[Liver X receptors define the immune response during general adaptation syndrome (GAS)]. / Les récepteurs hépatiques X définissent la réaction immunitaire pendant le syndrome général d'adaptation (SGA).

The impact of stressful conditions on immunity seems mixed and at times counterbalanced. Such inconsistencies can often be attributed to the fact that the notion of stress has a very wide meaning and covers a large number of different situations. Research on liver X receptors using both natural and synthetic ligands may help to solve this conflict. When an infectious agent is present in a stressed body, LXR activation is likely to be a key element in the regulation of POMC, IFN-γ, and IL-18; moreover, it is a unique anti-inflammatory mode of action. They concurrently stimulate a non-specific immune reaction as they suppress inflammatory and autoimmune processes.

"Stress" is 80 Years Old: From Hans Selye Original Paper in 1936 to Recent Advances in GI Ulceration.

The first scientific publication on 'general adaption syndrome', or as we know today 'biologic stress' has been published in Nature in 1936 by the 29-year old Hans Selye. His results in that short publication that contained no references or illustrations, were based on experiments in rats that were exposed to severe insults/ stressors, but his idea about a 'nonspecific bodily response' originated from his observations of sick patients whom he had seen as a medical student and young clinician. Autopsy of stressed rats revealed three major, grossly visible changes: hyperemia and enlargement of the adrenals, atrophy of the thymus and lymph nodes as well as hemorrhagic gastric erosions/ulcers (the "stress triad"). Based on this and additional observations, he concluded that the key master organ in stress reactions is the adrenal cortex (although he also accepted the limited and short lasting effect of catecholamines released from the adrenal medulla) which stimulated by an increased secretion of ACTH, secreted by the anterior pituitary gland. He thus identified the first molecular mediators of the stress reaction, i.e., steroids released from the adrenal cortex that we call today glucocorticoids, based on his classification and naming of steroids. At the end of a very productive life in experimental medicine, Selye recognized that under both unpleasant and demanding stressors as well as positive, rewarding stimuli adrenal cortex releases the same glucocorticoids and only certain brain structures may distinguish the stimuli under distress and eustress - terms he introduced in 1974, that also contained his last definition of stress: the nonspecific response of the body on any demand on it. After brief description of the history of stress research, the rest of this review is focused on one element of stress triad, i.e., gastroduodenal ulceration, especially its pathogenesis, prevention and treatment. Following a short description of acute gastroprotection, discovered by one of Selye's students, we discuss new molecular mediators of gastroduodenal ulceration like dopamine and new drugs that either only heal (very potently, on molar basis) or prevent and heal ulcers like sucralfate derivatives and the relatively new peptide BPC-157. We conclude that despite the extensive and multidisciplinary research on stress during the last 80 years, a lot of basic and clinical research is needed to better understand the manifestations, central and peripheral molecular regulators of stress response, especially the modes of prevention/management of distress or its transformation into eustress and the treatment of stress-related diseases.

[Emotional stress as a clinical model to study the pathogenesis of the initial phase of the general adaptation syndrome].

INTRODUCTION: General adaptation syndrome (GAS), the basis of the development of which is stress phenomenon, is an essential component of the pathogenesis of many diseases and syndromes. However, the patho genesis of GAS hitherto is considered exclusively from the endocrinological viewpoint. This relates primarily to the initial phase of the GAS, a clinical model for the study of which may be psycho-emotional stress (PES), which we studied using three groups of volunteers. METHODS: The first one consists of 25 students who were waiting for unaccustomed physical activity (17 men) and play debut on the stage (8 women). The second group consists of 48 children (2-14 years) who expected for "planned" surgery. The third group of volunteers is made up of 80 students (41 women and 39 men) during the first exam. The concentration of cortisol, endotoxin (ET), the activity of antiendotoxin immunity (AEI) and the haemostatic system parameters were determined in the blood serum of volunteers in various combinations. RESULTS: We found laboratory evidence for PES at 92% of students of the first group, 58% of children of the second one and in 21% of students of the third group of volunteers (mostly women). The concentration of ET increased at 13 (52%) volunteers of the first group with a significant increase of average indicators in the whole group (from 0.84 ± 0.06 to 1.19 ± 0.04 EU/ml). At children of the second group, the average concentration of ET increased even more significantly (from 0.42 ± 0.02 to 1.63 ± 0.11 EU/ml), which was accompanied by the activation of the hemostasis system. A degree of the activation was directly dependent on the level of ET in the general circulation and on an activity of AEI. Examination stress in the third group of volunteers is accompanied by activation of plasma hemostasis (increased initial thrombosis rate and reduced the time it starts, lag-period) in 26% of female students and 15% of male students. CONCLUSION: We suggest that it is possible to use the PES as a clinical model for studying the initial phase of the GAS, examine the role of excess of intestinal ET in the general blood circulation (endotoxin aggression) in the induction of systemic inflammation, which is very likely participated in the initiation of the GAS.

[Effect of adrenocorticotropic hormone (ACTH4-10) on information network of the cardiovascular systems].

The polyparametric description of adaptation syndromes in students using a uniform set of parameters of cardiovascular system and their relationships is presented. An analog of adrenocorticotropic hormone (ACTH4-10) is shown to exert varying effects on the development of different adaptation syndromes. Adaptation syndromes characterized by moderately active physiological processes (as judged by EGG, rheovasogram, respiration rate) and lowered vascular tonus were associated with marked improvement of the health status.

[Psychological stress in oncology: the role of glucocorticoids]. / Stress psychologique en oncologie: le rôle des glucocorticoïdes.

During the last years, the correlations between biological processes, psychological adjustment and stress disorders have received increasing attention and a growing body of research results has been published in the general literature. In the realm of psycho-oncology, however, conceptual models on this topic and studies aimed at their validation have remained relatively scanty. On the basis of our observations and available literature in the field of post-traumatic and depressive stress disorders in oncology, we have proposed to apply the concept of allostatic load to the study and understanding of the psychological experience of cancer. This strategy has led us to the formulation of a novel classification of adjustment disorders in oncology and the creation of the clinical entity named "cancer-specific stress syndrome". Depending on clinical presentation of the syndrome, one distinguishes three subtypes, namely the depressive, post-traumatic and "dysallostatic" (mixed) forms. In the present paper, we examine the role of glucocorticoids and their relationships with one of the basic components of allostatic load--a failure to counter-regulate the immune system by the hypothalamic-pituitary-adrenal axis--in the physiopathology of stress disorders in oncology. Conflicting theories are presented--glucocorticoid cascade versus insufficient glucocorticoid signal transmission--and studies measuring potential correlations between stress and cortisol in oncology are critically reviewed. The results of this process provide substantial support for the application of the allostatic load model and post-traumatic phenomenology, but important advances have yet to be achieved before definitive conclusions can be established in this field. Such advances could lead to profound changes in the way we understand and treat psychological distress in patients with cancer, both pharmacologically and psychotherapeutically.

Relação entre nível de estresse e supersensibilidade à norepinefrina em ratas no proestro / Relationship between the level of stress and supersensitivity to norepinephrine in female rats at proestrus

Nosso objetivo foi estudar a relação entre o nível de estresse avaliado comportamentalmente, e a sensibilidade da resposta cronotrópica à norepinefrina (NE) de ratas submetidas ao estresse por natação. Ratas em estro ou proestro foram submetidas a uma sessão de 50 min. de natação. Foram avaliados o tempo de tentativa de fuga e o tempo de imobilidade durante a natação. Imediatamente após o estresse, ratas estressadas e controles foram sacrificadas e o átrio direito foi isolado para obtenção de curvas concentração-efeito à NE. No proestro, o tempo de tentativa de fuga foi maior do que no estro (p<0,05). O tempo de imobilidade, por outro lado, foi menor no proestro do que no estro (p<0.05)...

The deprivation syndrome is the driving force of phylogeny, ontogeny and oncogeny.

Energy is the motor of life. Energy ensures the organism's survival and competitive advantage for reproductive success. For almost 3 billion years, unicellular organisms were the only life form on earth. Competition for limited energy resources and raw materials exerted an incessant selective pressure on organisms. In the adverse environment and due to their 'feast and famine' life style, hardiness to a variety of stressors, particularly to nutrient deprivation, was the selection principle. Both resistance and mutagenic adaptation to stressors were established as survival strategies by means of context-specific processes creating stability or variability of DNA sequence. The conservation of transduction pathways and functional homology of effector molecules clearly bear witness that the principles of life established during prokaryotic and eukaryotic unicellular evolution, although later diversified, have been unshakably cast to persist during metazoan phylogenesis. A wealth of evidence suggests that unicellular organisms evolved the phenomena of differentiation and apoptosis, sexual reproduction, and even aging, as responses to environmental challenges. These evolutionary accomplishments were elaborated from the dichotomous resistance/mutagenesis response and sophisticated the capacity of cells to tune their genetic information to changing environmental conditions. Notably, the social deprivation responses, differentiation and apoptosis, evolved as intercellularly coordinated events: a multitude of differentiation processes were elaborated from sporulation, the prototypic stress resistance response, while apoptosis, contrary to current concepts, is no altruistic cell suicide but was programmed as a mutagenic survival response; this response, however, is socially thwarted leading into mutagenic error catastrophe. In the hybrid differentiation-apoptosis process, cytocide and cannibalism of apoptotic cells thus serve the purpose of fueling the survival of the selfish genes in the differentiating cells. However, successful mutagenesis, although repressed, persisted in the asocial stress response of carcinogenesis as a regression to primitive unicellular behavior following failure of intercellular communication. While somatic mutagenesis was largely prevented, Metazoa elaborated germ cell mutagenesis as an evolutionary vehicle. Genetic competence, a primitive, stress-induced mating behavior, evolved into sexual reproduction which harnessed mutagenesis by subjecting highly mutable germ cells to a rigid viability selection. These processes were programmatically fixed as life- and cell-cycle events but retained their deprivation response phenotypes. Thus, the differentiation-apoptosis tandem evolved as the 'clay' to mold the specialized structures and functions of a multicellular organism while sexual reproduction elaborated the principle of quality-checked mutagenesis to create the immense diversity of Metazoa following the Cambrian explosion. Throughout these events, reactive oxygen and nitrogen species, which are regulated by energy homeostasis, shape the genetic information in a regulated but random, uncoded process providing the fitness-related feedback of phenotype to genotype. The interplay of genes and environment establishes a dynamic stimulus-response feedback cycle which, in animate nature, may be the organizing principle to contrive the reciprocal duality of energy and matter.

Stress-induced arrhythmic disease of the heart--Part I.

This review deals with the following principal concepts: (1) Heart injuries in single severe stress episodes manifested primarily in disturbances of membrane lipid bilayer, sarcolemmal Na, K-pump, and sarcoplasmic Ca-pump with concurrent limited disturbances of the heart energy supply, namely, of the creatine kinase and glycolysis systems. These disturbances cause small focal myocardial lesions and reduce cardiac electrical stability: the fibrillation threshold falls and ectopic activity increases. In repeated stress, this damage, localized mainly in the richly innervated conduction system, accumulates to cause even more pronounced disturbances of electrical stability and severe arrhythmias. (2) Severe stress and beta-adrenergic effects on the heart regularly result in coronary vasodilation and increased coronary blood flow. However, the entire primary complex of stress-induced injuries and disturbances of the heart's electrical stability occurs despite the increased coronary blood flow. Thus, beta-adrenergic stress-induced injuries may indeed develop as primary stress damage to cardiomyocytes without any relation to ischemia. (3) The main factor determining high vulnerability or, on the contrary, resistance of the heart to stress is the state of stress-limiting systems, namely, the opioidergic, GABAergic, cholinergic, adenosinergic, and other systems. Activation of these systems by adaptation to repeated stress or other factors prevents serious injuries to the heart in severe stress. Conversely, genetically determined or acquired dysfunction of these systems predisposes to severe arrhythmias and sudden death. Thus, in stress-induced arrhythmic disease as well as in ischemic heart disease, the main pathogenetic links are outside the heart, but they differ from those observed in ischemia. (4) The clinical picture of stress-induced arrhythmic disease, that is, alterations in electrocardiogram, coronarogram, and patient responses to stress, physical loads, and tranquilizers differ, as do pathologic alterations in the heart. These differences are summarized at the end of this review.

Changes in blood glucose induced by upper GI diagnostic endoscopy: the influence of various premedications.

In this study we measured the blood glucose before and after diagnostic upper GI endoscopy as an index of the stress induced by the procedure. The possible influence of various premedications in the blood glucose was also studied. One hundred and twenty consecutive non-diabetic patients of both sexes aged 20-75 years were randomly allocated into four groups (A,B,C,D) according to the premedication used. Sixty non-diabetic patients, who were not endoscoped, were allocated into three groups (C1, C2, C3) and served as controls. Blood glucose increased significantly in the patients but not in the controls. No correlation was found between the changes in the blood glucose and the time needed for the endoscopy. Changes in the blood glucose did not differ among the patients (F = 0.214; p = 0.886) irrespective of the premedication; however the increase was numerically less when 10% lidocaine spray was used as a premedication (Groups A and C). It is concluded that diagnostic upper GI endoscopy induced a significant increase in blood glucose, irrespective of the premedication. This increase seemed to be mainly the result of the stress induced by the irritation of the pharynx during the intubation.

Regulation of protein metabolism during stress.

Stress induces a hypermetabolic state of increased urinary nitrogen loss and increased metabolic rate. The principal reason for such a response is the mobilization of amino acids and the production of glucose to provide energy for the cells involved in the host immune response and wound repair. The endocrine hormones, eg, cortisol, the catecholamines, and glucagon, are largely responsible for these effects. Insulin and growth hormone administration can produce anabolic effects to block the loss of body protein. Administration of specific amino acids, such as glutamine, also appears to be beneficial. However, the hypermetabolic state goes beyond derangement of endocrine hormone levels. Although the cytokines are also important mediators, it is not clear how these mediators, in concert with hormonal changes, produce all of the manifestations of the hypermetabolic state seen in stress.

Lipid fuel metabolism in health and disease.

Rates of adipose tissue lipolysis are increased in critically ill patients, thus increasing the systemic supply of free fatty acids. This increase in the availability of free fatty acids is probably mediated by various factors including increases in counterregulatory hormones and tumor necrosis factor alpha. The cytokines tumor necrosis factor and interleukin-1 also promote de novo lipogenesis in the liver and may be responsible for impaired triglyceride removal in peripheral tissues; these effects together contribute to the hypertriglyceridemia often seen in septic states. This hypertriglyceridemia may have a teleologic basis, because triglyceride-rich lipoproteins have been shown to bind and inactivate endotoxin. When present in excess, free fatty acids may be responsible for tissue injury in the cold-stored liver allograft, in ischemic-reperfusion cardiac injury, and in ischemic brain injury. Hypoketonemia commonly occurs in septic states and may be due to the combination of a defect in hepatic ketogenesis and accelerated ketone body uptake by peripheral tissues. Both tumor necrosis factor and interleukin-1 have a hypoketonemic effect in animals. Whether ketone bodies have significant protein-sparing properties remains controversial.

[Ultrastructural changes in somatotropinocytes of the adenohypophysis during development of transplantation immunity]. / Ul'trastrukturnye izmeneniia v somatotropotsitakh adenogipofiza pri razvitii transplantatsionnogo immuniteta.

The authors conducted two series of experiments on 144 mice of BAL/c and C57B1 line. It was established that in autotransplantation submicroscopical changes developing in somatotropinocytes are typical of stressor situation and reflect various phases of general adaptation syndrome. An increase in the number of cells in the phase of active proteinic synthesis and degranulation is observed in allotransplantation in inductive phase of immunogenesis. Before rejection the number of cells in the phase of active proteinic synthesis is decreased, and in degranulation phase--is increased.

[Stress and the endogenous opioid system. II. Stress, stress models and endogenous opioid peptides]. / Stress und endogenes Opioidsystem. II. Stress, Stressmodelle und endogene Opioidpeptide.

Biochemical and pharmacological findings indicate an activation of the opioid system under certain stress influences. In this paper findings are discussed, according to which the activation of the opioid system depends on the temporary distribution pattern and the kind of the stressor. In response to stress opioid peptides are involved in excitatory and inhibitory processes. The participation of different types of opioids in central and peripheral stress-induced effects is discussed. Some findings suggest that beta-endorphin acts mainly centrally rather than peripherally, whereas the enkephalins take part in peripheral regulatory processes (gastrointestinal system, adrenal glands). Now there is evidence that the endogenous opioids modulate stress-induced effects, but there has been much controversy on how this fact should be established. These controversies mainly resulted from the many factors that influence activation.