Auditory verbal hallucinations form an essential criterial feature in the schizophrenia definition in the Diagnostic and Statistical Manual of Mental Disorders -IV and International Classification of Diseases -10. In both classificatory systems, the presence of a hallucinatory voice that continuously comments the patient’s behavior or thoughts, or the presence of several voices that discuss the patient with each other, is a sufficient criterion to diagnose schizophrenia. The DSM-IV defines a hallucination as “a sensory perception that has the..

This article retrieves Freud’s Paul as a forgotten predecessor and untapped critic of the “return to Paul” in contemporary political theology and continental philosophy. Given that Sigmund Freud published Moses and Monotheism in 1939 having barely escaped from Vienna, the text’s reception has justly been dominated by the question of Freud’s identification with Moses and the relationship between psychoanalysis and Judaism. However, I argue that this narrow focus has obscured the more fundamental problem of the connection between religion and Freud’s (...) enigmatic notion of “historical truth,” which he works out not through Moses but through Saint Paul. To do so, I first show how Freud’s genealogy of monotheism is modeled on the pathogenesis of hysterical symptoms. I then trace how Freud deepens his investigation into the etiology of symptom-formation until he arrives at the notion of historical truth and the archaic heritage that transmits it. Lastly, I demonstrate that Freud presents himself less as a Pauline figure than he does Paul as a proto-analyst. Through this staging, I contend that Freud parochializes the claims of Christianity as symptomatic of a more archaic historical truth that psychoanalysis alone is able to access. Freud’s Paul demonstrates that it is not a question of whether but how ostensibly modern secular discourses inherit the theological traditions in which they are imbedded. Reading Freud as a philosopher of religion ultimately offers an indictment of any philosophy or emancipatory politics naively modeled on theological universalism. (shrink)

The discovery of a novel polypeptide (Islet Amyloid Polypeptide: IAPP) isolated from human and cat islet amyloid and from amyloid of a human insulinoma is reviewed. Structurally, IAPP from the human and cat resembles calcitonin gene‐related peptide (CGRP). The structural similarities between the neuropeptide CGRP and IAPP support the premise that IAPP is hormonal in nature. Our immunohistochemical studies also indicate that normal islet B‐cells of several mammalian species (including man and cat) give strong immunoreactivity with antiserum directed to a (...) synthetic peptide segment of IAPP. The fact that IAPP is deposited as amyloid in the pancreatic islets of type 2 (noninsulin‐dependent) diabetics strongly supports an important but yet unknown link between IAPP and the development of this disease. (shrink)

Leukoaraiosis is a common imaging marker of cerebral small vessel disease. In recent years, with the continuous advances in brain imaging technology, the detection rate of leukoaraiosis is higher and its clinical subtypes are gradually gaining attention. Although leukoaraiosis has long been considered an incidental finding with no therapeutic necessity, there is now growing evidence linking it to, among other things, cognitive impairment and a high risk of death after stroke. Due to different research methods, some of the findings are (...) inconsistent and even contradictory. Therefore, a comprehensive and in-depth study of risk factors for leukoaraiosis is of great clinical significance. In this review, we summarize the literature on leukoaraiosis in recent years with the aim of elucidating the disease in terms of various aspects. (shrink)

Effective therapies are now available that can stop the progression of HIV infection and significantly delay the onset of AIDS. The “highly active antiretroviral therapy” (HAART) is a combination of potent antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors, that has a variety of serious side effects, including lipodystrophy, a pathology characterized by accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia, insulin resistance as well as fat wasting in face and limbs. There is still an open (...) debate that concerns the precise responsibility of HAART as well as metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. The similarities with multiple symmetric lipomatosis (MSL), in which mitochondria impairment plays a crucial role, lead to the hypothesis that drug-induced damages to mitochondrial DNA are able to alter mitochondria functionality to an extent that is similar to what occurs in MSL. In addition, several evidences indicate that HAART is also linked to a deregulated production of tumour necrosis factor-α, which uses mitochondria as intracellular targets. In this paper, we review data concerning the role of mitochondria in the pathogenesis of lipodystrophy, and advance a unifying hypothesis involving either direct or indirect effects of the drugs employed during HAART. BioEssays 23:1070–1080, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

We review mathematical models of HIV dynamics, disease progression, and therapy. We start by introducing a basic model of virus infection and demonstrate how it was used to study HIV dynamics and to measure crucial parameters that lead to a new understanding of the disease process. We discuss the diversity threshold model as an example of the general principle that virus evolution can drive disease progression and the destruction of the immune system. Finally, we show how mathematical models can be (...) used to understand correlates of long‐term immunological control of HIV, and to design therapy regimes that convert a progressing patient into a state of long‐term non‐progression. BioEssays 24:1178–1187, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

In this way progressive bourgeois philosophy, which seemed to offer the promise of a unified and peaceful world, in fact produced just the opposite.The book ...

Dandruff is a common scalp condition, which frequently causes psychological distress in those affected. Dandruff is considered to be caused by an interplay of several factors. However, the pathogenesis of dandruff remains under‐investigated, especially with respect to the contribution of the hair follicle. As the hair follicle exhibits unique immune‐modulatory properties, including the creation of an immunoinhibitory, immune‐privileged milieu, we propose a novel hypothesis taking into account the role of the hair follicle. We hypothesize that the changes and imbalance (...) of yeast and bacterial species, along with increasing proinflammatory sebum by‐products, leads to the activation of immune response and inflammation. Hair follicle keratinocytes may then detect these changes in scalp microbiota resulting in the recruitment of leukocytes to the inflammation site. These changes in the scalp skin immune‐microenvironment may impact hair follicle immune privilege status, which opens new avenues into exploring the role of the hair follicle in dandruff pathogenesis. Also see the video abstract here: https://youtu.be/mEZEznCYtNs. (shrink)

Recent studies have found abnormal levels of brain-derived neurotrophic factor in a variety of central nervous system diseases. This suggests that BDNF may be involved in the pathogenesis of these diseases. Moreover, regulating BDNF signaling may represent a potential treatment for such diseases. With reference to recent research papers in related fields, this article reviews the production and regulation of BDNF in CNS and the role of BDNF signaling disorders in these diseases. A brief introduction of the clinical application (...) status of BDNF is also provided. (shrink)

The most developed and the latest-to-mature mental skills represented in the creation of mono- versus polysemantic contexts are related respectively to the left and right frontal lobe. A polysemantic way of thinking is responsible for the subject's successful integration in the polydimensional world. The functional insufficiency of this right-hemispheric way of thinking displays a predisposition toward the development of mental disorders, including schizophrenia.

A recent paper by Leclerc et al(1) describes how recombinant hamster prion protein can undergo a spontaneous change in conformation to a structure that has features in common with PrPSc. Structural change in the host prion protein, PrPC to an insoluble and aggregated form with increased β‐sheet content (PrPSc) is central to the pathology of prion diseases.(2) A detailed understanding of the nature of these conformational changes will increase our knowledge of the molecular basis of prion pathology. These findings may (...) have implications for how the disease is initiated and provide a format for further investigation. BioEssays 23:772–774, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Opitz BBB/G syndrome is a monogenic disorder that is characterized by malformations of the ventral midline. Investigations into the underlying genetic defects and the pathobiochemistry of this syndrome have already shed light on the mechanisms of both the physiological and the pathological development of the ventral midline, a complicated multistep process. Moreover, these studies have revealed the ubiquitin‐dependent regulation of microtubule‐associated phosphatase 2A, a central mechanism in many cellular processes. In this review, we summarize recent findings and speculate upon their (...) implications for both medical and general research. BioEssays 25:356–366, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

A number of observations have led researchers to postulate that, despite being replication‐defective, human endogenous retroviruses (HERVs) may have retained the potential to cause or contribute to disease. However, mechanisms of HERV pathogenicity might differ substantially from those of modern infectious retroviruses or of the infectious precursors of HERVs. Therefore, novel pathways of HERV involvement in disease pathogenesis should be investigated. Recent technological advances in sequencing and bioinformatics are making this task increasingly feasible. The accumulating knowledge of HERV biology (...) may also facilitate the definition and general acceptance of criteria that establish HERV pathogenicity. Here, we explore possible mechanisms whereby HERVs may cause disease and examine the evidence that either has been or should be obtained in order to decisively address the pathogenic potential of HERVs. (shrink)

Pathogenesis in tauopathies involves the accumulation of tau in the brain and progressive synapse loss accompanied by cognitive decline. Pathological tau is found at synapses, and it promotes synaptic dysfunction and memory deficits. The specific role of toxic tau in disrupting the molecular networks that regulate synaptic strength has been elusive. A novel mechanistic link between tau toxicity and synaptic plasticity involves the acetylation of two lysines on tau, K274, and K281, which are associated with dementia in Alzheimer's disease (...) (AD). We propose that an increase in tau acetylated on these lysines blocks the expression of long‐term potentiation at hippocampal synapses leading to impaired memory in AD. Acetylated tau could inhibit the activity‐dependent recruitment of postsynaptic AMPA‐type glutamate receptors required for plasticity by interfering with the postsynaptic localization of KIBRA, a memory‐associated protein. Strategies that reduce the acetylation of tau may lead to effective treatments for cognitive decline in AD. (shrink)

The pathogenesis of dengue haemorrhagic fever has been the subject of intense research and considerable controversy. One hypothesis proposes that the immune response in a sensitized host is the primary mechanism. In contrast, others have suggested that the disease is caused by a more virulent, variant strain of dengue virus. Recent advances in molecular biology and hybridoma technology are providing valuable clues toward a solution and illustrating the fact that the course of a human viral disease is often a (...) net result of unseparated interactions between host and virus. (shrink)

The type III secretion system (T3SS) is a specialized nanomachine that enables bacteria to secrete proteins in a specific order and directly deliver a specific set of them, collectively known as effectors, into eukaryotic organisms. The core structure of the T3SS is a syringe‐like apparatus composed of multiple building blocks, including both membrane‐associated and soluble proteins. The cytosolic components organize together in a chamber‐like structure known as the sorting platform (SP), responsible for recruiting, sorting, and initiating the substrates destined to (...) engage this secretion pathway. In this article, we provide an overview of recent findings on the SP's structure and function, with a particular focus on its assembly pathway. Furthermore, we discuss the molecular mechanisms behind the recruitment and hierarchical sorting of substrates by this cytosolic complex. Overall, the T3SS is a highly specialized and complex system that requires precise coordination to function properly. A deeper understanding of how the SP orchestrates T3S could enhance our comprehension of this complex nanomachine, which is central to the host‐pathogen interface, and could aid in the development of novel strategies to fight bacterial infections. (shrink)

Neither the pathogenesis nor the aetiology of Down's syndrome (DS) are clearly understood. Numerous studies have examined whether clinical features of DS are a consequence of specific chromosome 21 segments being triplicated. There is no evidence, however, that individual loci are responsible, or that the oxidative damage in DS could be solely explained by a gene dosage effect. Using astrocytes and neuronal cultures from DS fetuses, a recent paper shows that altered metabolism of the amyloid precursor protein and oxidative (...) stress result from mitochondrial dysfunction.1 These findings are consistent with considerable data implicating the role of the mitochondrial genome in DS pathogenesis and aetiology. BioEssays 24:681–684, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Purposeful infection of healthy volunteers with a microbial pathogen seems at odds with acceptable ethical standards, but is an important contemporary research avenue used to study infectious diseases and their treatments. Generally termed ‘controlled human infection studies’, this research is particularly useful for fast tracking the development of candidate vaccines and may provide unique insight into disease pathogenesis otherwise unavailable. However, scarce bioethical literature is currently available to assist researchers and research ethics committees in negotiating the distinct issues raised (...) by research involving purposefully infecting healthy volunteers. In this article, we present two separate challenge studies and highlight the ethical issues of human challenge studies as seen through a well-constructed framework. Beyond the same stringent ethical standards seen in other areas of medical research, we conclude that human challenge studies should also include: independent expert reviews, including systematic reviews; a publicly available rationale for the research; implementation of measures to protect the public from spread of infection beyond the research setting; and a new system for compensation for harm. We hope these additions may encourage safer and more ethical research practice and help to safeguard public confidence in this vital research alternative in years to come. (shrink)

Some monothematic types of delusions may arise because subjects have unusual experiences. The role of this experiential component in the pathogenesis of delusion is still not understood. Focussing on delusions of alien control, we outline a model for reality testing competence on unusual experiences. We propose that nascent delusions arise when there are local failures of reality testing performance, and that monothematic delusions arise as normal responses to these. In the course of this we address questions concerning the tenacity (...) with which delusions are maintained, their often bizarre content, the patients' inability to dismiss them, and their often circumscribed character. (shrink)

This paper focuses on the causation of diseases, particularly on the idea of a “genetic cause” taking Alzheimer’s Disease (AD) as an example. We (1) provide some historical information and a synopsis of the current knowledge on the etiology and pathogenesis of AD, (2) analyse some conceptual problems related to the notion of “genetic disease” (3) elaborate on the alleged (genetic) cause of AD, and (4) place the discussion on the cause of AD in a broader philosophical context, paying (...) attention to a constructivist perspective, the notions of causal connection and causal selection, and to some practical and normative consequences of our analysis. We conclude (a) that AD is not a specific disease entity with one specific cause, (b) that the idea of a single (sufficient) cause can still function as a heuristic tool in AD research and practice, and (c) that a “belief” in causation can go together with the notions of multicausality and probability. (shrink)

Ontologies, as the term is used in informatics, are structured vocabularies comprised of human- and computer-interpretable terms and relations that represent entities and relationships. Within informatics fields, ontologies play an important role in knowledge and data standardization, representation, integra- tion, sharing and analysis. They have also become a foundation of artificial intelligence (AI) research. In what follows, we outline the Coronavirus Infectious Disease Ontology (CIDO), which covers multiple areas in the domain of coronavirus diseases, including etiology, transmission, epidemiology, pathogenesis, (...) diagnosis, prevention, and treatment. We emphasize CIDO development relevant to COVID-19. (shrink)

What kind of a thing are chronic diseases? Are they objects, bundles of signs and symptoms, properties, processes, or fictions? Rather than using concept analysis—the standard approach to disease in the philosophy of medicine—to answer this metaphysical question, I use a bottom-up, inductive approach. I argue that chronic diseases are bodily states or properties—often dispositional, but sometimes categorical. I also investigate the nature of related pathological entities: pathogenesis, etiology, and signs and symptoms. Finally, I defend my view against alternate (...) accounts of the nature of disease. (shrink)

Forty years’ experience as a bacterial geneticist has taught me that bacteria possess many cognitive, computational and evolutionary capabilities unimaginable in the first six decades of the twentieth century. Analysis of cellular processes such as metabolism, regulation of protein synthesis, and DNA repair established that bacteria continually monitor their external and internal environments and compute functional outputs based on information provided by their sensory apparatus. Studies of genetic recombination, lysogeny, antibiotic resistance and my own work on transposable elements revealed multiple (...) widespread bacterial systems for mobilizing and engineering DNA molecules. Examination of colony development and organization led me to appreciate how extensive multicellular collaboration is among the majority of bacterial species. Contemporary research in many laboratories on cell–cell signaling, symbiosis and pathogenesis show that bacteria utilise sophisticated mechanisms for intercellular communication and even have the ability to commandeer the basic cell biology of ‘higher’ plants and animals to meet their own needs. This remarkable series of observations requires us to revise basic ideas about biological information processing and recognise that even the smallest cells are sentient beings. Previous article in issue. (shrink)

Diseases of complex origin have a component of quantitative genetics that contributes to their susceptibility and phenotypic variability. However, after several studies, a major part of the genetic component of complex phenotypes has still not been found, a situation known as “missing heritability.” Although there have been many hypotheses put forward to explain the reasons for the missing heritability, its definitive causes remain unknown. Complex diseases are caused by multiple intermediate phenotypes involved in their pathogenesis and, very often, each (...) one of these intermediate phenotypes also has a component of quantitative inheritance. Here we propose that at least part of the missing heritability can be explained by the genetic component of intermediate phenotypes that is not detectable at the level of the main complex trait. At the same time, the identification of the genetic component of intermediate phenotypes provides an opportunity to identify part of the missing heritability of complex diseases. (shrink)

We highlight the various domains of the flavivirus virulence factor NS1 and speculate on potential implications of the NS1 3D structure in understanding its role in flavivirus pathogenesis. Flavivirus non‐structural protein 1 (NS1) is a virulence factor with dual functions in genome replication and immune evasion. Crystal structures of NS1, combined with reconstructions from electron microscopy (EM), provide insight into the architecture of dimeric NS1 on cell membranes and the assembly of a secreted hexameric NS1‐lipid complex found in patient (...) sera. Three structural domains of NS1 likely have distinct roles in membrane association, replication complex assembly, and immune system avoidance. A conserved hydrophobic inner face is sequestered either on the membrane or in the interior of the secreted hexamer and contains regions implicated in viral replication. The exposed variable outer face is presented to cellular and secreted components of the immune system in infected patients and contains candidate regions for immune system modulation. We anticipate that knowledge of the distinct NS1 domains and assembly will lead to advances in elucidating virus‐host interactions mediated through NS1 and in dissecting the role of NS1 in viral genome replication. (shrink)

When first published twenty years ago, The Logic of Medicine presented a new way of thinking about clinical medicine as a scholarly discipline as well as a profession. Since then, advances in research and technology have revolutionized both the practice and theory of medicine. In this new, extensively rewritten edition, Dr. Murphy includes changes to show how these different areas of scholarship may affect details of "the logic of medicine" without compromising its fundamental coherence. New to this edition are discussions (...) of the challenge of the flood of new empirical data, new ideas in genetics, molecular biology, homeostasis, pathogenesis, cancer, aging, and Alzheimer's disease. Murphy also comments on such new theoretical topics as dynamic systems, chaos, and fractals and their impact on the burgeoning fields of philosophy and practice of medicine. Written with medical students in mind, the book includes a glossary, many new examples, and problems for solutions with comments on each. An entirely new chapter deals with modeling. Clinicians and researchers will also find the principles thought-provoking and illuminating. (shrink)

The natural source for new pancreatic beta cells is an important issue both for understanding the pathogenesis of diabetes, and for possibly curing diabetes by increasing the number of beta cells. Dor et al.1 investigated beta‐cell renewal and regeneration by genetic lineage analysis in mice during physiological growth and after partial pancreatectomy. The data conclusively showed that beta‐cell replication was the only source for new beta cells without contributions from stem cells or other non‐beta cells. This underlines the capacity (...) for beta‐cell self‐renewal and casts doubt that other cell types are able to generate new beta cells in the intact pancreas. BioEssays 26:1156–1159, 2004. © 2004 Wiley Periodicals, Inc. (shrink)