Coxiella burnetii is a macrophage-tropic, Gram-negative organism, which causes acute Q fever infection in humans. This zoonotic infection causes illness ranging from asymptomatic seroconversion to severe and protracted disease featuring hepatitis and pneumonia. Interactions between C. burnetii lipopolysaccharide (LPS) and host Toll-like receptors (TLR)-2 and -4 have been implicated in pathogen recognition, phagocytosis and signaling responses. Nonconservative single nucleotide polymorphisms in the coding regions of TLR-2 (Arg677Trp and Arg753Gln) and TLR-4 (Asp299Gly) have been found to correlate with mycobacterial infections and Gram-negative sepsis respectively. Associations between the TLR-2 and -4 polymorphisms, illness characteristics and immune response parameters were examined in subjects with acute Q fever (n=85) and comparison subjects with viral infections (n=162). No correlation was demonstrated between these polymorphisms and susceptibility to Q fever, illness severity or illness course.Genes and Immunity advance online publication, 13 September 2007; doi:10.1038/sj.gene.6364428.

OBJECTIVE: The aim of this study is to review research examining an immunological basis for chronic fatigue syndrome (CFS) and to discuss how a disturbance in immunity could produce central nervous system (CNS)-mediated symptoms. METHOD: Data relevant to the hypothesis that abnormal cytokine release plays a role in the pathogenesis of CFS are reviewed as well as recent evidence relating to potential mechanisms by which immune products may enter the brain and produce a disturbance in CNS processes. RESULTS: Examinations of cytokine levels in patients with CFS have produced inconclusive results. Recent evidence suggests that abnormal release of cytokines within the CNS may cause neural dysfunction by a variety of complex mechanisms. CONCLUSION: Neuropsychiatric symptoms in patients with CFS may be more closely related to disordered cytokine production by glial cells within the CNS than to circulating cytokines. This possibility is discussed in the context of unresolved issues in the pathogenesis of CFS.

BACKGROUND: Patients with chronic fatigue syndrome (CFS) report neuro-psychological symptoms as a characteristic feature. We sought to assess cognitive performance in patients with CFS, and compare cognitive performance and subjective workload experience of these patients with that of two disease comparison groups (non-melancholic depression and acute infection) and healthy controls. METHOD: A computerized performance battery employed to assess cognitive functioning included tests of continuous attention, response speed, performance accuracy and memory. Severity of mood disturbance and subjective fatigue were assessed by questionnaire. RESULTS: All patient groups demonstrated increased errors and slower reaction times, and gave higher workload ratings than healthy controls. Patients with CFS and non-melancholic depression had more severe deficits than patients with acute infection. All patient groups reported more severe mood disturbance and fatigue than healthy controls, but patients with CFS and those with acute infection reported less severe mood disturbance than patients with depression. CONCLUSIONS: As all patients demonstrated similar deficits in attention and response speed, it is possible that common pathophysiological processes are involved. The differences in severity of mood disturbance, however, suggest that the pathophysiological processes in patients with CFS and acute infection are not simply secondary to depressed mood.

PURPOSE: To determine whether the reported therapeutic benefit of intravenous immunoglobulin in patients with chronic fatigue syndrome (CFS) is dose dependent. PATIENTS AND METHODS: Ninety-nine adult patients, who fulfilled diagnostic criteria for CFS, participated in this double-blind, randomized, and placebo-controlled trial. Patients received intravenous infusions with either a placebo solution (1% albumin) or one of three doses of immunoglobulin (0.5, 1, or 2 g/kg) on a monthly basis for 3 months, followed by a treatment-free follow-up period of 3 months. Outcome was assessed by changes in a series of self-reported measures (quality-of-life visual analog scales, standardized diaries of daily activities, the profile of mood states questionnaire) and the Karnofsky performance scale. Cell-mediated immunity was evaluated by T-cell subset analysis and delayed-type hypersensitivity (DTH) skin testing. RESULTS: No dose of intravenous immunoglobulin was associated with a specific therapeutic benefit. Adverse reactions, typically constitutional symptoms, were reported by 70% to 80% of patients, with no relationship to immunoglobulin treatment. CONCLUSIONS: Intravenous immunoglobulin cannot be recommended as a therapy for the treatment of CFS. A better understanding of the pathophysiology of this disorder is needed before effective treatment can be developed.

Disabling fatigue and psychological symptoms of depression or anxiety are commonly reported by women with treated breast cancer. However, most instruments designed to assess fatigue do not assess concurrent psychological symptoms. This study compared the characteristics of two conceptually different, self-report instruments assessing fatigue to determine the extent to which common psychological symptoms co-exist with the symptom of fatigue in women treated for breast cancer. Women attending an oncology day-care facility for adjuvant treatment of breast cancer or ongoing surveillance post-treatment, completed two self-report questionnaires. The Somatic and Psychological Health REport-34 items (SPHERE) and the Functional Assessment of Cancer Therapy-Fatigue (FACT-F subscale-13 items).One hundred and nine women (mean age 52.8 years) completed both questionnaires and total scores on both fatigue assessment scales, FACT-F and SOMA-6, were highly correlated (r = 0.72, P < 0.001). Using the SPHERE case criteria, prolonged fatigue (37%[40/109]) and psychological distress 31%(34/109) were common in women treated for breast cancer. However, those who reported fatigue were much more likely to also report psychological symptoms (22/40 vs. 12/69, X(2)= 16.7: degrees of freedom (df)=1; P < 0.001) and the levels of fatigue on the FACT-F were not significantly different between those who reported "fatigue only" and those who reported "psychological distress only"(18.8 vs. 17.8, P = 0.79).Thus the recent emphasis on recording fatigue during and following treatments for cancer needs to be accompanied by concurrent measurement of psychological symptoms.

OBJECTIVE: We sought to compare the characteristics of patients presenting with chronic fatigue (CF) and related syndromes in eight international centres and to subclassify these subjects based on symptom profiles. The validity of the subclasses was then tested against clinical data. METHOD: Subjects with a clinical diagnosis of CF completed a 119-item self-report questionnaire to provide clinical symptom data and other information such as illness course and functional impairment. Subclasses were generated using a principal components-like analysis followed by latent profile analysis (LPA). RESULTS: 744 subjects returned complete data sets (mean age 40.8 years, mean length of illness 7.9 years, female to male ratio 3:1). Overall, the subjects had a high rate of reporting typical CF symptoms (fatigue, neuropsychological dysfunction, sleep disturbance). Using LPA, two subclasses were generated. Class one (68% sample) was characterized by: younger age, lower female to male ratio; shorter episode duration; less premorbid, current and familial psychiatric morbidity; and, less functional disability. Class two subjects (32%) had features more consistent with a somatoform illness. There was substantial variation in subclass prevalences between the study centres (Class two range 6-48%). CONCLUSIONS: Criteria-based approaches to the diagnosis of CF and related syndromes do not select a homogeneous patient group. While substratification of patients is essential for further aetiological and treatment research, the basis for allocating such subcategories remains controversial.

PURPOSE: To examine the potential therapeutic effect of a neutralizing anti-IL-8 monoclonal antibody in endotoxin-induced uveitis (EIU) in the rabbit. METHODS: An anti-IL-8 antibody (WS-4) was injected intravitreal 2 hours before, simultaneously with, or 6 hours after endotoxin challenge in rabbits. Eyes were examined for clinical signs of inflammation, and aqueous humor (AH) was sampled to study cellular infiltration and protein content. Leukocyte subset analysis was performed on Giemsa-stained AH cytospins. Histologic grading of inflammation was performed on hematoxylin-eosin-stained sagittal sections of enucleated eyes. In separate experiments, animals received the anti-IL-8 antibody simultaneously with the endotoxin challenge, before repeated anterior chamber paracentesis was performed (at 6, 12, 24, 48, and 72 hours after injection) to estimate the kinetics and durability of changes in total cell count and protein concentration in AH. RESULTS: Anti-IL-8 therapy caused a decrease in the clinical and histologic grade of inflammation in EIU. The mean cell count in the AH at the peak of inflammation (24 hours) in eyes receiving endotoxin only was 6419+/-1165/microl (mean +/- SE) compared to 2546+/-573/microl in rabbits treated simultaneously with 250 microg of anti-IL-8 antibody (P < 0.05). The protein concentration in the AH was not significantly altered by anti-IL-8 treatment. Kinetic analysis of the leukocyte count in the AH demonstrated persistent inhibition of leukocyte accumulation (range, 60%-91% compared to control eyes) by the anti-IL-8 antibody administered simultaneously with endotoxin. This inhibition was sustained for up to 72 hours after injection. CONCLUSIONS: Anti-IL-8 antibody treatment partially blocks EIU in rabbits. A consistent decrease in the recruitment of polymorphonuclear leukocytes into the anterior chamber was obtained when neutralizing antibody was injected simultaneously with endotoxin. These findings suggest that IL-8 contributes to the chemotactic signal for the recruitment of leukocytes in EIU.

OBJECTIVE: To describe the rationale for investigating the dopaminergic system in patients with melancholia by applying molecular biological (notably, in situ hybridisation) and histopathological techniques in postmortem brain tissue. METHOD: Relevant advances in the functional neuroanatomy of frontostriatal circuits, as well as insights from clinical neuroimaging studies in primary and secondary depressive disorders, are presented. These are integrated with developments in the pharmacological and molecular characteristics of dopamine receptor subtypes and recognition of their selective anatomical distribution. RESULTS: Converging data from the basic and clinical neurosciences suggest that the pathophysiology of depressive disorders characterised by psychomotor phenomena, such as melancholia, may involve dysregulation of dopaminergic mechanisms within complex frontostriatal circuits. CONCLUSIONS: The key feature of in situ hybridisation is its capacity to test for variations in the functional components of designated biochemical systems within highly specific anatomical regions. We utilise this approach, in combination with relevant histopathological techniques, to test the structural and functional integrity of the dopaminergic system within key fronto-striatal circuits in patients who had exhibited psychomotor phenomena. The same approach can also be used to study the integrity of other relevant biochemical systems, such as the serotoninergic and noradrenergic systems, in patients with other mood disorders.

OBJECTIVE: To highlight the potential role of molecular biological studies in examining the expression of genes of interest in brain tissue to elucidate the pathophysiological basis of the major psychoses. METHOD: To review the principles underlying the available techniques for expression studies. RESULTS: Detection of messenger RNA by in situ hybridisation and quantitation by Northern analysis are powerful tools to detect abnormalities in gene expression in brain tissue. CONCLUSION: The availability of simple techniques to examine the expression of RNA and protein products of individual genes, including examination at the level of individual cells, offers a clear opportunity to define the molecular basis of the major psychoses.

Prolonged fatigue syndromes are common in general practice. Most of these syndromes are secondary to other common medical or psychological disorders. It appears, however, that some specific infectious illnesses are associated with prolonged recovery. Theories as to the mechanisms for such post infection fatigue syndromes include a range of immunological, psychological and neurobiological processes. Current evidence suggests disruption of fundamental central nervous system mechanisms, such as the sleep-wake cycle and the hypothalamic-pituitary-adrenal axis, may underpin the clinical features of this disorder. Treatment should focus on the provision of continuous medical care, physical rehabilitation and adjunctive psychological therapies.

The psychologic and behavioral components of sickness represent, together with fever response and associated neuroendocrine changes, a highly organized strategy of the organism to fight infection. This strategy, referred to as sickness behavior, is triggered by the proinflammatory cytokines produced by activated cells of the innate immune system in contact with specific pathogen-associated molecular patterns (PAMPs). Interleukin-1 and other cytokines act on the brain via (1) a neural route represented by the primary afferent neurons that innervate the body site where the infectious process takes place and (2) a humoral pathway that involves the production of proinflammatory cytokines. This article presents the current knowledge on the way this communication system is organized and regulated and the implications of these advances for understanding brain physiology and pathology.

INTRODUCTION: In studied analyzed role of the cytokines in pathology of neoplasms of various origin the importance of these proteins in regulation of immunocompetent cells function has been described. The aim of this study was to estimate of cho sen cytokines concentration produced by peripheral blood mononuclear cells and in whole blood in patients with laryngeal carcinoma and to analyze the connection of cytokines profile with clinicopathological features. MATERIALA AND METHODS: 55 patients with squamous cell carcinoma of the larynx treated at ENT Department Medical University of Lodz between 2003-2007 were analyzed. For estimation of cytokine secretion the cultures of isolated peripheral blood mononuclear cells (T lymphocytes) and the whole blood were established. Production of cytokines in supernatants was detected by Elisa. Connections with clinicomorphological features (pT, pN, Anneroth, Batsakis i Lunas' classification) were analyzed. RESULTS: Authors reported statistical correlation between chosen cytokines concentration and clinicomorphological parameters: pT and IL-2, IL-6, IL-8, TNFalpha produced by isolated cells and IL-2, IL-6, TNFa and IFNgamma in whole blood, pN and IL-8, IL-10, IFNgamma; ABL score and IL-6, TNFalpha, IFNgamma produced by isolated cells and IL-2, IL-6, IL-10, TNFalpha, IFNgamma in whole blood. CONCLUSION: Our studied indicated the important influence of proinflammatory and regulatory cytokines produced by immunocompetent cells for course of neoplasm disease, aggressiveness and advance in laryngeal carcinoma.

BACKGROUND: Fibrin-ring granuloma (FRG), which can be found in bone marrow or the liver, is a subtype of epithelioid granuloma characterized by a central fat vacuole and annular peripheral fibrinoid materials. FRG has been proven to be associated with many etiologies such as several infectious organisms (Coxiella burnett; Epstein-Barr Virus, EBV; cytomegalovirus, CMV; and hepatitis A virus), allopurinol induced hepatitis, Hodgkin's lymphoma, and peripheral T-cell lymphoma. METHODS: We retrospectively reviewed 24 patients diagnosed with FRG by bone marrow biopsy at a single institute between 1995 and 2004. We reviewed clinical symptoms and laboratory findings of the patients, classified them by etiology, and compared prognosis of each group. RESULTS: The most common cause of FRG was acute or chronic EBV infection. Chronic or acute EBV infection was associated with 41.4% of patients (10/24). Of the remaining patients, 33.3%(8/24) were leukemia or lymphoma patients after chemotherapy, 4.2%(1/24) was a patient with hepatic failure, and 20.8%(5/24) were diagnosed as fever of unknown origin. The most common symptom and clinical finding were fever and cytopenia. EBV-associated group comprised chronic active EBV infection, EBV-associated hemophagocytic histiocytosis, acute EBV infection, EBV-associated lymphoproliferative disease, and Langerhans' cell histiocytosis. The EBV-associated group showed a lower survival probability compared with the non-EBV group (P<0.05). CONCLUSIONS: Patients with bone marrow fibrin ring granuloma accompanied by fever require an active workup to find out the cause of infectious agents including EBV infection particularly due to their poor prognosis.

In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.

The communication between the central nervous system and the immune system occurs via a complex network of bidirectional signals linking the nervous, endocrine and immune systems. The field of psychoneuroimmunology (PNI) has provided new insights to help understand the pathophysiological processes that are linked to the immune system. Work in this field has established that psychological stress disrupts the functional interaction between the nervous and immune systems. Stress-induced immune dysregulation has been shown to be significant enough to result in health consequences, including reducing the immune response to vaccines, slowing wound healing, reactivating latent herpesviruses, such as Epstein-Barr virus (EBV), and enhancing the risk for more severe infectious disease. Chronic stress/depression can increase the peripheral production of proinflammatory cytokines, such as interleukin (IL)-6. High serum levels of IL-6 have been linked to risks for several conditions, such as cardiovascular disease, type 2 diabetes, mental health complications, and some cancers. This overview will discuss the evidence that psychological stress promotes immune dysfunction that negatively impacts human health.

Acute hypoxia is experienced by a variety of individuals (neonates to the elderly) and in an assortment of conditions and diseases (terrorist bomb attack to decompensated heart failure). Increasingly, elaboration of inflammatory cytokines appears key to the brain-based response to hypoxia, as evidenced by the biobehaviors of malaise, fatigue, lethargy, and loss of interest in the physical and social environment. These sickness symptoms implicate hypoxia-dependent activation of the neuroimmune system as a key component of acute hypoxia. Type 2 diabetes (T2D) is associated with increased incidence, severity, and delayed recovery from hypoxic events. Why T2D negatively affects acute hypoxia is not well understood. Recent work, however, reveals that anti-inflammatory pathways tied to the interleukin (IL)-1beta arm of the neuroimmune system may be critical. In this review, the authors examine the link between acute hypoxia, T2D, and neuroimmunity. DOI: 10.1177/1073858407309544.

Cytokine-induced sickness behavior was recognized within a few years of the cloning and expression of interferon-alpha, IL-1 and IL-2, which occurred around the time that the first issue of Brain, Behavior, and Immunity was published in 1987. Phase I clinical trials established that injection of recombinant cytokines into cancer patients led to a variety of psychological disturbances. It was subsequently shown that physiological concentrations of proinflammatory cytokines that occur after infection act in the brain to induce common symptoms of sickness, such as loss of appetite, sleepiness, withdrawal from normal social activities, fever, aching joints and fatigue. This syndrome was defined as sickness behavior and is now recognized to be part of a motivational system that reorganizes the organism's priorities to facilitate recovery from the infection. Cytokines convey to the brain that an infection has occurred in the periphery, and this action of cytokines can occur via the traditional endocrine route via the blood or by direct neural transmission via the afferent vagus nerve. The finding that sickness behavior occurs in all mammals and birds indicates that communication between the immune system and brain has been evolutionarily conserved and forms an important physiological adaptive response that favors survival of the organism during infections. The fact that cytokines act in the brain to induce physiological adaptations that promote survival has led to the hypothesis that inappropriate, prolonged activation of the innate immune system may be involved in a number of pathological disturbances in the brain, ranging from Alzheimer's disease to stroke. Conversely, the newly-defined role of cytokines in a wide variety of systemic co-morbid conditions, ranging from chronic heart failure to obesity, may begin to explain changes in the mental state of these subjects. Indeed, the newest findings of cytokine actions in the brain offer some of the first clues about the pathophysiology of certain mental health disorders, including depression. The time is ripe to begin to move these fundamental discoveries in mice to man and some of the pharmacological tools are already available to antagonize the detrimental actions of cytokines.

Infection commonly triggers nonspecific psychological and behavioral changes including fatigue and malaise, anhedonia, inability to concentrate, and disturbed sleep that collectively are termed "sickness behaviors". Converging evidence from several lines of research implicate the activities of proinflammatory cytokines as a cause of sickness behaviors. Here we elaborate upon the findings of previous research by examining whether infection-associated elevations in local proinflammatory cytokines are associated with increased negative mood and decreased positive mood. One hundred and eighty-nine healthy adults were experimentally exposed to rhinovirus or influenza virus during a 6-day period of quarantine. Infection, objective signs of illness, nasal IL-1beta, IL-6, and TNF-alpha, and self-reported affect were assessed at baseline and on each of the five post-challenge quarantine days. In the 153 persons who became infected following exposure to the challenge virus, daily production of IL-6, but not IL-1beta or TNF-alpha, was associated with reduced concurrent daily positive affect. One-day lagged analyses showed that daily production of all three cytokines was related to lower positive affect on the next day. All lagged associations were independent of previous-day positive affect and objective signs of illness (mucus production, mucociliary clearance function). There were no associations between cytokines and negative affect. Findings support a causal association between pathogen-induced local cytokine production and changes in positive affect over a 24-h timeline.

Chronic Q fever is characterized by deficient cell-mediated immune response, lack of granulomas, and dysregulation of the cytokine network. Altered transendothelial migration (TM) of peripheral-blood mononuclear cells might account for impaired immune response. TM of lymphocytes and monocytes was decreased in patients with Q fever endocarditis, compared with that in patients recovering from acute Q fever and in control subjects. This defect is related to interleukin (IL)-10, a cytokine involved in the chronic evolution of the disease; neutralizing anti-IL-10 antibodies corrected TM of mononuclear cells from patients with Q fever endocarditis. IL-10 may account for deficient protective immunity in patients with Q fever endocarditis by impairing TM.