Background: Meditation is gaining recognition as a tool to impact health and well-being. Samyama is an 8-day intensive residential meditation experience conducted by Isha Foundation requiring several months of extensive preparation and vegan diet. The health effects of Samyama have not been previously studied. The objective was to assess physical and emotional well-being before and after Samyama participation by evaluating psychological surveys and objective health biomarkers.Methods: This was an observational study of 632 adults before and after the Isha Samyama retreat. (...) All participants were invited to complete surveys. Controls included household significant others. Surveys were completed at baseline, just before Samyama, immediately after Samyama, and 3 months later to assess anxiety, depression, mindfulness, joy, vitality, and resilience through validated psychometric scales. Voluntary blood sampling for biomarker analysis was done to assess hemoglobin, HbA1c, lipid profile, and C-reactive protein. Primary outcomes were changes in psychometric scores, body weight, and blood biomarkers.Results: Depression and anxiety scores decreased from T1 to T3, with the effect most pronounced in participants with baseline depression or anxiety. Scores at T4 remained below baseline for those with pre-existing depression or anxiety. Vitality, resilience, joy, and mindfulness increased from T1 to T3. Body weight decreased by 3% from T1 to T3. Triglycerides were lower from T2 to T3. Participants had lower HbA1c and HDL at T2, and lower CRP at all timepoints compared with controls.Conclusions: Participation in the Isha Samyama program led to multiple benefits. The 2-month preparation reduced anxiety, and participants maintained lower anxiety levels at 3 months post-retreat. Physical health improved over the course of the program as evidenced by weight loss and improved HbA1C and lipid profile. Practices associated with the Samyama preparation phase and the retreat may serve as an effective way to improve physical and mental health. Future studies may examine their use as an alternative therapy in patients with depression and/or anxiety.Clinical Trial Registration:www.ClinicalTrials.gov, Identifier: 1801728792. Registered retrospectively on 4/17/2020. (shrink)

A striking and unexplained feature of granulomatous inflammation is its anatomical association with the lymphatic system. Accumulating evidence suggests that lymphatic tracks and granulomas may alter the function of each other. The formation of new lymphatics, or lymphangiogenesis, is an adaptive response to tumor formation, infection, and wound healing. Granulomas also may induce lymphangiogenesis which, through a variety of mechanisms, could contribute to disease outcomes in tuberculosis and sarcoidosis. On the other hand, alterations in lymph node function and lymphatic (...) draining may be primary events which attenuate the risk and severity of granulomatous inflammation. This review begins with an introduction of granulomatous inflammation and the lymphatic system. A role of the lymphatic system in tuberculosis and sarcoidosis is then hypothesized. With a focus on lymphangiogenesis in these diseases, and on the potential for this process to promote dissemination, parallels are established with the well‐established role of lymphangiogenesis in tumor biology. (shrink)

Inflamm‐aging is a relatively new terminology used to describe the age‐related increase in the systemic pro‐inflammatory status of humans. Here, we represent inflamm‐aging as a breakdown in the multi‐shell cytokine network, in which stem cells and stromal fibroblasts (referred to as the stem cell niche) become pro‐inflammatory cytokine over‐expressing cells due to the accumulation of DNA damage. Inflamm‐aging self‐propagates owing to the capability of pro‐inflammatory cytokines to ignite the DNA‐damage response in other cells surrounding DNA‐damaged cells. Macrophages, the major (...) cellular player in inflamm‐aging, amplify the phenomenon, by broadcasting pro‐inflammatory signals at both local and systemic levels. On the basis of this, we propose that inflamm‐aging is a major contributor to the increase in cancer incidence and progression in aged people. Breast cancer will be presented as a paradigmatic example for this relationship. (shrink)

We propose that hyper‐inflammation (HYPi) is a ‘‘runaway’’ consequence of acute inflammation (ACUi) that arises more easily (and also abates less easily) in those who host a pre‐existing chronic inflammation (CHRi), because (i) most factors involved in generating an ACUi to limit viral proliferation are already present when there is an underlying CHRi, and also because (ii) anti‐inflammatory (AI) mechanisms for the abatement of ACUi (following containment of viral proliferation) are suppressed and desensitized where there is an (...) underlying CHRi, with this causing the ACUi to spiral into a HYPi. Stress, pollution, diet, and gut microbiomes (alterable in weeks through dietary changes) have an intimate and bidirectional cause‐effect relationship with CHRi. We propose that avoidance of CHRi‐promoting foods and adoption of CHRi‐suppressing foods could reduce susceptibility to HYPi, in Covid‐19 and in other viral diseases, such as influenza, which are characterized by episodic and unpredictable HYPi. (shrink)

In the past decade, the availability of genetically modified animals has enabled the discovery of interesting roles for phosphatidylinositol 3‐kinase‐γ (PI3Kγ) and ‐δ (PI3Kδ) in different cell types orchestrating innate and adaptive immune responses. Therefore, these PI3K isoforms appear to be attractive drug targets for the treatment of diseases caused by unrestrained immune reactions. Currently, pharmacological targeting of PI3Kγ and/or PI3Kδ represents one of the most promising challenges for companies interested in the development of novel safe treatments for inflammatory diseases. (...) In this review we provide a general outline of PI3Kγ‐ and PI3Kδ‐specific functions in distinct subsets of inflammatory cells. We also discuss the therapeutic impact of novel compounds targeting PI3Kγ, PI3Kδ or both, in mouse models of autoimmune disorders (systemic lupus erythematosus (SLE) and rheumatoid arthritis), respiratory diseases (allergic asthma and chronic obstructive pulmonary disease) and cardiovascular dysfunctions (atherosclerosis and myocardial infarction). (shrink)

Biomarkers are widely used not only as prognostic or diagnostic indicators, or as surrogate markers of disease in clinical trials, but also to formulate theories of pathogenesis. We identify two problems in the use of biomarkers in mechanistic studies. The first problem arises in the case of multifactorial diseases, where different combinations of multiple causes result in patient heterogeneity. The second problem arises when a pathogenic mediator is difficult to measure. This is the case of the oxidative stress (OS) theory (...) of disease, where the causal components are reactive oxygen species (ROS) that have very short half-lives. In this case, it is usual to measure the traces left by the reaction of ROS with biological molecules, rather than the ROS themselves. Borrowing from the philosophical theories of signs, we look at the different facets of biomarkers and discuss their different value and meaning in multifactorial diseases and system medicine to inform their use in patient stratification in personalized medicine. (shrink)

Ecological Immunology assumes that immunological defenses must be minimized in terms of cost (energy expenditure). To reach this goal, a complex and still largely unexplored strategy has evolved to assure survival. From invertebrates to vertebrates, an integrated immune–neuroendocrine response appears to be crucial for the hierarchical redistribution of resources within the body according to the specific ecological demands. Thus, on the basis of experimental data on the intimate relationship between stress and immune responses that has been maintained during evolution, we (...) argue that a broader perspective based on the integration of immune and neuroendocrine responses should be adopted to describe the comprehensive strategy that the body utilizes to adapt to dynamic environmental conditions. We discuss the hypothesis that a bow‐tie architecture might be suitable to describe the variety of immune–neuroendocrine inputs that continuously target cells and organs while, at the same time, fulfilling the basic requirement of minimizing the cost of immune–neuroendocrine responses. Bow‐tie architectures are able to convert a variety of stimuli (fan in) into a wide range of fine‐tuned responses (fan out) by passing through the integrating activity of a core (knot) constituted by a limited number of elements. Finally, we argue that the ecologically negotiated immune–neuroendocrine strategies may have deleterious effects in the post‐reproductive period of life when, at least in humans, chronic, low‐grade, systemic inflammation develops, in accordance with the antagonistic pleiotropy theory of aging. BioEssays 30:868–874, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Background: Arthritis is very common but is not well understood. Actually, “arthritis” is not a single disease; it is an informal way of referring to joint pain or joint disease. There are more than 100 different types of arthritis and related conditions. People of all ages, sexes and races can and do have arthritis, and it is the leading cause of disability in America. More than 50 million adults and 300,000 children have some type of arthritis. It is most common (...) among women and occurs more frequently as people get older. Common arthritis joint symptoms include swelling, pain, stiffness and decreased range of motion. Symptoms may come and go. They can be mild, moderate or severe. They may stay about the same for years, but may progress or get worse over time. Severe arthritis can result in chronic pain, inability to do daily activities and make it difficult to walk or climb stairs. Arthritis can cause permanent joint changes. These changes may be visible, such as knobby finger joints, but often the damage can only be seen on X-ray. Some types of arthritis also affect the heart, eyes, lungs, kidneys and skin as well as the joints. Objectives: The main goal of this expert system is to get the appropriate diagnosis of disease and the correct treatment and give the appropriate method of treatment through several tips that concern the disease and how to treat it and we will see it through the application on the expert system. Methods: in this paper the design of the proposed Expert System which was produced to help Orthopedist in diagnosing Arthritis disease through its symptoms such as: pain on pressure in a joint , Inflammation indicated by joint swelling, Stiffness especially in the morning , Loss of flexibility of joint, Limited, joint movement, Deformity of the joints , Weight loss and fatigue , Non-specific fever and Crepitus. The proposed expert system presents an overview about Arthritis disease is given, the cause of diseases is outlined and the treatment of disease whenever possible is given out. SL5 Object Expert System language was used for designing and implementing the proposed expert system. Results: The proposed Arthritis disease diagnosis expert system was evaluated by Orthopedics students and they were satisfied with its performance. Conclusions: The Proposed expert system is very useful for Orthopedist, patients with arthritis and newly graduated Orthopedics students. (shrink)

The human intestines are constantly under the influence of numerous pathological factors: enteropathogenic microorganisms, food antigens, physico‐chemical stress associated with digestion and bacterial metabolism, therefore it must be provided with a system of protection against adverse impact. Recent studies have shown that Paneth cells play a crucial role in maintaining homeostasis of the small intestines. Paneth cells perform many vital functions aimed at maintaining a homeostatic balance between normal microbiota, infectious pathogens and the human body, regulate the qualitative composition and (...) number of intestinal microorganisms, prevent the introduction of potentially pathogenic species, and protect stem cells from damage. Paneth cells take part in adaptive and protective‐inflammatory reactions. Paneth cells maintain dynamic balance between microbial populations, and the macroorganism, preventing the development of intestinal infections and cancer. They play a crucial role in gastrointestinal homeostasis and may be key factors in the etiopathological progression of intestinal diseases. (shrink)

The human blood coagulation system comprises a series of linked glycoproteins that upon activation induce the generation of downstream enzymes ultimately forming fibrin. This process is primarily important to arrest bleeding (hemostasis). Hemostasis is a typical example of a molecular machine, where the assembly of substrates, enzymes, protein cofactors and calcium ions on a phospholipid surface markedly accelerates the rate of coagulation. Excess, pathological, coagulation activity occurs in “thrombosis”, the formation of an intravascular clot, which in the most dramatic form (...) precipitates in the microvasculature as disseminated intravascular coagulation. Thrombosis occurs according to a biochemical machine model in the case of atherothrombosis on a ruptured atherosclerotic plaque, but may develop at a slower rate in venous thrombosis, illustrating that the coagulation machinery can act at different velocities. The separate coagulation enzymes are also important in other biological processes, including inflammation for which the rapid conversion of one coagulation factor by the other is not a prerequisite. The latter role of coagulation enzymes may be related to the old and probably maintained function of the coagulation machine in innate immunity. BioEssays 25:1220–1228, 2003. © 2003 Wiley Perioicals, Inc. (shrink)

The mammary gland is a skin gland unique to the class Mammalia. Despite a growing molecular and histological understanding of the development and physiology of the mammary gland, its functional and morphological origins have remained speculative. Numerous theories on the origin of the mammary gland and lactation exist. The purpose of the mammary gland is to provide the newborn with copious amounts of milk, a unique body fluid that has a dual role of nutrition and immunological protection. Interestingly, antimicrobial enzymes, (...) such as xanthine oxidoreductase or lysozyme, are directly involved in the evolution of the nutritional aspect of milk. We outline that xanthine oxidoreductase evolved a dual role in the mammary gland and hence provide new evidence supporting the hypothesis that the nutritional function of the milk evolved subsequent to its protective function. Therefore, we postulate that the mammary gland evolved from the innate immune system. In addition, we suggest that lactation partly evolved as an inflammatory response to tissue damage and infection, and discuss the observation that the two signaling pathways, NF‐kB and Jak/Stat, play central roles in inflammation as well as in lactation. BioEssays 28: 606–616, 2006. © 2006 Wiley Periodicals, Inc. (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)

Retinopathy of prematurity (ROP) is a complex neonatal disorder with multiple contributing factors. In this paper we have mounted the evidence in support of the proposal that neonatal sepsis meets all requirements for being a cause of ROP (not a condition, mechanism, or even innocent bystander) by means of initiating the early stages of the pathomechanism of ROP occurrence, systemic inflammation. We use the model of etiological explanation, which distinguishes between two overlapping processes in ROP causation. It can (...) be shown that sepsis can initiate the early stages of the pathomechanism via systemic inflammation (causation process) and that systemic inflammation can contribute to growth factor aberrations and the retinal characteristics of ROP (disease process). The combined contribution of these factors with immaturity at birth (as intrinsic risk modifier) and prenatal inflammation (as extrinsic facilitator) seems to provide a cogent functional framework of ROP occurrence. Finally, we apply the Bradford Hill heuristics to the available evidence. Taken together, the above suggests that neonatal sepsis is a causal inducer of ROP. (shrink)

Frailty is an age-related dynamic status, characterised by a reduced resistance to stressors due to the cumulative decline of multiple physiological systems. Several researches have highlighted a relationship between physical frailty and cognitive decline; however, the role of specific cognitive domains has not been deeply clarified yet. Current studies have hypothesised that physical frailty and neuropsychological deficits may share systemic inflammation and increased oxidative stress in different neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. However, the role of (...) the executive dysfunction should be investigated in a more detailed way using a multidimensional approach. With this aim, we conducted a review of the literature on the few experimental articles published to discuss the existence of a relationship between frailty and cognitive impairment in neurocognitive disorders, particularly focusing on the domain of executive dysfunction. The data suggest that physical frailty and cognitive decline, especially executive dysfunction, are two aspects strongly linked in mild and major neurocognitive disorders due to Alzheimer's and Parkinson's disease. In light of this, a new framework linking ageing, cognitive decline, and neurodegenerative diseases is needed. In order to analyse the effects that ageing processes have on neural decline and neurocognitive disease, and to identify relevant groups of users and patients, future longitudinal studies should adopt a multidimensional approach, in the field of primary prevention and in the continuum from mild to major neurocognitive disorder. (shrink)

The information contained in DNA is not definitive, but modifiable. Indeed, the environment has the power to modify the genetic material expression without altering the DNA genes sequence. The principal environmental factors that work in this way, whether in a positive or in a negative way, are diet and stress with their ruling hormones, insulin and cortisol; these hormones are normally antagonists but, when they reach their respective resistances, they become the ubiquitary etiopathogenetic factors in bidirectional convergent relationship, each other (...) causing the disinhibition and development of low grade systemic inflammation that opens the door to a myriad of interconnected sets of problems. Among these problems the greater one is cancer, which represents the extreme junction between hyperinsulinemia and hypercortisolemia, just because cancer cells never become insulin resistant and/or cortisol resistant. (shrink)

The prevalence of obesity skyrocketed over the past decades to become a significant public health problem. Obesity is recognized as a low-grade inflammatory disease and is linked with several comorbidities such as diabetes, circulatory disease, common neurodegenerative diseases, as well as chronic pain. Adipocytes are a major neuroendocrine organ that continually, and systemically, releases pro-inflammatory factors. While the exact mechanisms driving obesity-induced pain remain poorly defined, nociceptors hypersensitivity may result from the systemic state of inflammation characteristic of obesity (...) as well as weight surplus-induced mechanical stress. Obesity and pain also share various genetic mutations, lifestyle risk factors, and metabolic pathways. For instance, fat pads are often found hyper-innervated and rich in immune cell types of multiple origins. These immunocytes release cytokines, amplifying nociceptor function, which, in turn, via locally-released neuropeptides sustain immunocytes’ function. Here, we posit that along with mechanical stressed stemming from extra weight, the local neuro-immune interplay occurring within the fat pads maintains the state of chronic low-grade inflammation and heightens sensory hypersensitivity. Overall, stopping the harmful neuro-immune crosstalk may constitute a novel pathway to prevent obesity-associated comorbidities, including neuronal hypersensitivity. (shrink)

To enable microbial colonisation of the gut mucosa, the intestinal immune system must not only react to danger signals but also recognize cues that indicate safety. Safety recognition, paradoxically, is mediated by the same environmental sensors that are involved in signalling danger. Indeed, in addition to their well established role in inducing inflammation in response to stress signals, pattern recognition receptors (PRRs) and a variety of metabolic sensors also promote gut-microbiota symbiosis by responding to "microbial symbiosis factors", "resolution-associated molecular (...) patterns", markers of energy extraction and other signals indicating the absence of pathogenic infection and tissue damage. Here we focus on how the paradoxical role of immune receptors and other environmental sensors define the microbiota signature of the individual. (shrink)

Complementary DNA clones corresponding to most of the proteins of a major amplification and effector of immune host defenses, the complement system, have been isolated and characterized. Availability of these molecular probes has substantially increased our information about and understanding of the structure of the complement proteins and regulation of complement gene expression. Information about the proteins has led to the generation of potential pharmacological agents for the selective control of inflammation. Understanding of the regulatory mechanism has provided insights (...) into the mechanisms accounting for the response to several cytokines including interferon‐gamma, interleukin‐1 and tumor necrosis factor. Finally, complement molecular genetics has been stimulated so that the basis for several complement deficiency disorders has been elucidated. (shrink)

Only recently has Jean-Jacques Rousseau’s Discourse on Inequality begun to be read as a genealogy rather than a variation on the social contract tradition. This article argues that reading Rousseau as a genealogist not only clarifies his analysis of amour-propre’s inflammation, but also illuminates a conception of freedom achieved through the continuous political practice of shaping of amour-propre. In the first section of this article, I situate this conception of freedom against two separate but relevant bodies of Rousseau scholarship: (...) those who read him as a genealogist, and those who emphasize the ambiguities of amour-propre. Next, I look to The Social Contract’s passages on censorship and court of honor in order to evaluate their roles as institutions that forestall the inflammation of amour-propre. Finally, I examine the social institutions that citizens actively participate in as they practice their freedom: the festivals, dances, balls and games described in The Letter to D’Alembert and Considerations on the Government of Poland. It is in these institutions that we see the political implications of Rousseau’s genealogical system manifest: because his genealogy illuminates the human tendency toward vice, the cultivation of virtuous citizenship appears as a constant struggle rather than an idealist achievement. (shrink)

There is a steadily growing literature on the role of the immune system in psychiatric disorders. So far, these advances have largely taken the form of correlations between specific aspects of inflammation (e.g. blood plasma levels of inflammatory markers, genetic mutations in immune pathways, viral or bacterial infection) with the development of neuropsychiatric conditions such as autism, bipolar disorder, schizophrenia and depression. A fundamental question remains open: why are psychiatric disorders and immune responses intertwined? To address this would require (...) a step back from a historical mind–body dualism that has created such a dichotomy. We propose three contributions of active inference when addressing this question: translation, unification, and simulation. To illustrate these contributions, we consider the following questions. Is there an immunological analogue of sensory attenuation? Is there a common generative model that the brain and immune system jointly optimise? Can the immune response and psychiatric illness both be explained in terms of self-organising systems responding to threatening stimuli in their external environment, whether those stimuli happen to be pathogens, predators, or people? Does false inference at an immunological level alter the message passing at a psychological level (or vice versa) through a principled exchange between the two systems? (shrink)

The interaction between science and technology in the Industrial Revolution has been debated by various authors over the years. Most recently, Ursula Klein has described eighteenth-century chemistry as an interconnected system of science and technology because of the inherently productive nature of chemical experimentation. The technology used in the nineteenth gaslight industry follows the pattern that Klein describes: gaslight technology was derived from the academic studies of eighteenth-century pneumatic chemists. The foundation of the technology in science included first, a knowledge (...) about inflammable gases and their properties, and second, various instruments and processes developed for the study of gases. Although inflammable exhalations had been known long before the eighteenth-century, it was only with the work of Priestley, Volta, Berthollet, and other chemists that their properties and characteristics, including the multiplicity of species of inflammable gases, became known. The instruments and processes of pneumatic chemistry that were incorporated into gaslight apparatus were the retort, the pneumatic trough, lime purification of carbon dioxide and hydrogen sulphide, and finally the gasometer. The first important instance of lighting with inflammable gases, that of J. P. Minckelers in 1785, demonstrates that pneumatic chemistry formed part of an interconnected network of science and technology, as does the work of other early gaslight pioneers such as Philippe Lebon, Zachäus Winzler, and William Murdoch. Lebon came to gaslight through the investigation of distillation processes, and later thought of using the inflammable gas produced in this way. Zachäus Winzler, an Austrian chemist, recreated Lebon's thermolamp from the instruments in his laboratory after hearing descriptions of it. In the case of William Murdoch, he incorporated the pneumatic apparatus that James Watt had built for Thomas Beddoes. (shrink)

Traditionally, autoimmune disease has been considered to be a case of false recognition; the immune system mistakenly identifies 'self' tissues as foreign, attacking them thus causing damage and malady. Accordingly, the history of autoimmunity is usually told as part ot the history of immunology, that is, of theories and experiments relating to the ability of the immune system to discriminate between self and nonself. This paper challenges this view, claiming that the emergence of the notion of autoimmunity in the 1950s (...) must be considered as part of a long develolpment in thought about pathology throughout the twentieth century, namely the conceptualisaiton of disease as a reactive and self-destructive process. During the first part of the twentieth century this notion became one of the cornerstones of pathology and was increasingly employed for the explanation of the non-infections, slow-burning diseases. Thus, the category of chronic disease had been defined anew, now encompassing all those diseases characterised by a persistent inflammatory process. Inflammation, in turn, was conceived as double-eged physiological mechanism, which was usually the direct mediator of damage, of the essence of disease. The paper also shows how this kind of analysis could emable a unified historical discussion of autoimmunity and allergy, hitherto considered to have distinct conceptual origins. (shrink)

Rheumatoid arthritis is a progressive systemic autoimmune disease characterized by inflammation of the joints and surrounding tissues, which seriously affects the life of patients. The Sharp/van der Heijde method has been widely used in clinical evaluation for the RA disease. However, this manual method is time-consuming and laborious. Even if two radiologists evaluate a specific location, their subjective evaluation may lead to low inter-rater reliability. Here, we developed an efficient model powered by deep convolutional neural networks to solve (...) these problems and automated the overall scoring on hand X-rays. The depthwise separable convolution technique is used based on ResNet-50 due to the high resolution of hand X-rays. An inverted residual block is introduced to devise a ResNet-Dwise50 model to enhance the efficiency of the model. The model was trained and tested using bilateral posteroanterior images of 3818 patients. The experiment results show the ResNet-Dwise50 model achieved an MAE of 14.90 and RMSE of 22.01 while ensuring high efficiency. There was no statistical difference between the average scores given by two experienced radiologists and predicted scores from our model. (shrink)

Tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) is a crucial signaling molecule regulating a diverse array of physiological processes, including adaptive immunity, innate immunity, bone metabolism and the development of several tissues including lymph nodes, mammary glands, skin and the central nervous system. It is a member of a group of six closely related TRAF proteins, which serve as adapter molecules, coupling the TNF receptor (TNFR) superfamily to intracellular signaling events. Among the TRAF proteins, TRAF6 is unique in (...) that, in addition to mediating TNFR family signaling, it is also essential for signaling downstream of an unrelated family of receptors, the interleukin‐1 (IL‐1) receptor/Toll‐like receptor (IL‐1R/TLR) superfamily. Gene targeting experiments have identified several indispensable physiological functions of TRAF6, and structural and biochemical studies have revealed the potential mechanisms of its action. By virtue of its many signaling roles, TRAF6 represents an important target in the regulation of many disease processes, including immunity, inflammation and osteoporosis. BioEssays 25:1096–1105, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The first clinical symptoms focused on the presentation of coronavirus disease 2019 have been respiratory failure, however, accumulating evidence also points to its presentation with neuropsychiatric symptoms, the exact mechanisms of which are not well known. By using a computational methodology, we aimed to explain the molecular paths of COVID-19 associated neuropsychiatric symptoms, based on the mimicry of the human protein interactions with SARS-CoV-2 proteins.Methods: Available 11 of the 29 SARS-CoV-2 proteins’ structures have been extracted from Protein Data Bank. HMI-PRED, (...) a recently developed web server for structural PREDiction of protein-protein interactions between host and any microbial species, was used to find the “interface mimicry” through which the microbial proteins hijack host binding surfaces. Classification of the found interactions was conducted using the PANTHER Classification System.Results: Predicted Human-SARS-CoV-2 protein interactions have been extensively compared with the literature. Based on the analysis of the molecular functions, cellular localizations and pathways related to human proteins, SARS-CoV-2 proteins are found to possibly interact with human proteins linked to synaptic vesicle trafficking, endocytosis, axonal transport, neurotransmission, growth factors, mitochondrial and blood-brain barrier elements, in addition to its peripheral interactions with proteins linked to thrombosis, inflammation and metabolic control.Conclusion: SARS-CoV-2-human protein interactions may lead to the development of delirium, psychosis, seizures, encephalitis, stroke, sensory impairments, peripheral nerve diseases, and autoimmune disorders. Our findings are also supported by the previous in vivo and in vitro studies from other viruses. Further in vivo and in vitro studies using the proteins that are pointed here, could pave new targets both for avoiding and reversing neuropsychiatric presentations. (shrink)

Sustainable Medicine is based on the premise that twenty-first century Western medicine--driven by vested interests--is failing to address the root causes of disease. Symptom-suppressing medication and "polypharmacy" have resulted in an escalation of disease and a system of so-called "health care," which more closely resembles "disease care." In this essential book, Dr. Sarah Myhill aims to empower people to heal themselves by addressing the underlying causes of their illness. She presents a logical progression from identifying symptoms, to understanding the underlying (...) mechanisms, to relevant interventions and tests and tools with which to tackle the root causes. As Myhill writes, "It's all about asking the question 'why?'" Sustainable Medicine covers a wide range of symptoms including inflammation (infection, allergy, autoimmunity), fatigue, pain, toxic symptoms, deficiency symptoms, and hormonal symptoms. And Dr. Myhill includes a toolbox of treatments for specific illnesses and ailments, as well as a general approach to avoiding and treating all disease. Finally, she offers a series of case histories to show how people have successfully taken control of their health and healed even in the face of the most discouraging symptoms--all without the harmful interventions of 21st century Western medicine. (shrink)

The spinal mechanisms of action of opioids under normal conditions are reasonably well understood. The spinal effects of opioids can be enhanced or reduced depending on pathology and activity in other segmental and nonsegmental pathways. This plasticity will be considered in relation to the control of different pain states using opioids. The complex and contradictory findings on the supraspinal actions of opioids are explicable in terms of heterogeneous descending pathways to different spinal targets using multiple transmitters and receptors – therefore (...) opioids can both increase and decrease activity in descending pathways. These pathways could exhibit considerable plasticity. There is increasing evidence that delta opioid receptor agonists have the potential to replace morphine as major analgesics with reduced side-effect profiles. The concept of preemptive analgesia, based on preventing the induction of some of the negative plastic influences on opioid controls and the detrimental effects of pain, is sound, but experimental verification in the clinical setting is difficult. For example, a delayed compensatory upregulation of inhibitory systems, particularly in inflammation, may counter persistent painful inputs. Combination therapy with opioids may be beneficial in many pain states where either negative influences are blocked or inhibitory controls are enhanced. Finally, developmental aspects of these systems are discussed in connection with the treatment of pain in young children, where inhibitory systems in the spinal cord are immature. (shrink)

Knowledge about eating habits is relevant for understanding the relations between diet, obesity and development of Chronic Non-Communicable Diseases. The storage of calories as body fat, mainly in the visceral subcutaneous adipose tissue, as consequence of hypercaloric diet poor in nutrients, is responsible for increasing sublinic inflammation and overloading the immune system. Diet plays an important role in reducing inflammation. In time of infectious pandemia, of the new corona virus (COVID-19), the food quality and nutritional status of Brazilians (...) may interfere in fighting this infection. Based on the literature, this article aims to discuss the Brazilians eating habbits and nutritional status. The data shows that Brazilian are gainning weight and tend to a diet poor in nutrient intake. Consequently this scenario favors the subclinical inflammation and the weakness of the immune response. We suggest that Brazilian Health Authorities pay attention to this issue. (shrink)

Using 2021 data and information related to COVID‐19, this paper discusses the contribution of colonization, medical mistrust and racism to vaccine hesitancy. Vaccine hesitancy is defined as ‘delay in acceptance or refusal of vaccines despite availability’. Colonization is described as the ‘way the extractive economic system of capitalism came to the United States, supported by systems of supremacy and domination, which are a necessary part of keeping the wealth and power accumulated in the hands of the colonizers and ultimately their (...) financiers’. The system of colonization results in policies and practices, including those related to health, that continue to create oppression and support racism. Persons experience trauma as the byproduct of colonization. Chronic stress and trauma create chronic inflammation and all diseases, whether genetic or lifestyle, have a common pathogenesis that is a component of inflammation. Medical mistrust is the absence of trust that healthcare providers and organizations genuinely care for patients' interests, are honest, practice confidentiality and have the competence to produce the best possible results. Finally, racism is described as everyday racism and perceived racism in healthcare. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Alzheimer's Disease, Mild Cognitive Impairment, and the Biology of Intrinsic AgingThomas B. L. Kirkwood (bio)Keywordsaging, Alzheimer’s disease, genetic mutation, mild cognitive impairment, telomereThe article by Gaines and Whitehouse (2006) raises key questions about the uncertain relationship between (i) the intrinsic, "normal" aging process, and (ii) the clinicopathologic states represented by the labels of Alzheimer's disease (AD) and mild cognitive impairment (MCI). This short commentary offers a perspective on this (...) debate that is drawn from a consideration of underlying biological mechanisms.Because age is unquestionably the greatest single risk factor associated with AD and MCI, I begin by asking what we know about the intrinsic processes of aging. The central feature of current understanding of intrinsic aging is that it consists of the gradual, lifelong accumulation of a wide variety of molecular and cellular faults that begins very early in life and eventually leads to overt functional impairments resulting in age-related frailty, disability, and disease (Kirkwood 2005). This is an essentially bottom-up process. A strong consensus has emerged in recent years that there is no active program for aging and that there are no genetic factors that have evolved specifically to cause aging or age-related diseases. Unquestionably, there are genes that influence susceptibility to disease and even length of life, but these genes are genes for maintenance and repair functions, not for aging. It is the limitation in the past evolutionary pressure to invest in greater longevity than was required, within an environment where life was usually truncated by hazards such as starvation, injury, or infection, that means that our maintenance systems—good as they are—are insufficient to keep us going indefinitely. Added to this is the idea that there are probably also genes that program processes that are good for the young organism, but which may in later life have harmful effects. Processes like inflammation and apoptosis, which are seen to occur extensively in aged tissues, including brain, surely evolved to help cope with infection and cellular damage arising earlier in life. That they are called into play in aged tissues is a direct, but secondary, consequence of accumulated damage.With this general framework to understand the intrinsic biology of aging, let us now ask what we might expect a priori for the aging of an organ such [End Page 79] as the brain. Although we cannot pretend complete ignorance of how the brain actually does age, our enquiry can be based entirely on data from other organ systems, so we can develop our predictions about brain aging without prejudice.Aging begins very early during human development, faults accumulating from the first stages of embryonic development. Each time a cell divides, each of the daughter cells is likely to acquire a few new mutations. We know this from the estimates for the error rate in DNA replication and the size of the human genome. It is confirmed by direct evidence that at individual gene loci where mutations have been measured, mutation frequency increases with age (Morley 1998; Vijg 2000). In addition to replication errors, DNA is damaged on a daily basis to a very considerable degree by agents such as reactive oxygen species (free radicals), which are formed as byproducts of normal cellular metabolism. Although most of this damage is corrected by repair, the repair mechanisms themselves are not error free and additional mutations accumulate through this route. If a mutation is lethal to the cell, the cell dies and thus the mutation is eliminated. However, the majority of mutations are nonlethal, either because the mutation is recessive and the cell carries an intact gene copy on the other chromosome, because the gene is not currently required, or because the mutation produces only a delayed deleterious effect. Examples of genes that produce delayed deleterious effects include the genes responsible for familial AD. It is interesting to reflect that on statistical grounds alone, it is almost certain that each of us carries a randomly determined fraction of cells in our brains that bear amyloid precursor protein or presenilin mutations associated with AD. We also carry a heterogeneous array of random mutations that compromise essential cell maintenance functions. How many such... (shrink)

The aging process involves changes in immune regulation, i.e. adaptive immunity declines whereas innate immunity becomes activated. NF‐κB signaling is the master regulator of the both immune systems. Two recent articles highlight the role of the NF‐κB system in aging and immune responses. Adler et al1 showed that the NF‐κB binding domain is the genetic regulatory motif which is most strongly associated with the aging process. Kwon et al2 studying HIV‐1 infection and subsequent immune deficiency process demonstrated that HIV‐1 Tat (...) protein binds to SIRT1 protein, a well‐known longevity factor, and inhibits the SIRT1‐mediated deacetylation of the p65 component of the NF‐κB complex. As a consequence, the transactivation efficiency of the NF‐κB factor was greatly potentiated, leading to the activation of immune system and later to the decline of adaptive immunity. These observations support the scenario where immune responses and aging process can be enforced by the potentiation of NF‐κB transactivation efficiency. Longevity factors, such as SIRT1 and its activators, might regulate the efficiency of the NF‐κB signaling, the major outcome of which is inflamm‐aging via proinflammatory responses. BioEssays 30:939–942, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Confidentiality and Its LimitsMaude Laliberté, John D. Lantos, and Sonia GowdaMultiple sclerosis is believed to be an autoimmune disease of the central nervous system. However, according to Italian physician Paolo Zamboni, it is related to cerebrospinal vascular insufficiency. Zamboni claims that MS can be treated by remedying this condition with venous angioplasty. This surgery is offered as treatment for MS in various countries—Poland, Bulgaria, and Costa Rica, for example. (...) But the Medical Board of Quebec, Canada, does not allow its members to perform the surgery and strongly advises patients against seeking it elsewhere. This opposition is based on the lack of evidence to support the procedure and the serious risks associated with it (including venous thrombosis, stroke, and pulmonary embolism). As a result, many Canadian MS patients have traveled to other countries to receive the surgery. Quebec physicians have been reluctant to provide surgical follow-up for patients who undergo the surgery in other countries due to the lack of information regarding the procedure. No alternative treatments are effective to partially or completely cure MS, and so the treatments available in Canada aim only to manage its symptoms.Jade is a forty-year-old Canadian woman with MS. She is on long-term disability leave, complains of growing fatigue and muscle stiffness, and has painful sensations in her limbs. She has been followed by an interdisciplinary team in a specialized hospital in Quebec for the past twenty years, since she was diagnosed. At her last appointment, Jade told her physical therapist that she recently underwent the experimental Zamboni surgery in Poland, despite her physician’s strong recommendation not to. Jade fears her physician’s reaction, so she asks the physical therapist to keep this information from the rest of her medical team.Jade is shy and tends to distrust health care professionals. It took many years for her physical therapist to gain her trust and to develop a positive therapeutic relationship with her. However, the physical therapist knows that serious complications can occur in patients who have had Zamboni’s surgery. Not telling Jade’s physician about the surgery could result in harm; Jade could have complications that are not recognized. Providing the information to the rest of the team would allow them to adjust her treatment to respond to the surgery and give her information and postoperative education that she will need. Moreover, keeping this secret could threaten team cohesion and trust if they find out about it later.Jade decided to undergo a risky surgery against her doctor’s advice in the hope of improving her quality of life. This was her autonomous choice. How should the physical therapist respond?CommentaryMaude Laliberte (bio)Laws and professional codes of ethics direct clinicians to respect their patients’ autonomy through confidentiality and informed consent unless there are compelling reasons not to do so. Health professionals are deeply committed to helping patients; above all, they want to avoid harming them. Therefore, a key component of this case is the possibility that respecting Jade’s desire to conceal information from the team may put her at direct risk if any postoperative complications are not detected, and at indirect risk if Jade’s trust in her medical team is undermined to the point where she turns away from them.The physical therapist must determine if the possible physical risks to Jade are imminent and serious enough to go against her autonomous choice. One risk that can occur following Zamboni’s surgery is inflammation of a vein caused by a blood clot. This is a life-threatening situation (although it may not be a likely complication for Jade). But the physical therapist can teach Jade to recognize the physical signs that can alert her to this problem, giving her ample time to seek treatment. Thus, even though she may be in danger from a life-threatening risk, there may be ways to manage it besides violating her confidentiality.The respect for autonomous choice is a crucial aspect of our democratic values. It promotes a process of exchange in the therapeutic alliance: the professional guides and informs the patient, but the patient is a partner in care planning and treatment. An important... (shrink)

ObjectiveLeveraging an integrative multimodal MRI paradigm to elaborate on the hippocampus-derived structural and functional changes in children and adolescents with juvenile idiopathic arthritis and to explore potential correlations within the “joint-inflammation-brain” axis during the period of central neural system development.MethodsTwenty-one patients with JIA all completed the multimodal MRI scanning, laboratory tests, and neuropsychological assessments; meanwhile, 23 matched controls were recruited. We then harnessed the spherical harmonics with a point distribution model and the ROI-to-voxel functional connectivity to measure the hippocampal (...) shape and hippocampo-cortical FC patterns. Correlation analysis was performed to explore the potential links in neuroimaging features with disease-related indices.ResultsCompared to controls, JIA patients only presented an atrophic tendency in the posterior part of the bilateral hippocampus. The hippocampo-cortical FC revealed the between-group divergences mainly located at the pain matrix, striatum, and temporal lobe. Remarkably, the enhanced FC between the right hippocampus and postcentral cortex is positively correlated with the disability index, while the weakened FC of right anterior hippocampus with right insula and that of left posterior hippocampus with left superior temporal gyrus was inversely related to the erythrocyte sedimentation rate and anxiety status, separately.ConclusionAs with macroscopic damages, the altered functional-connectome patterns of the hippocampus in JIA patients might be more sensitive to detect the early neuropathological changes. Moreover, the functional disturbances were demonstrated associated with the physical disability, inflammation, and emotional status. These findings may enlighten us on the underlying neuropathological mechanism of CNS comorbidities in JIA. (shrink)

Much of the attention of philosophy of science, history of science, and psychology in the twentieth century has focused on the nature of conceptual change. Conceptual change in science has occupied pride of place in these disciplines, as either the subject of inquiry or the source of ideas about the nature of conceptual change in other domains. There have been numerous conceptual changes in the history of science, some more radical than others. One of the most radical was the chemical (...) revolution. In the seventeenth century, chemists believed that the processes of combustion and calcination involved the absorption or release of a substance called phlogiston. On this theory, when an ore is heated with charcoal, it absorbs phlogiston to produce a metal; when a metal is burned, it releases phlogiston and leaves behind a residue, or calx. The concept of phlogiston derived from a quite complex Aristotelian/medieval structure that included three concepts central to chemical theory: sulphur, the principle of inflammability; mercury, the principle of fluidity; and salt, the principle of inertness. All material substances were believed to contain these three principles in the form of earths. The phlogiston theory held that in combustion, the sulphurous earth (phlogiston) returns to the substance from which it escaped during some earlier burning process in its history, and that in calcination the process is reversed. However, chemists also knew that a calx is heavier than the metal from which it was derived. So, the theory implies that phlogiston has a negative weight, or a positive lightness. This did not present a problem, though, because it was compatible with the Aristotelian elements of fire and air (the others being earth and water), which were not attracted towards the center of the earth. The development of the oxygen theory of combustion and calcination by Lavoisier in the late eighteenth century has been called the chemical revolution because it required replacing the whole conceptual structure with, for example, different concepts of substance and element and new concepts of oxygen and caloric. In the new system, it was no longer possible to believe in the existence of substances with negative weight. According to the oxygen theory, oxygen gas is released in combustion and absorbed in calcination. Thus calx is metal (substance) plus oxygen, rather than metal minus phlogiston. The concept of phlogiston was eliminated from the chemical lexicon. The reconceptualization of chemical phenomena that took place in the chemical revolution made possible the atomic theory of matter, which, as we know, posits quite different constituents of material substances from the principles central to the earlier conceptual structure. Just what constitutes conceptual change, how it relates to theory change, and how it relates to changes in belief continues to be a subject of much debate. Clearly, though, as the preceding example demonstrates, the three are significantly interrelated. (shrink)

Volume 25, Issue 2, February 2025, Page 157-159.

Galectin-3 and LTB4 are pro-inflammatory molecules recently shown to directly cause insulin resistance in mouse and human cells. They are highly expressed in the obese state, and can be targeted both genetically and pharmacologically to improve insulin sensitivity in vivo. This expands on previous research showing that targeting inflammatory cytokines can be insulin sensitizing in animal models. However, translating these potential therapies into the human setting remains challenging. Here we review this latest research, and discuss how balancing their pleiotropic functions, (...) the action of the microbiome, and the ability to identify relevant patient populations are vital considerations for successful anti-inflammatory insulin sensitizing therapy. Recent advances have indicated that a diverse range of inflammatory molecules, including leukotriene B4 and Galectin-3 can cause insulin resistance. Key challenges for translating these new targets into therapies include their pleiotropic effects and likely patient heterogeneity, such as is caused by the intestinal microbiome. (shrink)

Inflammatory mediators have an established role in inducing insulin resistance and promoting hyperglycemia. In turn, hyperglycemia has been argued to drive immune cell dysfunction as a result of mitochondrial dysfunction. Here, the authors review the evidence challenging this view. First, it is pointed out that inflammatory mediators are known to induce altered mitochondrial function. In this regard, critical care patients suffer both an elevated inflammatory tone as well as hyperglycemia, rendering it difficult to distinguish between the effects of inflammation (...) and hyperglycemia. Second, emerging evidence indicates that a decrease in mitochondrial respiration and an increase in reactive oxygen species (ROS) production are not necessarily manifestations of pathology, but adaptations taking shape as the mitochondria is abdicating its adenosine triphosphate (ATP)‐producing function (which is taken over by glycolysis) and instead becomes “retooled” for an immunological role. Collectively, these observations challenge the commonly held belief that acute hyperglycemia induces mitochondrial damage leading to immune cell dysfunction. (shrink)

In this paper I develop a systemic discrimination approach to defining a narrowly construed category of ‘hate speech’, as speech that harms to a sufficient degree to warrant government regulation. This is important due to the lack of definitional clarity, and the extraordinarily wide usage, of the term. This article extends current literature on how hate speech can harm by identifying under what circumstances speakers have the capacity to harm, and under what circumstances targets are vulnerable to harm. It (...) also shows how the capacity to harm can be mobile and involve the construction of new targets. Finally, it bridges the gap between conceptual understandings of hate speech and policy designed to regulate it. (shrink)

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

The environment can elicit biological responses such as oxidative stress (OS) and inflammation as a consequence of chemical, physical, or psychological changes. As population studies are essential for establishing these environment-organism interactions, biomarkers of OS or inflammation are critical in formulating mechanistic hypotheses. By using examples of stress induced by various mechanisms, we focus on the biomarkers that have been used to assess OS and inflammation in these conditions. We discuss the difference between biomarkers that are the (...) result of a chemical reaction (such as lipid peroxides or oxidized proteins that are a result of the reaction of molecules with reactive oxygen species) and those that represent the biological response to stress, such as the transcription factor NRF2 or inflammation and inflammatory cytokines. The high-throughput and holistic approaches to biomarker discovery used extensively in large-scale molecular epidemiological exposome are also discussed in the context of human exposure to environmental stressors. We propose to consider the role of biomarkers as signs and to distinguish between signs that are just indicators of biological processes and proxies that one can interact with and modify the disease process. (shrink)