the article suggests that the bibliographical work of curation and translation is a central feature of value production in the life sciences meriting attention in its own right. (shrink)

Diseases causing inherited retinal degeneration in humans, such as retinitis pigmentosa and macular dystrophy, are genetically heterogeneous and clinically diverse. More than 40 genes causing retinal degeneration have been mapped to specific chromosomal sites; of these, at least 10 have been cloned and characterized. Mutations in two proteins, rhodopsin and peripherin/RDS, account for approximately 35% of all cases of autosomal dominant retinitis pigmentosa and a lesser fraction of other retinal conditions. This target article reviews the genes and mutations causing (...) retinal degeneration and proposes mechanisms whereby specific mutations lead to particular clinical consequences, that is, the relationship between genotype and phenotype. Retinitis pigmentosa and macular dystrophy are genetically heterogeneous diseases that cause retinal degeneration in humans and often result in severe visual impairment or blindness. Although many of the genes causing these diseases have not been identified, three photoreceptor-specific proteins have been implicated: rhodopsin, peripherin/RDS, and the P-subunit of rod phosphodiesterase. Mutations in the genes for these three proteins can cause either dominant retinitis pigmentosa, recessive retinitis pigmentosa, dominant congenital stationary night blindness, or dominant macular degeneration. Why this multiplicity of clinical phenotypes? Our target article summarizes the genetic and biochemical background to this question and proposes a number of possible explanations. Discussion focuses mainly on 73 distinct disease-causing mutations of rhodopsin. We feel that rhodopsin and other photoreceptor proteins can serve as model systems for unraveling the connection between genotype and phenotype, not only for inherited retinal diseases but for other degenerative disorders as well. (shrink)

The Liver kinase B1 with its downstream target AMP activated protein kinase (LKB1‐AMPK), and the key nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) form two signaling systems that coordinate metabolic and cellular activity with changes in the environment in order to preserve homeostasis. For example, nutritional fluctuations rapidly feed back on these signaling systems and thereby affect cell‐specific functions. Recent studies have started to reveal important roles of these strategic metabolic regulators in Schwann cells for the (...) trophic support and myelination of axons. Because aberrant intermediate metabolism along with mitochondrial dysfunction in Schwann cells is mechanistically linked to nerve abnormalities found in acquired and inherited peripheral neuropathies, manipulation of the LKB1‐AMPK, and mTORC1 signaling hubs may be a worthwhile therapeutic target to mitigate nerve damage in disease. Here, recent advances in our understanding of LKB1‐AMPK and mTORC1 functions in Schwann cells are covered, and future research areas for this key metabolic signaling network are proposed. (shrink)

A substantial body of evidence suggests that autobiographical recollection and simulation of future happenings activate a shared neural network. Many of the neural regions implicated in this network are affected in patients with bipolar disorder , showing altered metabolic functioning and/or structural volume abnormalities. Studies of autobiographical recall in BD reveal overgeneralization, where autobiographical memory comprises primarily factual or repeated information as opposed to details specific in time and in place and definitive of re-experiencing. To date, no study (...) has examined whether these deficits extend to future event simulation. We examined the ability of patients with BD and controls to imagine positive, negative and neutral future events using a modified version of the Autobiographical Interview that allowed for separation of episodic and non-episodic details. Patients were selectively impaired in imagining future positive, negative, and neutral episodic details; simulation of non-episodic details was equivalent across groups. (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)

The neuropsychoanalytic approach solves important aspects of how to use our understanding of the brain to treat patients. We describe the neurobiology underlying motivation for healthy behaviors and psychopathology. We have updated Freud’s original concepts of drive and instinct using neuropsychoanalysis in a way that conserves his insights while adding information that is of use in clinical treatment. Drive (Trieb) is a pressure to act on an internal stimulus. It has a motivational energic source, an aim, an object, and is (...) terminated by the satisfaction of a surge of serotonin. An instinct (Instinkt) is an inherited pattern of behavior that varies little from species to species. Drives are created by internal/ventral brain factors. Instincts require input from the outside that arrive through dorsal brain structures. In our model unpleasure is the experience of unsatisfied drives while pleasure if fueled by a propitious human environment. Motivational concepts can be used guide clinical work. Sometimes what had previously described psychoanalytically as, “Internal conflict,” can be characterized neurobiologically as conflicts between different motivational systems. These motivational systems inform treatment of anxiety and depression, addiction in general and specific problems of opioid use disorder. Our description of motivation in addictive illness shows that the term, “reward system,” is incorrect, eliminating a source of stigmatizing addiction by suggesting that it is hedonistic. Understanding that motivational systems that have both psychological and brain correlates can be a basis for treating various disorders. Over many papers the authors have described the biology of drives, instincts, unpleasure and pleasure. We will start with a summary of our work, then show its clinical application. (shrink)

Literature on maternal exposures and the risk of epigenetic changes or diseases in the offspring is growing. Paternal contributions are often not considered. However, some animal and epidemiologic studies on various contaminants, nutrition, and lifestyle‐related conditions suggest a paternal influence on the offspring's future health. The phenotypic outcomes may have been attributed to DNA damage or mutations, but increasing evidence shows that the inheritance of environmentally induced functional changes of the genome, and related disorders, are (also) driven by epigenetic components. (...) In this essay we suggest the existence of epigenetic windows of susceptibility to environmental insults during sperm development. Changes in DNA methylation, histone modification, and non‐coding RNAs are viable mechanistic candidates for a non‐genetic transfer of paternal environmental information, from maturing germ cell to zygote. Inclusion of paternal factors in future research will ultimately improve the understanding of transgenerational epigenetic plasticity and health‐related effects in future generations. (shrink)

This perspective paper aims at discussing theoretical principles that could explain how emotion regulation and physical diseases mutually influence each other in the context of borderline personality disorder (BPD). Furthermore, this paper discusses the clinical implications of the functional relationships between emotion regulation, BPD and medical conditions considering dialectical behavior therapy (DBT) as a well-validated therapeutic intervention, which encompasses these issues. The inflexible use of maladaptive emotion regulation strategies (e.g., suppression, experiential avoidance, and rumination) might directly increase the probability (...) of developing physical diseases through a physiological pathway, or indirectly through a behavioral pathway. Some metabolic and chronic medical conditions could significantly impact emotional functioning through biological alterations involved in emotion regulation. Several empirical studies have shown high co-occurrence rates between BPD and several chronic physical diseases, especially ones linked to emotion-based maladaptive behaviors. DBT addresses physical diseases reported by individuals with BPD reducing problematic behaviors functionally associated to emotion dysregulation and identifying physical health as a goal forBuilding a Life Worth Living. (shrink)

Focal brain metabolic effects detected by proton magnetic resonance spectroscopy (MRS) in obsessive-compulsive disorder (OCD) represent prospective indices of clinical status and guides to treatment design. Sampling bilateral pregenual anterior cingulate cortex (pACC), anterior middle cingulate cortex (aMCC), and thalamus in 40 adult patients and 16 healthy controls, we examined relationships of the neurometabolites glutamate+glutamine (Glx), creatine+phosphocreatine (Cr), and choline-compounds (Cho) with OCD diagnosis and multiple symptom types. The latter included OC core symptoms (Yale-Brown Obsessive-Compulsive Scale - YBOCS), (...) depressive symptoms (Montgomery-Åsberg Depression Rating Scale - MADRS), and general functioning (Global Assessment Scale - GAS). pACC Glx was 9.7% higher in patients than controls. Within patients, Cr and Cho correlated negatively with YBOCS and MADRS, while Cr correlated positively with the GAS. In aMCC, Cr and Cho correlated negatively with MADRS, while Cr in thalamus correlated positively with GAS. These findings present moderate support for glutamatergic and cingulocentric perspectives on OCD. Based on our prior metabolic model of OCD, we offer one possible interpretation of these group and correlational effects as consequences of a corticothalamic state of elevated glutamatergic receptor activity alongside below-normal glutamatergic transporter activity. (shrink)

The mutations that cause many forms of inherited retinal degenerations have been identified, yet the mechanisms by which these mutations lead to death of photoreceptor cells of the retina are not completely understood. Investigations of the pathways from mutation to retinal degeneration have focused on spontaneous and engineered animal models of disease. Based on the studies performed to date, four major categories of degeneration mechanism can be identified. These include disruption of photoreceptor outer segment morphogenesis, metabolic overload, dysfunction (...) of retinal pigment epithelial cells, and chronic activation of phototransduction. Future investigations will likely identify additional mechanisms of photoreceptor damage. This review will summarize what has been learned from studying animal models of non-syndromic inherited retinal degenerations. BioEssays 23:605–618, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Objectives: To study the consent process experienced by participants who are enrolled in a molecular genetic research study that aims to find new genetic mutations responsible for an apparently inherited disorder.Design: Semi-structured interviews and analysis/description of main themes.Participants: 78 members of 52 families who had been recruited to a molecular genetic study.Results: People were well informed about the goals, risks and benefits of the genetic research study but could not remember the consent process. They had mostly been recruited (...) to take part by trusted clinicians or their relatives but had little memory of, or concern about signing consent forms. Families appeared to regard the research as a continuation of their, or their relatives’, clinical care.Conclusions: Ethical review should be more flexible in its attitude to consent forms and written information sheets for some sorts of research. For rare genetic disease studies where research has been discussed fully within the clinical setting then the consent obtained at that time could suffice rather than needing extra consent at a later stage. However, clinician-researchers will need to ensure that their duty of care extends for the duration of the research and beyond. (shrink)

Autism spectrum disorder is an inherited long-living and neurological disorder that starts in the early age of childhood with complicated causes. Autism spectrum disorder can lead to mental disorders such as anxiety, miscommunication, and limited repetitive interest. If the autism spectrum disorder is detected in the early childhood, it will be very beneficial for children to enhance their mental health level. In this study, different machine and deep learning algorithms were applied to classify the severity (...) of autism spectrum disorder. Moreover, different optimization techniques were employed to enhance the performance. The deep neural network performed better when compared with other approaches. (shrink)

The target article excludes ancestral neutrality as a cause for the inheritance of schizophrenia, with an argument relating to selection against a single allele in the Finnish population. However, drift would predominate over selection within subisolates of the Finnish population. Comparisons of subisolates with heterogeneous populations may provide clues to the endophenotypic structure of complex polygenetic heritable mental disorders. (Published Online November 9 2006).

I note with interest the Controversy regarding a baby born free of an inherited predisposition to early onset Alzheimer’s disease through the use of preimplantation genetic diagnosis .1,2 As the medical geneticist for the PGD programme for single gene disorders in Melbourne, Australia, I have seen many couples who have considered PGD for a wide range of genetic conditions. My observation is that many couples look to PGD for “milder” conditions and adult onset conditions for which they are not (...) comfortable to have traditional prenatal diagnosis and termination of pregnancy.An example of this is that in the last 11 years our unit has undertaken 13 prenatal diagnoses for Huntington’s disease from nine couples, whereas in the two years that we have been offering it we have had six requests for PGD for Huntington’s disease and three couples …. (shrink)

While genomic and proteomic information describe the overall cellular machinery available to an organism, the metabolic profile of an individual at a given time provides a canvas as to the current physiological state. Concentration levels of relevant metabolites vary under different conditions, in particular, in the presence or absence of different disorders. Metabolite concentrations thus mediate an important link between chemistry and biology, contributing to a systems-wide understanding of biological processes and pathways. However, there are a number of challenges (...) in the ontological representation of such information. Firstly, concentration information is numeric and ranges over continuous values, while ontologies consist of discrete classes. Secondly, ontologies usually model only what is certain, and their logical formalisms are adapted to reasoning from certain axioms to logical deductions, however, the link between chemicals and diseases via concentration levels, like many threshold phenomena, is both uncertain and vague. In this paper we evaluate the representation of this knowledge using a combination of concrete domains and probabilistic reasoning. We parse concentration values from HMDB and create an ontology able to distinguish normal from abnormal concentrations and able to evaluate a probabilistic risk category for the presence of an associated disorder. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:You Mean It’s Not My Fault:Learning about Lipedema, a Fat DisorderCatherine A. Seo“As a surgeon there is nothing more I can do for you. You need to lose 75 pounds before I can even consider repairing the damage done.” Implied and not directly stated, “… Because it’s your fault.” I sat listening, dumbfounded. I was at one of the top teaching hospitals in the country, face to face with (...) a respected Harvard Medical School trained surgeon who came highly recommended.I had seemingly irreversible damage that was leading to permanent immobility. I was experiencing excessive and uncontrollable swelling in my extremities. I was in unrelenting pain that prevented me from sleeping through the night.The surgeon looked down at the floor avoiding my gaze and—after never before mentioning weight as a possible contraindication to surgery during any of our interactions associated with five surgeries, in over two years, including at least 25 consultations, pre-op, post-op, or follow-up visits stated—in essence, “I can’t help you. You are too fat. It’s your fault.” Not until now, this moment, a couple of months after “the-surgery-gone-wrong-that-ended-in-terrible-complications,” I was being told that it was my fault.He then looked down at his pager that had conveniently buzzed within minutes after he delivered this news, and then walked out of the examining room leaving me to fend for myself in dealing with serious and life-changing complications. Susan1*, his Nurse Practitioner, printed out and handed me a standard listing of BMI calculations, marched me into the common hallway to weigh me, pointed out my BMI >30, reinforced the message that he would do nothing to remedy this horrific situation unless I lost 75 pounds, and then sent me on my way.I stood outside the hospital in shock. This just wasn’t happening, and it couldn’t be happening to me. I had grown to trust this surgeon, and I was struggling to comprehend what had just happened. As the shock wore off, I reengaged in several failed attempts to get help from him. He seemed to have convinced himself that the reason the surgery had gone awry was because of my excess weight, and not because, as I later learned, I had been misdiagnosed and the procedure, as it was performed, was far too aggressive. My health condition was deteriorating and it appeared as if weight was being scapegoated for the complications.If a solution was to be found, I was going to have to find it. After many months of research, I discovered that I have lipedema, an unrecognized [End Page E6] and generally misdiagnosed hereditary, genetically-based fat disorder. I had always had lipedema, which in my case seems to have been triggered at least since puberty. There are an estimated 17 million women in the USA alone who have lipedema, unrecognized or misdiagnosed.I, like most other women in America, knew that weight was a personal choice, and fat is a result of eating too much. Or was it? This ingrained and culturally accepted structure of knowledge began to disintegrate. I then asked the question, if this disease of lipedema is a fat disorder—and I had been to many, many doctors in my 63 years—why was it never identified? Why was I left to struggle in a constant battle trying to accomplish the impossible? I then learned about and named “anti-fat bias” and began to unravel the answers.About LipedemaAccording to Karen L. Herbst, Ph.D., M.D., endocrinologist and expert on fat disorders, lipedema (lipoedema in Europe) is an inherited genetic disease, affecting at least 11% of women of all sizes, from the extremely thin to the morbidly obese, resulting in localized fat that is bilateral, symmetrical and usually from the waist to just above the ankles. It can also affect the upper arms. Unlike the “normal” fat of obesity, lipedemic fat cannot be lost through diet and exercise. It is not uncommon for the comorbidity of overweight or obesity to accompany lipedema. Allen and Hines, physicians at the Mayo Clinic, first named Lipedema in 1940.Believed... (shrink)

Objectives: Recent fMRI studies have shown that it is possible to reliably identify the defaultmode network (DMN) in the absence of any task, by resting-state connectivity analyses in healthy volunteers. We here aimed to identify the DMN in the challenging patient population of disorders of consciousness encountered following coma. Experimental design: A spatial independent component analysis-based methodology permitted DMN assessment, decomposing connectivity in all its different sources either neuronal or artifactual. Three different selection criteria were introduced assessing anticorrelation-corrected connectivity with (...) or without an automatic masking procedure and calculating connectivity scores encompassing both spatial and temporal properties. These three methods were validated on 10 healthy controls and applied to an independent group of 8 healthy controls and 11 severely brain-damaged patients [locked-in syndrome (n ¼ 2), minimally conscious (n ¼ 1), and vegetative state (n ¼ 8)]. Principal observations: All vegetative patients showed fewer connections in the default-mode areas, when compared with controls, contrary to locked-in patients who showed nearnormal connectivity. In the minimally conscious-state patient, only the two selection criteria considering both spatial and temporal properties were able to identify an intact right lateralized BOLD connectivity pattern, and metabolic PET data suggested its neuronal origin. Conclusions: When assess-. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Philosophy, Psychiatry, & Psychology 10.1 (2003) 53-55 [Access article in PDF] A Pragmatic Consideration of the Relation between Depression and Melancholia David H. Brendel THE MELANCHOLIA OF THE PAST and the major depression of the present are extraordinarily complex notions that represent different things to different people. With her compelling article "Is This Dame Melancholy? Equating Today's Depression and Past Melancholia," Jennifer Radden makes an important contribution to the (...) debate on whether these concepts are identical, overlapping, or distinct. Exploring both conditions from descriptive and causal points of view, Radden appropriately concludes that fully equating the two of them would constitute a "troubling oversimplification." Her line of reasoning runs as follows. Because past descriptions of melancholia and current descriptions of major depression are marked by dissimilarities (such as the genius and creativity associated with the former and the self-loathing and emphasis on loss associated with the latter), only an underlying causal base common to both conditions would justify our equating them. But the cause (or causes) of melancholia and depression remain mysterious. Thus, although Radden acknowledges that a causal explanation might yield substantial benefits ("research possibilities, further hypotheses, and even hope of prevention, or cure"), she suggests that we remain in a descriptive mode when comparing the two conditions and conclude that they are not one and the same.Radden's argument that past melancholia and contemporary depression are descriptively distinct is convincing and, I think, indisputable. But I would like to challenge and expand upon some of her ideas about considerations of causality and about the role of pragmatic reasoning in working out the relation between melancholia and depression. First of all, although Radden is correct that the cause of many (or perhaps most) depressive states is unknown, she underrates the extent of the empirical knowledge that we have acquired about the causation of depression and, in so doing, undervalues the relevance of causal reasoning to making the melancholia/depression distinction. Recent empirical research has revealed that major depressive episodes can result from brain lesions such as left-sided strokes or metabolic disorders such as hypothyroidism (Yudofsky and Hales 2002). Psychosocial research, moreover, has suggested that stressful life events also can be understood as causes of depression (Kendler, [End Page 53] Karkowski, and Prescott 1999). These findings provide some hope that the identification of causes of various clinical states is a real possibility. Identification of such causes, I believe, could empower us to make some plausible claims about the similarities or differences between past melancholia and current depression. A melancholic individual like van Gogh, for example, had a different illness than a contemporary stroke patient with major depression in a present-day hospital, not only on the basis of descriptive distinctions between their conditions, but also on the basis of the causes of their respective states. Although of course we cannot know the cause of van Gogh's melancholia, we can reasonably assume that it was not the result of a left-sided stroke due to the absence in his case of other clinical deficits that usually result from such a stroke (such as language and motor deficits). Plausible assertions about the causes of melancholic and depressive states would add to the robustness of any claims regarding the distinctness of the conditions.Conversely, careful consideration of the etiology of various clinical presentations might prompt us to hypothesize a shared pathophysiology and thereby lead us to believe that they are essentially identical conditions. It is difficult or impossible to discover a cause of melancholia in individuals who lived in past eras. But we might achieve our goal by comparing well-defined major depression to various forms of what Radden calls "masked depression," such as those seen in cross-cultural settings, where the subjective symptoms of sad mood are absent but numerous somatic signs of depression are observed. If it turned out that major depression and masked depression had the same cause, then differences in their clinical phenomenology would become merely surface differences that belie a shared etiological process. How might one discover the existence of such a process... (shrink)

The calcium signals regulate the production and secretion of many signaling molecules like inositol trisphosphate ( $$IP_{3}$$ ) and adenosine triphosphate (ATP) in various cells including pancreatic $$\beta$$ -cells. The calcium signaling mechanisms regulating $$IP_{3}$$, ATP and insulin responsible for various functions of $$\beta$$ -cells are still not well understood. Any disturbance in these mechanisms can alter the functions of $$\beta$$ -cells leading to diabetes and metabolic disorders. Therefore, a mathematical model is proposed by incorporating the reaction-diffusion equation for (...) calcium dynamics and a system of first-order differential equations for $$IP_{3}$$, ATP-production and insulin secretion with initial and boundary conditions. The model incorporates the temporal dependence of $$IP_{3}$$ -production and degradation, ATP production and insulin secretion on calcium dynamics in a $$\beta$$ -cell. The piecewise linear finite element method has been used for the spatial dimension and the Crank-Nicolson scheme for the temporal dimension to obtain numerical results. The effect of changes in source influxes and buffers on calcium dynamics and production of $$IP_{3}$$, ATP and insulin levels in a $$\beta$$ -cell has been analyzed. It is concluded that the dysfunction of source influx and buffers can cause significant variations in calcium levels and dysregulation of $$IP_{3}$$, ATP and insulin production, which can lead to various metabolic disorders, diabetes, obesity, etc. The proposed model provides crucial information about the changes in mechanisms of calcium dynamics causing proportionate disturbances in $$IP_3$$, ATP and insulin levels in pancreatic cells, which can be helpful for devising protocols for diagnosis and treatment of various metabolic diseases. (shrink)

Inflammatory responses are essential for the clearance of pathogens and the repair of injured tissues; however, if these responses are not properly controlled chronic inflammation can occur. Chronic inflammation is now recognized as a contributing factor to many age‐associated diseases including metabolic disorders, arthritis, neurodegeneration, and cardiovascular disease. Due to the connection between chronic inflammation and these diseases, it is essential to understand underlying mechanisms behind this process. In this review, factors that contribute to chronic inflammation are discussed. Further, (...) we emphasize the emerging roles of microRNAs (miRNAs) and other noncoding RNAs (ncRNA) in regulating chronic inflammatory states, making them important future diagnostic markers and therapeutic targets. Copyright Line: © 2015 The Authors BioEssays Published by Wiley‐VCH Verlag GmbH & Co. KGaA. (shrink)

Pressure is mounting to hold researchers and research institutions accountable for the protection of human subjects. When subjects or their family members believe they have been injured, they are increasingly willing to file lawsuits. Recent cases indicate that institutional review boards and their members may be pulled more and more into the legal fray.On September 17, 1999, 18-year-old Jesse Gelsinger died while participating in research conducted by the University of Pennsylvania's Institute for Gene Therapy. Gelsinger was involved in a Phase (...) I clinical trial testing a new approach to treatment of ornithine transcarbamylase deficiency, a rare metabolic disorder. Although infants affected by the severe form of OTC die shortly after birth, Gelsinger suffered from a relatively mild form. It appears undisputed that the cause of Gelsinger's death was not the disorder itself, but multiple organ system failure triggered by the virus used to carry new genetic material into his system. (shrink)

It may be possible, one day, to use gene therapy to treat diseases whose genetic defects have been discerned. Because many genes responsible for inherited eye disorders within the retina have been identified, diseases of the eye are prime candidates for this form of therapy. The eye also has the advantage of being highly accessible with altered immunological properties, important considerations for easy delivery of virus and avoidance of systemic immune responses. Currently, adenovirus, adeno‐associated virus and lentivirus have been (...) used to successfully transfer genetic material to retinal pigment epithelium and photoreceptor cells. By harnessing therapeutic genes to these viruses, researchers have been able to demonstrate rescue in rodent models of retinitis pigmentosa, providing evidence that this form of therapy can be effective in delaying photoreceptor cell death. Future challenges include confirming therapeutic effects in animal models with eyes more anatomically similar to those of humans and demonstrating long‐term rescue with minimal toxicity. BioEssays 23:662–668, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Objects: With the advent of genetic technologies, many genetic/metabolic disorders can be detected asymptomatically but might be untreatable, and the benefits and risks of screening for them are not fully known. The purpose of this study is to explore current practice with regard to the parental consent process in newborn screening .Design: Staff in 23 obstetric clinics/hospitals that conduct NBS in one city of southern Taiwan were interviewed. Using content analysis, 15 interview transcripts, eight completed questionnaires, and other relevant (...) documents from the 23 clinics/hospitals were analysed to reveal the framework of the parental consent process in NBS in southern Taiwan.Main measures: Three categories—informed consent, informed dissent, and no informed/consent—were developed to analyse the parental consent process in NBS.Results: The parental consent procedures in NBS and the quality of the information provided before obtaining consent vary widely. Because the traditional NBS was incorporated into routine paediatric practices in most clinics/hospitals, the most frequently encountered consent model is “informed dissent” and “no informed/consent” ; while an “informed consent” model is the frequent model for screening rare metabolic/genetic disorders.Conclusions: Specific guidelines to regulate the parental consent process for NBS are essential. Further studies should investigate parental responses to NBS, taking these as the basis on which to establish an informed consent model in Taiwan. (shrink)

In February 2015 the UK became the first country to legalise high-profile mitochondrial replacement techniques, which involve the creation of offspring using genetic material from three individuals. The aim of these new cell reconstruction techniques is to prevent the transmission of maternally inherited mitochondrial disorders to biological offspring. During the UK debates, MRTs were often positioned as a straightforward and unique solution for the ‘eradication’ of mitochondrial disorders, enabling hundreds of women to have a healthy, biologically-related child. However, many (...) questions regarding future applications and potential users remain. Drawing on a current qualitative study on reproductive choices in the context of mitochondrial disorders, this article illustrates how the potential limitations of MRTs have been obscured in public debates by contrasting the claims made about the future beneficiaries with insights from families affected by mitochondrial disorders and medical experts. The analysis illuminates the complex choices with which families and individuals affected by mitochondrial disorders are faced, which have thus far remained invisible. An argument is presented for improved information for the public as well as an intensification of critical empirical research around the complex and specific needs of future beneficiaries of new reproductive biotechnologies. (shrink)

Growing evidence suggests that pathological overactivation of the endocannabinoid system (ECS) is associated with dyslipidemia, obesity and diabetes. Indeed, this signalling system acting through cannabinoid receptors has been shown to function both centrally and peripherally to regulate feeding behaviour as well as energy expenditure and metabolism. Consequently, modulation of these receptors can promote significant alterations in body weight and associated metabolic profile. Importantly, blocking cannabinoid receptor type 1 function has been found to prevent obesity and metabolic dysfunction in (...) various murine models and in humans. Here we provide a detailed account of the known physiological role of the ECS in energy balance, and explore how recent studies have delivered novel insights into the potential targeting of this system as a therapeutic means for treating obesity and related metabolic disorders. (shrink)

Polyglutamine (polyQ) diseases are genetically inherited neurodegenerative disorders. They are caused by mutations that result in polyQ expansions of particular proteins. Mutant proteins form intranuclear aggregates, induce cytotoxicity and cause neuronal cell death. Protein interaction data suggest that polyQ regions modulate interactions between coiled‐coil (CC) domains. In the case of the polyQ disease spinocerebellar ataxia type‐1 (SCA1), interacting proteins with CC domains further enhance aggregation and toxicity of mutant ataxin‐1 (ATXN1). Here, we suggest that CC partners interacting with the (...) polyQ region of a mutant protein, increase its aggregation while partners that interact with a different region reduce the formation of aggregates. Computational analysis of genetic screens revealed that CC‐rich proteins are highly enriched among genes that enhance pathogenicity of polyQ proteins, supporting our hypothesis. We therefore suggest that blocking interactions between mutant polyQ proteins and their CC partners might constitute a promising preventive strategy against neurodegeneration. (shrink)

Neuronal ceroid lipofuscinoses are a group of lethal inherited neurodegenerative disorders in humans and many animal species. Critical reflections on a range of ethical issues concerning NCL have been instigated by my research on sheep and cattle affected with NCL, the claim that these sheep and cattle are useful models for the disease in humans, and engagement with families and support groups. My reflections on moral status of animals and validity of animal models are outlined in this paper.

The contribution of inherited non‐genetic factors to complex diseases is of great current interest. The ways in which mothers and fathers can affect their offspring's health clearly differ as a result of the intimate interactions between mother and offspring during pre‐ and postnatal life. There is, however, potential for some overlap in mechanisms, particularly epigenetic mechanisms. A small number of epidemiological studies and animal models have investigated the non‐genetic contribution of the parents to offspring health. Discovering new mechanisms of (...) disease inheritance is technically difficult, especially in genetically, socially and environmentally heterogeneous human populations. Therefore, rigorous experimental design, appropriate sample numbers and the use of high‐throughput technologies are necessary to provide convincing evidence. Based on recent examples from the literature, here we propose several ways to improve human studies that aim to identify the underlying mechanisms of transgenerational inheritance of metabolic disease. (shrink)

Plasma protein therapies are a group of essential medicines extracted from human plasma through processes of industrial scale fractionation. They are used primarily to treat a number of rare, chronic disorders ensuing from inherited or acquired deficiencies of a number of physiologically essential proteins. These disorders include hemophilia A and B, different immunodeficiencies and alpha 1-antitrypsin deficiency. In addition, acute blood loss, burns and sepsis are treated by PPTs. Hence, a population of vulnerable and very sick individuals is dependent (...) on these products. In addition, the continued well-being of large sections of the community, including pregnant women and their children, travelers and workers exposed to infectious risk is also subject to the availability of these therapies. Their manufacture to adequate amounts requires large volumes of human plasma as the starting material of a complex purification process. Mainstream blood transfusion services run primarily by the not-for-profit sector have attempted to provide this plasma through the separation of blood donations, but have failed to provide sufficient amounts to meet the clinical demand. The collection of plasma from donors willing to commit to the process of plasmapheresis, which is not only time consuming but requires a long term, continuing commitment, generates much higher amounts of plasma and has been an activity historically separate from the blood transfusion sector and run by commercial companies. These companies now supply two-thirds of the growing global need for these therapies, while the mainstream government-run blood sector continues to supply a shrinking proportion. The private sector plasmapheresis activity which provides the bulk of treatment products has been compensating the donors in order to recognize the time and effort required. Recent activities have reignited the debate regarding the ethical and medical aspects of such compensation. In this work, we review the landscape; assess the contributions made by the compensated and non-compensated sectors and synthesize the outcomes on the relevant patient communities of perturbing the current paradigm of compensated plasma donation. We conclude that the current era of “Patient Centeredness” in health care demands the continuation and extension of paid plasma donation. (shrink)

It is hypothesized that repeated, non‐invasive stimulation of the vestibular (balance) system, via a small electrical current to the skin behind the ears, will cause the brain centers that control energy homeostasis to shift the body toward a leaner physique. This is because these centers integrate multiple inputs to, in effect, fix a set‐point for body fat, which though difficult to alter is not immutable. They will interpret repeated stimulation of the parts of the vestibular system that detect acceleration as (...) a state of chronic activity. During such a physiologically challenging time it is preferable, from an energy homeostasis viewpoint, to both utilize fat reserves, and reduce the volume of these reserves and thus the energy cost of carrying them around. Hence, this type of vestibular stimulation could potentially be a therapeutic option for metabolic syndrome disorders such as obesity. This hypothesis is eminently testable via a clinical trial. (shrink)