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      Homeostasis and the concept of 'interstitial fluids hierarchy': Relevance of cerebrospinal fluid sodium concentrations and brain temperature control (Review)

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          Abstract

          In this review, the aspects and further developments of the concept of homeostasis are discussed also in the perspective of their possible impact in the clinical practice, particularly as far as psychic homeostasis is concerned. A brief historical survey and comments on the concept of homeostasis and allostasis are presented to introduce our proposal that is based on the classical assumption of the interstitial fluid (ISF) as the internal medium for multicellular organisms. However, the new concept of a hierarchic role of ISF of the various organs is introduced. Additionally, it is suggested that particularly for some chemico-physical parameters, oscillatory rhythms within their proper set-ranges should be considered a fundamental component of homeostasis. Against this background, we propose that the brain ISF has the highest hierarchic role in human beings, providing the optimal environment, not simply for brain cell survival, but also for brain complex functions and the oscillatory rhythms of some parameters, such as cerebrospinal fluid sodium and brain ISF pressure waves, which may play a crucial role in brain physio-pathological states. Thus, according to this proposal, the brain ISF represents the real internal medium since the maintenance of its dynamic intra-set-range homeostasis is the main factor for a free and independent life of higher vertebrates. Furthermore, the evolutionary links between brain and kidney and their synergistic role in H 2O/Na balance and brain temperature control are discussed. Finally, it is surmised that these two interrelated parameters have deep effects on the Central Nervous System (CNS) higher integrative actions such those linked to psychic homeostasis.

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          Stress and the individual. Mechanisms leading to disease.

          This article presents a new formulation of the relationship between stress and the processes leading to disease. It emphasizes the hidden cost of chronic stress to the body over long time periods, which act as a predisposing factor for the effects of acute, stressful life events. It also presents a model showing how individual differences in the susceptibility to stress are tied to individual behavioral responses to environmental challenges that are coupled to physiologic and pathophysiologic responses. Published original articles from human and animal studies and selected reviews. Literature was surveyed using MEDLINE. Independent extraction and cross-referencing by us. Stress is frequently seen as a significant contributor to disease, and clinical evidence is mounting for specific effects of stress on immune and cardiovascular systems. Yet, until recently, aspects of stress that precipitate disease have been obscure. The concept of homeostasis has failed to help us understand the hidden toll of chronic stress on the body. Rather than maintaining constancy, the physiologic systems within the body fluctuate to meet demands from external forces, a state termed allostasis. In this article, we extend the concept of allostasis over the dimension of time and we define allostatic load as the cost of chronic exposure to fluctuating or heightened neural or neuroendocrine response resulting from repeated or chronic environmental challenge that an individual reacts to as being particularly stressful. This new formulation emphasizes the cascading relationships, beginning early in life, between environmental factors and genetic predispositions that lead to large individual differences in susceptibility to stress and, in some cases, to disease. There are now empirical studies based on this formulation, as well as new insights into mechanisms involving specific changes in neural, neuroendocrine, and immune systems. The practical implications of this formulation for clinical practice and further research are discussed.
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            A new look at cerebrospinal fluid circulation

            According to the traditional understanding of cerebrospinal fluid (CSF) physiology, the majority of CSF is produced by the choroid plexus, circulates through the ventricles, the cisterns, and the subarachnoid space to be absorbed into the blood by the arachnoid villi. This review surveys key developments leading to the traditional concept. Challenging this concept are novel insights utilizing molecular and cellular biology as well as neuroimaging, which indicate that CSF physiology may be much more complex than previously believed. The CSF circulation comprises not only a directed flow of CSF, but in addition a pulsatile to and fro movement throughout the entire brain with local fluid exchange between blood, interstitial fluid, and CSF. Astrocytes, aquaporins, and other membrane transporters are key elements in brain water and CSF homeostasis. A continuous bidirectional fluid exchange at the blood brain barrier produces flow rates, which exceed the choroidal CSF production rate by far. The CSF circulation around blood vessels penetrating from the subarachnoid space into the Virchow Robin spaces provides both a drainage pathway for the clearance of waste molecules from the brain and a site for the interaction of the systemic immune system with that of the brain. Important physiological functions, for example the regeneration of the brain during sleep, may depend on CSF circulation.
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              Allostasis: a model of predictive regulation.

              The premise of the standard regulatory model, "homeostasis", is flawed: the goal of regulation is not to preserve constancy of the internal milieu. Rather, it is to continually adjust the milieu to promote survival and reproduction. Regulatory mechanisms need to be efficient, but homeostasis (error-correction by feedback) is inherently inefficient. Thus, although feedbacks are certainly ubiquitous, they could not possibly serve as the primary regulatory mechanism. A newer model, "allostasis", proposes that efficient regulation requires anticipating needs and preparing to satisfy them before they arise. The advantages: (i) errors are reduced in magnitude and frequency; (ii) response capacities of different components are matched -- to prevent bottlenecks and reduce safety factors; (iii) resources are shared between systems to minimize reserve capacities; (iv) errors are remembered and used to reduce future errors. This regulatory strategy requires a dedicated organ, the brain. The brain tracks multitudinous variables and integrates their values with prior knowledge to predict needs and set priorities. The brain coordinates effectors to mobilize resources from modest bodily stores and enforces a system of flexible trade-offs: from each organ according to its ability, to each organ according to its need. The brain also helps regulate the internal milieu by governing anticipatory behavior. Thus, an animal conserves energy by moving to a warmer place - before it cools, and it conserves salt and water by moving to a cooler one before it sweats. The behavioral strategy requires continuously updating a set of specific "shopping lists" that document the growing need for each key component (warmth, food, salt, water). These appetites funnel into a common pathway that employs a "stick" to drive the organism toward filling the need, plus a "carrot" to relax the organism when the need is satisfied. The stick corresponds broadly to the sense of anxiety, and the carrot broadly to the sense of pleasure. This design constrains anxieties to be non-adapting and pleasures to be brief -- fast-adapting -- to make way for the next anxiety. The stick/carrot mechanisms evolved early and expanded so that in humans they govern higher level learning and social organization. Correspondingly, the "funnel" widened to allow innumerable activities and experiences to each provide non-adapting anxieties and brief pleasures, their reward values depending partly on the effort expended. But modern life narrows the variety of small pleasures and reduces effort, thereby reducing their reward value and requiring larger portions for equivalent satisfaction - a cycle that generates addictive behaviors. Homeostasis and allostasis locate pathology at different levels. Homeostasis identifies proximate causes; for example, it attributes essential hypertension to excess salt water in too small a vascular reservoir. Thus it directs pharmacotherapy toward reducing salt and water, expanding the reservoir, and blocking feedbacks that would counteract these measures. Allostasis attributes essential hypertension to the brain. Chronically anticipating a need for higher pressure, the brain mobilizes all the low level mechanisms in concert: kidney to retain salt and water, vascular system to tighten, and salt appetite to rise. Correspondingly, allostasis would direct therapy toward higher levels - to reduce demand and increase sense of control -- so that the brain can down-shift its prediction and relax all the low-level mechanisms in concert. For disorders of addiction homeostasis pursues pharmacological treatments: drugs to treat drug addiction, obesity, and other compulsive behaviors. Allostasis suggests broader approaches - such as re-expanding the range of possible pleasures and providing opportunities to expend effort in their pursuit. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Int J Mol Med
                Int. J. Mol. Med
                IJMM
                International Journal of Molecular Medicine
                D.A. Spandidos
                1107-3756
                1791-244X
                March 2017
                03 February 2017
                03 February 2017
                : 39
                : 3
                : 487-497
                Affiliations
                [1 ]Department of Biomedical Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy
                [2 ]Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
                [3 ]Department of Pharmacy, Unit of Pharmacology and Toxicology, and Center of Excellence for Biomedical Research, University of Genova, 16126 Genova
                [4 ]Department of Molecular Medicine, University of Padova, 35121 Padova, Italy
                Author notes
                Correspondence to: Professor Luigi F. Agnati, Department of Biomedical Sciences, University of Modena and Reggio Emilia, via Giuseppe Campi 287, 41125 Modena, Italy, E-mail: luigiagnati@ 123456tin.it
                Dr Diego Guidolin, Department of Molecular Medicine, University of Padova, via Gabelli 65, 35121 Padova, Italy, E-mail: diego.guidolin@ 123456unipd.it
                Article
                ijmm-39-03-0487
                10.3892/ijmm.2017.2874
                5360360
                28204813
                6d9728e3-4b46-47a0-bc51-54b0417038bf
                Copyright: © Agnati et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 11 August 2016
                : 12 December 2016
                Categories
                Articles

                brain,h2o/na balance,integrative actions,interstitial fluid,kidney,psychic homeostasis,temperature

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