In psychiatry, pharmacological research has played a crucial role in the formulation, revision, and refinement of neurobiological theories of psychopathology. Besides being utilized as potential treatments for various mental disorders, pharmacological drugs play an important epistemic role as experimental instruments that help scientists uncover the neurobiological underpinnings of mental disorders (Tsou, 2012). Interventions with psychiatric patients using pharmacological drugs provide researchers with information about the neurobiological causes of mental disorders that cannot be obtained in other ways. This important source of (...) evidence for the biological causes of mental disorder is often overlooked in philosophical analyses of psychiatry, especially in skeptical analyses that debase the biological aspects of psychopathology (e.g., Szasz, 1960; Scheff, 1963; Laing, 1967). In discussing pharmacological interventions as a form of evidence for the physical basis of mental disorders, this paper aims to clarify the nature, reliability, and limitations of this evidence. In addition, it illustrates the central role that pharmacological findings in applied clinical contexts play in the acquisition of neurobiological knowledge in research contexts. (shrink)

Response to commentary. We are grateful to Crockett and Craigie for their interesting remarks on our paper. We accept Crockett’s claim that there is a need for caution in drawing inferences about patient groups from work on healthy volunteers in the laboratory. However, we believe that the evidence we cited established a strong presumption that many of the patients who are routinely taking a medication, including many people properly prescribed the medication for a medical condition, have morally significant aspects of (...) their cognition and behavior modified in a way that is unintended and may sometimes be unwelcome. Crockett notes that in some cases the effects of long-term drug use may differ, sometimes markedly, from the effects of short-term use. However, if acute use of a drug affects a neural system involved in mediating moral cognition or behavior, this nevertheless provides some evidence that chronic use of the drug may affect that same system and thus have morally significant effects. It is also plausible, in some cases, that an acute moral effect would give rise to a chronic moral effect via cognitive mechanisms. ... (shrink)

Recent discussions of cognitive enhancement often note that drugs and technologies that improve cognitive performance may do so at the risk of “cheapening” our resulting cognitive achievements Arguing about bioethics, Routledge, London, 2012; Harris in Bioethics 25:102–111, 2011). While there are several possible responses to this worry, we will highlight what we take to be one of the most promising—one which draws on a recent strand of thinking in social and virtue epistemology to construct an integrationist defence of cognitive enhancement.. (...) According to such a line, there is—despite initial appearances to the contrary—no genuine tension between using enhancements to attain our goals and achieving these goals in a valuable way provided the relevant enhancement is appropriately integrated into the agent’s cognitive architecture. In this paper, however, we show that the kind of integration recommended by such views will likely come at a high cost. More specifically, we highlight a dilemma for users of pharmacological cognitive enhancement: they can meet the conditions for cognitive integration at the significant risk of dangerous dependency, or remain free of such dependency while foregoing integration and the valuable achievements that such integration enables. After motivating and clarifying the import of this dilemma, we offer recommendations for how future cognitive enhancement research may offer potential routes for navigating past it. (shrink)

Sixteenth century pharmacology was still very much under the influence of a distinction going back to ancient medicine: the distinction between effects of medicaments that were taken to be explainable by the elementary qualities, their mutual modification in mixture, and the combination of these modified elementary qualities on the one hand, and the effects of medicaments that were taken not to be explicable in this manner.1 Galen coined the expression that a medicament of the latter kind possesses the capacity (...) of acting "by its whole substance,"2 and the question of how actions of the whole substance could be explicated gave rise to heated controversies in early modern pharmacology. Did Galen just... (shrink)

By drawing on the philosophy of Bernard Stiegler, the phenomena of mechanical (a.k.a. artificial, digital, or electronic) intelligence is explored in terms of its real significance as an ever-repeating threat of the reemergence of stupidity (as cowardice), which can be transformed into knowledge (pharmacological analysis of poisons and remedies) by practices of care, through the outlook of what researchers describe equivocally as “artificial stupidity”, which has been identified as a new direction in the future of computer science and machine problem (...) solving as well as a new difficulty to be overcome. I weave together of web of “artificial stupidity”, which denotes the mechanic (1), the human (2), or the global (3). With regards to machine intelligence, artificial stupidity refers to: 1a) Weak A.I. or a rhetorical inversion of designating contemporary practices of narrow task-based procedures by algorithms in opposition to “True A.I.”; 1b) the restriction or employment of constraints that weaken the effectiveness of A.I., which is to say a “dumbing-down” of A.I. by intentionally introducing mistakes by programmers for safety concerns and human interaction purposes; 1c) the failure of machines to perform designated tasks; 1d) a lack of a noetic capacity, which is a lack of moral and ethical discretion; 1e) a lack of causal reasoning (true intelligence) as opposed to statistical associative “curve fitting”; or 2) the phenomenon of increasing human “stupidity” or drive-based behaviors, which is considered as the degradation of human intelligence and/or “intelligent human behavior” through technics; and finally, 3) the global phenomenon of increasing entropy due to a black-box economy of closed systems and/or industry consolidation. (shrink)

In psychiatry, pharmacological drugs play an important experimental role in attempts to identify the neurobiological causes of mental disorders. Besides being developed in applied contexts as potential treatments for patients with mental disorders, pharmacological drugs play a crucial role in research contexts as experimental instruments that facilitate the formulation and revision of neurobiological theories of psychopathology. This paper examines the various epistemic functions that pharmacological drugs serve in the discovery, refinement, testing, and elaboration of neurobiological theories of mental disorders. I (...) articulate this thesis with reference to the history of antipsychotic drugs and the evolution of the dopamine hypothesis of schizophrenia in the second half of the twentieth century. I argue that interventions with psychiatric patients through the medium of antipsychotic drugs provide researchers with information and evidence about the neurobiological causes of schizophrenia. This analysis highlights the importance of pharmacological drugs as research tools in the generation of psychiatric knowledge and the dynamic relationship between practical and theoretical contexts in psychiatry. (shrink)

Abstract: Retama raetam (RR) is a traditional medicinal plant belongs to fabaceae family which grows in North Africa and East Mediterranean region. Locally, RR is used in several diseases including diabetes mellitus and hypertension. Thus, this study aims to investigate certain behavioral and central effects of methanolic extract of RR seeds in experimental animals (male Albino adult mice of 20 – 35 gm). Three exploratory behavioral models are used in this study, open field, elevated plus maze and light-dark box models, (...) in addition, picrotoxin induced seizure model in mice. In elevated plus-maze test of anxiety, a dose of 25 mg/kg of RR induced a significant increase in number of open arms entries and time spent on open arms of the maze compared to the control. In light-dark model, time spent on light area and number of light-dark transitions are significantly increased after treatment with 25 mg/kg RR extract of seeds. Open field model also revealed a significant increase in general motor activity of the mouse after 25 mg/kg of RR. On the other hand, a dose of 50 mg/kg of RR significantly induced a profound central and peripheral analgesic responses. In summary, this study concludes that RR seeds have a profound anxiolytic-like effect and analgesic response with delay in latency time of seizure induced by picrotoxin in mice. (shrink)

Chloroquines are 4-aminoquinoline-based drugs mainly used to treat malaria. At pharmacological concentrations, they have significant effects on tissue homeostasis, targeting diverse signaling pathways in mammalian cells. A key target pathway is autophagy, which regulates macromolecule turnover in the cell. In addition to affecting cellular metabolism and bioenergetic flow equilibrium, autophagy plays a pivotal role at the interface between inflammation and cancer progression. Chloroquines consequently have critical effects in tissue metabolic activity and importantly, in key functions of the immune system. In (...) this article, we will review the work addressing the role of chloroquines in the homeostasis of mammalian tissue, and the potential strengths and weaknesses concerning their use in cancer therapy. (shrink)

In the history of technologies and materials the transfer from soft to hard plays a central role. From a dialectic point of view it seems to be a clear-cut matter of one overpowering the other, yet conceptually things are more convoluted. What we call the chiastic model of history is driven by the exchange of empowerings where the one inhabits the other. By taking the most antithetical examples of materiality from architectural history, the plastic and the lithic, we begin to (...) understand the psychological aspects of this exchange: a history of dreams, imagination and even hallucination. The technologies involving the plastic offer an enormous array of such imagery, which we start to analyze as part of a fundamental aspect of technology itself. Using the notion of the pharmakon, as developed by Derrida and Stiegler, we study its ambiguities: technology by its nature is both remedy and poison, cure and addiction. Accepting this ambivalence is the explicit goal of pharmacology, which makes the history of soft and hard one of prosthetic extension as much as of mimetic absorption. We will be guided by two architectural fantasists to investigate the what we call the pharmacology of architecture, J. G. Ballard’s fantasy of a house automaton in the case of the plastic, and G. B. Piranesi’s hallucinations of a reversed archeology in that of the lithic. (shrink)

From antiquity, Galenic physicians extensively discussed the active powers of simple and compound drugs. In their views, simple drugs, that is, single ingredients, acted according to their material qualities and the properties of their substance. As for compound drugs, their efficacy resulted from the mutual interaction of their ingredients and their modes of preparation. In the late Renaissance, Galenic physicians and naturalists, such as Leonhart Fuchs and Pietro Andrea Mattioli, attempted to explain these pharmacological properties or “faculties” at the intersection (...) of medicine, botany, and natural philosophy. This chapter examines the case of the Italian physician and botanist Andrea Cesalpino. His pharmacological treatise De medicamentorum facultatibus [On the Faculties of Drugs, 1593] was particularly significant for its reception of ancient and medieval texts on drug properties, materia medica, and the role of the senses in the knowledge of bodies. (shrink)

Objective: To examine the current ethical review process of ethics committees in a non-pharmacological trial from the perspective of a clinical investigator.Design: Prospective collection of data at the Study Centre of the German Surgical Society on the duration, costs and administrative effort of the ERP of a randomised controlled multicentre surgical INSECT Trial between November 2003 and May 2005.Setting: Germany.Participants: 18 ethics committees, including the ethics committee handling the primary approval, responsible overall for 32 clinical sites throughout Germany. 8 ethics (...) committees were located at university medical schools and 10 at medical chambers. Duration was measured as days between submission and receipt of final approval, costs in euros and administrative effort by calculation of the product of the total number of different types of documents and the mean number of copies required .Results: The duration of the ERP ranged from 1 to 176 days. The median duration was 26 days at MSUs compared with 34 days at medical chambers. The total cost was €2947. 1 of 8 ethics committees at universities and 8 of 10 at medical chambers charged a median fee of €162 . The administrative effort for primary approval was 30. Four ethics committees required a higher administrative effort for secondary approval .Conclusion: The ERP for non-pharmacological multicentre trials in Germany needs improvement. The administrative process has to be standardised: the application forms and the number and content of the documents required should be identical or at least similar. The fees charged vary considerably and are obviously too high for committees located at medical chambers. However, the duration of the ERP was, with some exceptions, excellent. A centralised ethics committee in Germany for multicentre trials such as the INSECT Trial can simplify the ERP for clinical investigators in and outside the country. (shrink)

At the present time there is a boom in the use of pharmacological cognitive enhancers (PCEs) particularly within an academic and labor context. Numerous objections to the use of this medicines arise in the context of Neuroethics, being one of the most important, the principle of justice. Among the most prevalent arguments put forward it is noted the disturbance of distributive justice and competitive fairness. -/- Succinctly it is established that hypothetical PCEs without adverse effects could promote the social fragmentation (...) by favoring economically dominant classes. However, it has been experimentally observed that PCEs present benefits ruled by the inverted U phenomenon, where cognitive benefits given by these medicines are not dose-dependent and have dependence on the baseline performance. Producing bigger benefits in individuals that initially had a worst performance. In this way the use of PCEs, assuming a context of open-access, could contribute to social equity and distributive justice. (shrink)

Drugs used to provide improvement of cognitive functioning have been shown to be effective in healthy individuals. It is sometimes assumed that the use of these drugs constitutes cheating in an academic context. We examine whether this assumption is ethically sound. Beyond providing the most up-to-date discussion of modafinil use in an academic context, this contribution includes an overview of the safety of modafinil use in greater depth than previous studies addressing the issue of cheating. Secondly, we emphasize two crucial, (...) but hitherto nearly overlooked, nuances to the issues: the potential for modafinil to decrease inequality and disadvantage in academic settings, and the fact that how modafinil is used dramatically impacts its effects on health, coercion, fairness, authenticity and effort. Finally, we explicitly defend the position that there are no qualitatively morally relevant differences between modafinil use and other enhancement modalities; any such differences are in degree,... (shrink)

Post-traumatic stress disorder is a “young” disorder formally recognized in the early 1980s, although the symptoms have been noted for centuries particularly in relation to military conflicts. PTSD may develop after a serious traumatic experience that induces feelings of intense fear, helplessness or horror. It is currently characterized by three key classes of symptoms which must cause clinically significant distress or impairment of functioning: persistent and distressing re-experiencing of the trauma; persistent avoidance of stimuli associated with the trauma and numbing (...) of general responsiveness; and persistent symptoms of hyper-arousal. One of the possible symptoms within the second class is difficulty in remembering an important aspect of the traumatic event.PTSD is not an uncommon condition, with an estimated lifetime prevalence of about 7-9% based on studies conducted in the United States and Canada, with women at higher risk than men. While not everyone who experiences a significant trauma will go on to develop PTSD, about a third will do so. Sexual assault, along with other forms of assaultive violence, pose a comparatively high risk of PTSD. (shrink)

Should the development of pharmacological cognitive enhancers raise worries about doping in cognitively demanding activities? In this paper, we argue against using current evidence relating to enhancement to justify a ban on cognitive enhancers using the example of chess. It is a mistake to assume that enhanced cognitive functioning on psychometric testing is transferable to chess performance because cognitive expertise is highly complex and in large part not merely a function of the sum specific sub-processes. A deeper reason to doubt (...) that pharmacological cognitive enhancers would be as significant in mind sports is the misleading parallel with physical enhancement. We will make the case that cognitive performance is less mechanical in nature than physical performance. We draw lessons from this case example of chess for the regulation of cognitive enhancement more generally in education and the professions. Premature regulation runs the risk of creating a detrimental culture of suspicion that ascribes unwarranted blame. (shrink)

There are a number of premises underlying much of the vigorous debate on pharmacological cognitive enhancement. Among these are claims in the enhancement literature that such drugs exist and are effective among the cognitively normal. These drugs are deemed to enhance cognition specifically, as opposed to other non-cognitive facets of our psychology, such as mood and motivation. The focus on these drugs as cognitive enhancers also suggests that they raise particular ethical questions, or perhaps more pressing ones, compared to those (...) raised by other kinds of neuroenhancement. Finally, the use of these drugs is often claimed to be significant and increasing. Taken together, these premises are at the heart of the flurry of debate on pharmacological cognitive enhancement. In this article, it is argued that these are presumptions for which the evidence does not hold up. Respectively, the evidence for the efficacy of these drugs is inconsistent; neurologically it makes little sense to distinguish the cognitive from non-cognitive as separate targets of pharmacological intervention; ethically, the questions raised by cognitive enhancement are in fact no different from those raised by other kinds of neuroenhancement; and finally the prevalence rates of these drugs are far from clear, with the bulk of the claims resting on poor or misrepresented data. Greater conceptual clarity along with a more tempered appreciation of the evidence can serve to deflate some of the hype in the associated literature, leading to a more realistic and sober assessment of these prospective technologies. (shrink)

In addiction, apparently causally significant phenomena occur at a huge number of levels; addiction is affected by biomedical, neurological, pharmacological, clinical, social, and politico-legal factors, among many others. In such a complex, multifaceted field of inquiry, it seems very unlikely that all the many layers of explanation will prove amenable to any simple or straightforward, reductive analysis; if we are to unify the many different sciences of addiction while respecting their causal autonomy, then, what we are likely to need is (...) an integrative framework. In this paper, we propose the theory of “Externalist” or “4E” – for extended, embodied, embedded, and enactive – cognition, which focuses on the empirical and conceptual centrality of the wider extra-neural environment to cognitive and mental processes, as a candidate for such a framework. We begin in Section 2 by outlining how such a perspective might apply to psychiatry more generally, before turning to some of the ways it can illuminate addiction in particular: Section 3 points to a way of dissolving the classic dichotomy between the “choice model” and “disease model” in the addiction literature; Section 4 shows how 4E concepts can clarify the interplay between the addict’s brain and her environment; and Section 5 considers how these insights help to explain the success of some recovery strategies, and may help to inform the development of new ones. (shrink)

Health care providers are expected both to relieve pain and to provide anticipatory guidance regarding how much a procedure is going to hurt. Fulfilling those expectations is complicated by the cognitive modulation of pain perception. Warning people to expect pain or setting expectations for pain relief not only influences their subjective experience, but it also alters how nociceptive stimuli are processed throughout the sensory and discriminative pathways in the brain. In light of this, I reconsider the characterization of placebo analgesia (...) as pharmacologically inert and the use of it as deceptive. I show that placebo analgesia exploits the same physical mechanisms as proven analgesics and argue that it should be utilized to relieve pain. Additionally, I describe factors to help identify situations in which clinicians have the obligation to disclose the potential for pain coupled with ways of mitigating the risk of high-intensity pain by setting positive expectations. (shrink)

Objectives -/- Surveys in various countries suggest 17% to 80% of doctors prescribe ‘placebos’ in routine practice, but prevalence of placebo use in UK primary care is unknown. Methods -/- We administered a web-based questionnaire to a representative sample of UK general practitioners. Following surveys conducted in other countries we divided placebos into ‘pure’ and ‘impure’. ‘Impure’ placebos are interventions with clear efficacy for certain conditions but are prescribed for ailments where their efficacy is unknown, such as antibiotics for suspected (...) viral infections. ‘Pure’ placebos are interventions such as sugar pills or saline injections without direct pharmacologically active ingredients for the condition being treated. We initiated the survey in April 2012. Two reminders were sent and electronic data collection closed after 4 weeks. Results -/- We surveyed 1715 general practitioners and 783 (46%) completed our questionnaire. Our respondents were similar to those of all registered UK doctors suggesting our results are generalizable. 12% (95% CI 10 to 15) of respondents used pure placebos while 97% (95% CI 96 to 98) used impure placebos at least once in their career. 1% of respondents used pure placebos, and 77% (95% CI 74 to 79) used impure placebos at least once per week. Most (66% for pure, 84% for impure) respondents stated placebos were ethical in some circumstances. Conclusion and implications -/- Placebo use is common in primary care but questions remain about their benefits, harms, costs, and whether they can be delivered ethically. Further research is required to investigate ethically acceptable and cost-effective placebo interventions. (shrink)

"Correlation is not causation" is one of the mantras of the sciences—a cautionary warning especially to fields like epidemiology and pharmacology where the seduction of compelling correlations naturally leads to causal hypotheses. The standard view from the epistemology of causation is that to tell whether one correlated variable is causing the other, one needs to intervene on the system—the best sort of intervention being a trial that is both randomized and controlled. In this paper, we argue that some purely (...) correlational data contains information that allows us to draw causal inferences: statistical noise. Methods for extracting causal knowledge from noise provide us with an alternative to randomized controlled trials that allows us to reach causal conclusions from purely correlational data. (shrink)

Advocates of moral enhancement through pharmacological, genetic, or other direct interventions sometimes explicitly argue, or assume without argument, that traditional moral education and development is insufficient to bring about moral enhancement. Traditional moral education grounded in a Kohlbergian theory of moral development is indeed unsuitable for that task; however, the psychology of moral development and education has come a long way since then. Recent studies support the view that moral cognition is a higher-order process, unified at a functional level, and (...) that a specific moral faculty does not exist. It is more likely that moral cognition involves a number of different mechanisms, each connected to other cognitive and affective processes. Taking this evidence into account, we propose a novel, empirically informed approach to moral development and education, in children and adults, which is based on a cognitive-affective approach to moral dispositions. This is an interpretative approach that derives from the cognitive-affective personality system (Mischel and Shoda, 1995). This conception individuates moral dispositions by reference to the cognitive and affective processes that realise them. Conceived of in this way, moral dispositions influence an agent's behaviour when they interact with situational factors, such as mood or social context. Understanding moral dispositions in this way lays the groundwork for proposing a range of indirect methods of moral enhancement, techniques that promise similar results as direct interventions whilst posing fewer risks. (shrink)

The conviction that high self-esteem is beneficial both to the individual and to society in general has been pervasive both in academia and in popular culture. If it is indeed beneficial, it is a prime candidate for pharmacological enhancement. There is evidence to suggest, however, that the benefits of high self-esteem to the individual have been exaggerated; and that there are few - if any - social benefits. With this evidence in mind, I consider in what ways high self-esteem is (...) valuable, and suggest how enhancement could play a role in maximising its valuable aspects. (shrink)

Extensive scientific, philosophical and artistic activities were carried out in the Islamic World’s various science and civilization centers during the early Middle Ages. In these centers, noteworthy works of mathematics, astronomy, geography, medicine, pharmacology, optics, botany, chemistry and other fields of science, which would later determine improvement paths for these fields, were created. Abu al-Izz Ismail ibn al-Razzaz al-Jazari (12th-13th centuries), was a magnificent Muslim scientist known for his work named The Book of Knowledge of Ingenious Mechanical Devices (Kitab (...) fi ma‘rifati’l-hiyal al-handasiyya) and he was born in geography where many scientists were trained. He contributed to the development of science and civilization, the joint legacy of humanity and demonstrated his true capability and success in the field of ilm al-hiyal (the scientific field which addresses the information and practices regarding mechanical technology and engineering in Islamic science history). From this perspective, it is evident that al-Jazari had a wide field of interest, made his mark in the age he lived in with his brave and innovative ideas, and was a wise engineer. al-Jazari’s detailed descriptions and explanations of water clocks, oil lamp clocks and water pumping machines, as well as their construction, were astounding. In addition, al-Jazari’s studies on metal casting techniques, cone valves, wheel balance and the real-world use of aspiration tubes are important in contemporary engineering studies. When all these are considered, it becomes clear that his designation as the “Leonardo da Vinci of the Islamic World” is not a coincidence. Many studies on al-Jazari’s scientific legacy have been conducted in various parts of the world. There are various manuscripts of his aforementioned book. Based on these manuscripts, the work has been -fully or partially- translated into many languages, including Turkish. The German and English translations served as a basis for studies on al-Jazari in other languages. In recent years, studies conducted on al-Jazari in Türkiye (books, articles, domestic and international symposiums, congresses etc.) have demonstrated his brilliance and competence as a scientist. Furthermore, studies on al-Jazari are still ongoing in Türkiye. As for Russia, the scientific legacy of the scientists raised in the Islamic World such as Avicenna, al-Farabi, Abu Bakr al-Razi, Abu Rayhan al-Biruni, Abu al-Qasim al-Zahrawi, Muhammad ibn Musa al-Khwarizmi, al-Battani, al-Kashi, Abd al-Rahman al-Khazini, Nasir al-Din al-Tusi was researched within the scope of a special plan and program. Depending on the relevant studies, al-Jazari and his work drew attention as well. A small portion of the aforementioned Russian studies is known in Türkiye. It is safe to assume that al-Jazari studies in Russia are virtually unknown in Türkiye. The present study primarily aims to contribute to the literature on the scientific legacy of al-Jazari, a Middle Age Islamic scientist best known for his famous work in the mechanical field. More specifically, the present study aims to: 1) to identify the studies on al-Jazari in Russia, and in the former USSR countries, where academic studies are still in Russian after the Soviet Union period, to create a chronological biography and to set forth their compilation; in other words, to create a bibliography which includes Russian studies on al-Jazari; 2) to provide information on the structure and content of the studies in question, to detect the methodological issues encountered in these works, and make solution recommendations to solve these issues; 3) to contribute to continuing and future studies in Türkiye on al-Jazari in terms of source and material index. In conclusion, it should be stated that comparative reading was conducted centered on The Book of Knowledge of Ingenious Mechanical Devices (Kitab fi ma‘rifati’l-hiyal al-handasiyya). It should also be noted that Russian popular internet publications (which are not based on academic research and are created/reproduced for commercial and personal purposes) were excluded from the assessment. (shrink)

Ontologies are being developed throughout the biomedical sciences to address standardization, integration, classification and reasoning needs against the background of an increasingly data-driven research paradigm. In particular, ontologies facilitate the translation of basic research into benefits for the patient by making research results more discoverable and by facilitating knowledge transfer across disciplinary boundaries. Addressing and adequately treating mental illness is one of our most pressing public health challenges. Primary research across multiple disciplines such as psychology, psychiatry, biology, neuroscience and (...) class='Hi'>pharmacology needs to be integrated in order to promote a more comprehensive understanding of underlying processes and mechanisms, and this need for integration only becomes more pressing with our increase in understanding of differences among individuals and populations at the molecular level concerning susceptibility to specific illnesses. Substance addiction is a particularly relevant public health challenge in the developed world, affecting a substantial percentage of the population, often co-morbid with other illnesses such as mood disorders. Currently, however, there is no straightforward automated method to combine data of relevance to the study of substance addiction across multiple disciplines and populations. In this contribution, we describe a framework of interlinked, interoperable bio-ontologies for the annotation of primary research data relating to substance addiction, and discuss how this framework enables easy integration of results across disciplinary boundaries. We describe entities and relationships relevant for the description of addiction within the Mental Functioning Ontology, Chemical Entities of Biological Interest Ontology, Protein Ontology, Gene Ontology and the Neuroscience Information Framework ontologies. (shrink)

Philosophers of science and medicine now aspire to provide useful, socially relevant accounts of mechanism. Existing accounts have forged the path by attending to mechanisms in historical context, scientific practice, the special sciences, and policy. Yet, their primary focus has been on more proximate issues related to therapeutic effectiveness. To take the next step toward social relevance, we must investigate the challenges facing researchers, clinicians, and policy makers involving values and social context. Accordingly, we learn valuable lessons about the connections (...) between mechanistic processes and more fundamental reasons for medical interventions, particularly moral, ethical, religious, and political concerns about health, agency, and power. This paper uses debates over the controversial morning-after pill to gain insight into the deeper reasons for the production and use of mechanistic knowledge throughout biomedical research, clinical practice, and governmental regulation. To practice socially relevant philosophy of science, I argue that we need to account for mechanistic knowledge beyond immediate effectiveness, such as how it can also provide moral guidance, aid ethical categorization in the clinic, and function as a political instrument. Such insights have implications for medical epistemology, including the value-laden dimensions of mechanistic reasoning and the “epistemic friction” of values. Furthermore, there are broader impacts for teaching research ethics and understanding the role of science advisors as political advocates. (shrink)

Despite the seemingly neutral vantage of using nature for widely-distributed computational purposes, neither post-biological nor post-humanist teleology simply concludes with the real "end of nature" as entailed in the loss of the specific ontological status embedded in the identifier "natural." As evinced by the ecological crises of the Anthropocene—of which the 2019 Brazil Amazon rainforest fires are only the most recent—our epoch has transfixed the “natural order" and imposed entropic artificial integration, producing living species that become “anoetic,” made to serve (...) as automated exosomatic residues, or digital flecks. I further develop Gilles Deleuze’s description of control societies to upturn Foucauldian biopower, replacing its spacio-temporal bounds with the exographic excesses in psycho-power; culling and further detailing Bernard Stiegler’s framework of transindividuation and hyper-control, I examine how becoming-subject is predictively facilitated within cognitive capitalism and what Alexander Galloway terms “deep digitality.” Despite the loss of material vestiges qua virtualization—which I seek to trace in an historical review of industrialization to postindustrialization—the drive-based and reticulated "internet of things" facilitates a closed loop from within the brain to the outside environment, such that the aperture of thought is mediated and compressed. The human brain, understood through its material constitution, is susceptible to total datafication’s laminated process of “becoming-mnemotechnical,” and, as neuroplasticity is now a valid description for deep-learning and neural nets, we are privy to the rebirth of the once-discounted metaphor of the “cybernetic brain.” Probing algorithmic governmentality while posing noetic dreaming as both technical and pharmacological, I seek to analyze how spirit is blithely confounded with machine-thinking’s gelatinous cognition, as prosthetic organ-adaptation becomes probabilistically molded, networked, and agentially inflected (rather than simply externalized). (shrink)

We argue that the fragility of contemporary marriages—and the corresponding high rates of divorce—can be explained (in large part) by a three-part mismatch: between our relationship values, our evolved psychobiological natures, and our modern social, physical, and technological environment. “Love drugs” could help address this mismatch by boosting our psychobiologies while keeping our values and our environment intact. While individual couples should be free to use pharmacological interventions to sustain and improve their romantic connection, we suggest that they may have (...) an obligation to do so as well, in certain cases. Specifically, we argue that couples with offspring may have a special responsibility to enhance their relationships for the sake of their children. We outline an evolutionarily informed research program for identifying promising biomedical enhancements of love and commitment. (shrink)

The questions concerning “who we are”, “where we go to”, and “where we come from”, preoccupied the humanity from immemorial times. During the last few decades, with the accelerated improvement of the investigation methods and of the advanced successful interventions allowing the life salvation, there have been reported some attempts to correlate the psychic phenomena with the body status by the recuperation, analysis and explanation of the symptoms recorded during the near-death experiences. Such special situations, in which the heart and (...) the brain, the support of mental activities, cease their activity, has become a fundamental tool to investigate the consciousness associated phenomena during the arrest status of the fundamental processes of the life. The fundamental question actually is whether consciousness really continues to exist even if the body has ceased its function by stopping the heartbeat and brain support activities [1,2]. An answer to such a question goes toward even further questions: can there be “life” beyond the death [3]? This exciting question includes also several aspects: what is consciousness and which is its nature [4]? Could consciousness exist as a disembodied entity? To answer these fundamental questions of existence, the collaboration of several disciplines such as neurology, psychology, medicine, biology, pharmacology and also physics, to call only the most important of them, is necessary, the geriatrics finding suitable responses within the multidisciplinary researches to its various questions related to the life prolongation and the improvement of the life quality. Within such a context, it was recently developed an informational model of consciousness, which can offer response to the above questions, based on the last discoveries of the quantum physics and cosmology [4,5]. (shrink)

Most mental disorders affect only a small segment of the population. On the reasonable assumption that minds or brains are prone to occasional malfunction, these disorders do not seem to pose distinctive explanatory problems. Depression, however, because it is so prevalent and costly, poses a conundrum that some try to explain by characterizing it as an adaptation—a trait that exists because it performed fitness-enhancing functions in ancestral populations. Heretofore, proposed evolutionary explanations of depression did not focus on thought processes; instead, (...) they emphasized that it facilitates navigation of adverse social circumstances or promotes immune response to infectious agents. According to a new hypothesis, the “analytical rumination hypothesis” (ARH), however, depression’s crucial adaptive trait is rumination—negative, intrusive thought. ARH holds that, (i) social dilemmas trigger depressed mood; (ii) depressed mood induces changes in body systems that facilitate ruminative analysis aimed at solving dilemmas; and, (iii) depressive rumination is a fitness-enhancing trait that was selected for in evolutionary time. Jointly, (i)~(iii) imply that we should not think of rumination as a disorder; instead, it is a trade-off, an eminently rational one. In the same way that fever solves a problem—coordination of the immune system in response to infection—so too does depressive rumination solve a problem, a social dilemma, albeit at the cost of inducing anhedonia and other maladies. But they argue that the cost is worthwhile, something that should be endured “until the problem is solved.” First, we argue that there are two distinct types of rumination, brooding and pondering; the former is associated with a disposition for depression, not the latter. But only the latter has the problem-solving capabilities that ARH requires. Second, recent brain imaging studies of depression reveal resting state hypoactivity in lateral regions and hyperactivity in paralimbic regions; this asymmetric pattern correlates with heightened levels of brooding, self-focused rumination. In other words, on the personal level, patients are trapped within self, isolated from the external world and suffused with negative affect; on the subpersonal level, this pattern is reflected by an asymmetric pattern of lateral vs. paralimbic resting state activity. Third, we proceed to conjecture that rational responses (e.g., pondering) to social dilemmas are those that strike a balance between internal and external considerations in the process of belief formation. Fourth, because the asymmetric resting state activity blocks those who suffer with depression from accessing and processing potentially positive stimuli from the external world, the capacity for rational, analytic response—hence, problem-solving—is constrained. Fifth, it follows that, although there might be conditions for which suffering should be endured rather than pharmacologically alleviated, depression is not one of those. Indeed, in view of the effects of the asymmetric resting state pattern, it is unlikely that depressive rumination would have been useful even for ancestral populations. (shrink)

The study of remembering is both compelling and challenging, in part, because of the multiplicity and the complexity of influences on memory. Whatever their interests, memory researchers are always aware of the many different factors that can drive the processes they care about. A search for the phrase ‘influences on memory’ confirms this daunting and exhilarating array of influences, of many different kinds, operating at many different timescales, and presumably often interacting in ways that we can’t yet imagine, let alone (...) model. There are hormonal and neuromodulatory, genetic and pharmacological, developmental and age-related influences; there are influences of arousal, stress, gender, mood, emotion, sleep and personality; there are unconscious, schematic or semantic influences, and there are influences of context, situation, task and environment. There are many aspects of ‘media influence on memory’ (Loftus and Banaji, 1989; Strange and Garry, 2007), and, of course, there are both ‘social influences on memory’ (Echterhoff and Hirst, 2009) and ‘cultural influences on memory’ (Gutchess and Indeck, 2009). Notoriously, there are numerous ‘suggestive influences’ on memory (Loftus, 2003): influences of misinformation (Seifert, 2002; Wright and Loftus, 1998), or of ‘memory conformity’ (Gabbert et al., 2006) and ‘memory contagion’ (Roediger et al., 2002). People who know each other well, such as intimate couples, ‘may be well practised in yielding to each other’s influence and incorporating their partner’s information into their own memories of the past’ (French et al., 2008: 264). (shrink)

In the year 1900, the German philosopher Carl Stumpf made one of the earliest phonograph recordings to document an example of traditional music. The ensemble he recorded was the Siamese Court Orchestra which was performing in Germany at that time. This led to the establishment of the Berlin Phonogramm-Archiv and the beginning of the extensive recording of world traditional music. While written scores have begun to break traditional music away from its dependence on initiation and apprenticeship, the recording of music (...) has had an even more powerful impact on the role of memory in traditional music. No longer is one required to attend a performance, one can simply listen to a recording. Likewise, one can use recordings and videos to learn a piece without the presence of a teacher and can learn the music of another tradition. To consider the future of traditional music, the transformations created by the externalization of memory needs to be examined. This paper hopes to take a step in this direction. It will first consider the psychology of music developed by Stumpf himself. Especially the opposition between the phenomenological reception of music and it’s tempering by the consciousness which allows for aesthetic experience. It will extend this by considering Alain Daniélou’s reflections on the impact of writing and recording on musical creativity. The externalization of memory and the recording of traditional music, leads to may benefits - we have historical records of beautiful musical performances and traditions, many of which have already been lost - but simultaneously this externalization of memory threatens the very essence of traditional and religious music. Finally, the paper will address these paradoxes by applying Jacques Derrida and Bernard Stiegler’s idea of the ‘pharmacon’, and ‘positive pharmacology’ to understand how to navigate these contradictions which face this externalization of musical memory. (shrink)

Enhancement is a basic principle of modern sport. Their increase of achievement is usually attributed to the sportsmen’s natural assessment, their health, their training methods and their employment. In contrast, increase in output by pharmacological means is outlawed. The modern medical techniques created a whole range, by which sportsmen are supported. Consequently, sometimes difficult decisions with concrete medications develop. It is not always clearly to be differentiated whether something is a pharmacological interference, which serves the therapy or leads however to (...) the outlawed increase in output. At present Enhancement is in discussion, a phenomenon, which is related to doping in sports, but which concerns achievement-increasing use of medicines not only in sportsmen. -/- Leistungssteigerung ist ein Grundprinzip des modernen Sports. Gewöhnlich werden für die Steigerung der Leistung die natürliche Veranlagung der Sportler, ihre Gesundheit, ihre Trainingsmethoden und ihr Einsatzwille veranschlagt. Leistungssteigerung durch pharmakologische Mittel ist dagegen geächtet. Die modernen medizinischen Techniken haben einen ganzen Bereich geschaffen, durch den die Sportler bei der Erbringung ihrer Leistung und deren Erhalt unterstützt werden. Dabei entstehen mitunter schwierige Entscheidungsfragen bei konkreten Medikationen. Nicht immer ist klar zu unterscheiden, ob etwas ein pharmakologischer Eingriff ist, der der Therapie dient oder aber zur geächteten Leistungssteigerung führt. Gegenwärtig wird über Enhancement diskutiert, ein Phänomen, das mit dem Doping verwandt ist, aber leistungssteigernde Verwendung von Medikamenten bei Gesunden im Allgemeinen, also nicht nur bei Sportlern, betrifft. (shrink)

Since the beginning of recorded history, Curcuma longa has been valued for its medicinal benefits as a root crop. Turmeric's phytochemicals, which include curcuminoids, essential oils, and other bioactive substances, are principally responsible for its therapeutic effects. The Phytochemistry of Curcuma longa is described in this narrative review, with special attention paid to the major classes of phytochemicals and their potential for medicinal use. The therapeutic properties of the curcuminoids, particularly curcumin, as well as their potential to prevent and cure (...) a variety of chronic disorders have all been thoroughly investigated. Turmeric possesses a variety of bioactive chemicals, which include turmerones and polysaccharides, which have shown to have important pharmacological effects, such as antibacterial, anticancer, and hepatoprotective properties. The antibacterial and antifungal qualities of turmeric’s essential oils have also been proved. Promising results have been found in studies looking at the phytochemical potential of Curcuma longa, and investigations into its medicinal uses are still ongoing. The objective of this study is to give a thorough review of what is currently known regarding the Phytochemistry & therapeutic potential of this valuable plant. (shrink)

This paper considers the practical question of why people do not behave in the way they ought to behave. This question is a practical one, reaching both into the normative and descriptive domains of morality. That is, it concerns moral norms as well as empirical facts. We argue that two main problems usually keep us form acting and judging in a morally decent way: firstly, we make mistakes in moral reasoning. Secondly, even when we know how to act and judge, (...) we still fail to meet the requirements due to personal weaknesses. This discussion naturally leads us to another question: can we narrow the gap between what people are morally required to do and what they actually do? We discuss findings from neuroscience, economics, and psychology, considering how we might bring our moral behavior better in line with moral theory. Potentially fruitful means include nudging, training, pharmacological enhancement, and brain stimulation. We conclude by raising the question of whether such methods could and should be implemented. (shrink)

Inflammation is said to be a healthy component of the body's immune system's reaction. Inflammation is characterised by four key symptoms: pain, redness, heat or warmth and swelling. As secondary metabolites, plants may produce a wide range of phytochemical compounds, which possess anti-inflammatory characteristics. Herbal remedies are important therapies for a wide range of ailments all over the world. There are around 7,500 species of medicinal plants, including representatives from over 17,000 flowering plant species. Even though synthetic chemistry has developed (...) its expectations, the use of natural ingredients in the manufacture of drugs used in contemporary medicine is unparalleled. By interfering with the biology of inflammation, anti-inflammatory medications may assist to minimising tissue damage and increase patient comfort. Because of the bulky figure of species reachable for study, the effective development of novel naturally taking place anti-inflammatory drugs is mostly dependent on a multidisciplinary approach to discovering new chemicals. Despite the statistic that many review papers have been produced in this field, the conventional of them simply examined the issue from an area perspective. Several non-steroidal anti-inflammatory drugs have been shown to reduce inflammation and pain by decreasing the isoform of the cyclooxygenase enzyme's digestion of arachidonic acid, hence lowering prostaglandin production. Non-steroidal anti-inflammatory drugs have a host of harmful effects. There are, however, medicinal herbs with anti-inflammatory pharmacological properties that have few or no negative effects. (shrink)

There are spells in the Greek and Demotic Magical Papyri which promise divine visitations, assistants, ecstatic states, vessel inquiries, and vivid dreams. They also require powerful psychoactive botanical ingredients. How did these spells work and what were the expectations of somebody purchasing them? Looking at the ingredients of visionary spells and relying on the pharmacology of Dioscorides and Theophrastus, I ascertain how these spells achieved the promised visions and altered states of consciousness for the user. These spells guarantee great (...) spiritual and recreational entertainment to the client who would need an abundance of money to purchase the ingredients. (shrink)

There is currently no generally agreed-upon definition of the mechanism of action of psychedelic therapy. Existing proposals have approached the issue from various perspectives, utilizing concepts on many layers of abstraction. Most commonly, mechanisms based on neurotransmitters have been proposed. From a clinical perspective, explanations on the psychological level would be more useful. This study provides one such explanation, focusing on the destabilization of trauma-related memories and their replacement with memories that allow for more adaptive behaviors. This mechanism is not (...) specific to psychedelics, and the study therefore illustrates a non-pharmacological process involving it. -/- The study features a male entrepreneur in his early fifties who suffered from chronic but non-debilitating anxiety and depression since his teenage years. In his mid-30s, he suffered from severe burnout but partially recovered. The amount of alcohol consumed was constantly relatively high. More recently, due to simultaneous relationship and workplace stress, he experienced a more severe episode of burnout, depression, anxiety, and insomnia. He felt completely exhausted when trying to get something done and became fearful of the workplace. Psychotherapy and various pharmaceutical medications provided little benefit. -/- After three months on sick leave, a trip to the mountains triggered severe insomnia. Sleep deprivation likely contributed to a spontaneous experience of altered states of mind, including a two-day period of hallucinatory visions. There was the feeling of being a complete failure, but through a new relationship initiated just before the trip, he received love and validation from his new partner, which contradicted the feeling of worthlessness. The combination of an altered state of mind and love induced an alteration of identity that resolved his depression, burnout, and sleep disorders. After three more months of self-organized rehabilitation, he successfully returned to work. -/- Six months after the trip, financial decline caused by his absence and unchanged stressful conditions at the workplace led to disappointment, motivational issues, and stress, but his work performance remained good regardless. One year after the trip, although his work-related stress had increased rather than decreased due to the financial situation of his company being more demanding than before his burnout, the positive outcome prevailed, proving its long-term stability. (shrink)

In this two-part article, I propose a new materialist understanding of behavior. The term “mattering” in the title refers to sense-making behavior that matters, that is, to significant habits and materialized behaviors. By significant habits I mean protocols, practices and routines that generate ways of reading material signs and fixed accounts of movement. I advance a notion of behaving that stresses its materiality and sensory shaping, and I provide select examples from music. I note that current definitions of behavior do (...) not capture its material dimension. This is because behavioral science has mostly viewed matter as passive, and not as an active agency. Such an approach has metaphysically framed behavior as a phenomenon of presence that is external from its environment. The approach of behavioral science to matter where there are fixed borders between the internal and external is lacking, since it does not account for agential cuts as conceptualized by Karen Barad. Instead, I consider behavior performatively; as an ongoing iterative practice and as integral to the growth of immanently self-caused matter that spawns metastable relational formations that produce different possibilities for successive formations. In this regard, behavior matters, and matter behaves. One key aspect of my article advances Bernard Stiegler as a critical new materialist thinker. This advancement concerns the technical doings of artworks, which include the material activity that is generative of sensitivity: feelings and beliefs associated with a sense or meaning. I outline an example of the materiality of habits as constitutive of music. After that, I coin the transformative doings of matter on the artist as a “caripulation,” which is a desired movement or motion that transforms the mover and the moved. Finally, I raise “pharmacological” considerations in terms of the Stieglerian aspects of organic and inorganic organized matter. (shrink)

The purpose of this study was to determine the attitudes, expectations, experiences, and barriers that physicians in Tripoli hospitals experienced when working alongside Clinical Pharmacists (CPs). A descriptive self-administered questionnaire was used for the study, and participants were selected from several Tripoli hospitals. Most of the respondents agreed that CPs are an essential part of patient care teams and that they have the legal authority to review a patient's medication regimen and response. More than half of respondents believe CPs must (...) be responsible for the medications they prescribe to patients. Half of the respondents agreed that CPs should be encouraged to play a more active role in hospitals and other healthcare facilities. The majority of participants agreed that CPs should participate in managing drug side effects and almost half agreed that CPs can contribute to decisions about drug interactions. By a low agreement rate, 42.7% of respondents thought CPs were specially qualified to counsel patients on drug therapy. A similar low trend was observed, with 40.9% agreeing to provide pharmacists with additional responsibility and authority in clinical departments, in contrast, 54.5% expressed their concern about the clinical responsibility of CPs in clinical practice. A minority of physicians agreed that Physicians should consult pharmacists in selecting the best pharmacological treatment. At the same time, the majority think that pharmacists lack clinical skills and 61.8% feel that physicians are unable to communicate effectively with CPs. 43.6% acknowledged that the traditional opposition between the two professions was a barrier to interprofessional collaboration while the absence of pharmacy space in clinical settings was cited by 39.1%. A majority of respondents agreed that physicians and pharmacists may improve their interprofessional collaboration by raising their awareness about it. A minority of respondents thought that laws and regulations governing physician collaboration should be put in place to promote effective collaboration between physicians and CPs. The study discovered that although most physicians endorse the introduction of clinical pharmacy services in hospitals and believe that physicians and pharmacists can collaborate on many tasks, respondents were not as impressed with the CPs' performance and believed that they lacked the professionalism required to carry out clinical responsibilities successfully. To facilitate the growth of clinical pharmacy services, laws and regulations must be put in place. (shrink)

The conceptions of lovesickness and of its remedies that emerge in the Decameron result from a medical tradition that in previous centuries was assimilated by the Latin culture. The case of the Decameron is particularly interesting because this work was composed during the Black Death epidemic, between 1348 and 1354. Boccaccio’s Decameron seems to be situated in a tension between two diseases: the black plague, from which the brigata tries to escape, and lovesickness. It is quite significant that Boccaccio dedicated (...) his work to women who love and need the comfort of literature, thereby addressing a new ideal of noble women, not based on their wealth, but on their intelligence and sensitivity. Women are often victims of their melancholy, because they have no opportunity to distract themselves, being confined to the private space of their rooms. Boccaccio describes women as being subject to passion and illness, so that the lovesickness cases described in the Decameron strongly allude to the discrimination of women and to the oppression they had to endure. An explicative example that testifies to the preeminent role that the medical culture played is Decameron X, 7, in which Lisa, the daughter of an apothecary, strangely cannot be healed by pharmacological remedies that her father knows, and not a single physician can help to heal her lovesickness. The case of Lisa can be interpreted as an exemplum: a woman afflicted by the same sickness as Lisa could understand how to behave by means of reading of this novella. Moreover, this paper will demonstrate that a useful outline of Lisa’s symptomatology can be found in Dino del Garbo’s commentary on Guido Cavalcanti’s poem Donna me prega. (shrink)

Introduction Current treatments for pain have limited benefits and worrying side effects. Some studies suggest that pain is reduced when clinicians deliver positive messages. However, the effects of positive messages are heterogeneous and have not been subject to meta-analysis. We aimed to estimate the efficacy of positive messages for pain reduction. -/- Methods We included randomized trials of the effects of positive messages in a subset of the studies included in a recent systematic review of context factors for treating pain. (...) Several electronic databases were searched. Reference lists of relevant studies were also searched. Two authors independently undertook study selection, data extraction, risk of bias assessment, and analyses. Our primary outcome measures were differences in patient- or observer-reported pain between groups who were given positive messages and those who were not. -/- Results Of the 16 randomized trials (1703 patients) that met the inclusion criteria, 12 trials had sufficient data for meta-analysis. The pooled standardized effect size was −0.31 (95% confidence interval [CI] −0.61 to −0.01, p = 0.04, I2 = 82%). The effect size remained positive but not statistically significant after we excluded studies considered to have a high risk of bias (standard effect size −0.17, 95% CI −0.54 to 0.19, P = 0.36, I2 = 84%). -/- Conclusion Care of patients with chronic or acute pain may be enhanced when clinicians deliver positive messages about possible clinical outcomes. However, we have identified several limitations of the present study that suggest caution when interpreting the results. We recommend further high-quality studies to confirm (or falsify) our result. -/- FUNDING -/- Alexander Mebius research has been funded through the ERC grant "Philosophy of Pharmacology: Safety, Statistical Standards, and Evidence Amalgamation" (GA: 639276). (shrink)

In biomedical measurement, biomarkers are used to achieve reliable prediction of, and useful causal information about patient outcomes while minimizing complexity of measurement, resources, and invasiveness. A biomarker is an assayable metric that discloses the status of a biological process of interest, be it normative, pathophysiological, or in response to intervention. The greatest utility from biomarkers comes from their ability to help clinicians (and researchers) make and evaluate clinical decisions. In this paper we discuss a specific methodological use of clinical (...) biomarkers in pharmacological measurement: Some biomarkers, called ‘surrogate markers’, are used to substitute for a clinically meaningful endpoint corresponding to events and their penultimate risk factors. We confront the reliability of clinical biomarkers that are used to gather information about clinically meaningful endpoints. Our aim is to present a systematic methodology for assessing the reliability of multiple surrogate markers (and biomarkers in general). To do this we draw upon the robustness analysis literature in the philosophy of science and the empirical use of clinical biomarkers. -/- After introducing robustness analysis we present two problems with biomarkers in relation to reliability. Next, we propose an intervention-based robustness methodology for organizing the reliability of biomarkers in general. We propose three relevant conditions for a robust methodology for biomarkers: (R1) Intervention-based demonstration of partial independence of modes: In biomarkers partial independence can be demonstrated through exogenous interventions that modify a process some number of “steps” removed from each of the markers. (R2) Comparison of diverging and converging results across biomarkers: By systematically comparing partially-independent biomarkers we can track under what conditions markers fail to converge in results, and under which conditions they successfully converge. (R3) Information within the context of theory: Through a systematic cross-comparison of the markers we can make causal conclusions as well as eliminate competing theories. We apply our robust methodology to currently developing Alzheimer’s research to show its usefulness for making causal conclusions. (shrink)

Background: As part of a consistent effort to examine and provide integrative medical approaches to the therapeutic offering for psychophysical health, this study investigates the utilization of Olfactory Virtual Reality (OVR) in an inpatient psychiatry unit, more specifically in the Shepardson 3 Inpatient Psychiatry Unit at the University of Vermont Medical Center, in Burlington, VT, USA. Objectives: The purpose of this protocol is to explore the therapeutic value of olfactory virtual reality (OVR) in the above described population, and to collect (...) statistically significant data to determine the feasibility of potential future OVR studies. Method: Direct subject observation and monitoring in the context of Olfactory Virtual Reality (OVR) sessions and Qualitative data collection via the administration of subject surveys, subdivided in: a) Pre-OVR experience, b) Immediate post-OVR experience, and c) 1-to-3-hour post-OVR experience questionnaires. Results: The research yielded positive outcomes in all areas investigated, despite challenges related to the utilization of the device itself, issues in individual olfactory threshold, and COVID-19 restrictions and limitations. Conclusion: The outcome of this study indicates that the utilization of olfactory virtual reality technologies is a safe and effective integrative approach to target several aspects of psychological and physical health such as anxiety, stress, and pain, in combination with the psychotherapeutic and pharmacological standards of care in inpatient psychiatry. (shrink)

DIFERENCIAÇÃO SEXUAL -/- Emanuel Isaque Cordeiro da Silva Instituto Agronômico de Pernambuco Embrapa Semiárido -/- • _____OBJETIVO -/- Os estudantes de Veterinária e de Zootecnia estão ligados à disciplina Reprodução Animal, um pelos mecanismos fisiológicos para evitar e tratar as possíveis patologias do trato reprodutivo dos animais domésticos, e outro para o entendimento dos processos fisiológicos visando o manejo reprodutivo e a procriação para a formação de um plantel geneticamente melhorado. Sendo assim, a finalidade do presente trabalho é apresentar os (...) mecanismos que regulam as diferenças sobre o desenvolvimento embrionário relativos à diferenciação e determinação sexual de machos e fêmeas, que também incluem o desenvolvimento dos órgãos envolvidos na reprodução e a origem das diferenças entre ambos os sexos. -/- •____INTRODUÇÃO -/- Os organismos que se reproduzem sexualmente são descendentes de organismos ao qual não existia a diferenciação sexual. Em algum momento da evolução surgiu a reprodução sexual como um mecanismo para incrementar a diversidade genética e facilitar a troca de informações genéticas mediante o material genético da fêmea com o do macho. Devido sua origem comum, na maioria das espécies, tanto os machos como as fêmeas possuem todos os genes necessários para desenvolverem-se em qualquer dos sexos. O que efetivamente faz diferença entre os sexos é a forma e a ordem ao qual se expressam os genes durante o processo de desenvolvimento. A diferenciação sexual é regulada principalmente por mecanismos epigenéticos, mais do que as diferenças genéticas de grande magnitude entre os sexos. Todo o controle epigenético de qualquer processo de desenvolvimento depende basicamente de uma série de expressões gênicas, através da qual a expressão de certa combinação de genes resulta na presença de determinadas proteínas, conhecidas como os fatores de transcrição, que induzem ou reprimem a expressão de outro(os) gene(es), a partir dos quais se produzem novas proteínas, que em certos casos também atuam como fatores de transcrição para outros genes, e assim sucessivamente. Logo, a expressão ou falta de expressão de um gene ao início da série pode resultar em um ladrão totalmente diferente da expressão de outros genes subsequentes, o que pode ocasionar profundas mudanças no processo de desenvolvimento e até a mutações indesejáveis. O padrão predeterminado de expressões gênica relativo a diferenciação sexual na maioria das espécies tanto domésticas quanto selvagens, leva ao desenvolvimento de um dos sexos (o padrão predeterminado dos mamíferos é o sexo feminino). Em consequência, a diferenciação faz com que um indivíduo do sexo oposto exija a expressão de um gene de determinação sexual que desvie a subsequente série de expressões gênica em direção ao dito sexo. Nos mamíferos, a expressão do gene SRY, localizado no cromossomo Y (e portanto ausente nas fêmeas), redige o padrão de diferenciação sexual de sua via pré-estabelecida feminina em direção ao padrão masculino. A existência de uma única diferença genética (presença do gene SRY nos machos e ausentes nas fêmeas), vai se amplificando e termina resultando no desenvolvimento de indivíduos diferentes entre si. Esse é um mecanismo de diferenciação sexual cromossômica. O primeiro passo de uma série de diferenciação sexual, em sentido estrito, não depende nem requer necessariamente a presença de um gene diferente em algum dos sexos. O gene “disparador” da diferenciação sexual pode estar presente em todos os embriões, porém pode expressar-se somente em algum deles, devido a fatores ambientais que formam parte da sua regulação epigenética, isto é, uma determinação sexual ambiental. Em algumas espécies de tartarugas ou de lagartos a expressão ou falta de expressão do gene “disparador”, por exemplo, depende da temperatura existente durante a incubação dos ovos, pelo qual alguns embriões desenvolvem-se como machos e outros como fêmeas, apesar de não existir diferença genética entre eles, simplesmente como consequência da temperatura: a determinação sexual depende da temperatura a que cada um deles foi submetido durante a incubação. Em certas espécies as temperaturas mais elevadas facilitam o desenvolvimento de fêmeas e outras de machos, enquanto que em outras espécies as temperaturas amenas (intermediárias) resultam em machos, e as inferiores como as superiores induzem o desenvolvimento de fêmeas. A existência dessa diversidade indica que a temperatura por si mesma não é a que induz ou a que provoca o desenvolvimento do macho e da fêmea, senão a que atua somente como um regulador inicial da diferenciação sexual. Em outras espécies o fator ambiental que regula a determinação sexual pode ser distinto. A densidade populacional, por exemplo, pode atuar como um regulador. Podemos concluir que a determinação sexual dependente da temperatura ou de outros fatores ambientais estabelece-se antes da determinação sexual cromossômica, a qual evoluiu depois como um método que oferece maior certeza e resultado, já que a proporção de machos e fêmeas não é afetada por mudanças ambientais ou de hábitat. -/- •___FORMAÇÃO INICIAL DA GÔNADA -/- Basicamente em todos os embriões, inicialmente se formam as chamadas gônadas indiferenciadas (com o potencial de desenvolver-se em ovários ou testículos) a partir da invasão das cristas genitais pelas células germinais primordiais, que migram desde seu local de origem no epiblasto, perto do lugar onde o saco vitelino se une com o intestino primitivo e que chegam até às cristas genitais que são engrossamentos de tecido situados na região mesonéfrica do embrião. A migração das células germinais primordiais ocorre muito cedo sobre o processo de desenvolvimento do embrião (dia 26 nos bovinos). Ao chegas as cristas genitais, as células germinativas proliferam-se e se organizam com as células somáticas já existentes nas cristas para ir formando a gônada (figura 1). Para regular essa remodelação e conformação adequada da gônada vários genes se expressam, como o OCT-4 (que aparentemente mantém a totipotencialidade da gônada), assim como o SF-1 (Fator esteroidogênico 1) e o WT-1 (gene associado ao tumor de Wilms). Esses dois últimos genes estimulam a proliferação celular e estabelecimento dos cordões sexuais. Nessa etapa inicial do desenvolvimento todos esses genes se expressam sem distinção de sexo, pelo que a gônada em formação mantém a capacidade de se diferenciar em testículo ou em ovário. -/- Figura 1: migração das células germinais primordiais em direção a crista gonodal. Diferenciação das gônadas femininas e masculinas. Fonte: ZARCO, 2018. -/- •___SEXO CROMOSSÔMICO -/- Têm-se observado que nos mamíferos a determinação sexual depende diretamente dos cromossomos. As fêmeas possuem dois cromossomos sexuais X (um contribuído do óvulo e o outro por um espermatozoide “X”). Os machos, por sua vez, possuem um cromossomo sexual X(proveniente do óvulo) e um cromossomo sexual Y, que provém de um espermatozoide “Y” (figura 2). A metade dos espermatozoides produzidos por um macho são X e a metade Y, isso porque durante a espermatogênese a divisão meiótica provoca que a partir de cada espermatócito primário, célula diploide que por pertencer a um indivíduo macho tem um cromossomo X e um Y, se originem das espermátides haploides a cada um das que eles tocam cromossomos X, e outras espermátides haploides as que eles tocam os cromossomos Y. Dessa forma, de acordo com o tipo do espermatozoide que fertilize o ovócito, se originará um indivíduo com cariótipo feminino “XX” ou um cariótipo masculino “XY” (figura 2). Esse processo é conhecido como sexo cromossômico, ao qual se determina o momento da fertilização. Figura 2: nos mamíferos todos os óvulos produzidos pelas fêmeas possuem um cromossomo sexual X. A metade dos espermatozoides produzidos pelos machos possuem um cromossomo X e a outra metade possui um cromossomo Y. Dependendo do cromossomo presente no espermatozoide que fertilize o óvulo pode-se gerar um indivíduo XX (fêmea) ou um XY (macho). Fonte: ZARCO, 2018. -/- O cromossomo “Y” é uma “invenção” relativamente recente na história da evolução das espécies e do estudo da genética. Surgiu a partir de uma mutação de um cromossomo “X”, que resultou na perda de um de seus braços, que é por onde se originou a morfologia do cromossomo Y. A maioria dos genes presentes no cromossomo Y também existem no cromossomo X; assim mesmo somente alguns genes do cromossomo Y foram evoluídos até ser diferentes dos genes do cromossomo X. Embora os machos possuam um cromossomo que não está presente nas fêmeas, esse mesmo cromossomo não aporta toda a informação genética original. Todos os genes existentes nas fêmeas estão também presentes nos dos machos, já que eles também possuem um cromossomo X. Uma particularidade do cromossomo Y, ao existir somente uma cópia nos machos, é que ele sofre um entrecruzamento com um cromossomo análogo durante o processo de meiose, pelo que o cromossomo Y de um macho é idêntico ao de seu progenitor e ao de seus descendentes, exceto no caso em que ocorra uma mutação espontânea. Em contraste, os cromossomos X das fêmeas (um proveniente do pai e outro da mãe) se entrecruzam durante a meiose, por onde cada óvulo produzido pela fêmea terá uma combinação de alelos distinta em seu cromossomo X. Ao estudar as diferenças presentes na sequência de DNA do cromossomo Y, é possível identificar a distância filogenética entre os indivíduos (quanto mais diferenças existirem entre os cromossomos significa que seu ancestral comum está mais longe). Algo análogo ocorre com o DNA das mitocôndrias, que sempre são aportados pela mãe e nunca sofrem recombinação genética. Gene SRY -/- Um dos poucos genes do cromossomo Y que não possuem correspondência com o cromossomo X é o gene SRY (Sex-determining Region of the Y chromossome – região do cromossomo Y determinante do sexo). Esse gene se expressa somente na gônada em formação nos embriões machos, em particular em células precursoras das células de Sertoli; ele codifica uma proteína da família SOX (SRY-like Box) que é uma família formada por proteínas que possuem um domínio de união ao DNA e que atuam como fatores de transcrição. Ao produzir-se a proteína SRY nas células precursoras das células de Sertoli estimula-se a expressão (transcrição) de outro gene análogo, denominado SOX-9 que, por sua vez, atua como um fator de transcrição que ativa a expressão de outros genes, como o FGF-9 (Fibroblast Growth Factor-9), ou seja ele é o estimulante de ativação dos demais. Os produtos dos genes SOX-9 e FGF-9 iniciam uma cascata de expressões que provocam a diferenciação das células de suporte da gônada indiferenciada (crista genital) em células de Sertoli. Em seguida, essas células dirigem a diferenciação das células intersticiais da crista genital em células de Leydig, o que finalmente resulta na formação de um testículo. Outro dos efeitos da proteína codificada por SOX-9 é um estímulo maior da expressão de seu próprio gene, pelo qual é produzido um ciclo de retroalimentação positiva que favorece a continuidade do processo de formação testicular. Como nos embriões da fêmea não existe o gene SRY, a gônada indiferenciada não é estimulada para expressar os genes SOX-9 nem o FGF-9 nas células de suporte (que nesse caso serão precursoras de células da granulosa). A gônada, em mudança, expressa em forma constitutiva, isto é, sem a necessidade de estimulação, outra cascata de genes que incluem o WNT4 (Wingless-integration Factor 4) e o RAPO1 (Respondina-1), que por sua vez iniciam uma cascata de expressão gênica, a qual provoca a diferenciação das células somáticas da gônada indiferenciada para formação das células da granulosa e células da teca, esse feito conduz, por sua vez, a formação de um ovário. No embrião macho a proteína SOX-9 inibe a expressão dos genes WNT4 e RSPO-1, pelo que a presença do gene SRY, e portanto de SOX-9, inibem a formação de um ovário ao mesmo tempo que estimulam a formação do testículo (figura 3). Em suma, se o embrião possui genótipo XY (um embrião macho), o gene SRY começa a expressar-se sobre as células precursoras da gônada imediatamente depois da formação da mesma, quando os cordões sexuais primários estão se desenvolvendo na medula. A expressão do gene, assim como a presença subsequente das proteínas SOX-9 e FGF-9 estimula a distinção das células de Sertoli e que se organizem os tubos seminíferos a partir dos cordões sexuais primários. Em contrapartida, em um embrião com genótipo XX (fêmea) não existe o gene SRY, pelo qual é impossível que se elevem os níveis das proteínas SOX-9 e FGF-9 e as células precursoras não se diferenciam em células de Sertoli, e portanto os cordões sexuais primários sofrem regressão. Depois de alguns dias, começam a organizar-se os cordões sexuais secundários e as células precursoras iniciam a expressão do gene WNT4, o que leva as mesmas a diferenciar-se em células da granulosa, que serão a base para a conformação dos folículos ovarianos. Se em um embrião XY, macho, a expressão do gene SRY demora, é formada um ovo-testículo devido a que algumas das células somáticas das cristas gonodais começam a expressar o gene WNT4, e a diferenciar-se em células da granulosa, enquanto que em outras a proteína SRY chega a tempo para dirigir a diferenciação para formação das células de Sertoli. No ovário em formação é expressado um gene denominado DAX-1 (Dosage-sensitive Sex Reversal). Esse gene, localizado no cromossomo X, codifica uma proteína que é um membro da família dos receptores nucleares ao que lhe falta o domínio de união ao DNA, pelo que parece atuar no bloqueio de diversos fatores de transcrição, entre os que se encontra o SRY. Como a proteína DAX-1 impede a ação da proteína SRY, um excesso de expressão do gene DAX-1 pode provocar a feminilização gonodal de indivíduos XY, macho, embora tenham SRY. Em condições normais, a expressão adequada do gene DAX-1 não é capaz de evitar a masculinização gonodal de embriões com o gene SRY, daqui o nome de reversão sexual dependente da dose. Figura 3: série de expressão gênica para a determinação gonodal. SRY (Região do cromossomo Y determinante do sexo), SOX-9 (SRY-like Box-9), FGF-9 (Fator de crescimento de fibroblastos-9), WNT4 (Wingless-integration Factor-4), RSPO-1 (Respondina-1). Uma vez que o SRY induz a expressão de SOX-9 na gônada masculina, inicia-se um processo de feedback positivo mediante o qual os níveis de expressão de SOX-9 e FGF-9 vão aumentando, ao mesmo tempo que inibem a expressão de WNT-4 e RSPO-1. Na gônada feminina não se expressam SRY, SOX-9 e nem FGF-9, o que permite que se expressem os genes WNT-4 e RSPO-1, que iniciam uma cascata de sinalização que dirige a formação de um ovário. Fonte: ZARCO, 2018. -/- • ___DIFERENCIAÇÃO SEXUAL DOS GENITAIS -/- Uma vez que se formam os testículos, todo o desenvolvimento subsequente dos órgãos e as características “masculinas” em lugar das femininas é em consequência dos hormônios produzidos pelos testículos em formação, incluindo os andrógenos e o hormônio inibidor dos ductos de Müller. Mediante a ausência de testículos todo o desenvolvimento dos órgãos genitais internos e externos segue um padrão feminino, sem levar em conta se estão presentes os ovários; o que significa a ausência de hormônios gonodais determina que o embrião se desenvolva como fêmea, uma vez que não requerem hormônios ovarianos para desencadear o padrão feminino. Por sua vez, as gônadas masculinas (os testículos), produzem substâncias que desviam o desenvolvimento em direção ao padrão masculino. Sob etapas relativamente rápidas da diferenciação todos os embriões possuem dois pares de dutos sexuais, os dutos de Wolff ou mesonéfricos e os dutos de Müller ou paramesonéfricos (figura 4). A testosterona secretada pelos testículos do feto macho em desenvolvimento atua sobre os dutos de Wolff, o que induz a formação posterior dos dutos deferentes, do epidídimo e das glândulas seminais (figura 4). Figura 4: formação dos órgãos genitais internos a partir dos dutos de Wolff no macho e dos dutos de Müller na fêmea. Fonte: ZARCO, 2018. -/- Os testículos produzem ao mesmo tempo, uma glicoproteína chamada Hormônio Inibidor dos Dutos de Müller (Müllerian Inhibiting Hormone, MIH, também chamado de Anti-Müllerian Hormone, AMH); como o seu nome indica, inibe o desenvolvimento dos dutos de Müller ou paramesonéfricos, provocando sua regressão, que impede a formação dos órgãos genitais característicos da fêmea como os ovidutos, o útero, a cérvix e a porção cranial da vagina (figura 4). O MIH é uma glicoproteína da família dos fatores de crescimento transformativo β (TGFβ). O gene MIH possui locais de união para os produtos dos genes SOX-9 e SF-1, pelo que a presença simultânea de ambos fatores de transcrição é necessária para a secreção do MIH e leva a cabo sua função de iniciação dos dutos de Müller sobre o embrião macho (vale lembrar que nessa etapa tanto a gônada de embriões machos como de embriões fêmeas expressam o gene SF-1, mas somente o macho expressa o SOX-9, para que unicamente esse último produza MIH). O certo é que na gônada do embrião fêmea não se produzem quantidades importantes da proteína SOX-9, além de que se produz a proteína DAX-1, mesma que antagoniza tanto a SOX-9 como a SF-1, todo o qual impede a produção de MIH e resulta no desenvolvimento dos dutos de Müller até a formação dos ovidutos, útero, cérvix e a porção cranial da vagina (figura 4). Assim, na fêmea, ao não haver testículos não circulam concentrações elevadas de andrógenos, o que impedirá o desenvolvimento dos dutos de Wolff, enquanto que os dutos de Müller se desenvolvem já que não haverá a presença do MIH para impedi-lo. O desenvolvimento dos genitais internos e externos femininos não requerem a presença de nenhum hormônio ovariano o que levará a cabo de maneira predeterminada (ou pré-estabelecida) na ausência de testículos. Outra estrutura interna que também se desenvolve de forma distinta nos machos e nas fêmeas é o seio urogenital, que no embrião macho é estimulado pela testosterona para formação da próstata, das glândulas bulbouretrais e da uretra peniana, enquanto que na fêmea forma a porção caudal da vagina. A respeito dos órgãos genitais externos (figura 5), nos embriões de ambos os sexos existem estruturas precursoras chamadas de tubérculo genital e pregas vestibulares. Na fêmea o tubérculo genital da origem ao clitóris e as pregas vestibulares dão origem aos lábios vulvares sem a necessidade da atuação de hormônios ovarianos, já que o padrão “por via pré-estabelecida” é feminino. Em contrapartida, no macho, tanto o tubérculo genital quanto as pregas vestibulares respondem ao hormônio 5α-dehidro-testosterona (DHT), ao qual se formam as células da pele da zona genital a partir da testosterona que é secretada pelos testículos. Para isso existem nas células a enzima 5α-reductasa, que transforma a testosterona em DHT. Uma vez formada, a DHT atua sobre as pregas vestibulares do embrião macho para que se fusionem e formem o escroto (em lugar dos lábios vulvares), e sobre o tubérculo genital para formar o pênis (em lugar do clitóris). Figura 5: estruturas que se desenvolvem nos embriões de cada sexo a partir do seio urogenital, o tubérculo genital e as pregas vestibulares. A cor do né de cada estrutura final corresponde com a cor do nome da estrutura a partir da qual se originou. Fonte: ZARCO, 2018. -/- • ___DIFERENCIAÇÃO SEXUAL DO SISTEMA NERVOSO -/- Existem inúmeras diferenças funcionais entre o sistema nervoso da fêmeas e o do machos, em humanos podem incluir diferenças tão complexas como a maior capacidade de verbal da mulher ou a maior capacidade de orientação espacial do homem. Nessa parte será abordada aquelas diferenças que influenciam diretamente sobre a função reprodutiva, como as diferenças na regulação da secreção de gonadotropinas ou as diferenças na capacidade de comportamento sexual masculino ou feminino. É necessário lembrar que, apesar de que essas diferenças se originem durante um período crítico da vida fetal ou neonatal (dependendo da espécie), geralmente se fazem presentes até que o animal chegue a vida adulta e demonstre obter ou não a capacidade para se comportar como macho ou como fêmea uma vez que é exposto aos hormônios sexuais que são secretada depois da puberdade. Igualmente aos processos acima citados, podemos afirmar que nos mamíferos o padrão pré-estabelecido de comportamento sexual e de secreção de gonadotropinas é o feminino. Se durante os primeiros dias de vida neonatal uma rata fêmea não é exposta a nenhum hormônio gonodal, ao chegar a vida adulta ela terá a capacidade de se comportar como fêmea na presença de estrógenos, assim como de secretar um pico pré-ovulatório de GnRH/LH em resposta aos mesmos (figura 6). Essa rata, portanto, não poderá se comportar como macho embora que em sua vida adulta seja exposta a testosterona. O sistema nervoso do rato macho recém-nascido que é exposto aos andrógenos produzidos pelos testículos, em detrimento, faz com que adquiram o potencial para se comportar como machos em sua vida adulta e que perdem o potencial para ter conduta de fêmeas na presença e/ou administração de estrógenos (processo conhecido como desfeminização do SNC). Se por meios de experimentos injetamos testosterona em uma rata fêmea recém-nascida, essa rata não poderá se comportar como fêmea em sua vida adulta, e passará a se comportar como macho. A castração neonatal de um rato (visando evitar a exposição de seu SNC a andrógenos testiculares), assim mesmo, resultará em sua vida adulta um padrão feminino (SNC feminizado e não masculinizado). O hipotálamo das ratas adultas possui uma área em que o número, características e densidade dos corpos neurais difere em machos e fêmeas, essa área é denominada como “núcleo sexualmente dimórfico do hipotálamo”, e tem demonstrado que quando as ratas são tratadas com testosterona na vida neonatal, a morfologia de seu núcleo sexualmente dimórfico será masculinizado em sua vida adulta, enquanto que a castração neonatal de ratos resulta em um núcleo sexualmente dimórfico feminizado em sua vida adulta. Isso significa que a exposição ou não a testosterona na vida neonatal é o que determina que tipo de núcleo sexualmente dimórfico se desenvolverá, o que por sua vez está relacionado com o tipo de conduta que o animal poderá expressar em sua vida adulta. Não deixa de ser um paradoxo que ao injetar uma dose elevada de estrógenos nos primeiros dias de vida de uma rata, os núcleos sexualmente dimórficos da mesma se desenvolverão como macho e em sua vida adulta seu potencial de conduta estará masculinizado e desfeminizado. O hormônio “feminino” conhecido como estradiol, masculiniza o hipotálamo e a conduta do animal. Logo, se a rata neonatal for exposta a injeção de andrógeno não-aromatizado (que não pode ser transformado em estrógenos pelas células) ela não se masculiniza. A masculinização e desfeminização dos ratos ou das ratas tratados com testosterona, na realidade, não são provocados pela própria testosterona, senão pelos estrógenos que se formam dentro dos neurônios quando absorvem a testosterona do sangue e a aromatizam para transformá-la em estrógenos (figura 6). Figura 6: desfeminização e masculinização do sistema nervoso central por meio da testosterona, que quando não absorvida pela α-fetoproteína pode entrar nos neurônios, onde se aromatizam para serem transformados em estrógenos, hormônio que é responsável pela desfeminização. Fonte: ZARCO, 2018. Por que as ratas, que possuem ovários funcionalmente produtores de estrógenos, não se masculinizam? A resposta está em uma proteína denominada α-fetoproteína que circula em altas concentrações nos fetos e nos recém-nascidos. Essa proteína possui a capacidade de unir-se aos estrógenos, ao qual impede seu entrada nas células. Os ratos, em desenvolvimento, produzem testosterona, no entanto não possui afinidade pela α-fetoproteína, o que permite com que ela circule livremente. Ao chegar ao SNC, a testosterona (que não foi absorvida) pode entrar nos neurônios e dentro deles se aromatizam e transformam-se em estrógenos, que finalmente masculinizam o SNC. A diferenciação sexual do hipotálamo depende, em síntese, da presença ou ausência dos testículos, o que permite que se produza ou não o hormônio testosterona que pode não ser absorvida por parte da α-fetoproteína, transformar-se em estrógenos e masculinizar o SNC. -/- •___CONCLUSÃO -/- Nos mamíferos todo o processo que se requerem para o desenvolvimento de um macho depende da existência de somente um gene do cromossomo Y, o gene SRY; a ausência desse gene resulta no desenvolvimento de uma fêmea. A presença ou ausência do gene SRY determina, então, a cadeia de eventos morfogênicos que ocorrerá em sua expressão ou não, para desenvolver todos os órgãos e características de um macho ou de uma fêmea. Por essa razão, os indivíduos com uma monossomia XOA (síndrome de Turner) são fêmeas (por não possuir o cromossomo Y nem o gene SRY), enquanto que os indivíduos triploides XXY (síndrome de Kleinefelter) são machos embora possuam dois cromossomos X. Em algumas espécies, no entanto, têm-se identificado machos que são cromossomicamente XX; nesses casos é determinado invariavelmente que por ser um erro durante a meiose a região do cromossomo Y em que reside o gene SRY tem sido transloucada ao cromossomo X. Da mesma forma, em alguns casos tem sido encontrado fêmeas com cariótipo XY; que nelas se identifica uma mutação inabilitante do gene SRY. Isso demonstra experimentalmente que por meio da engenharia genética é possível produzir machos com cariótipo XY mas com o gene SRY eliminado (knockout). Como é de se esperar, esses machos desenvolvem ovários e todos seus órgãos genitais, tanto internos quanto externos, e se desenvolvem como fêmeas. Os machos cromossomicamente XX transgênicos aos que se insertam uma cópia do gene SRY, desenvolvem testículos e um fenótipo masculino, embora sejam estéreis por causa da ausência de alguns genes do cromossomo Y que são necessários para a realização de uma espermatogênese normal. As falhas nos mecanismos de diferenciação sexual podem, diretamente, ocasionar anormalidades como as observadas nas bezerras Freemartin, que são bezerras originadas de uma gestação gemelar em que seu gêmeo era macho. O que sucede é que na espécie bovina, quando há uma gestação gemelar, é produzido um certo grau de anastomose entre as placentas dos fetos, o que permite a troca de sangue e de células entre ambos. Os produtos recebem, então, algumas células de seu gêmeos, que encontram seu lugar no órgão correspondente e se integram a ele. No caso particular das gônadas, quando o ovário primitivo de um embrião fêmea é colonizado por algumas células gonodais de seu gêmeo macho, essas células expressam o gene SRY, o que fará com que essa região da gônada se diferencie como testículo. Como resultado, se desenvolve um ovo-testículo (com maior ou menor proporção de tecido testicular dependendo do grau de colonização da gônada em formação por células provenientes do gêmeo macho). Ademais, ao haver certa quantidade de tecido testicular produtor de MIH, circularão sobre o feto fêmea níveis desse hormônio que, embora baixos, afetarão o desenvolvimento normal dos dutos de Müller, fazendo com que as bezerras Freemartin possuam genitálias internas ausentes ou pouco desenvolvidas. Os andrógenos produzidos pelas zonas de tecido testicular, por fim, são suficientes para causar um certo grau de masculinização, que se manifesta como um clitóris mais grande que o normal ou um desenvolvimento corporal masculinizado. -/- REFERÊNCIAS BIBLIOGRÁFICAS -/- ARNOLD, Arthur P.; CHEN, Xuqi; ITOH, Yuichiro. What a difference an X or Y makes: sex chromosomes, gene dose, and epigenetics in sexual differentiation. In: Sex and gender differences in pharmacology. Springer, Berlin, Heidelberg, 2013. p. 67-88. CUNNINGHAM, James. Tratado de fisiologia veterinária. Elsevier Health Sciences, 2011. DERIVAUX, Jules; BARNABÉ, Renato Campanarut. Reprodução dos animais domésticos. Zaragoza: Acribia, 1980. DA SILVA, Emanuel Isaque Cordeiro. Desenvolvimento Embrionário e Diferenciação Sexual nos Animais Domésticos. Disponível em:. Acesso em: Julho de 2020. HAFEZ, Elsayed Saad Eldin; HAFEZ, Bahaa. Reprodução animal. São Paulo: Manole, 2004. HIDALGO, C. Galina et al. Reproducción de animales domésticos. México: Limusa, 2008. MACLAUGHLIN, David T.; DONAHOE, Patricia K. Sex determination and differentiation. New England Journal of Medicine, v. 350, n. 4, p. 367-378, 2004. MCCARTHY, Margaret M.; ARNOLD, Arthur P. Reframing sexual differentiation of the brain. Nature neuroscience, v. 14, n. 6, p. 677, 2011. PLANT, Tony M.; ZELEZNIK, Anthony J. (Ed.). Knobil and Neill's physiology of reproduction. Academic Press, 2014. REY, Rodolfo. Diferenciación sexual embrio-fetal: De las moléculas a la anatomía. Revista chilena de anatomía, v. 19, n. 1, p. 75-82, 2001. SENGER, P. L. Embryogenesis of the pituitary gland and male or female reproductive system. In. Pathways to Pregnancy and Parturition. Current Conception Inc, v. 1, p. 8-76, 1997. ZARCO, L. Diferenciación sexual. In. PORTA, L. R.; MEDRANO, J. H. H. Fisiología reproductiva de los animales domésticos. Cidade do México: FMVZ-UNAM, 2018. -/- REALIZAÇÃO -/- . (shrink)

The evaluation of universities from different perspectives is important for their scientific development. Analyzing the scientific papers of a university under the bibliometric approach is one main evaluative approach. The aim of this study was to conduct a bibliometric analysis and visualization of papers published by Hamadan University of Medical Science (HUMS), Iran, during 1992-2018. This study used bibliometric and visualization techniques. Scopus database was used for data collection. 3753 papers were retrieved by applying Affiliation Search in Scopus advanced search (...) section. Excel and VOSviewer software packages were used for data analysis and bibliometric indicator extraction. An increasing trend was seen in the numbers of HUMS's published papers and received citations. The highest rate of collaboration in national level was with Tehran University of Medical Sciences. Internationally, HUMS's researchers had the highest collaboration with the authors from the United States, the United Kingdom and Switzerland, respectively. All highly-cited papers were published in high level Q1 journals. Term clustering demonstrated four main clusters: epidemiological studies, laboratory studies, pharmacological studies, and microbiological studies. The results of this study can be beneficial to the policy-makers of this university. In addition, researchers and bibliometricians can use this study as a pattern for studying and visualizing the bibliometric indicators of other universities and research institutions. (shrink)

“Love hurts”—as the saying goes—and a certain amount of pain and difficulty in intimate relationships is unavoidable. Sometimes it may even be beneficial, since adversity can lead to personal growth, self-discovery, and a range of other components of a life well-lived. But other times, love can be downright dangerous. It may bind a spouse to her domestic abuser, draw an unscrupulous adult toward sexual involvement with a child, put someone under the insidious spell of a cult leader, and even inspire (...) jealousy-fueled homicide. How might these perilous devotions be diminished? The ancients thought that treatments such as phlebotomy, exercise, or bloodletting could “cure” an individual of love. But modern neuroscience and emerging developments in psychopharmacology open up a range of possible interventions that might actually work. These developments raise profound moral questions about the potential uses—and misuses—of such anti-love biotechnology. In this article, we describe a number of prospective love-diminishing interventions, and offer a preliminary ethical framework for dealing with them responsibly should they arise. (shrink)

Amongst invertebrates, molluscs show great variability in their nervous system ranging from primitive arrangement in Chitons to the complex mass of fused ganglia forming the ‘brain’ of cephalopods. Most of the effector organs used for pharmacological or physiological experiments. The neurosecretory cells (NSCs) with their combination of neuronal and glandular capabilities are perfectly suited to translate a neuronal input into the hormonal output best suited to long-term process. In this capacity, the NSCs may produce hormones, which act directly upon the (...) peripheral target or it may exert its effect indirectly by influencing the activity of other non-neural, endocrine organs. Neurosecretory cells have been detected in the cerebral, pedal and visceral ganglia of Lamellidens corrianus. The distribution and biology of freshwater bivalve like Lamellidens corrianus is influenced by local ecological factors (like temperature, pH, inorganic salts, type of soil etc.), water flow system and presence of micro-organisms, teleost fishes and seasonal variations in these parameters. Nitrogenous excretory changes which include ammonia in these molluscs is also influenced by these local ecological factors in which temperature is plays very crucial role. It is well known fact that the high stress conditions during drought or severe winter conditions have been conquered by several lineage of gastropods and sand bivalves and their ability to enter the resistant or dormant stages (low food) protein catabolism increased. Present investigation deals with the oxygen consumption and ammonia excretion ratio of these freshwater pelecypode Lamellidens corrianus. Study on Lemellidens corrianus directed in understanding the different behavioral and physiological aspects after cerebral ganglia removal and injection of their extracts revealed significant changes during summer (April-May). (shrink)

In this article, I argue that the neuroethics of cognitive enhancement can help us bridge the explanatory gap between metaethics and bioethics and throw light on the classic gap between moral beliefs and neural correlates of brain processes. Insofar as it unveils the irreducibility of first-person propositional attitudes, neuroethics allows for justifying cosmetic, pharmacological interventions so as to bring about human enhancement, regardless of descriptive accounts of its neural correlates and independently of the cognitivist, noncognitivist or hybrid inputs of metanormative (...) theories. Precisely because it cannot provide the ultimate grounds for any conservative, libertarian or liberal attitudes towards cognitive enhancement, neuroethics is better conceived in terms of a Rawlsian-like wide reflective equilibrium, procedurally and without any specific substantive commitment to any moral or comprehensive doctrine of sorts. (shrink)

Despite their centrality to medicine, drugs are not easily defined. We introduce two desiderata for a basic definition of medical drugs. It should: (a) capture everything considered to be a drug in medical contexts and (b) rule out anything that is not considered to be a drug. After canvassing a range of options, we find that no single definition of drugs can satisfy both desiderata. We conclude with three responses to our exploration of the drug concept: maintain a monistic concept, (...) or choose one of two pluralistic outcomes. Notably, the distinction between drugs and other substances is placed under pressure by the most plausible of the options available. (shrink)

Placebos are often used by clinicians, usually deceptively and with little rationale or evidence of benefit, making their use ethically problematic. In contrast with their typical current use, a provocative line of research suggests that placebos can be intentionally exploited to extend analgesic therapeutic effects. Is it possible to extend the effects of drug treatments by interspersing placebos? We reviewed a database of placebo studies, searching for studies that indicate that placebos given after repeated administration of active treatments acquire medication-like (...) effects. We found a total of 22studies in both animals and humans hinting of evidence that placebos may work as a sort of dose extender of active painkillers. Wherever effective in relieving clinical pain, such placebo use would offer several advantages. First, extending the effects of a painkiller through the use of placebos may reduce total drug intake and side effects. Second, dose-extending placebos may decrease patient dependence. Third, using placebos along with active medication, for part of the course of treatment, should limit dose escalation and lower costs. Importantly, provided that nondisclosure is pre-authorized in the informed consent process and that robust evidence indicates therapeutic benefit comparable to that of standard full-dose therapeutic regimens, introducing dose-extending placebos into the clinical arsenal should be considered. This novel prospect of placebo use has the potential to change our general thinking about painkiller treatments, the typical regimens of painkiller applications, and the ways in which treatments are evaluated. (shrink)