Stress as a risk factor in the pathogenesis of rheumatoid arthritis

Stress is now recognized as an important risk factor in the pathogenesis of autoimmune rheumatic diseases (i.e. rheumatoid arthritis) by considering that the activation of the stress response system influences the close relationships existing between the hypothalamic-pituitary-adrenal axis, the sympathetic nervous system and the immune system. The stress response results in the release of neurotransmitters (norepinephrine), hormones (cortisol) and immune cells which serve to send an efferent message from the brain to the periphery. Major life events lead to an intense release of stress mediators (large time integral of released neurotransmitters and hormones), whereas in minor life events, only short-lived surges of neurotransmitters and hormones are expected. Therefore, it is suggested that neurotransmitters such as norepinephrine or stress hormones such as cortisol might have different effects on immune/inflammatory responses at high and low concentrations present during short or extended periods of time, respectively. Long-lasting (chronic) stress may lead to proinflammatory effects because no adequate long-term responses of stress axes (anti-inflammatory) are to be expected.     

Stress hormones in Ménière's disease and acoustic neuroma

Stress has been postulated to trigger or contribute to inner ear pathologies but there is little objective evidence. We investigated stress hormones in Ménière's patients and patients with acoustic neuroma. Data were compared with those from a control group of patients with facial spasm. We assayed classic stress hormones including adrenocorticotropic hormone, cortisol, growth hormone and prolactin. We found a strong positive correlation between cortisol and adrenocorticotropic hormone in Ménière patients and patients with acoustic neuroma but no correlation in patients with facial spasm. The data also revealed in female patients with Ménière's disease or with acoustic neuroma an unexpected significant positive correlation between cortisol and prolactin. The data showed the expected negative correlation or no correlation between cortisol and prolactin associated with males and females in the other patient groups. Both cortisol and prolactin increases are known to represent alternative strategies to cope with stress, and our data point to prolactin being possibly more dominant in Ménière's disease and cortisol in acoustic neuroma. These data provide further evidence for modification of different stress hormones in audiovestibular pathologies, which might provide a valuable diagnostic or prognostic tool in the future.     

Stress and the practice of medicine— The myth and reality

The nature of stress is reviewed in its role of producing physical illness and mental maladaptions with an emphasis on physician's morbidity from both. A review of existing studies indicates that physicians compare favorably with the general population in mortality from physical illness but unfavorably with regard to mental illness, notably the affective, suicide and addiction.The definition of illness is examined with relation to stress, physical and phychosocial. It is accepted that disease presupposes the existence of special vulnerability. In mental illness, however, the vulnerability stems from inner sources. In the doctor this consists of a neuroticism originating in the fear of death which has motivated him to become a physician in the first place. A study of the writer supports these theoretical assumptions.It is proposed that the neuroticism thus created facilitates various degrees of maladaptive patterns. It is, however, also a direct effect of negative personality features created by it in the first place. Stress of medical practice does influence the emotional adjustment but does not seem to exert a greater negative influence on the physical health of doctors than does stress encountered in other occupations. This may be due to the better care physicians are able to secure for themselves.     

Embryonic inner ear cells use migratory mechanisms to establish cell patterns in vitro

The hair cells of the sensory epithelium in the inner ear are among the most precisely organized cells in vertebrates. The mechanisms that lead to this orderly arrangement are only beginning to be understood. It has been suggested that hair cells use migratory mechanisms to help achieve their final position in the organ of Corti. The small size and complex organization of the intact inner ear have made it difficult to monitor changes in hair cell location over time in vivo. In the present study, an established in vitro assay of dissociated, embryonic inner ear cells was used to monitor how hair cells reorganize over time. The hair cell specific marker myosin-VI demonstrated that hair cell precursors from both cochlear and vestibular regions reorganized into specific patterns between 3-24 hr in vitro. In contrast to the unlabeled cells, the myosin-VI-positive cells extended processes while establishing the hair cell patterning within an aggregate. These studies support the hypothesis that hair cell precursors actively migrate to help achieve final patterning within the inner ear sensory epithelium.     

Stress, inflammation and cardiovascular disease.

Various psychosocial factors have been implicated in the etiology and pathogenesis of certain cardiovascular diseases such as atherosclerosis, now considered to be the result of a chronic inflammatory process. In this article, we review the evidence that repeated episodes of acute psychological stress, or chronic psychologic stress, may induce a chronic inflammatory process culminating in atherosclerosis. These inflammatory events, caused by stress, may account for the approximately 40% of atherosclerotic patients with no other known risk factors. Stress, by activating the sympathetic nervous system, the hypothalamic-pituitary axis, and the renin-angiotensin system, causes the release of various stress hormones such as catecholamines, corticosteroids, glucagon, growth hormone, and renin, and elevated levels of homocysteine, which induce a heightened state of cardiovascular activity, injured endothelium, and induction of adhesion molecules on endothelial cells to which recruited inflammatory cells adhere and translocate to the arterial wall. An acute phase response (APR), similar to that associated with inflammation, is also engendered, which is characterized by macrophage activation, the production of cytokines, other inflammatory mediators, acute phase proteins (APPs), and mast cell activation, all of which promote the inflammatory process. Stress also induces an atherosclerotic lipid profile with oxidation of lipids and, if chronic, a hypercoagulable state that may result in arterial thromboses. Shedding of adhesion molecules and the appearance of cytokines, and APPs in the blood are early indicators of a stress-induced APR, may appear in the blood of asymptomatic people, and be predictors of future cardiovascular disease. The inflammatory response is contained within the stress response, which evolved later and is adaptive in that an animal may be better able to react to an organism introduced during combat. The argument is made that humans reacting to stressors, which are not life-threatening but are "perceived" as such, mount similar stress/inflammatory responses in the arteries, and which, if repetitive or chronic, may culminate in atherosclerosis.     

Studying inner ear protein-protein interactions using FRET and FLIM

Molecular genetic studies of the inner ear have recently revealed a large number of previously undescribed proteins, but their functions remain unclear. Optical methods such as FRET and FLIM are just beginning to be applied to the study of functional interactions between novel inner ear proteins. This review discusses the various methods for employing FRET and FLIM in protein-protein interaction studies, their advantages and pitfalls, with examples drawn from inner ear studies.     

Meniere’s Attacks Occur in the Inner Ear with Excessive Vasopressin Type‐2 Receptors

Meniere’s disease is peculiar to humans and is characterised by episodic vertigo, fluctuating hearing loss and tinnitus, and attacks of the affliction occurring under conditions of stress. Its pathology was first revealed to be inner ear hydrops through temporal bone studies in 1938. Although subsequently proposed as a disorder of water metabolism in the inner ear, its pathogenesis remains unsolved. The present study aimed to assess the link between the inner ear pathology in Meniere’s disease and vasopressin, an anti‐diuretic stress hormone with a potential role in inner ear fluid homeostasis. Blood samples were obtained from Meniere’s disease patients in the morning, before any surgical treatment, to examine plasma vasopressin (pAVP) levels, and then from inner ear tissue during surgical treatment, to examine vasopressin type‐2 receptor (V2R) in the endolymphatic sac. pAVP and the relative V2R mRNA expression in the endolymphatic sac were examined using a real‐time polymerase chain reaction. Relative cAMP activity in the endolymphatic sac was also examined using tissue culture and cAMP assay. Both pAVP (1.6‐fold versus controls; P = 0.048) and inner ear V2R mRNA expression (41.5‐fold versus controls; P = 0.022) were significantly higher in Meniere’s patients. cAMP activity was basally up‐regulated (2.1‐fold versus controls) and cAMP sensitivity to vasopressin application was largely elevated (4.9‐fold versus controls) in Meniere’s patients. We conclude that, in the pathogenesis of inner ear hydrops, resulting in Meniere’s attacks, elevation of pAVP levels (probably as a result of stress) may present as a matter of consequence, but susceptibility of the V2R‐overexpressed and cAMP‐hypersensitised inner ear to pAVP elevation might be essential as the basis of this disease. Further experimental and clinical studies are needed to better clarify the relationship between Meniere’s disease and stress.     

Up-regulation of cochlear aquaporin-3 mRNA expression after intra-endolymphatic sac application of dexamethasone

The final aim of the present study is to see if the endolymphatic sac is really available as a drug delivery system to have effect on the inner ear organs. In the present study, we examined effects of a single insertion of dexamethasone into the rat unilateral endolymphatic sac on mRNA expression of the inner ear aquaporin (AQP) family, transmembrane water transporters and putative endolymphatic fluid modulators, by means of real-time quantitative PCR. Only AQP-3 mRNA expression in the ipsilateral cochlea was significantly up-regulated in comparison with controls and the up-regulation was demonstrated both in dose-dependent and time-dependent manners. These findings suggest that the intra-endolymphatic sac steroids could make regulatory effects on the inner ear AQP-3 expression via vestibular aqueduct and modulate the homeostasis of endolymphatic fluids, encouraging the possibility that the endolymphatic sac could be a therapeutic window for the inner ear disease.     

与应力调控相关的基因选择性剪接*****☆◆

背景：适当的力学环境是生物体正常生长发育、结构重建以及功能维持的重要因素,也是损伤组织功能性修复的关键因素之一。应力调控基因表达不仅体现在基因的开关或表达水平的调节,还可以体现在转录后的选择性剪接。 目的：结合力生长因子介绍选择性剪接这种新的应力调控方式,并推测可能的调控机制。 方法：检索PubMed 数据库(1964/2010)、CNKI数据库(2000/2009)有关力信号转导和基因选择性剪接方面的综述文章和研究报告,分析二者的联系和可能的调控机制。 结果与结论：应力刺激可以导致肌细胞、成骨细胞中的胰岛素样生长因子1基因发生选择性剪接,产生一种新的应力敏感的生长因子力生长因子,这种新型调控方式的机制还不明确,推测与应力导致的剪接小体的位置(位移运动)以及改变了剪接酶(如RNP酶)的位置和空间结构(变形)有关。     

Stress as a modulator of motor system function and pathology

Stress is one of the most significant influences on behaviour and performance. The classical account is that stress mainly affects functions of the limbic system, such as learning, memory and emotion. Recent evidence, however, suggests that stress also modulates motor system function and influences the pathology of movement disorders. Most parts of the motor system show the presence of glucocorticoid receptors that render their circuits susceptible to the influence of stress hormones. Stress and glucocorticoids have been shown to modulate temporal and spatial aspects of motor performance. Skilled movements seem to be most prone to stress-induced disturbances, but locomotion and posture can also be affected. Stress can modulate movement through activation of the hypothalamic-pituitary-adrenal axis and via stress-associated emotional changes. The dopaminergic system seems to play a central role in mediating the effects of stress on motor function. This route might also account for the finding that stress influences the pathology of dopamine-related diseases of the motor system, such as Parkinson's disease. Clinical observations have indicated that stress might lead to the onset of Parkinsonian symptoms or accelerate their progression. Glucocorticoids are modulators of neuronal plasticity, thus determining the degree of structural and functional compensation of the damaged motor system. This may particularly affect slowly progressive neurodegenerative diseases, such as Parkinson's disease. That stress represents a significant modulator of motor system function in both the healthy and the damaged brain should be recognized when developing future therapies for neurodegenerative diseases.     

Up-regulation of cochlear aquaporin-3 mRNA expression after intra-endolymphatic sac application of dexamethasone

Abstract

The final aim of the present study is to see if the endolymphatic sac is really available as a drug delivery system to have effect on the inner ear organs. In the present study, we examined effects of a single insertion of dexamethasone into the rat unilateral endolymphatic sac on mRNA expression of the inner ear aquaporin (AQP) family, transmembrane water transporters and putative endolymphatic fluid modulators, by means of real-time quantitative PCR. Only AQP-3 mRNA expression in the ipsilateral cochlea was significantly up-regulated in comparison with controls and the up-regulation was demonstrated both in dose-dependent and time-dependent manners. These findings suggest that the intra-endolymphatic sac steroids could make regulatory effects on the inner ear AQP-3 expression via vestibular aqueduct and modulate the homeostasis of endolymphatic fluids, encouraging the possibility that the endolymphatic sac could be a therapeutic window for the inner ear disease.     

Imaging of the osseous, membranous, and perilymphatic labyrinths

The inner ear is located within the petrous portion of the temporal bone and consists of the membranous, perilymphatic, and the outer osseous labyrinths. Together, these structures form the end organs for mediating hearing and balance. This article provides a detailed review of the neonatal anatomy and development of these structures, knowledge of which derives in great part from advances in CT and sophisticated MR imaging. Current research should soon enable clinicians to identify a wide variety of subtle lesions of the inner ear that heretofore have been inaccessible to imaging diagnosis.     

Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment

The hippocampus is one of several limbic brain structures implicated in the pathophysiology and treatment of mood disorders. Preclinical and clinical studies demonstrate that stress and depression lead to reductions of the total volume of this structure and atrophy and loss of neurons in the adult hippocampus. One of the cellular mechanisms that could account for alterations of hippocampal structure as well as function is the regulation of adult neurogenesis. Stress exerts a profound effect on neurogenesis, leading to a rapid and prolonged decrease in the rate of cell proliferation in the adult hippocampus. In contrast, chronic antidepressant treatment up-regulates hippocampal neurogenesis, and could thereby block or reverse the atrophy and damage caused by stress. Recent studies also demonstrate that neurogenesis is required for the actions of antidepressants in behavioral models of depression. This review discusses the literature that has lead to a neurogenic hypothesis of depression and antidepressant action, as well as the molecular and cellular mechanisms that underlie the regulation of adult neurogenesis by stress and antidepressant treatment.     

The inner ear and the neurologist

Inner ear disorders are common and patients with vestibular failure often present to a neurology clinic because of their dizziness, gait unsteadiness and oscillopsia. Vestibular disorders can be divided into peripheral and central vestibular disorders. Most of the peripheral vestibular disorders have a clinical diagnosis, and a thorough history and examination will often provide a clear direction as to the diagnosis. Correct diagnosis allows treatment for many of the peripheral and central vestibular disorders. As inner ear damage is generally irreversible, early diagnosis allowing prompt treatment is important. The aim of this review is to discuss some audiovestibular conditions that may well appear in a neurology clinic, and to discuss some recent advances within the audiovestibular field that may be of interest to neurologists. Some of the most common audiovestibular conditions will be discussed along side more uncommon conditions.     

Stress-induced cytokines and neuronal dysfunction in Alzheimer's disease

Increasing evidence has been accumulating about the role of stress as an important challenge to the onset and progression of Alzheimer's disease (AD). The hippocampus, one of the areas of the brain damaged during AD, was the first brain region, besides the hypothalamus, to be recognized as a target of stress hormones, including cortisol, sympathetic and parasympathetic transmitters, cytokines, and metabolic hormones. The present review aims at summarizing neuroinflammatory mechanisms induced by stress, resulting in neuronal dysfunction and impaired neurogenesis. Lifestyle and environmental factors related to metabolic and inflammatory alterations observed in stressed subjects and thought to favor AD development and progression, as well as the possible ways of prevention, are discussed.     

Non-invasive measurement of intracranial pressure changes by otoacoustic emissions (OAEs)--a report of preliminary data

Up to now changes of intracranial pressure can only be objectively assessed by invasive measurement tools e.g. epidural transducers or intraventricular or intraparenchymatous catheters. Changes of intracranial pressure (ICP) are known to influence the inner ear since the subarachnoid space is linked to the perilymphatic space of the inner ear via the cochlear aquaeduct. A new method for assessing cochlear disorders is based on otoacoustic emissions (OAE) which are generated by the outer hair cells (OHCs) of the inner ear. The aim of the present study was to find out whether changes of intracranial pressure can be monitored by spontaneous otoacoustic emissions (SOAEs), transient evoked otoacoustic emissions (TEOAEs) and distortionproduct otoacoustic emissions (DPOAEs). SOAEs, TEOAEs and DPOAEs were measured in 12 young normally hearing subjects (volunteer group) in different body postures (horizontal, -30 degrees and +30 degrees supine position). In 5 patients undergoing continuous intraventricular pressure monitoring for the assessment of normal pressure hydrocephalus (NPH), DPOAEs were measured simultaneously in different body postures as well (patient group). At an increase of ICP the SOAE-level of the volunteer group decreased by -3.3 dB SPL (sound pressure level) and the TEOAE-level by -2.1 dB SPL. The DPOAEs showed a frequency dependent reduction of its level with maximal changes at the lowest frequency tested (f2 = 1 kHz; -7.9 dB SPL). In the patient group the ICP amounted to 19.2 cm H(2)0 and the DPOAE-level also decreased particularly at lower frequencies (-2.0 dB SPL). In conclusion otoacoustic emissions, particularly DPOAEs, may provide a new clinical tool for non-invasive monitoring of ICP.     

Transgenic studies on the regulation of the anterior pituitary gland function by the hypothalamus

The anterior pituitary gland is composed of five different cell types secreting hormones whose functions include the regulation of post-natal growth (growth hormone, GH), lactation (prolactin, PRL), reproduction (luteinising hormone, LH, and follicle stimulating hormone, FSH), metabolism (thyroid stimulating hormone, TSH), and stress (adrenocorticotrophic hormone, ACTH). The synthesis and secretion of the anterior pituitary hormones is under the control of neuropeptides released from the hypothalamus into a capillary portal plexus which flows through the external zone of the median eminence to the anterior lobe. This review describes the ways that gene transfer technologies have been applied to whole animals in order to study the regulation of anterior pituitary function by the hypothalamus. The extensive studies on these neuronal systems, within the context of the physiological integrity of the intact organism, not only exemplify the successful application of transgenic technologies to neuroendocrine systems, but also illustrate the problems that have been encountered, and the challenges that lie ahead.     

Sexual dimorphism in the effect of sound stress on neutrophil function

It has been hypothesized that stress contributes to the severity of inflammatory diseases. However, the mechanisms underlying this effect are incompletely understood. In this study we investigated the effects of sound stress on function of the polymorphonuclear neutrophil-immune cells that play key roles in both the acute and chronic inflammatory response. Specifically, we examined the effect of stress on the production of reactive oxygen species (ROS) and phagocytosis by rat neutrophils, and the role of sympathoadrenal stress axis in these effects. Since many inflammatory diseases exhibit sexual dimorphism, we also investigated the contribution of sex and gonadal hormones to the effects of stress on neutrophil function. Peripheral blood neutrophils were harvested from male and female rats exposed to intermittent sound stress (over 4 days). Stress suppressed ROS production in males (but not females) an effect that was eliminated in adrenal medullectomized males. Stress also suppressed neutrophil phagocytosis in males and females. Again, this effect was absent following adrenal medullectomy. To investigate the role of sex hormones in these sexual dimorphic responses to stress, rats were gonadectomized prepubertally and exposed to stress as adults. In gonadectomized males, stress produced an even larger decrease in ROS production, but had no effect on the stress-induced inhibition of phagocytosis. Gonadectomy prevented the stress-induced inhibition of neutrophil phagocytosis in females. These data indicate that the adrenal medulla, perhaps via release of epinephrine, suppresses neutrophil ROS production in males and phagocytosis in males and females.