Giardia-specific cellular immune responses in post-giardiasis chronic fatigue syndrome.

PubMed

Hanevik, Kurt; Kristoffersen, Einar; Mørch, Kristine; Rye, Kristin Paulsen; Sørnes, Steinar; Svärd, Staffan; Bruserud, Øystein; Langeland, Nina

2017-01-28

The role of pathogen specific cellular immune responses against the eliciting pathogen in development of post-infectious chronic fatigue syndrome (PI-CFS) is not known and such studies are difficult to perform. The aim of this study was to evaluate specific anti-Giardia cellular immunity in cases that developed CFS after Giardia infection compared to cases that recovered well. Patients reporting chronic fatigue in a questionnaire study three years after a Giardia outbreak were clinically evaluated five years after the outbreak and grouped according to Fukuda criteria for CFS and idiopathic chronic fatigue. Giardia specific immune responses were evaluated in 39 of these patients by proliferation assay, T cell activation and cytokine release analysis. 20 Giardia exposed non-fatigued individuals and 10 healthy unexposed individuals were recruited as controls. Patients were clinically classified into CFS (n = 15), idiopathic chronic fatigue (n = 5), fatigue from other causes (n = 9) and recovered from fatigue (n = 10). There were statistically significant antigen specific differences between these Giardia exposed groups and unexposed controls. However, we did not find differences between the Giardia exposed fatigue classification groups with regard to CD4 T cell activation, proliferation or cytokine levels in 6 days cultured PBMCs. Interestingly, sCD40L was increased in patients with PI-CFS and other persons with fatigue after Giardia infection compared to the non-fatigued group, and correlated well with fatigue levels at the time of sampling. Our data show antigen specific cellular immune responses in the groups previously exposed to Giardia and increased sCD40L in fatigued patients.

Unstimulated cortisol secretory activity in everyday life and its relationship with fatigue and chronic fatigue syndrome: a systematic review and subset meta-analysis.

PubMed

Powell, Daniel J H; Liossi, Christina; Moss-Morris, Rona; Schlotz, Wolff

2013-11-01

The hypothalamic-pituitary-adrenal (HPA) axis is a psychoneuroendocrine regulator of the stress response and immune system, and dysfunctions have been associated with outcomes in several physical health conditions. Its end product, cortisol, is relevant to fatigue due to its role in energy metabolism. The systematic review examined the relationship between different markers of unstimulated salivary cortisol activity in everyday life in chronic fatigue syndrome (CFS) and fatigue assessed in other clinical and general populations. Search terms for the review related to salivary cortisol assessments, everyday life contexts, and fatigue. All eligible studies (n=19) were reviewed narratively in terms of associations between fatigue and assessed cortisol markers, including the cortisol awakening response (CAR), circadian profile (CP) output, and diurnal cortisol slope (DCS). Subset meta-analyses were conducted of case-control CFS studies examining group differences in three cortisol outcomes: CAR output; CAR increase; and CP output. Meta-analyses revealed an attenuation of the CAR increase within CFS compared to controls (d=-.34) but no statistically significant differences between groups for other markers. In the narrative review, total cortisol output (CAR or CP) was rarely associated with fatigue in any population; CAR increase and DCS were most relevant. Outcomes reflecting within-day change in cortisol levels (CAR increase; DCS) may be the most relevant to fatigue experience, and future research in this area should report at least one such marker. Results should be considered with caution due to heterogeneity in one meta-analysis and the small number of studies. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Fatigue-Related Gene Networks Identified in CD14+ Cells Isolated From HIV-Infected Patients—Part I: Research Findings

PubMed Central

Voss, Joachim G.; Dobra, Adrian; Morse, Caryn; Kovacs, Joseph A.; Danner, Robert L.; Munson, Peter J.; Logan, Carolea; Rangel, Zoila; Adelsberger, Joseph W.; McLaughlin, Mary; Adams, Larry D.; Raju, Raghavan; Dalakas, Marinos C.

2016-01-01

Purpose Human immunodeficiency virus (HIV)–related fatigue (HRF) is multicausal and potentially related to mitochondrial dysfunction caused by antiretroviral therapy with nucleoside reverse transcriptase inhibitors (NRTIs). Methodology The authors compared gene expression profiles of CD14+ cells of low versus high fatigued, NRTI-treated HIV patients to healthy controls (n = 5/group). The authors identified 32 genes predictive of low versus high fatigue and 33 genes predictive of healthy versus HIV infection. The authors constructed genetic networks to further elucidate the possible biological pathways in which these genes are involved. Relevance for nursing practice Genes including the actin cytoskeletal regulatory proteins Prokineticin 2 and Cofilin 2 along with mitochondrial inner membrane proteins are involved in multiple pathways and were predictors of fatigue status. Previously identified inflammatory and signaling genes were predictive of HIV status, clearly confirming our results and suggesting a possible further connection between mitochondrial function and HIV. Isolated CD14+ cells are easily accessible cells that could be used for further study of the connection between fatigue and mitochondrial function of HIV patients. Implication for Practice The findings from this pilot study take us one step closer to identifying biomarker targets for fatigue status and mitochondrial dysfunction. Specific biomarkers will be pertinent to the development of methodologies to diagnosis, monitor, and treat fatigue and mitochondrial dysfunction. PMID:23324479

Humoral and cellular immune responses after influenza vaccination in patients with postcancer fatigue

PubMed Central

Prinsen, Hetty; van Laarhoven, Hanneke WM; Pots, Jeanette M; Duiveman-de Boer, Tjitske; Mulder, Sasja F; van Herpen, Carla ML; Jacobs, Joannes FM; Leer, Jan Willem H; Bleijenberg, Gijs; Stelma, Foekje F; Torensma, Ruurd; de Vries, I Jolanda M

2015-01-01

The aim of this study was to compare humoral and cellular immune responses to influenza vaccination in cancer survivors with and without severe symptoms of fatigue. Severely fatigued (n = 15) and non-fatigued (n = 12) disease-free cancer survivors were vaccinated against seasonal influenza. Humoral immunity was evaluated at baseline and post-vaccination by a hemagglutination inhibition assay. Cellular immunity was evaluated at baseline and post-vaccination by lymphocyte proliferation and activation assays. Regulatory T cells were measured at baseline by flow cytometry and heat-shock protein 90 alpha levels by ELISA. Comparable humoral immune responses were observed in fatigued and non-fatigued patients, both pre- and post-vaccination. At baseline, fatigued patients showed a significantly diminished cellular proliferation upon virus stimulation with strain H3N2 (1414 ± 1201 counts), and a trend in a similar direction with strain H1N1 (3025 ± 2339 counts), compared to non-fatigued patients (3099 ± 2401 and 5877 ± 4604 counts, respectively). The percentage of regulatory T lymphocytes was significantly increased (4.4 ± 2.1% versus 2.4 ± 0.8%) and significantly lower amounts of interleukin 2 were detected prior to vaccination in fatigued compared to non-fatigued patients (36.3 ± 44.3 pg/ml vs. 94.0 ± 45.4 pg/ml with strain H3N2 and 28.4 ± 44.0 pg/ml versus 74.5 ± 56.1 pg/ml with strain H1N1). Pre-vaccination heat-shock protein 90 alpha concentrations, post-vaccination cellular proliferation, and post-vaccination cytokine concentrations did not differ between both groups. In conclusion, influenza vaccination is favorable for severely fatigued cancer survivors and should be recommended when indicated. However, compared to non-fatigued cancer survivors, fatigued cancer survivors showed several significant differences in immunological reactivity at baseline, which warrants further investigation. PMID:25996472

Electroencephalogram power changes as a correlate of chemotherapy-associated fatigue and cognitive dysfunction.

PubMed

Moore, Halle C F; Parsons, Michael W; Yue, Guang H; Rybicki, Lisa A; Siemionow, Wlodzimierz

2014-08-01

Persistent fatigue and cognitive dysfunction are poorly understood potential long-term effects of adjuvant chemotherapy. In this pilot study, we assessed the value of electroencephalogram (EEG) power measurements as a means to evaluate physical and mental fatigue associated with chemotherapy. Women planning to undergo adjuvant chemotherapy for breast cancer and healthy controls underwent neurophysiologic assessments at baseline, during the time of chemotherapy treatment, and at 1 year. Repeated measures analysis of variance was used to analyze the data. Compared with controls, patients reported more subjective fatigue at baseline that increased during chemotherapy and did not entirely resolve by 1 year. Performance on endurance testing was similar in patients versus controls at all time points; however, values of EEG power increased after a physical task in patients during chemotherapy but not controls. Compared with controls, subjective mental fatigue was similar for patients at baseline and 1 year but worsened during chemotherapy. Patients performed similarly to controls on formal cognitive testing at all time points, but EEG activity after the cognitive task was increased in patients only during chemotherapy. EEG power measurement has the potential to provide a sensitive neurophysiologic correlate of cancer treatment-related fatigue and cognitive dysfunction.

Traditional Chinese Medicine for Chronic Fatigue Syndrome

PubMed Central

Chen, Rui; Moriya, Junji; Yamakawa, Jun-ichi; Takahashi, Takashi

2010-01-01

More and more patients have been diagnosed as having chronic fatigue syndrome (CFS) in recent years. Western drug use for this syndrome is often associated with many side-effects and little clinical benefit. As an alternative medicine, traditional Chinese medicine (TCM) has provided some evidences based upon ancient texts and recent studies, not only to offer clinical benefit but also offer insights into their mechanisms of action. It has perceived advantages such as being natural, effective and safe to ameliorate symptoms of CFS such as fatigue, disordered sleep, cognitive handicaps and other complex complaints, although there are some limitations regarding the diagnostic standards and methodology in related clinical or experimental studies. Modern mechanisms of TCM on CFS mainly focus on adjusting immune dysfunction, regulating abnormal activity in the hypothalamic-pituitary-adrenal (HPA) axis and serving as an antioxidant. It is vitally important for the further development to establish standards for ‘zheng’ of CFS, i.e. the different types of CFS pathogenesis in TCM, to perform randomized and controlled trials of TCM on CFS and to make full use of the latest biological, biochemical, molecular and immunological approaches in the experimental design. PMID:18955323

Frontier studies on fatigue, autonomic nerve dysfunction, and sleep-rhythm disorder.

PubMed

Tanaka, Masaaki; Tajima, Seiki; Mizuno, Kei; Ishii, Akira; Konishi, Yukuo; Miike, Teruhisa; Watanabe, Yasuyoshi

2015-11-01

Fatigue is defined as a condition or phenomenon of decreased ability and efficiency of mental and/or physical activities, caused by excessive mental or physical activities, diseases, or syndromes. It is often accompanied by a peculiar sense of discomfort, a desire to rest, and reduced motivation, referred to as fatigue sensation. Acute fatigue is a normal condition or phenomenon that disappears after a period of rest; in contrast, chronic fatigue, lasting at least 6 months, does not disappear after ordinary rest. Chronic fatigue impairs activities and contributes to various medical conditions, such as cardiovascular disease, epileptic seizures, and death. In addition, many people complain of chronic fatigue. For example, in Japan, more than one third of the general adult population complains of chronic fatigue. It would thus be of great value to clarify the mechanisms underlying chronic fatigue and to develop efficient treatment methods to overcome it. Here, we review data primarily from behavioral, electrophysiological, and neuroimaging experiments related to neural dysfunction as well as autonomic nervous system, sleep, and circadian rhythm disorders in fatigue. These data provide new perspectives on the mechanisms underlying chronic fatigue and on overcoming it.

Endocrinological side-effects of immune checkpoint inhibitors.

PubMed

Torino, Francesco; Corsello, Salvatore M; Salvatori, Roberto

2016-07-01

Three mAbs targeting immune checkpoint proteins are available for the treatment of patients with melanoma, lung, and kidney cancer, and their use will likely expand in the future to additional tumor types. We here update the literature on the incidence and pathophysiology of endocrine toxicities induced by these agents, and discuss management guidance. Immune checkpoint inhibition may trigger autoimmune syndromes involving different organs, including several endocrine glands (pituitary, thyroid, adrenals, and endocrine pancreas). Hypophysitis is more frequently associated with ipilimumab, whereas the incidence of thyroid dysfunction is higher with nivolumab/pembrolizumab. Primary adrenal insufficiency can rarely occur with either treatment. Autoimmune diabetes is very rare. As hypophysitis and adrenalitis may be life-threatening, endocrinological evaluation is essential particularly in patients developing fatigue and other symptoms consistent with adrenal insufficiency. Corticosteroids should be promptly used when hypophysitis-induced adrenal insufficiency or adrenalitis are diagnosed, but not in thyroiditis or diabetes. No impact of corticosteroids on the efficacy/activity of immune checkpoint-inhibiting drugs is reported. Hormonal deficiencies are often permanent. In absence of predicting factors, accurate information to patients provided by the oncology care team is essential for early diagnosis and to limit the consequences of checkpoint inhibition-related endocrine toxicity.

Epigenetic modifications and glucocorticoid sensitivity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

PubMed

de Vega, Wilfred C; Herrera, Santiago; Vernon, Suzanne D; McGowan, Patrick O

2017-02-23

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating idiopathic disease characterized by unexplained fatigue that fails to resolve with sufficient rest. Diagnosis is based on a list of symptoms and exclusion of other fatigue-related health conditions. Despite a heterogeneous patient population, immune and hypothalamic-pituitary-adrenal (HPA) axis function differences, such as enhanced negative feedback to glucocorticoids, are recurring findings in ME/CFS studies. Epigenetic modifications, such as CpG methylation, are known to regulate long-term phenotypic differences and previous work by our group found DNA methylome differences in ME/CFS, however the relationship between DNA methylome modifications, clinical and functional characteristics associated with ME/CFS has not been examined. We examined the DNA methylome in peripheral blood mononuclear cells (PBMCs) of a larger cohort of female ME/CFS patients using the Illumina HumanMethylation450 BeadChip Array. In parallel to the DNA methylome analysis, we investigated in vitro glucocorticoid sensitivity differences by stimulating PBMCs with phytohaemagglutinin and suppressed growth with dexamethasone. We explored DNA methylation differences using bisulfite pyrosequencing and statistical permutation. Linear regression was implemented to discover epigenomic regions associated with self-reported quality of life and network analysis of gene ontology terms to biologically contextualize results. We detected 12,608 differentially methylated sites between ME/CFS patients and healthy controls predominantly localized to cellular metabolism genes, some of which were also related to self-reported quality of life health scores. Among ME/CFS patients, glucocorticoid sensitivity was associated with differential methylation at 13 loci. Our results indicate DNA methylation modifications in cellular metabolism in ME/CFS despite a heterogeneous patient population, implicating these processes in immune and HPA axis dysfunction in ME/CFS. Modifications to epigenetic loci associated with differences in glucocorticoid sensitivity may be important as biomarkers for future clinical testing. Overall, these findings align with recent ME/CFS work that point towards impairment in cellular energy production in this patient population.

Contractile dysfunctions in ATP-dependent K+ channel-deficient mouse muscle during fatigue involve excessive depolarization and Ca2+ influx through L-type Ca2+ channels.

PubMed

Cifelli, Carlo; Boudreault, Louise; Gong, Bing; Bercier, Jean-Philippe; Renaud, Jean-Marc

2008-10-01

Muscles deficient in ATP-dependent potassium (KATP) channels develop contractile dysfunctions during fatigue that may explain their apparently faster rate of fatigue compared with wild-type muscles. The objectives of this study were to determine: (1) whether the contractile dysfunctions, namely unstimulated force and depressed force recovery, result from excessive membrane depolarization and Ca2+ influx through L-type Ca2+ channels; and (2) whether reducing the magnitude of these two contractile dysfunctions reduces the rate of fatigue in KATP channel-deficient muscles. To reduce Ca2+ influx, we lowered the extracellular Ca2+ concentration ([Ca2+]o) from 2.4 to 0.6 mM or added 1 microM verapamil, an L-type Ca2+ channel blocker. Flexor digitorum brevis (FDB) muscles deficient in KATP channels were obtained by exposing wild-type muscles to 10 microM glibenclamide or by using FDB from Kir6.2-/- mice. Fatigue was elicited with one contraction per second for 3 min at 37 degrees C. In wild-type FDB, lowered [Ca2+]o or verapamil did not affect the decrease in peak tetanic force and unstimulated force during fatigue and force recovery following fatigue. In KATP channel-deficient FDB, lowered [Ca2+]o or verapamil slowed down the decrease in peak tetanic force recovery, reduced unstimulated force and improved force recovery. In Kir6.2-/- FDB, the rate of fatigue became slower than in wild-type FDB in the presence of verapamil. The cell membrane depolarized from -83 to -57 mV in normal wild-type FDB. The depolarizations in some glibenclamide-exposed fibres were similar to those of normal FDB, while in other fibres the cell membrane depolarized to -31 mV in 80 s, which was also the time when these fibres supercontracted. It is concluded that: (1) KATP channels are crucial in preventing excessive membrane depolarization and Ca2+ influx through L-type Ca2+ channels; and (2) they contribute to the decrease in force during fatigue.

Association between autonomic dysfunction and fatigue in Parkinson disease.

PubMed

Chou, Kelvin L; Gilman, Sid; Bohnen, Nicolaas I

2017-06-15

Fatigue is a disabling non-motor symptom in Parkinson disease (PD). We investigated the relationship between autonomic dysfunction and fatigue in PD while accounting for possible confounding factors. 29 subjects with PD (8F/21M; mean age 61.6±5.9; mean disease duration 4.8±3.0years), underwent clinical assessment and completed several non-motor symptom questionnaires, including a modified version of the Mayo Clinic Composite Autonomic Symptom Score (COMPASS) scale and the Fatigue Severity Scale (FSS). The mean modified COMPASS was 21.6±14.2 (range 1.7-44.2) and the mean FSS score was 3.3±1.6 (range 1.0-6.7). There was a significant bivariate relationship between the modified COMPASS and FSS scores (R=0.69, P<0.0001). Stepwise regression analysis was used to assess the specificity of the association between the modified COMPASS and FSS scores while accounting for possible confounder effects from other variables that were significantly associated with autonomic dysfunction. Results showed that the modified COMPASS (R 2 =0.52, F=28.4, P<0.0001) was highly associated with fatigue, followed by ESS (R 2 =0.13, F=8.4, P=0.008) but no other co-variates. Post-hoc analysis exploring the association between the different modified COMPASS autonomic sub-domain scores and FSS scores found significant regressor effects for the orthostatic intolerance (R 2 =0.45, F=21.2, P<0.0001) and secretomotor sub-domains (R 2 =0.09, F=4.8, P=0.04) but not for other autonomic sub-domains. Autonomic dysfunction, in particular orthostatic intolerance, is highly associated with fatigue in PD. Copyright © 2017 Elsevier B.V. All rights reserved.

Chemotherapy Necessitates Increased Immune Control of HHVs: A Cause of Persistent Inflammation Enabling Protracted Fatigue in Breast Cancer Survivors

DTIC Science & Technology

2014-10-01

14. ABSTRACT This work hypothesizes that chemotherapy can permanently alter the balance between the immune system and chronic herpes virus...infections. We predicted that herpes virus-driven inflammatory cytokines exacerbate cancer treatment related fatigue (CTRF). Here we report the significant...TERMS breast cancer, chemotherapy, immunology, human herpes viruses, survivor fatigue 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT

Immune dysfunction in cirrhosis.

PubMed

Sipeki, Nora; Antal-Szalmas, Peter; Lakatos, Peter L; Papp, Maria

2014-03-14

Innate and adaptive immune dysfunction, also referred to as cirrhosis-associated immune dysfunction syndrome, is a major component of cirrhosis, and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function. During the evolution of the disease, acute decompensation events associated with organ failure(s), so-called acute-on chronic liver failure, and chronic decompensation with progression of liver fibrosis and also development of disease specific complications, comprise distinct clinical entities with different immunopathology mechanisms. Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations. Acute and chronic exposure to bacteria and/or their products, however, can result in variable clinical consequences. The immune status of patients is not constant during the illness; consequently, alterations of the balance between pro- and anti-inflammatory processes result in very different dynamic courses. In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis. We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms. Moreover, we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease. Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications, delaying progression and reducing mortality.

Immune dysfunction in cirrhosis

PubMed Central

Sipeki, Nora; Antal-Szalmas, Peter; Lakatos, Peter L; Papp, Maria

2014-01-01

Innate and adaptive immune dysfunction, also referred to as cirrhosis-associated immune dysfunction syndrome, is a major component of cirrhosis, and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function. During the evolution of the disease, acute decompensation events associated with organ failure(s), so-called acute-on chronic liver failure, and chronic decompensation with progression of liver fibrosis and also development of disease specific complications, comprise distinct clinical entities with different immunopathology mechanisms. Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations. Acute and chronic exposure to bacteria and/or their products, however, can result in variable clinical consequences. The immune status of patients is not constant during the illness; consequently, alterations of the balance between pro- and anti-inflammatory processes result in very different dynamic courses. In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis. We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms. Moreover, we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease. Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications, delaying progression and reducing mortality. PMID:24627592

Dysregulated stress signal sensitivity and inflammatory disinhibition as a pathophysiological mechanism of stress-related chronic fatigue.

PubMed

Strahler, Jana; Skoluda, Nadine; Rohleder, Nicolas; Nater, Urs M

2016-09-01

Chronic stress and its subsequent effects on biological stress systems have long been recognized as predisposing and perpetuating factors in chronic fatigue, although the exact mechanisms are far from being completely understood. In this review, we propose that sensitivity of immune cells to glucocorticoids (GCs) and catecholamines (CATs) may be the missing link in elucidating how stress turns into chronic fatigue. We searched for in vitro studies investigating the impact of GCs or CATs on mitogen-stimulated immune cells in chronically stressed or fatigued populations, with 34 original studies fulfilling our inclusion criteria. Besides mixed cross-sectional findings for stress- and fatigue-related changes of GC sensitivity under basal conditions or acute stress, longitudinal studies indicate a decrease with ongoing stress. Research on CATs is still scarce, but initial findings point towards a reduction of CAT sensitivity under chronic stress. In the long run, resistance of immune cells to stress signals under conditions of chronic stress might translate into self-maintaining inflammation and inflammatory disinhibition under acute stress, which in turn lead to fatigue. Copyright © 2016 Elsevier Ltd. All rights reserved.

Efficacy of kinesiology tape versus postural correction exercises on neck disability and axioscapular muscles fatigue in mechanical neck dysfunction: A randomized blinded clinical trial.

PubMed

El-Abd, Aliaa M; Ibrahim, Abeer R; El-Hafez, Haytham M

2017-04-01

Mechanical neck dysfunction (MND), with axioscapular muscles fatigue, is highly prevalent worldwide. While postural correction is commonly used for its treatment, efficacy of kinesiology tape (KT) has received considerable attention. To determine the effectiveness of KT versus correction exercises on neck disability, and axioscapular muscles fatigue in MND patients. 46 MND patients were randomly assigned into 1 of 2 groups receiving 4 weeks treatment of either KT or correction exercises. Neck disability and axioscapular muscles fatigue as median frequency of electromyography (EMG-MF) were measured pre and post treatment. Group-by-time interaction was not significant in the multivariable test. Post hoc tests revealed that KT produced more disability reduction than the postural exercises. However, there was no significant interaction for EMG-MF. KT has been found to be more effective than postural exercises to reduce neck disability. However, both modalities have similar effects to reduce axioscapular muscles fatigue. Copyright © 2016 Elsevier Ltd. All rights reserved.

The role of immune dysfunction in the pathophysiology of autism

PubMed Central

Onore, Charity; Careaga, Milo; Ashwood, Paul

2012-01-01

Autism spectrum disorders (ASD) are a complex group of neurodevelopmental disorders encompassing impairments in communication, social interactions and restricted stereotypical behaviors. Although a link between altered immune responses and ASD was first recognized nearly 40 years ago, only recently has new evidence started to shed light on the complex multifaceted relationship between immune dysfunction and behavior in ASD. Neurobiological research in ASD has highlighted pathways involved in neural development, synapse plasticity, structural brain abnormalities, cognition and behavior. At the same time, several lines of evidence point to altered immune dysfunction in ASD that directly impacts some or all these neurological processes. Extensive alterations in immune function have now been described in both children and adults with ASD, including ongoing inflammation in brain specimens, elevated pro-inflammatory cytokine profiles in the CSF and blood, increased presence of brain-specific auto-antibodies and altered immune cell function. Furthermore, these dysfunctional immune responses are associated with increased impairments in behaviors characteristic of core features of ASD, in particular, deficits in social interactions and communication. This accumulating evidence suggests that immune processes play a key role in the pathophysiology of ASD. This review will discuss the current state of our knowledge of immune dysfunction in ASD, how these findings may impact on underlying neuro-immune mechanisms and implicate potential areas where the manipulation of the immune response could have an impact on behavior and immunity in ASD. PMID:21906670

Identifying patterns of immune-related disease: use in disease prevention and management.

PubMed

Dietert, Rodney R; Zelikoff, Judith T

2010-05-01

Childhood susceptibility to diseases linked with immune dysfunction affects over a quarter of the pediatric population in some countries. While this alone is a significant health issue, the actual impact of immune-related diseases extends over a lifetime and involves additional secondary conditions. Some comorbidities are well known (e.g., allergic rhinitis and asthma). However, no systematic approach has been used to identify life-long patterns of immune-based disease where the primary condition arises in childhood. Such information is useful for both disease prevention and treatment approaches. Recent primary research papers as well as review articles were obtained from PubMed, Chem Abstracts, Biosis and from the personal files of the authors. Search words used were: the diseases and conditions shown Figs. 1 and 2 in conjunction with comorbid, comorbidities, pediatric, childhood, adult, immune, immune dysfunction, allergy, autoimmune, inflammatory, infectious, health risks, environment, risk factors. Childhood diseases such as asthma, type-1 diabetes, inflammatory bowel disease, respiratory infections /rhinitis, recurrent otitis media, pediatric celiac, juvenile arthritis and Kawasaki disease are examples of significant childhood health problems where immune dysfunction plays a significant role. Each of these pediatric diseases is associated with increased risk of several secondary conditions, many of which appear only later in life. To illustrate, four prototypes of immune-related disease patterns (i.e., allergy, autoimmunity, inflammation and infectious disease) are shown as tools for: 1) enhanced disease prevention; 2) improved management of immune-based pediatric diseases; and 3) better recognition of underlying pediatric immune dysfunction. Identification of immune-related disease patterns beginning in childhood provides the framework for examining the underlying immune dysfunctions that can contribute to additional diseases in later life. Many pediatric diseases associated with dysfunctional immune responses have been linked with an elevated risk of other diseases or conditions as the child ages. Diseases within a pattern may be interlinked based on underlying immune dysfunctions and/or current therapeutic approaches for managing the entryway diseases. It may be beneficial to consider treatment options for the earliest presenting diseases that will concomitantly reduce the risk of immune-linked secondary conditions. Additionally, improved disease prevention is possible with more relevant and age-specific immune safety testing.

Chemotherapy Necessitates Increased Immune Control of HHVs: A Cause of Persistent Inflammation Enabling Protracted Fatigue in Breast Cancer Survivors

DTIC Science & Technology

2013-10-01

survivors. 15. SUBJECT TERMS breast cancer, chemotherapy, immunology, human herpes viruses, survivor fatigue 16. SECURITY CLASSIFICATION OF...hypothesizes that chemotherapy can permanently alter the balance between the immune system and chronic herpes virus infections and the resultant

Psychological distress, iron deficiency, active disease and female gender are independent risk factors for fatigue in patients with ulcerative colitis

PubMed Central

Jonefjäll, Börje; Simrén, Magnus; Lasson, Anders; Öhman, Lena; Strid, Hans

2017-01-01

Background Patients with ulcerative colitis often report fatigue. Objectives To investigate prevalence of and risk factors for fatigue in patients with ulcerative colitis with active disease and during deep remission. Methods In this cross-sectional study, disease activity was evaluated with endoscopy and calprotectin, and patients were classified as having active disease (n = 133) or being in deep remission (n = 155). Blood samples were analysed to assess anaemia, iron deficiency and systemic immune activity. Patients completed questionnaires to assess fatigue, psychological distress, gastrointestinal symptoms and quality of life. Results The prevalence of high fatigue (general fatigue ≥ 13, Multidimensional Fatigue Inventory) was 40% in the full study population. Among patients with high fatigue, female gender and iron deficiency were more prevalent, and these patients had more severe disease activity and reported higher levels of anxiety, depression and decreased quality of life compared with patients with no/mild fatigue. A logistic regression analysis identified probable psychiatric disorder (odds ratio (OR) (confidence interval) 6.1 (3.1–12.2)), iron deficiency (OR 2.5 (1.2–5.1)), active disease (OR 2.2 (1.2–3.9)) and female gender (OR 2.1 (1.1–3.7)) as independent risk factors for high fatigue. Similar results were found concerning psychological distress, gender and quality of life, but immune markers did not differ in patients in deep remission with high vs. no/mild fatigue. Conclusions Probable psychiatric disorder, iron deficiency, active disease and female gender are independent risk factors for high fatigue in patients with ulcerative colitis. Low-grade immune activity does not seem to be the cause of fatigue among patients in deep remission. PMID:29435325

Effect of Eischens Yoga During Radiation Therapy on Prostate Cancer Patient Symptoms and Quality of Life: A Randomized Phase II Trial.

PubMed

Ben-Josef, Avital Mazar; Chen, Jerry; Wileyto, Paul; Doucette, Abigail; Bekelman, Justin; Christodouleas, John; Deville, Curtiland; Vapiwala, Neha

2017-08-01

A randomized phase II study was performed to measure the potential therapeutic effects of yoga on fatigue, erectile dysfunction, urinary incontinence, and overall quality of life (QOL) in prostate cancer (PCa) patients undergoing external beam radiation therapy (RT). The participants were randomized to yoga and no-yoga cohorts (1:1). Twice-weekly yoga interventions were offered throughout the 6- to 9-week courses of RT. Comparisons of standardized assessments were performed between the 2 cohorts for the primary endpoint of fatigue and the secondary endpoints of erectile dysfunction, urinary incontinence, and QOL before, during, and after RT. From October 2014 to January 2016, 68 eligible PCa patients underwent informed consent and agreed to participate in the study. Of the 68 patients, 18 withdrew early, mostly because of treatment schedule-related time constraints, resulting in 22 and 28 patients in the yoga and no-yoga groups, respectively. Throughout treatment, those in the yoga arm reported less fatigue than those in the control arm, with global fatigue, effect of fatigue, and severity of fatigue subscales showing statistically significant interactions (P<.0001). The sexual health scores (International Index of Erectile Function Questionnaire) also displayed a statistically significant interaction (P=.0333). The International Prostate Symptom Score revealed a statistically significant effect of time (P<.0001) but no significant effect of treatment (P=.1022). The QOL measures had mixed results, with yoga having a significant time by treatment effect on the emotional, physical, and social scores but not on functional scores. A structured yoga intervention of twice-weekly classes during a course of RT was associated with a significant reduction in pre-existing and RT-related fatigue and urinary and sexual dysfunction in PCa patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Adolescent Fatigue, POTS, and Recovery: A Guide for Clinicians

PubMed Central

Kizilbash, Sarah J.; Ahrens, Shelley P.; Bruce, Barbara K.; Chelimsky, Gisela; Driscoll, Sherilyn W.; Harbeck-Weber, Cynthia; Lloyd, Robin M.; Mack, Kenneth J.; Nelson, Dawn E.; Ninis, Nelly; Pianosi, Paolo T.; Stewart, Julian M.; Weiss, Karen E.; Fischer, Philip R.

2018-01-01

Many teenagers who struggle with chronic fatigue have symptoms suggestive of autonomic dysfunction that may include lightheadedness, headaches, palpitations, nausea, and abdominal pain. Inadequate sleep habits and psychological conditions can contribute to fatigue, as can concurrent medical conditions. One type of autonomic dysfunction, postural orthostatic tachycardia syndrome, is increasingly being identified in adolescents with its constellation of fatigue, orthostatic intolerance, and excessive postural tachycardia (more than 40 beats/min). A family-based approach to care with support from a multidisciplinary team can diagnose, treat, educate, and encourage patients. Full recovery is possible with multi-faceted treatment. The daily treatment plan should consist of increased fluid and salt intake, aerobic exercise, and regular sleep and meal schedules; some medications can be helpful. Psychological support is critical and often includes biobehavioral strategies and cognitive–behavioral therapy to help with symptom management. More intensive recovery plans can be implemented when necessary. PMID:24819031

Exercising Impacts on Fatigue, Depression, and Paresthesia in Female Patients with Multiple Sclerosis.

PubMed

Razazian, Nazanin; Yavari, Zeinab; Farnia, Vahid; Azizi, Akram; Kordavani, Laleh; Bahmani, Dena Sadeghi; Holsboer-Trachsler, Edith; Brand, Serge

2016-05-01

Multiple sclerosis (MS) is a chronic progressive autoimmune disease impacting both body and mind. Typically, patients with MS report fatigue, depression, and paresthesia. Standard treatment consists of immune modulatory medication, though there is growing evidence that exercising programs have a positive influence on fatigue and psychological symptoms such as depression. We tested the hypothesis that, in addition to the standard immune regulatory medication, either yoga or aquatic exercise can ameliorate both fatigue and depression, and we examined whether these interventions also influence paresthesia compared with a nonexercise control condition. Fifty-four women with MS (mean age: M = 33.94 yr, SD = 6.92) were randomly assigned to one of the following conditions: yoga, aquatic exercise, or nonexercise control. Their existing immune modulatory therapy remained unchanged. Participants completed questionnaires covering symptoms of fatigue, depression, and paresthesia, both at baseline and on completion of the study 8 wk later. Compared with the nonexercise control condition and over time, fatigue, depression, and paresthesia decreased significantly in the yoga and aquatic exercise groups. On study completion, the likelihood of reporting moderate to severe depression was 35-fold higher in the nonexercise control condition than in the intervention conditions (yoga and aquatic exercising values collapsed). The pattern of results suggests that for females with MS and treated with standard immune regulatory medication, exercise training programs such as yoga and aquatic exercising positively impact on core symptoms of MS, namely, fatigue, depression, and paresthesia. Exercise training programs should be considered in the future as possible complements to standard treatments.

Early Immune Function and Duration of Organ Dysfunction in Critically Ill Septic Children.

PubMed

Muszynski, Jennifer A; Nofziger, Ryan; Moore-Clingenpeel, Melissa; Greathouse, Kristin; Anglim, Larissa; Steele, Lisa; Hensley, Josey; Hanson-Huber, Lisa; Nateri, Jyotsna; Ramilo, Octavio; Hall, Mark W

2018-02-22

Late immune suppression is associated with nosocomial infection and mortality in septic adults and children. Relationships between early immune suppression and outcomes in septic children remain unclear. Prospective observational study to test the hypothesis that early innate and adaptive immune suppression are associated with longer duration of organ dysfunction in children with severe sepsis/septic shock. Methods, Measurements and Main Results: Children aged < 18 years meeting consensus criteria for severe sepsis or septic shock were sampled within 48 hours of sepsis onset. Healthy controls were sampled once. Innate immune function was quantified by whole blood ex vivo lipopolysaccharide-induced TNFα production capacity. Adaptive immune function was quantified by ex vivo phytohemagglutinin-induced IFNγ production capacity. 102 septic children and 35 healthy children were enrolled. Compared to healthy children, septic children demonstrated lower LPS-induced TNFα production (p < 0.0001) and lower PHA-induced IFNγ production (p<0.0001). Among septic children, early innate and adaptive immune suppression were associated with greater number of days with multiple organ dysfunction (MODS) and greater number of days with any organ dysfunction. On multivariable analyses, early innate immune suppression remained independently associated with increased MODS days [aRR 1.2 (1.03, 1.5)] and organ dysfunction days [aRR 1.2 (1.1, 1.3)]. Critically ill children with severe sepsis or septic shock demonstrate early innate and adaptive immune suppression. Early suppression of both innate and adaptive immunity are associated with longer duration of organ dysfunction and may be useful markers to guide investigations of immunomodulatory therapies in septic children.

Metabolic abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a mini-review.

PubMed

Tomas, Cara; Newton, Julia

2018-04-17

Chronic fatigue syndrome (CFS), commonly known as myalgic encephalomyelitis (ME), is a debilitating disease of unknown etiology. CFS/ME is a heterogeneous disease associated with a myriad of symptoms but with severe, prolonged fatigue as the core symptom associated with the disease. There are currently no known biomarkers for the disease, largely due to the lack of knowledge surrounding the eitopathogenesis of CFS/ME. Numerous studies have been conducted in an attempt to identify potential biomarkers for the disease. This mini-review offers a brief summary of current research into the identification of metabolic abnormalities in CFS/ME which may represent potential biomarkers for the disease. The progress of research into key areas including immune dysregulation, mitochondrial dysfunction, 5'-adenosine monophosphate-activated protein kinase activation, skeletal muscle cell acidosis, and metabolomics are presented here. Studies outlined in this mini-review show many potential causes for the pathogenesis of CFS/ME and identify many potential metabolic biomarkers for the disease from the aforementioned research areas. The future of CFS/ME research should focus on building on the potential biomarkers for the disease using multi-disciplinary techniques at multiple research sites in order to produce robust data sets. Whether the metabolic changes identified in this mini-review occur as a cause or a consequence of the disease must also be established. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Stress management skills, neuroimmune processes and fatigue levels in persons with chronic fatigue syndrome

PubMed Central

Lattie, Emily G.; Antoni, Michael H.; Fletcher, Mary Ann; Penedo, Frank; Czaja, Sara; Lopez, Corina; Perdomo, Dolores; Sala, Andreina; Nair, Sankaran; Fu, Shih Hua; Klimas, Nancy

2012-01-01

Objectives Stressors and emotional distress responses impact chronic fatigue syndrome (CFS) symptoms, including fatigue. Having better stress management skills might mitigate fatigue by decreasing emotional distress. Because CFS patients comprise a heterogeneous population, we hypothesized that the role of stress management skills in decreasing fatigue may be most pronounced in the subgroup manifesting the greatest neuroimmune dysfunction. Methods In total, 117 individuals with CFS provided blood and saliva samples, and self-report measures of emotional distress, perceived stress management skills (PSMS), and fatigue. Plasma interleukin-1-beta (IL-1β, IL-2, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α), and diurnal salivary cortisol were analyzed. We examined relations among PSMS, emotional distress, and fatigue in CFS patients who did and did not evidence neuroimmune abnormalities. Results Having greater PSMS related to less fatigue (p = .019) and emotional distress (p < .001), greater diurnal cortisol slope (p = .023) and lower IL-2 levels (p = .043). PSMS and emotional distress related to fatigue levels most strongly in CFS patients in the top tercile of IL-6, and emotional distress mediated the relationship between PSMS and fatigue most strongly in patients with the greatest circulating levels of IL-6 and a greater inflammatory (IL-6):anti-inflammatory (IL-10) cytokine ratio. Discussion CFS patients having greater PSMS show less emotional distress and fatigue, and the influence of stress management skills on distress and fatigue appear greatest among patients who have elevated IL-6 levels. These findings support the need for research examining the impact of stress management interventions in subgroups of CFS patients showing neuroimmune dysfunction. PMID:22417946

Stress management skills, neuroimmune processes and fatigue levels in persons with chronic fatigue syndrome.

PubMed

Lattie, Emily G; Antoni, Michael H; Fletcher, Mary Ann; Penedo, Frank; Czaja, Sara; Lopez, Corina; Perdomo, Dolores; Sala, Andreina; Nair, Sankaran; Fu, Shih Hua; Klimas, Nancy

2012-08-01

Stressors and emotional distress responses impact chronic fatigue syndrome (CFS) symptoms, including fatigue. Having better stress management skills might mitigate fatigue by decreasing emotional distress. Because CFS patients comprise a heterogeneous population, we hypothesized that the role of stress management skills in decreasing fatigue may be most pronounced in the subgroup manifesting the greatest neuroimmune dysfunction. In total, 117 individuals with CFS provided blood and saliva samples, and self-report measures of emotional distress, perceived stress management skills (PSMS), and fatigue. Plasma interleukin-1-beta (IL-1β, IL-2, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α), and diurnal salivary cortisol were analyzed. We examined relations among PSMS, emotional distress, and fatigue in CFS patients who did and did not evidence neuroimmune abnormalities. Having greater PSMS related to less fatigue (p=.019) and emotional distress (p<.001), greater diurnal cortisol slope (p=.023) and lower IL-2 levels (p=.043). PSMS and emotional distress related to fatigue levels most strongly in CFS patients in the top tercile of IL-6, and emotional distress mediated the relationship between PSMS and fatigue most strongly in patients with the greatest circulating levels of IL-6 and a greater inflammatory (IL-6):anti-inflammatory (IL-10) cytokine ratio. CFS patients having greater PSMS show less emotional distress and fatigue, and the influence of stress management skills on distress and fatigue appear greatest among patients who have elevated IL-6 levels. These findings support the need for research examining the impact of stress management interventions in subgroups of CFS patients showing neuroimmune dysfunction. Copyright © 2012 Elsevier Inc. All rights reserved.

Psychological profiles in patients with Sjögren's syndrome related to fatigue: a cluster analysis.

PubMed

van Leeuwen, Ninke; Bossema, Ercolie R; Knoop, Hans; Kruize, Aike A; Bootsma, Hendrika; Bijlsma, Johannes W J; Geenen, Rinie

2015-05-01

Fatigue is a highly prevalent and debilitating symptom in the autoimmune disease SS. Although the disease process plays a role in fatigue, psychological factors may influence fatigue and the ability to deal with its consequences. Profiles of co-occurring psychological factors may suggest potential targets for the treatment of fatigue. The aim of this study was to identify psychological profiles in patients with SS and the accompanying levels of fatigue. Three hundred patients with primary SS (mean age 57 years, 93% female) completed questionnaires on fatigue (multidimensional fatigue inventory), physical activity cognitions (TAMPA-SK), illness cognitions, cognitive regulation, emotion processing and regulation [Toronto Alexithymia Scale 20, Emotion Regulation Questionnaire (ERQ), Berkeley Expressivity Questionnaire], coping strategies (Brief COPE) and social support. Principal axis factor analysis (oblimin rotation) yielded six psychological factors: social support, negative thinking, positive thinking, emotional expressivity, avoidance and alexithymia (i.e. the inability to differentiate emotions). Using cluster analyses, these factors were grouped in four psychological profiles: functional (39%), alexithymic (27%), self-reliant (23%) and dysfunctional (11%). Irrespective of the psychological profile, the level of fatigue was substantially higher in patients than in the general population. Patients with a dysfunctional or an alexithymic profile reported more fatigue than those with a self-reliant profile. Our study in SS yielded four psychological profiles that were differentially associated with fatigue. These profiles can be used to examine determinants and prognosis of fatigue as well as the possibility of customizing cognitive behavioural interventions for chronic fatigue. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The status of and future research into Myalgic Encephalomyelitis and Chronic Fatigue Syndrome: the need of accurate diagnosis, objective assessment, and acknowledging biological and clinical subgroups

PubMed Central

Twisk, Frank N. M.

2014-01-01

Although Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS) are used interchangeably, the diagnostic criteria define two distinct clinical entities. Cognitive impairment, (muscle) weakness, circulatory disturbances, marked variability of symptoms, and, above all, post-exertional malaise: a long-lasting increase of symptoms after a minor exertion, are distinctive symptoms of ME. This latter phenomenon separates ME, a neuro-immune illness, from chronic fatigue (syndrome), other disorders and deconditioning. The introduction of the label, but more importantly the diagnostic criteria for CFS have generated much confusion, mostly because chronic fatigue is a subjective and ambiguous notion. CFS was redefined in 1994 into unexplained (persistent or relapsing) chronic fatigue, accompanied by at least four out of eight symptoms, e.g., headaches and unrefreshing sleep. Most of the research into ME and/or CFS in the last decades was based upon the multivalent CFS criteria, which define a heterogeneous patient group. Due to the fact that fatigue and other symptoms are non-discriminative, subjective experiences, research has been hampered. Various authors have questioned the physiological nature of the symptoms and qualified ME/CFS as somatization. However, various typical symptoms can be assessed objectively using standardized methods. Despite subjective and unclear criteria and measures, research has observed specific abnormalities in ME/CFS repetitively, e.g., immunological abnormalities, oxidative and nitrosative stress, neurological anomalies, circulatory deficits and mitochondrial dysfunction. However, to improve future research standards and patient care, it is crucial that patients with post-exertional malaise (ME) and patients without this odd phenomenon are acknowledged as separate clinical entities that the diagnosis of ME and CFS in research and clinical practice is based upon accurate criteria and an objective assessment of characteristic symptoms, as much as possible that well-defined clinical and biological subgroups of ME and CFS patients are investigated in more detail, and that patients are monitored before, during and after interventions with objective measures and biomarkers. PMID:24734022

Immune Dysfunction in Cirrhosis

PubMed Central

Noor, Mohd Talha; Manoria, Piyush

2017-01-01

Abstract Cirrhosis due to any etiology disrupts the homeostatic role of liver in the body. Cirrhosis-associated immune dysfunction leads to alterations in both innate and acquired immunity, due to defects in the local immunity of liver as well as in systemic immunity. Cirrhosis-associated immune dysfunction is a dynamic phenomenon, comprised of both increased systemic inflammation and immunodeficiency, and is responsible for 30% mortality. It also plays an important role in acute as well as chronic decompensation. Immune paralysis can accompany it, which is characterized by increase in anti-inflammatory cytokines and suppression of proinflammatory cytokines. There is also presence of increased gut permeability, reduced gut motility and altered gut flora, all of which leads to increased bacterial translocation. This increased bacterial translocation and consequent endotoxemia leads to increased blood stream bacterial infections that cause systemic inflammatory response syndrome, sepsis, multiorgan failure and death. The gut microbiota of cirrhotic patients has more pathogenic microbes than that of non-cirrhotic individuals, and this disturbs the homeostasis and favors gut translocation. Prompt diagnosis and treatment of such infections are necessary for better survival. We have reviewed the various mechanisms of immune dysfunction and its consequences in cirrhosis. Recognizing the exact pathophysiology of immune dysfunction will help treating clinicians in avoiding its complications in their patients and can lead to newer therapeutic interventions and reducing the morbidity and mortality rates. PMID:28507927

Development and validation of immune dysfunction score to predict 28-day mortality of sepsis patients

PubMed Central

Fang, Wen-Feng; Douglas, Ivor S.; Chen, Yu-Mu; Lin, Chiung-Yu; Kao, Hsu-Ching; Fang, Ying-Tang; Huang, Chi-Han; Chang, Ya-Ting; Huang, Kuo-Tung; Wang, Yi-His; Wang, Chin-Chou

2017-01-01

Background Sepsis-induced immune dysfunction ranging from cytokines storm to immunoparalysis impacts outcomes. Monitoring immune dysfunction enables better risk stratification and mortality prediction and is mandatory before widely application of immunoadjuvant therapies. We aimed to develop and validate a scoring system according to patients’ immune dysfunction status for 28-day mortality prediction. Methods A prospective observational study from a cohort of adult sepsis patients admitted to ICU between August 2013 and June 2016 at Kaohsiung Chang Gung Memorial Hospital in Taiwan. We evaluated immune dysfunction status through measurement of baseline plasma Cytokine levels, Monocyte human leukocyte-DR expression by flow cytometry, and stimulated immune response using post LPS stimulated cytokine elevation ratio. An immune dysfunction score was created for 28-day mortality prediction and was validated. Results A total of 151 patients were enrolled. Data of the first consecutive 106 septic patients comprised the training cohort, and of other 45 patients comprised the validation cohort. Among the 106 patients, 21 died and 85 were still alive on day 28 after ICU admission. (mortality rate, 19.8%). Independent predictive factors revealed via multivariate logistic regression analysis included segmented neutrophil-to-monocyte ratio, granulocyte-colony stimulating factor, interleukin-10, and monocyte human leukocyte antigen-antigen D–related levels, all of which were selected to construct the score, which predicted 28-day mortality with area under the curve of 0.853 and 0.789 in the training and validation cohorts, respectively. Conclusions The immune dysfunction scoring system developed here included plasma granulocyte-colony stimulating factor level, interleukin-10 level, serum segmented neutrophil-to-monocyte ratio, and monocyte human leukocyte antigen-antigen D–related expression appears valid and reproducible for predicting 28-day mortality. PMID:29073262

Effects of fatigue on immune function in nurses performing shift work.

PubMed

Nagai, Makie; Morikawa, Yuko; Kitaoka, Kazuyo; Nakamura, Koshi; Sakurai, Masaru; Nishijo, Muneko; Hamazaki, Yuko; Maruzeni, Shoko; Nakagawa, Hideaki

2011-01-01

We investigated the effects of fatigue on NK cell function and lymphocyte subpopulations in nurses performing shift work using a longitudinal design. Fifty-seven female nurses engaged in shift work at a hospital in Japan were selected for our study cohort. The hospital used a counterclockwise rotating three-shift system. Night shifts followed day shifts after a seven-hour interval. Immune parameters measured at the beginning of the day shift through to the end of the night shift were compared between two groups stratified by their level of fatigue. Statistical differences were evaluated after adjusting for baseline immune values and other demographic features. Subjective feelings of fatigue increased progressively from the beginning of day shifts to the end of night shifts. From the beginning of day shifts to the end of night shifts, NK cell activity and CD16(+)CD56(+) lymphocytes decreased, while CD3(+) and CD4(+) lymphocytes increased. The group with the greater increase in fatigue showed a larger decrease in NK cell activity and a larger increase in CD4(+)lymphocytes when compared with the group reporting less fatigue. These findings did not change after adjusting for demographic factors and sleep hours. Our data suggest that shift work has deleterious effects on NK cell function and that the effects depend on the degree of fatigue. Proper management of shift work may lessen fatigue in workers and also ameliorate many health problems experienced by shift workers.

Perinatal stress, fatigue, depressive symptoms, and immune modulation in late pregnancy and one month postpartum.

PubMed

Cheng, C Y; Pickler, R H

2014-01-01

Stress and fatigue are common complaints of pregnant and postpartum women as is depression. These symptoms may be related to immunomodulation. However, few studies have examined these relationships. The aim of this study was to examine the relationships among stress, fatigue, depression, and cytokines as markers of immune modulation in prenatal and postpartum women. Women completed questionnaires and gave blood samples during late pregnancy and again at 4-6 weeks postpartum. Blood was analyzed for cytokines as measures of immune modulation. Stress, fatigue, and depression were experienced at moderately high levels, with higher levels of fatigue and depression in the postpartum but higher stress in the prenatal period. Levels of several cytokines were increased in the postpartum over the prenatal period. Stress and depression were related in the prenatal period and stress, depression, and fatigue were related in the postpartum. While various cytokines were related to each other in both periods, only stress was related to MIP-1β, a cytokine that may be important for childbirth processes. More studies, especially longitudinal and interventional studies, are needed to increase our knowledge about etiology, patterns, symptoms, factors, and management of maternal distress. The search for reliable biomarkers for at-risk mothers remains a priority.

Increased autoimmune activity against 5-HT: a key component of depression that is associated with inflammation and activation of cell-mediated immunity, and with severity and staging of depression.

PubMed

Maes, Michael; Ringel, Karl; Kubera, Marta; Berk, Michael; Rybakowski, Janusz

2012-02-01

Depression is characterized by inflammation and cell-mediated immune (CMI) activation and autoimmune reactions directed against a multitude of self-epitopes. There is evidence that the inflammatory response in depression causes dysfunctions in the metabolism of 5-HT, e.g. lowering the 5-HT precursor tryptophan, and upregulating 5-HT receptor mRNA. This study has been undertaken to examine autoimmune activity directed against 5-HT in relation to CMI activation and inflammation. 5-HT antibodies were examined in major depressed patients (n=109) versus normal controls (n=35) in relation to serum neopterin and lysozyme, and plasma pro-inflammatory cytokines (PIC), i.e. interleukin-1 (IL-1) and tumor necrosis factor-α (TNFα). Severity of depression was assessed with the Hamilton Depression Rating Scale (HDRS) and severity of fatigue and somatic symptoms with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale. The incidence of anti-5-HT antibody activity was significantly higher in depressed patients (54.1%), and in particular in those with melancholia (82.9%), than in controls (5.7%). Patients with positive 5-HT antibodies showed increased serum neopterin and lysozyme, and plasma TNFα and IL-1; higher scores on the HDRS and FF scales, and more somatic symptoms, including malaise and neurocognitive dysfunctions. There was a significant association between autoimmune activity to 5-HT and the number of previous depressive episodes. The autoimmune reactions directed against 5-HT might play a role in the pathophysiology of depression and the onset of severe depression. The strong association between autoimmune activity against 5-HT and inflammation/CMI activation is explained by multiple, reciprocal pathways between these factors. Exposure to previous depressive episodes increases the incidence of autoimmune activity directed against 5-HT, which in turn may increase the likelihood to develop new depressive episodes. These findings suggest that sensitization (kindling) and staging of depression are in part based on progressive autoimmune responses. Copyright © 2011 Elsevier B.V. All rights reserved.

Fatigue in older adults with stable heart failure.

PubMed

Stephen, Sharon A

2008-01-01

The purpose of this study was to describe fatigue and the relationships among fatigue intensity, self-reported functional status, and quality of life in older adults with stable heart failure. A descriptive, correlational design was used to collect quantitative data with reliable and valid instruments. Fifty-three eligible volunteers completed a questionnaire during an interview. Those with recent changes in their medical regimen, other fatigue-inducing illnesses, and isolated diastolic dysfunction were excluded. Fatigue intensity (Profile of Mood States fatigue subscale) was associated with lower quality of life, perceived health, and satisfaction with life. Fatigue was common, and no relationship was found between fatigue intensity and self-reported functional status. Marital status was the only independent predictor of fatigue. In stable heart failure, fatigue is a persistent symptom. Clinicians need to ask patients about fatigue and assess the impact on quality of life. Self-reported functional status cannot serve as a proxy measure for fatigue.

Detection of Urine Metabolites in a Rat Model of Chronic Fatigue Syndrome before and after Exercise

PubMed Central

Shao, Changzhuan; Ren, Yiming; Wang, Zinan; Kang, Chenzhe

2017-01-01

Purpose. The aim of the present study was to elucidate the metabolic mechanisms associated with chronic fatigue syndrome (CFS) via an analysis of urine metabolites prior to and following exercise in a rat model. Methods. A rat model of CFS was established using restraint-stress, forced exercise, and crowded and noisy environments over a period of 4 weeks. Behavioral experiments were conducted in order to evaluate the model. Urine metabolites were analyzed via gas chromatography-mass spectrometry (GC-MS) in combination with multivariate statistical analysis before and after exercise. Results. A total of 20 metabolites were detected in CFS rats before and after exercise. Three metabolic pathways (TCA cycle; alanine, aspartate, and glutamate metabolism; steroid hormone biosynthesis) were significantly impacted before and after exercise, while sphingolipid metabolism alone exhibited significant alterations after exercise only. Conclusion. In addition to metabolic disturbances involving some energy substances, alterations in steroid hormone biosynthesis and sphingolipid metabolism were detected in CFS rats. Sphingosine and 21-hydroxypregnenolone may be key biomarkers of CFS, potentially offering evidence in support of immune dysfunction and hypothalamic-pituitary-adrenal (HPA) axis hypoactivity in patients with CFS. PMID:28421200

Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease.

PubMed

Underhill, R A

2015-12-01

The etiology of myalgic encephalomyelitis also known as chronic fatigue syndrome or ME/CFS has not been established. Controversies exist over whether it is an organic disease or a psychological disorder and even the existence of ME/CFS as a disease entity is sometimes denied. Suggested causal hypotheses have included psychosomatic disorders, infectious agents, immune dysfunctions, autoimmunity, metabolic disturbances, toxins and inherited genetic factors. Clinical, immunological and epidemiological evidence supports the hypothesis that: ME/CFS is an infectious disease; the causal pathogen persists in patients; the pathogen can be transmitted by casual contact; host factors determine susceptibility to the illness; and there is a population of healthy carriers, who may be able to shed the pathogen. ME/CFS is endemic globally as sporadic cases and occasional cluster outbreaks (epidemics). Cluster outbreaks imply an infectious agent. An abrupt flu-like onset resembling an infectious illness occurs in outbreak patients and many sporadic patients. Immune responses in sporadic patients resemble immune responses in other infectious diseases. Contagion is shown by finding secondary cases in outbreaks, and suggested by a higher prevalence of ME/CFS in sporadic patients' genetically unrelated close contacts (spouses/partners) than the community. Abortive cases, sub-clinical cases, and carrier state individuals were found in outbreaks. The chronic phase of ME/CFS does not appear to be particularly infective. Some healthy patient-contacts show immune responses similar to patients' immune responses, suggesting exposure to the same antigen (a pathogen). The chronicity of symptoms and of immune system changes and the occurrence of secondary cases suggest persistence of a causal pathogen. Risk factors which predispose to developing ME/CFS are: a close family member with ME/CFS; inherited genetic factors; female gender; age; rest/activity; previous exposure to stress or toxins; various infectious diseases preceding the onset of ME/CFS; and occupational exposure of health care professionals. The hypothesis implies that ME/CFS patients should not donate blood or tissue and usual precautions should be taken when handling patients' blood and tissue. No known pathogen has been shown to cause ME/CFS. Confirmation of the hypothesis requires identification of a causal pathogen. Research should focus on a search for unknown and known pathogens. Finding a causal pathogen could assist with diagnosis; help find a biomarker; enable the development of anti-microbial treatments; suggest preventive measures; explain pathophysiological findings; and reassure patients about the validity of their symptoms.

[Effects of aroma self-foot reflexology massage on stress and immune responses and fatigue in middle-aged women in rural areas].

PubMed

Kim, Ja Ok; Kim, In Sook

2012-10-01

This study was done to examine the effects of aroma self-foot reflexology massage on stress and immune responses and fatigue in middle-aged women in rural areas. The study was a nonequivalent control group pre-post test design. The participants were 52 middle-aged women from rural areas of which 26 were assigned to the experimental group and 26 to the control group. Data were collected from July to September, 2011 and analyzed using SPSS Win 17.0 version program. The intervention was conducted 3 times a week for six weeks. There were significant differences in reported perceived stress, systolic blood pressure, diastolic blood pressure and fatigue between the two groups. However, the issue of salivary cortisol and immune response were not significant. Aroma self-foot reflexology massage can be utilized as an effective intervention for perceived stress, systolic blood pressure, diastolic blood pressure and fatigue in middle-aged woman in rural areas.

Nursing Fatigue: An Evidence-Based Practice Review for Oncology Nurses
.

PubMed

Ferris, Jordan

2015-12-01

Nursing fatigue is a current and well-researched topic. Many negative outcomes and consequences exist for patients and nurses that have been linked to nursing fatigue. Medical errors are one such consequence, and these errors have become one of the top three preventable deaths in the United States. Oncology nurses are not immune to fatigue, and the consequences of their fatigue can be much more harmful to patients.

Immune dysfunction prior to Staphylococcus aureus bacteremia is a determinant of long-term mortality.

PubMed

Greenberg, Jared A; David, Michael Z; Hall, Jesse B; Kress, John P

2014-01-01

The clinical implications for patients who survive serious infections are not well understood. It has been hypothesized that the excess mortality for survivors of sepsis observed in epidemiological studies is due to increased vulnerability to subsequent infections. We undertook this study to identify characteristics of patients who are at high risk for death after surviving a common type of blood-stream infection. At a single academic medical center, 237 patients with Staphylococcus aureus bacteremia admitted during a three-year period were retrospectively identified. The primary outcomes were 30-day and 31 to 90-day mortality after the first positive blood culture. The primary predictor variable of interest was clinical immune dysfunction prior to bacteremia. The 30-day mortality was not significantly different for patients with and without prior immune dysfunction. However, during days 31 to 90, 11 patients (20%) with prior immune dysfunction compared to 10 patients (8.6%) without prior immune dysfunction died (OR 2.59, 95% CI 1.03-6.53, p = 0.04). In a Cox-proportional hazard model controlling for age, there was a significant association between prior immune dysfunction and greater 31 to 90 day mortality (HR 2.44, 95% CI 1.01-5.90, p = 0.05) and a non-significant trend towards occurrence of subsequent infections and greater 31 to 90 day mortality (HR 2.12, 95% CI 0.89-5.07, p = 0.09). Patients with prior immune dysfunction are at high risk for death 31 to 90 days, but not <30 days, after S. aureus bacteremia. Further investigation is needed to determine if this finding is due to poor prognosis of chronic disease or increased vulnerability to subsequent infections.

Health Status and Performance of United States Air Force Airmen Following Mild Traumatic Brain Injury

DTIC Science & Technology

2010-09-01

adrenal insufficiency, hypopituitarism, hypothyroidism , growth- hormone deficiency and posterior pituitary dysfunction [53, 54, 56-60]. Growth...central hypothyroidism which can result in fatigue, apathy, decreased strength and cognitive dysfunction, symptoms commonly observed in PTSD [54

Increasing quality of life in pulmonary arterial hypertension: is there a role for nutrition?

PubMed

Vinke, Paulien; Jansen, Suzanne M; Witkamp, Renger F; van Norren, Klaske

2018-06-16

Pulmonary arterial hypertension (PAH) is a progressive disease primarily affecting the pulmonary vasculature and heart. PAH patients suffer from exercise intolerance and fatigue, negatively affecting their quality of life. This review summarizes current insights in the pathophysiological mechanisms underlying PAH. It zooms in on the potential involvement of nutritional status and micronutrient deficiencies on PAH exercise intolerance and fatigue, also summarizing the potential benefits of exercise and nutritional interventions. Pubmed/Medline, Scopus, and Web of Science were searched for publications on pathophysiological mechanisms of PAH negatively affecting physical activity potential and nutritional status, and for potential effects of interventions involving exercise or nutritional measures known to improve exercise intolerance. Pathophysiological processes that contribute to exercise intolerance and impaired quality of life of PAH patients include right ventricular dysfunction, inflammation, skeletal muscle alterations, and dysfunctional energy metabolism. PAH-related nutritional deficiencies and metabolic alterations have been linked to fatigue, exercise intolerance, and endothelial dysfunction. Available evidence suggests that exercise interventions can be effective in PAH patients to improve exercise tolerance and decrease fatigue. By contrast, knowledge on the prevalence of micronutrient deficiencies and the possible effects of nutritional interventions in PAH patients is limited. Although data on nutritional status and micronutrient deficiencies in PAH are scarce, the available knowledge, including that from adjacent fields, suggests that nutritional intervention to correct deficiencies and metabolic alterations may contribute to a reduction of disease burden.

Divergent Annexin A1 expression in periphery and gut is associated with systemic immune activation and impaired gut immune response during SIV infection

PubMed Central

Sena, Angela A. S.; Glavan, Tiffany; Jiang, Guochun; Sankaran-Walters, Sumathi; Grishina, Irina; Dandekar, Satya; Goulart, Luiz R.

2016-01-01

HIV-1 disease progression is paradoxically characterized by systemic chronic immune activation and gut mucosal immune dysfunction, which is not fully defined. Annexin A1 (ANXA1), an inflammation modulator, is a potential link between systemic inflammation and gut immune dysfunction during the simian immunodeficiency virus (SIV) infection. Gene expression of ANXA1 and cytokines were assessed in therapy-naïve rhesus macaques during early and chronic stages of SIV infection and compared with SIV-negative controls. ANXA1 expression was suppressed in the gut but systemically increased during early infection. Conversely, ANXA1 expression increased in both compartments during chronic infection. ANXA1 expression in peripheral blood was positively correlated with HLA-DR+CD4+ and CD8+ T-cell frequencies, and negatively associated with the expression of pro-inflammatory cytokines and CCR5. In contrast, the gut mucosa presented an anergic cytokine profile in relation to ANXA1 expression. In vitro stimulations with ANXA1 peptide resulted in decreased inflammatory response in PBMC but increased activation of gut lymphocytes. Our findings suggest that ANXA1 signaling is dysfunctional in SIV infection, and may contribute to chronic inflammation in periphery and with immune dysfunction in the gut mucosa. Thus, ANXA1 signaling may be a novel therapeutic target for the resolution of immune dysfunction in HIV infection. PMID:27484833

Does stress affect the joints? Daily stressors, stress vulnerability, immune and HPA axis activity, and short-term disease and symptom fluctuations in rheumatoid arthritis.

PubMed

Evers, Andrea W M; Verhoeven, Elisabeth W M; van Middendorp, Henriët; Sweep, Fred C G J; Kraaimaat, Floris W; Donders, A Rogier T; Eijsbouts, Agnes E; van Laarhoven, Antoinette I M; de Brouwer, Sabine J M; Wirken, Lieke; Radstake, Timothy R D J; van Riel, Piet L C M

2014-09-01

Both stressors and stress vulnerability factors together with immune and hypothalamus-pituitary-adrenal (HPA) axis activity components have been considered to contribute to disease fluctuations of chronic inflammatory diseases, such as rheumatoid arthritis (RA). The aim of the present study was to investigate whether daily stressors and worrying as stress vulnerability factor as well as immune and HPA axis activity markers predict short-term disease activity and symptom fluctuations in patients with RA. In a prospective design, daily stressors, worrying, HPA axis (cortisol) and immune system (interleukin (IL)-1β, IL-6, IL-8, interferon (IFN)-γ, tumour necrosis factor α) markers, clinical and self-reported disease activity (disease activity score in 28 joints, RA disease activity index), and physical symptoms of pain and fatigue were monitored monthly during 6 months in 80 RA patients. Multilevel modelling indicated that daily stressors predicted increased fatigue in the next month and that worrying predicted increased self-reported disease activity, swollen joint count and pain in the next month. In addition, specific cytokines of IL-1β and IFN-γ predicted increased fatigue 1 month later. Overall, relationships remained relatively unchanged after controlling for medication use, disease duration and demographic variables. No evidence was found for immune and HPA axis activity markers as mediators of the stress-disease relationship. Daily stressors and the stress-vulnerability factor worrying predict indicators of the short-term course of RA disease activity and fatigue and pain, while specific cytokines predict short-term fluctuations of fatigue. These stress-related variables and immune markers seem to affect different aspects of disease activity or symptom fluctuations independently in RA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Increased nuclear factor-κB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS).

PubMed

Morris, Gerwyn; Maes, Michael

2012-11-01

Fukuda's criteria are adequate to make a distinction between Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) and chronic fatigue (CF), but ME/CFS patients should be subdivided into those with (termed ME) and without (termed CFS) post exertional malaise [Maes et al. 2012]. ME/CFS is considered to be a neuro-immune disease. ME/CFS is characterized by activated immuno-inflammatory pathways, including increased levels of pro-inflammatory cytokines, nuclear factor κB (NF-κB) and aberrations in mitochondrial functions, including lowered ATP. These processes may explain typical symptoms of ME/CFS, e.g. fatigue, malaise, hyperalgesia, and neurologic and autonomic symptoms. Here we hypothesize that increased NF-κB together with a loss of p53 are key phenomena in ME/CFS that further explain ME/CFS symptoms, such as fatigue and neurocognitive dysfunction, and explain ME symptoms, such as post-exertional malaise following mental and physical activities. Inactivation of p53 impairs aerobic mitochondrial functions and causes greater dependence on anaerobic glycolysis, elevates lactate levels, reduces mitochondrial density in skeletal muscle and reduces endurance during physical exercise. Lowered p53 and increased NF-κB are associated with elevated reactive oxygen species. Increased NF-κB induces the production of pro-inflammatory cytokines, which increase glycolysis and further compromise mitochondrial functions. All these factors together may contribute to mitochondrial exhaustion and indicate that the demand for extra ATP upon the commencement of increased activity cannot be met. In conditions of chronic inflammation and oxidative stress, high NF-κB and low p53 may conspire to promote neuron and glial cell survival at a price of severely compromised metabolic brain function. Future research should examine p53 signaling in ME/CFS. Copyright © 2012. Published by Elsevier Ltd.

Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis.

PubMed

Brenu, Ekua Weba; Huth, Teilah K; Hardcastle, Sharni L; Fuller, Kirsty; Kaur, Manprit; Johnston, Samantha; Ramos, Sandra B; Staines, Don R; Marshall-Gradisnik, Sonya M

2014-04-01

Perturbations in immune processes are a hallmark of a number of autoimmune and inflammatory disorders. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is an inflammatory disorder with possible autoimmune correlates, characterized by reduced NK cell activity, elevations in regulatory T cells (Tregs) and dysregulation in cytokine levels. The purpose of this article is to examine innate and adaptive immune cell phenotypes and functional characteristics that have not been previously examined in CFS/ME patients. Thirty patients with CFS/ME and 25 non-fatigued controls were recruited for this study. Whole blood samples were collected from all participants for the assessment of cell phenotypes, functional properties, receptors, adhesion molecules, antigens and intracellular proteins using flow cytometric protocols. The cells investigated included NK cells, dendritic cells, neutrophils, B cells, T cells, γδT cells and Tregs. Significant changes were observed in B-cell subsets, Tregs, CD4(+)CD73(+)CD39(+) T cells, cytotoxic activity, granzyme B, neutrophil antigens, TNF-α and IFN-γ in the CFS/ME patients in comparison with the non-fatigued controls. Alterations in B cells, Tregs, NK cells and neutrophils suggest significant impairments in immune regulation in CFS/ME and these may have similarities to a number of autoimmune disorders.

[Effects of self-foot reflexology on stress, fatigue, skin temperature and immune response in female undergraduate students].

PubMed

Lee, Young-Mee

2011-02-01

The purpose of this study was to evaluate the effects of self-foot reflexology on stress (perceived stress, urine cortisol level, and serum cortisol level), fatigue, skin temperature and immune response in female undergraduate students. The research design was a nonequivalent control group pretest-post test design. Participants were 60 university students: 30 in the experiment group and 30 in the control group. The period of this study was from April to June 2010. The program was performed for 1 hr a session, three times a week for 6 weeks. The data were analyzed using the SPSS/WIN 17.0 program. The results showed that self-foot reflexology was effective in reducing perceived stress and fatigue, and raised skin temperature in female undergraduate students. But cortisol levels and immune response were not statistically significant different. The results of this study indicate that self-foot reflexology is an effective nursing intervention in reducing perceived stress and fatigue and, in improving skin temperature. Therefore, it is recommended that this be used in clinical practice as an effective nursing intervention for in female undergraduate students.

Immune Dysfunction as a Cause and Consequence of Malnutrition.

PubMed

Bourke, Claire D; Berkley, James A; Prendergast, Andrew J

2016-06-01

Malnutrition, which encompasses under- and overnutrition, is responsible for an enormous morbidity and mortality burden globally. Malnutrition results from disordered nutrient assimilation but is also characterized by recurrent infections and chronic inflammation, implying an underlying immune defect. Defects emerge before birth via modifications in the immunoepigenome of malnourished parents, and these may contribute to intergenerational cycles of malnutrition. This review summarizes key recent studies from experimental animals, in vitro models, and human cohorts, and proposes that immune dysfunction is both a cause and a consequence of malnutrition. Focusing on childhood undernutrition, we highlight gaps in current understanding of immune dysfunction in malnutrition, with a view to therapeutically targeting immune pathways as a novel means to reduce morbidity and mortality. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome.

PubMed

Nagy-Szakal, Dorottya; Williams, Brent L; Mishra, Nischay; Che, Xiaoyu; Lee, Bohyun; Bateman, Lucinda; Klimas, Nancy G; Komaroff, Anthony L; Levine, Susan; Montoya, Jose G; Peterson, Daniel L; Ramanan, Devi; Jain, Komal; Eddy, Meredith L; Hornig, Mady; Lipkin, W Ian

2017-04-26

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling. Topological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS. Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways. Independent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups.

Neuroendocrine and immune network re-modeling in chronic fatigue syndrome: an exploratory analysis.

PubMed

Fuite, Jim; Vernon, Suzanne D; Broderick, Gordon

2008-12-01

This work investigates the significance of changes in association patterns linking indicators of neuroendocrine and immune activity in patients with chronic fatigue syndrome (CFS). Gene sets preferentially expressed in specific immune cell isolates were integrated with neuroendocrine data from a large population-based study. Co-expression patterns linking immune cell activity with hypothalamic-pituitary-adrenal (HPA), thyroidal (HPT) and gonadal (HPG) axis status were computed using mutual information criteria. Networks in control and CFS subjects were compared globally in terms of a weighted graph edit distance. Local re-modeling of node connectivity was quantified by node degree and eigenvector centrality measures. Results indicate statistically significant differences between CFS and control networks determined mainly by re-modeling around pituitary and thyroid nodes as well as an emergent immune sub-network. Findings align with known mechanisms of chronic inflammation and support possible immune-mediated loss of thyroid function in CFS exacerbated by blunted HPA axis responsiveness.

Post-traumatic hypopituitarism and fatigue.

PubMed

Masel, Brent E; Zgaljardic, Dennis J; Forman, Jack

2017-10-01

Post-traumatic hypopituitarism (PTH) associated with chronic cognitive, psychiatric, and/or behavioural sequelae is common following moderate to severe traumatic brain injury (TBI). More specifically, due to a cascade of hormonal deficiencies secondary to PTH, individuals with TBI may experience debilitating fatigue that can negatively impact functional recovery, as it can limit participation in brain injury rehabilitation services and lead to an increase in maladaptive lifestyle practices. While the mechanisms underlying fatigue and TBI are not entirely understood, the current review will address the specific anatomy and physiology of the pituitary gland, as well as the association between pituitary dysfunction and fatigue in individuals with TBI.

NLRP3 inflammasome activation mediates fatigue-like behaviors in mice via neuroinflammation.

PubMed

Zhang, Ziteng; Ma, Xiujuan; Xia, Zhenna; Chen, Jikuai; Liu, Yangang; Chen, Yongchun; Zhu, Jiangbo; Li, Jinfeng; Yu, Huaiyu; Zong, Ying; Lu, Guocai

2017-09-01

Numerous experimental and clinical studies have suggested that the interaction between the immune system and the brain plays an important role in the pathophysiology of chronic fatigue syndrome (CFS). The NLRP3 inflammasome is an important part of the innate immune system. This complex regulates proinflammatory cytokine interleukin-1β (IL-1β) maturation, which triggers different kinds of immune-inflammatory reactions. We employed repeated forced swims to establish a model of CFS in mice. NLRP3 knockout (KO) mice were also used to explore NLRP3 inflammasome activation in the mechanisms of CFS, using the same treatment. After completing repeated swim tests, the mice displayed fatigue-like behaviors, including locomotor activity and reduced fall-off time on the rota-rod test, which was accompanied by significantly higher mature IL-1β level in the prefrontal cortex (PFC) and malondialdehyde (MDA) level in serum. We also found increased NLRP3 protein expression, NLRP3 inflammasome formation and increased mature IL-1β production in the PFC, relative to untreated mice. The NLRP3 KO mice displayed significantly moderated fatigue behaviors along with decreased PFC and serum IL-1β levels under the same treatment. These findings demonstrated the involvement of NLRP3 inflammasome activation in the mechanism of swimming-induced fatigue. Future therapies targeting the NLRP3/IL-1β pathway may have significant potential for fatigue prevention and treatment. Copyright © 2017. Published by Elsevier Ltd.

Is there a cognitive signature for MS-related fatigue?

PubMed

Hanken, Katrin; Eling, Paul; Hildebrandt, Helmut

2015-04-01

The compensatory approach of fatigue argues that it is a state caused by task load. The neuropsychiatric approach argues that fatigue is a trait (like depression), unrelated to environmental challenges. We propose that fatigue is an internal state that can be measured behaviorally only by applying specific cognitive tasks. PubMed was searched for articles concerning the relation between fatigue and cognitive performance or brain atrophy or functional MRI, distinguishing between the following cognitive domains: learning/memory, cognitive speed/selective attention, language, visuospatial processing, working memory, alerting/vigilance. Only tasks assessing alerting/vigilance are strongly related to fatigue. Areas with brain atrophy in fatigue patients overlap with brain regions activated in healthy controls performing alerting/vigilance tasks. Fatigue is not a compensatory state, nor a psychogenic trait. It is a feeling with behavioral effects that seems to be caused by brain atrophy or a neurochemical dysfunction of the alerting/vigilance system. © The Author(s), 2014.

The potential of treating Gulf War Illness with curcumin.

PubMed

Leibowitz, Jeffrey A; Ormerod, Brandi K

2018-05-01

A large proportion of Gulf War Veterans suffer from Gulf War Illness (GWI) - a devastating chronic disorder characterized by heterogeneous fatigue, pain and neuropsychological symptoms. In their recent Brain, Behavior and Immunity publication entitled "Curcumin Treatment Leads to Better Cognitive and Mood Function in a Model of Gulf War Illness with Enhanced Neurogenesis, and Alleviation of Inflammation and Mitochondrial Dysfunction in the Hippocampus", Kodali and colleagues (2018) report that the polyphenol curcumin improves cognition and mood in a rat model of GWI, potentially by increasing the expression of antioxidant genes and by reversing the effects of chronic combined acetylcholinesterase inhibitor exposure on neuroinflammation, mitochondrial respiration and hippocampal neurogenesis. This preclinical work is encouraging for our veterans who suffer chronically from GWI as well as for developing strategies to protect our troops during future deployments in similar environments. Copyright © 2018 Elsevier Inc. All rights reserved.

Investigating unexplained fatigue in general practice with a particular focus on CFS/ME.

PubMed

Bansal, Amolak S

2016-07-19

Unexplained fatigue is not infrequent in the community. It presents a number of challenges to the primary care physician and particularly if the clinical examination and routine investigations are normal. However, while fatigue is a feature of many common illnesses, it is the main problem in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). This is a poorly understood condition that is accompanied by several additional symptoms which suggest a subtle multisystem dysfunction. Not infrequently it is complicated by sleep disturbance and alterations in attention, memory and mood.Specialised services for the diagnosis and management of CFS/ME are markedly deficient in the UK and indeed in virtually all countries around the world. However, unexplained fatigue and CFS/ME may be confidently diagnosed on the basis of specific clinical criteria combined with the normality of routine blood tests. The latter include those that assess inflammation, autoimmunity, endocrine dysfunction and gluten sensitivity. Early diagnosis and intervention in general practice will do much to reduce patient anxiety, encourage improvement and prevent expensive unnecessary investigations.There is presently an on-going debate as to the precise criteria that best confirms CFS/ME to the exclusion of other medical and psychiatric/psychological causes of chronic fatigue. There is also some disagreement as to best means of investigating and managing this very challenging condition. Uncertainty here can contribute to patient stress which in some individuals can perpetuate and aggravate symptoms. A simple clinical scoring system and a short list of routine investigations should help discriminate CFS/ME from other causes of continued fatigue.

Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the 'autoimmune (auto-inflammatory) syndrome induced by adjuvants' (ASIA).

PubMed

Agmon-Levin, Nancy; Zafrir, Yaron; Kivity, Shaye; Balofsky, Ari; Amital, Howard; Shoenfeld, Yehuda

2014-12-01

The objectives of this study were to gather information regarding demographic and clinical characteristics of patients diagnosed with either fibromyalgia (FM) or chronic fatigue (CFS) following hepatitis B vaccination (HBVv) and furthermore to apply the recently suggested criteria of autoimmune (auto-inflammatory) syndromes induced by adjuvants (ASIA), in the aim of identifying common characteristics that may suggest an association between fibromyalgia, chronic fatigue and HBV vaccination. Medical records of 19 patients with CFS and/or fibromyalgia following HBVv immunization were analyzed. All of which were immunized during 1990-2008 in different centers in the USA. All medical records were evaluated for demographics, medical history, the number of vaccine doses, as well as immediate and long term post-immunization adverse events and clinical manifestations. In addition, available blood tests, imaging results, treatments and outcomes were analyzed. ASIA criteria were applied to all patients. The mean age of patients was 28.6 ± 11 years, of which 68.4 % were females. 21.05 % had either personal or familial background of autoimmune disease. The mean latency period from the last dose of HBVv to onset of symptoms was 38.6 ± 79.4 days, ranging from days to a year. Eight (42.1 %) patients continued with the immunization program despite experiencing adverse events. Manifestations that were commonly reported included neurological manifestations (84.2 %), musculoskeletal (78.9 %), psychiatric (63.1 %), fatigue (63.1 %), gastrointestinal complains (58 %) and mucocutaneous manifestations (36.8 %). Autoantibodies were detected in 71 % of patients tested. All patients fulfilled the ASIA criteria. This study suggests that in some cases CFS and FM can be temporally related to immunization, as part of ASIA syndrome. The appearance of adverse event during immunization, the presence of autoimmune susceptibility and higher titers of autoantibodies all can be suggested as risk factors. ASIA criteria were fulfilled in all patients eluding the plausible link between ASIA and CFS/FM.

Safety behaviors and sleep effort predict sleep disturbance and fatigue in an outpatient sample with anxiety and depressive disorders.

PubMed

Fairholme, Christopher P; Manber, Rachel

2014-03-01

Theoretical and empirical support for the role of dysfunctional beliefs, safety behaviors, and increased sleep effort in the maintenance of insomnia has begun to accumulate. It is not yet known how these factors predict sleep disturbance and fatigue occurring in the context of anxiety and mood disorders. It was hypothesized that these three insomnia-specific cognitive-behavioral factors would be uniquely associated with insomnia and fatigue among patients with emotional disorders after adjusting for current symptoms of anxiety and depression and trait levels of neuroticism and extraversion. Outpatients with a current anxiety or mood disorder (N = 63) completed self-report measures including the Dysfunctional Beliefs About Sleep Scale (DBAS), Sleep-Related Safety Behaviors Questionnaire (SRBQ), Glasgow Sleep Effort Scale (GSES), Pittsburgh Sleep Quality Index (PSQI), NEO Five-Factor Inventory (FFI), and the 21-item Depression Anxiety and Stress Scale (DASS). Multivariate path analysis was used to evaluate study hypotheses. SRBQ (B = .60, p < .001, 95% CI [.34, .86]) and GSES (B = .31, p < .01, 95% CI [.07, .55]) were both significantly associated with PSQI. There was a significant interaction between SRBQ and DBAS (B = .25, p < .05, 95% CI [.04, .47]) such that the relationship between safety behaviors and fatigue was strongest among individuals with greater levels of dysfunctional beliefs. Findings are consistent with cognitive behavioral models of insomnia and suggest that sleep-specific factors might be important treatment targets among patients with anxiety and depressive disorders with disturbed sleep. Copyright © 2013 Elsevier Inc. All rights reserved.

'Exercise to me is a scary word': perceptions of fatigue, sleep dysfunction, and exercise in people with fibromyalgia syndrome-a focus group study.

PubMed

Russell, D; Álvarez Gallardo, I C; Wilson, I; Hughes, C M; Davison, G W; Sañudo, B; McVeigh, J G

2018-03-01

Fibromyalgia syndrome (FMS) is a common and complex chronic pain condition. Exercise is recommended in the management of the FMS; however, people with FMS often find exercise exacerbates their condition and causes overwhelming fatigue. The objective of this study was to explore the perceptions of fatigue and sleep dysfunction, and exercise in people with FMS. Three, 60-90 min focus groups were conducted with people with FMS (n = 14). Participants were recruited from patient support groups who had experienced therapeutic exercise in the management of their condition. Focus groups were video and audio recorded and transcriptions analysed for thematic content by three independent evaluators. Fatigue, sleep dysfunction, and pain were universally reported by participants. The over-arching theme to emerge was a lack of understanding of the condition by others. A huge sense of loss was a major sub-theme and participants felt that they had fundamentally changed since the onset of FMS. Participants reported that they were unable to carry out their normal activities, including physical activity and exercise. The invisibility of FMS was associated with the lack of understanding by others, the sense of loss, and the impact of FMS. People with FMS perceive that there is a lack of understanding of the condition among health care professionals and the wider society. Those with FMS expressed a profound sense of loss of their former 'self'; part of this loss was the ability to engage in normal physical activity and exercise.

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective.

PubMed

Harder, Jeffrey M; Braine, Catherine E; Williams, Pete A; Zhu, Xianjun; MacNicoll, Katharine H; Sousa, Gregory L; Buchanan, Rebecca A; Smith, Richard S; Libby, Richard T; Howell, Gareth R; John, Simon W M

2017-05-09

Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wld s allele, which protects from axon dysfunction. We demonstrate that DBA/2J .Wld s mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2J .Wld s mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/2J. Wld s mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma.

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

PubMed Central

Harder, Jeffrey M.; Braine, Catherine E.; Williams, Pete A.; Zhu, Xianjun; MacNicoll, Katharine H.; Sousa, Gregory L.; Buchanan, Rebecca A.; Smith, Richard S.; Howell, Gareth R.; John, Simon W. M.

2017-01-01

Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wlds allele, which protects from axon dysfunction. We demonstrate that DBA/2J.Wlds mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2J.Wlds mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/2J.Wlds mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma. PMID:28446616

Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome.

PubMed

Zhang, Zi-Teng; Du, Xiu-Ming; Ma, Xiu-Juan; Zong, Ying; Chen, Ji-Kuai; Yu, Chen-Lin; Liu, Yan-Gang; Chen, Yong-Chun; Zhao, Li-Jun; Lu, Guo-Cai

2016-04-05

The NLRP3 inflammasome (NOD-like receptor family, pyrin domain containing 3) is an intracellular protein complex that plays an important role in innate immune sensing. Its activation leads to the maturation of caspase-1 and regulates the cleavage of interleukin (IL)-1β and IL-18. Various studies have shown that activation of the immune system plays a pivotal role in the development of fatigue. However, the mechanisms underlying the association between immune activation and fatigue remained elusive, and few reports have described the involvement of NLRP3 inflammasome activation in fatigue. We established a mouse fatigue model with lipopolysaccharide (LPS, 3 mg/kg) challenge combined with swim stress. Both behavioural and biochemical parameters were measured to illustrate the characteristics of this model. We also assessed NLRP3 inflammasome activation in the mouse diencephalon, which is the brain region that has been suggested to be responsible for fatigue sensation. To further identify the role of NLRP3 inflammasome activation in the pathogenesis of chronic fatigue syndrome (CFS), NLRP3 KO mice were also subjected to LPS treatment and swim stress, and the same parameters were evaluated. Mice challenged with LPS and subjected to the swim stress test showed decreased locomotor activity, decreased fall-off time in a rota-rod test and increased serum levels of IL-1β and IL-6 compared with untreated mice. Serum levels of lactic acid and malondialdehyde (MDA) were not significantly altered in the treated mice. We demonstrated increased NLRP3 expression, IL-1β production and caspase-1 activation in the diencephalons of the treated mice. In NLRP3 KO mice, we found remarkably increased locomotor activity with longer fall-off times and decreased serum IL-1β levels compared with those of wild-type (WT) mice after LPS challenge and the swim stress test. IL-1β levels in the diencephalon were also significantly decreased in the NLRP3 KO mice. By contrast, IL-6 levels were not significantly altered. These findings suggest that LPS-induced fatigue is an IL-1β-dependent process and that the NLRP3/caspase-1 pathway is involved in the mechanisms of LPS-induced fatigue behaviours. NLRP3/caspase-1 inhibition may be a promising therapy for fatigue treatment.

Sleep-wake and melatonin pattern in craniopharyngioma patients.

PubMed

Pickering, Line; Jennum, Poul; Gammeltoft, Steen; Poulsgaard, Lars; Feldt-Rasmussen, Ulla; Klose, Marianne

2014-06-01

To assess the influence of craniopharyngioma or consequent surgery on melatonin secretion, and the association with fatigue, sleepiness, sleep pattern and sleep quality. Cross-sectional study. A total of 15 craniopharyngioma patients were individually matched to healthy controls. In this study, 24-h salivary melatonin and cortisol were measured. Sleep-wake patterns were characterised by actigraphy and sleep diaries recorded for 2 weeks. Sleepiness, fatigue, sleep quality and general health were assessed by Multidimensional Fatigue Inventory, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Short-Form 36. Patients had increased mental fatigue, daytime dysfunction, sleep latency and lower general health (all, P≤0.05), and they tended to have increased daytime sleepiness, general fatigue and impaired sleep quality compared with controls. The degree of hypothalamic injury was associated with an increased BMI and lower mental health (P=0.01). High BMI was associated with increased daytime sleepiness, daytime dysfunction, mental fatigue and lower mental health (all, P≤0.01). Low midnight melatonin was associated with reduced sleep time and efficiency (P≤0.03) and a tendency for increased sleepiness, impaired sleep quality and physical health. Midnight melatonin remained independently related to sleep time after adjustment for cortisol. Three different patterns of melatonin profiles were observed; normal (n=6), absent midnight peak (n=6) and phase-shifted peak (n=2). Only patients with absent midnight peak had impaired sleep quality, increased daytime sleepiness and general and mental fatigue. Craniopharyngioma patients present with changes in circadian pattern and daytime symptoms, which may be due to the influence of the craniopharyngioma or its treatment on the hypothalamic circadian and sleep regulatory nuclei. © 2014 European Society of Endocrinology.

The Association between Daytime Napping and Cognitive Functioning in Chronic Fatigue Syndrome

PubMed Central

Gotts, Zoe M.; Ellis, Jason G.; Deary, Vincent; Barclay, Nicola; Newton, Julia L.

2015-01-01

Objectives The precise relationship between sleep and physical and mental functioning in chronic fatigue syndrome (CFS) has not been examined directly, nor has the impact of daytime napping. This study aimed to examine self-reported sleep in patients with CFS and explore whether sleep quality and daytime napping, specific patient characteristics (gender, illness length) and levels of anxiety and depression, predicted daytime fatigue severity, levels of daytime sleepiness and cognitive functioning, all key dimensions of the illness experience. Methods 118 adults meeting the 1994 CDC case criteria for CFS completed a standardised sleep diary over 14 days. Momentary functional assessments of fatigue, sleepiness, cognition and mood were completed by patients as part of usual care. Levels of daytime functioning and disability were quantified using symptom assessment tools, measuring fatigue (Chalder Fatigue Scale), sleepiness (Epworth Sleepiness Scale), cognitive functioning (Trail Making Test, Cognitive Failures Questionnaire), and mood (Hospital Anxiety and Depression Scale). Results Hierarchical Regressions demonstrated that a shorter time since diagnosis, higher depression and longer wake time after sleep onset predicted 23.4% of the variance in fatigue severity (p <.001). Being male, higher depression and more afternoon naps predicted 25.6% of the variance in objective cognitive dysfunction (p <.001). Higher anxiety and depression and morning napping predicted 32.2% of the variance in subjective cognitive dysfunction (p <.001). When patients were classified into groups of mild and moderate sleepiness, those with longer daytime naps, those who mainly napped in the afternoon, and those with higher levels of anxiety, were more likely to be in the moderately sleepy group. Conclusions Napping, particularly in the afternoon is associated with poorer cognitive functioning and more daytime sleepiness in CFS. These findings have clinical implications for symptom management strategies. PMID:25575044

The association between daytime napping and cognitive functioning in chronic fatigue syndrome.

PubMed

Gotts, Zoe M; Ellis, Jason G; Deary, Vincent; Barclay, Nicola; Newton, Julia L

2015-01-01

The precise relationship between sleep and physical and mental functioning in chronic fatigue syndrome (CFS) has not been examined directly, nor has the impact of daytime napping. This study aimed to examine self-reported sleep in patients with CFS and explore whether sleep quality and daytime napping, specific patient characteristics (gender, illness length) and levels of anxiety and depression, predicted daytime fatigue severity, levels of daytime sleepiness and cognitive functioning, all key dimensions of the illness experience. 118 adults meeting the 1994 CDC case criteria for CFS completed a standardised sleep diary over 14 days. Momentary functional assessments of fatigue, sleepiness, cognition and mood were completed by patients as part of usual care. Levels of daytime functioning and disability were quantified using symptom assessment tools, measuring fatigue (Chalder Fatigue Scale), sleepiness (Epworth Sleepiness Scale), cognitive functioning (Trail Making Test, Cognitive Failures Questionnaire), and mood (Hospital Anxiety and Depression Scale). Hierarchical Regressions demonstrated that a shorter time since diagnosis, higher depression and longer wake time after sleep onset predicted 23.4% of the variance in fatigue severity (p <.001). Being male, higher depression and more afternoon naps predicted 25.6% of the variance in objective cognitive dysfunction (p <.001). Higher anxiety and depression and morning napping predicted 32.2% of the variance in subjective cognitive dysfunction (p <.001). When patients were classified into groups of mild and moderate sleepiness, those with longer daytime naps, those who mainly napped in the afternoon, and those with higher levels of anxiety, were more likely to be in the moderately sleepy group. Napping, particularly in the afternoon is associated with poorer cognitive functioning and more daytime sleepiness in CFS. These findings have clinical implications for symptom management strategies.

Epigenetic alterations are associated with monocyte immune dysfunctions in HIV-1 infection.

PubMed

Espíndola, Milena S; Soares, Luana S; Galvão-Lima, Leonardo J; Zambuzi, Fabiana A; Cacemiro, Maira C; Brauer, Verônica S; Marzocchi-Machado, Cleni M; de Souza Gomes, Matheus; Amaral, Laurence R; Martins-Filho, Olindo A; Bollela, Valdes R; Frantz, Fabiani G

2018-04-03

Monocytes are key cells in the immune dysregulation observed during human immunodeficiency virus (HIV) infection. The events that take place specifically in monocytes may contribute to the systemic immune dysfunction characterized by excessive immune activation in infected individuals, which directly correlates with pathogenesis and progression of the disease. Here, we investigated the immune dysfunction in monocytes from untreated and treated HIV + patients and associated these findings with epigenetic changes. Monocytes from HIV patients showed dysfunctional ability of phagocytosis and killing, and exhibited dysregulated cytokines and reactive oxygen species production after M. tuberculosis challenge in vitro. In addition, we showed that the expression of enzymes responsible for epigenetic changes was altered during HIV infection and was more prominent in patients that had high levels of soluble CD163 (sCD163), a newly identified plasmatic HIV progression biomarker. Among the enzymes, histone acetyltransferase 1 (HAT1) was the best epigenetic biomarker correlated with HIV - sCD163 high patients. In conclusion, we confirmed that HIV impairs effector functions of monocytes and these alterations are associated with epigenetic changes that once identified could be used as targets in therapies aiming the reduction of the systemic activation state found in HIV patients.

Impaired interferon signaling is a common immune defect in human cancer

PubMed Central

Critchley-Thorne, Rebecca J.; Simons, Diana L.; Yan, Ning; Miyahira, Andrea K.; Dirbas, Frederick M.; Johnson, Denise L.; Swetter, Susan M.; Carlson, Robert W.; Fisher, George A.; Koong, Albert; Holmes, Susan; Lee, Peter P.

2009-01-01

Immune dysfunction develops in patients with many cancer types and may contribute to tumor progression and failure of immunotherapy. Mechanisms underlying cancer-associated immune dysfunction are not fully understood. Efficient IFN signaling is critical to lymphocyte function; animals rendered deficient in IFN signaling develop cancer at higher rates. We hypothesized that altered IFN signaling may be a key mechanism of immune dysfunction common to cancer. To address this, we assessed the functional responses to IFN in peripheral blood lymphocytes from patients with 3 major cancers: breast cancer, melanoma, and gastrointestinal cancer. Type-I IFN (IFN-α)-induced signaling was reduced in T cells and B cells from all 3 cancer-patient groups compared to healthy controls. Type-II IFN (IFN-γ)-induced signaling was reduced in B cells from all 3 cancer patient groups, but not in T cells or natural killer cells. Impaired-IFN signaling was equally evident in stage II, III, and IV breast cancer patients, and downstream functional defects in T cell activation were identified. Taken together, these findings indicate that defects in lymphocyte IFN signaling arise in patients with breast cancer, melanoma, and gastrointestinal cancer, and these defects may represent a common cancer-associated mechanism of immune dysfunction. PMID:19451644

Cognition, depression, fatigue, and quality of life in primary Sjögren's syndrome: correlations.

PubMed

Koçer, Belgin; Tezcan, Mehmet Engin; Batur, Hale Zeynep; Haznedaroğlu, Şeminur; Göker, Berna; İrkeç, Ceyla; Çetinkaya, Rümeysa

2016-12-01

The aim of the present study was to investigate the prevalence and pattern of cognitive dysfunction observed in primary Sjögren's syndrome (PSS) and to examine the relationships between cognitive abilities, depression, fatigue, and quality of life. Thirty-two subjects with PSS were compared with 19 healthy controls on comprehensive neuropsychological, depression, fatigue, health state, and daily-life activities tests. There was low performance in Clock Drawing, COWAT, Paced Auditory Serial Addition Test (PASAT), Colorless Word Reading (Stroop1) and Recognizing Colors (Stroop2) Patterns of STROOP test, SDLT, Auditory-Verbal Learning Test (AVLT), immediate and long-term verbal memory, Benton Judgment of Line Orientation Test (BJLOT), and in all the patterns of RCFT in PSS patients compared to the healthy control group ( p  < .05). It was observed an increased depression frequency and fatigue severity, impairment in health condition, and a decreased quality of life in PSS cases compared to the healthy controls ( p  < .05). All the depression, fatigue severity, and quality of life tests showed a significant positive correlation with each other ( p  < .05). A significant negative correlation between Clock Drawing and SF-36-BP ( p  = .031, r  = -.382) and SF-36-GH ( p  = .027, r  = -.392) was observed. Clock Drawing, PASAT, and AVLT are very useful tests to determine the subclinical and clinical cognitive dysfunction to evaluate attention, information processing speed, executive functions, and short-term and long-term verbal memory in PSS patients. Depression and fatigue may not affect the neuropsychological tests performance.

Overactivation of Mitogen-Activated Protein Kinase and Suppression of Mitofusin-2 Expression Are Two Independent Events in High Mobility Group Box 1 Protein–Mediated T Cell Immune Dysfunction

PubMed Central

Tang, Lu-ming; Zhao, Guang-ju; Zhu, Xiao-mei; Dong, Ning; Yu, Yan

2013-01-01

High mobility group box 1 protein (HMGB1), a critical proinflammatory cytokine, has recently been identified to be an immunostimulatory signal involved in sepsis-related immune dysfunction when released extracellularly, but the potential mechanism involved remains elusive. Here, we showed that the treatment with HMGB1 in vitro inhibited T lymphocyte immune response and expression of mitofusin-2 (Mfn-2; a member of the mitofusin family) in a dose- and time-dependent manner. Upregulation of Mfn-2 expression attenuated the suppressive effect of HMGB1 on T cell immune function. The phosphorylation of both extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) was markedly upregulated by treating with high amount of HMGB1, while pretreatment with ERK1/2 and p38 MAPK-specific inhibitors (U0126 and SB203580) could attenuate suppression of T cell immune function and nuclear factor of activated T cell (NFAT) activation induced by HMGB1, respectively. HMGB1-induced activity of ERK1/2 and p38 was not fully inhibited in the presence of U0126 or SB203580. Interestingly, overexpression of Mfn-2 had no marked effect on HMGB1-mediated activation of MAPK, but could attenuate the suppressive effect of HMGB1 on the activity of NFAT. Thus, the mechanisms involved in HMGB1-induced T cell immune dysfunction in vitro at least partly include suppression of Mfn-2 expression, overactivation of ERK1/2, p38 MAPK, and intervention of NFAT activation, while the protective effect of Mfn-2 on T cell immune dysfunction induced by HMGB1 is dependent on other signaling pathway associated with NFAT, but not MAPK. Taken together, we conclude that overactivation of MAPK and suppression of Mfn-2 expression are two independent events in HMGB1-mediated T cell immune dysfunction. PMID:23697559

Differing leukocyte gene expression profiles associated with fatigue in patients with prostate cancer versus chronic fatigue syndrome.

PubMed

Light, Kathleen C; Agarwal, Neeraj; Iacob, Eli; White, Andrea T; Kinney, Anita Y; VanHaitsma, Timothy A; Aizad, Hannah; Hughen, Ronald W; Bateman, Lucinda; Light, Alan R

2013-12-01

Androgen deprivation therapy (ADT) often worsens fatigue in patients with prostate cancer, producing symptoms similar to chronic fatigue syndrome (CFS). Comparing expression (mRNA) of many fatigue-related genes in patients with ADT-treated prostate cancer versus with CFS versus healthy controls, and correlating mRNA with fatigue severity may clarify the differing pathways underlying fatigue in these conditions. Quantitative real-time PCR was performed on leukocytes from 30 fatigued, ADT-treated prostate cancer patients (PCF), 39 patients with CFS and 22 controls aged 40-79, together with ratings of fatigue and pain severity. 46 genes from these pathways were included: (1) adrenergic/monoamine/neuropeptides, (2) immune, (3) metabolite-detecting, (4) mitochondrial/energy, (5) transcription factors. PCF patients showed higher expression than controls or CFS of 2 immune transcription genes (NR3C1 and TLR4), chemokine CXCR4, and mitochondrial gene SOD2. They showed lower expression of 2 vasodilation-related genes (ADRB2 and VIPR2), 2 cytokines (TNF and LTA), and 2 metabolite-detecting receptors (ASIC3 and P2RX7). CFS patients showed higher P2RX7 and lower HSPA2 versus controls and PCF. Correlations with fatigue severity were similar in PCF and CFS for only DBI, the GABA-A receptor modulator (r=-0.50, p<0.005 and r=-0.34, p<0.05). Purinergic P2RY1 was correlated only with PCF fatigue and pain severity (r=+0.43 and +0.59, p=0.025 and p=0.001). PCF patients differed from controls and CFS in mean expression of 10 genes from all 5 pathways. Correlations with fatigue severity implicated DBI for both patient groups and P2RY1 for PCF only. These pathways may provide new targets for interventions to reduce fatigue. Copyright © 2013 Elsevier Ltd. All rights reserved.

Differing Leukocyte Gene Expression Profiles Associated with Fatigue in Patients with Prostate Cancer versus Chronic Fatigue Syndrome

PubMed Central

Light, Kathleen C.; Agarwal, Neeraj; Iacob, Eli; White, Andrea T.; Kinney, Anita Y.; VanHaitsma, Timothy A.; Aizad, Hannah; Hughen, Ronald W.; Bateman, Lucinda; Light, Alan R.

2013-01-01

Summary Background Androgen deprivation therapy (ADT) often worsens fatigue in patients with prostate cancer, producing symptoms similar to Chronic Fatigue Syndrome (CFS). Comparing expression (mRNA) of many fatigue-related genes in patients with ADT-treated prostate cancer versus with CFS versus healthy controls, and correlating mRNA with fatigue severity may clarify the differing pathways underlying fatigue in these conditions. Methods Quantitative real-time PCR was performed on leukocytes from 30 fatigued, ADT-treated prostate cancer patients (PCF), 39 patients with CFS and 22 controls aged 40–79, together with ratings of fatigue and pain severity. 46 genes from these pathways were included: 1) adrenergic/monoamine/neuropeptides, 2) immune, 3) metabolite-detecting, 4) mitochondrial/energy, 5) transcription factors. Results PCF patients showed higher expression than controls or CFS of 2 immune transcription genes (NR3C1 and TLR4), chemokine CXCR4, and mitochondrial gene SOD2. They showed lower expression of 2 vasodilation-related genes (ADRB2 and VIPR2), 2 cytokines (TNF and LTA), and 2 metabolite-detecting receptors (ASIC3 and P2RX7). CFS patients showed higher P2RX7 and lower HSPA2 versus controls and PCF. Correlations with fatigue severity were similar in PCF and CFS for only DBI, the GABA-A receptor modulator (r=−0.50, p<0.005 and r=−0.34, p<0.05). Purinergic P2RY1 was correlated only with PCF fatigue and pain severity (r= +0.43 and +0.59, p=0.025 and p=0.001). Conclusions PCF patients differed from controls and CFS in mean expression of 10 genes from all 5 pathways. Correlations with fatigue severity implicated DBI for both patient groups and P2RY1 for PCF only. These pathways may provide new targets for interventions to reduce fatigue. PMID:24054763

38 CFR 4.88a - Chronic fatigue syndrome.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2011-07-01 2011-07-01 false Chronic fatigue syndrome. 4.88a Section 4.88a Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS SCHEDULE FOR RATING DISABILITIES Disability Ratings Infectious Diseases, Immune Disorders and Nutritional...

Neuro-immune dysfunction during brain aging: new insights in microglial cell regulation.

PubMed

Matt, Stephanie M; Johnson, Rodney W

2016-02-01

Microglia, the resident immune cells of the brain, are at the center of communication between the central nervous system and immune system. While these brain-immune interactions are balanced in healthy adulthood, the ability to maintain homeostasis during aging is impaired. Microglia develop a loss of integrated regulatory networks including aberrant signaling from other brain cells, immune sensors, and epigenetic modifiers. The low-grade chronic neuroinflammation associated with this dysfunctional activity likely contributes to cognitive deficits and susceptibility to age-related pathologies. A better understanding of the underlying mechanisms responsible for neuro-immune dysregulation with age is crucial for providing targeted therapeutic strategies to support brain repair and healthy aging. Copyright © 2015 Elsevier Ltd. All rights reserved.

Exercise, inflammation, and fatigue in cancer survivors

PubMed Central

LaVoy, Emily C.P.; Fagundes, Christopher P.; Dantzer, Robert

2016-01-01

Cancer-related fatigue significantly disrupts normal functioning and quality of life for a substantial portion of cancer survivors, and may persist for years following cancer treatment. While the causes of persistent fatigue among cancer survivors are not yet fully understood, accumulating evidence suggests that several pathways, including chronic inflammation, autonomic imbalance, HPA-axis dysfunction, and/or mitochondrial damage, could contribute towards the disruption of normal neuronal function and result in the symptom of cancer-related fatigue. Exercise training interventions have been shown to be some of the more successful treatment options to address cancer-related fatigue. In this review, we discuss the literature regarding the causes of persistent fatigue in cancer survivors and the mechanisms by which exercise may relieve this symptom. There is still much work to be done until the prescription of exercise becomes standard practice for cancer survivors. With improvements in the quality of studies, evidenced-based exercise interventions will allow exercise scientists and oncologists to work together to treat cancer-related fatigue. PMID:26853557

Do Active Duty Cancer Survivors with a Concurrent Behavioral Health Diagnosis Have Distinct Survivorship Care Needs

DTIC Science & Technology

2014-09-23

edema, cognitive dysfunction, pain , fatigue, sleep disturbance, and vocal difficulties (72). Cancer survivorship Cancer survivorship became a...involves physical symptoms such as: fatigue, insomnia, pain , cognitive impairments, and edema, as well as emotional symptoms such as depression and...conditions such as high blood pressure, back pain , diabetes, and obesity (65). Cancer survivors often report living with increased health concerns and the

Study of the Neurophysiology of Central Fatigue

DTIC Science & Technology

2014-11-05

AGENCY NAME(S) AND ADDRESS (ES) U.S. Army Research Office P.O. Box 12211 Research Triangle Park, NC 27709-2211 cognitive, fatigue, fatigability...Fatigability in Parkinson Disease. Movement Disorders 2012;27:e6. 4. Wang C, Ding M, Kluger BM. High-density EEG study of cue-evoked preparatory...258. 3. Kluger B, Wang C, Proemsey J, Ding M. Neuronal Correlates of Executive Dysfunction and Fatigability in Parkinson Disease. Movement Disorders

Gender differences in chronic fatigue syndrome.

PubMed

Faro, Mònica; Sàez-Francás, Naia; Castro-Marrero, Jesús; Aliste, Luisa; Fernández de Sevilla, Tomás; Alegre, José

2016-01-01

Chronic fatigue syndrome (CFS) is a chronic condition that predominantly affects women. To date, there are few epidemiologic studies on CFS in men. The objective of the study was to assess whether there are gender-related differences in CFS, and to define a clinical phenotype in men. A prospective, cross-sectional cohort study was conducted including CFS patients at the time of diagnosis. Sociodemographic data, clinical variables, comorbid phenomena, fatigue, pain, anxiety/depression, and health quality of life, were assessed in the CFS population. A comparative study was also conducted between genders. The study included 1309 CFS patients, of which 119 (9.1%) were men. The mean age and symptoms onset were lower in men than women. The subjects included 30% single men vs. 15% single women, and 32% of men had specialist work vs. 20% of women. The most common triggering factor was an infection. Widespread pain, muscle spasms, dizziness, sexual dysfunction, Raynaud's phenomenon, morning stiffness, migratory arthralgias, drug and metals allergy, and facial oedema were less frequent in men. Fibromyalgia was present in 29% of men vs. 58% in women. The scores on physical function, physical role, and overall physical health of the SF-36 were higher in men. The sensory and affective dimensions of pain were lower in men. The clinical phenotype of the men with CFS was young, single, skilled worker, and infection as the main triggering agent. Men had less pain and less muscle and immune symptoms, fewer comorbid phenomena, and a better quality of life. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Longitudinal peripheral blood transcriptional analysis of a patient with severe Ebola virus disease

PubMed Central

Kash, John C.; Walters, Kathie-Anne; Kindrachuk, Jason; Baxter, David; Scherler, Kelsey; Janosko, Krisztina B.; Adams, Rick D.; Herbert, Andrew S.; James, Rebekah M.; Stonier, Spencer W.; Memoli, Matthew J.; Dye, John M.; Davey, Richard T.; Chertow, Daniel S.; Taubenberger, Jeffery K.

2017-01-01

The 2013–2015 outbreak of Ebola virus disease in Guinea, Liberia, and Sierra Leone was unprecedented in the number of documented cases, but there have been few published reports on immune responses in clinical cases and their relationships with the course of illness and severity of Ebola virus disease. Symptoms of Ebola virus disease can include severe headache, myalgia, asthenia, fever, fatigue, diarrhea, vomiting, abdominal pain, and hemorrhage. Although experimental treatments are in development, there are no current U.S. Food and Drug Administration–approved vaccines or therapies. We report a detailed study of host gene expression as measured by microarray in daily peripheral blood samples collected from a patient with severe Ebola virus disease. This individual was provided with supportive care without experimental therapies at the National Institutes of Health Clinical Center from before onset of critical illness to recovery. Pearson analysis of daily gene expression signatures revealed marked gene expression changes in peripheral blood leukocytes that correlated with changes in serum and peripheral blood leukocytes, viral load, antibody responses, coagulopathy, multiple organ dysfunction, and then recovery. This study revealed marked shifts in immune and antiviral responses that preceded changes in medical condition, indicating that clearance of replicating Ebola virus from peripheral blood leukocytes is likely important for systemic viral clearance. PMID:28404864

The Gut Microbiome and the Brain

PubMed Central

Galland, Leo

2014-01-01

Abstract The human gut microbiome impacts human brain health in numerous ways: (1) Structural bacterial components such as lipopolysaccharides provide low-grade tonic stimulation of the innate immune system. Excessive stimulation due to bacterial dysbiosis, small intestinal bacterial overgrowth, or increased intestinal permeability may produce systemic and/or central nervous system inflammation. (2) Bacterial proteins may cross-react with human antigens to stimulate dysfunctional responses of the adaptive immune system. (3) Bacterial enzymes may produce neurotoxic metabolites such as D-lactic acid and ammonia. Even beneficial metabolites such as short-chain fatty acids may exert neurotoxicity. (4) Gut microbes can produce hormones and neurotransmitters that are identical to those produced by humans. Bacterial receptors for these hormones influence microbial growth and virulence. (5) Gut bacteria directly stimulate afferent neurons of the enteric nervous system to send signals to the brain via the vagus nerve. Through these varied mechanisms, gut microbes shape the architecture of sleep and stress reactivity of the hypothalamic-pituitary-adrenal axis. They influence memory, mood, and cognition and are clinically and therapeutically relevant to a range of disorders, including alcoholism, chronic fatigue syndrome, fibromyalgia, and restless legs syndrome. Their role in multiple sclerosis and the neurologic manifestations of celiac disease is being studied. Nutritional tools for altering the gut microbiome therapeutically include changes in diet, probiotics, and prebiotics. PMID:25402818

Symptoms of fatigue and coping strategies in maritime pilotage.

PubMed

Chambers, Timothy P; Main, Luana C

2015-01-01

Little is known regarding the symptoms of fatigue that maritime pilots experience during shift work. Moreover, the strategies these individuals use to cope with the onset of fatigue are also unknown. The current study explored the symptoms of fatigue and coping strategies experienced by maritime pilots when on-shift. Fifty maritime pilots were recruited via an advertisement in the national association's quarterly newsletter (Mage = 51.42; SD = 9.81). Participants responded to a modified version of the questionnaire used with aviation pilots that assessed overall fatigue, and the symptoms pilots associated with fatigue on duty. Methods pilots used to cope with fatigue before shift and when on the bridge were also assessed. There were significant effects for pilot vitality on 4 categories of fatigue: cognitive dysfunction; emotional disturbance; mean physical effects; and sleepiness. There were no significant effects for vitality on any of the self-reported coping strategy factors. The findings indicated that maritime pilots experience a variety of physical, behavioural, and cognitive fatigue symptoms when on shift. Some of these symptoms are similar to those reported by aviation pilots. However, unlike aviation pilots, maritime pilots reported utilising self-sufficient coping strategies to deal with the experience of fatigue.

The emerging role of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs).

PubMed

Morris, Gerwyn; Berk, Michael; Galecki, Piotr; Maes, Michael

2014-04-01

The World Health Organization classifies myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) as a nervous system disease. Together with other diseases under the G93 heading, ME/cfs shares a triad of abnormalities involving elevated oxidative and nitrosative stress (O&NS), activation of immuno-inflammatory pathways, and mitochondrial dysfunctions with depleted levels of adenosine triphosphate (ATP) synthesis. There is also abundant evidence that many patients with ME/cfs (up to around 60 %) may suffer from autoimmune responses. A wide range of reported abnormalities in ME/cfs are highly pertinent to the generation of autoimmunity. Here we review the potential sources of autoimmunity which are observed in people with ME/cfs. The increased levels of pro-inflammatory cytokines, e.g., interleukin-1 and tumor necrosis factor-α, and increased levels of nuclear factor-κB predispose to an autoimmune environment. Many cytokine abnormalities conspire to produce a predominance of effector B cells and autoreactive T cells. The common observation of reduced natural killer cell function in ME/cfs is a source of disrupted homeostasis and prolonged effector T cell survival. B cells may be pathogenic by playing a role in autoimmunity independent of their ability to produce antibodies. The chronic or recurrent viral infections seen in many patients with ME/cfs can induce autoimmunity by mechanisms involving molecular mimicry and bystander activation. Increased bacterial translocation, as observed in ME/cfs, is known to induce chronic inflammation and autoimmunity. Low ATP production and mitochondrial dysfunction is a source of autoimmunity by inhibiting apoptosis and stimulating necrotic cell death. Self-epitopes may be damaged by exposure to prolonged O&NS, altering their immunogenic profile and become a target for the host's immune system. Nitric oxide may induce many faces of autoimmunity stemming from elevated mitochondrial membrane hyperpolarization and blockade of the methionine cycle with subsequent hypomethylation of DNA. Here we also outline options for treatment involving rituximab and endotherapia.

Use of valganciclovir in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue.

PubMed

Kogelnik, Andreas M; Loomis, Kristin; Hoegh-Petersen, Mette; Rosso, Fernando; Hischier, Courtney; Montoya, Jose G

2006-12-01

Twelve patients with long-standing symptoms of central nervous system (CNS) dysfunction were found to have elevated antibody titres to human herpesvirus-6 (HHV-6) and Epstein-Barr virus (EBV). All patients had four or more of the following neurocognitive symptoms: impaired cognitive functioning, slowed processing speed, sleep disturbance, short-term memory deficit, fatigue and symptoms consistent with depression. We sought to determine whether elevated antibodies to EBV and HHV-6 indicated chronic viral activation in patients with CNS dysfunction and if their symptoms could be improved by suppressing viral activity with oral valganciclovir. Patients with high IgG antibody titers against HHV-6 and EBV who were suffering from central nervous system dysfunction and debilitating fatigue for more than one year (median 3 years, range 1-8 years) were treated with 6 months of valganciclovir in an open label study. Nine out of 12 (75%) patients experienced near resolution of their symptoms, allowing them all to return to the workforce or full time activites. In the nine patients with a symptomatic response to treatment, EBV VCA IgG titers dropped from 1:2560 to 1:640 (p = 0.008) and HHV-6 IgG titers dropped from a median value of 1:1280 to 1:320 (p = 0.271). Clinically significant hematological toxicity or serious adverse events were not observed among the 12 patients. These preliminary clinical and laboratory observations merit additional studies to establish whether this clinical response is mediated by an antiviral effect of the drug, indirectly via immunomodulation or by placebo effect.

Curcumin reverses T cell-mediated adaptive immune dysfunctions in tumor-bearing hosts.

PubMed

Bhattacharyya, Sankar; Md Sakib Hossain, Dewan; Mohanty, Suchismita; Sankar Sen, Gouri; Chattopadhyay, Sreya; Banerjee, Shuvomoy; Chakraborty, Juni; Das, Kaushik; Sarkar, Diptendra; Das, Tanya; Sa, Gaurisankar

2010-07-01

Immune dysfunction is well documented during tumor progression and likely contributes to tumor immune evasion. CD8(+) cytotoxic T lymphocytes (CTLs) are involved in antigen-specific tumor destruction and CD4(+) T cells are essential for helping this CD8(+) T cell-dependent tumor eradication. Tumors often target and inhibit T-cell function to escape from immune surveillance. This dysfunction includes loss of effector and memory T cells, bias towards type 2 cytokines and expansion of T regulatory (Treg) cells. Curcumin has previously been shown to have antitumor activity and some research has addressed the immunoprotective potential of this plant-derived polyphenol in tumor-bearing hosts. Here we examined the role of curcumin in the prevention of tumor-induced dysfunction of T cell-based immune responses. We observed severe loss of both effector and memory T-cell populations, downregulation of type 1 and upregulation of type 2 immune responses and decreased proliferation of effector T cells in the presence of tumors. Curcumin, in turn, prevented this loss of T cells, expanded central memory T cell (T(CM))/effector memory T cell (T(EM)) populations, reversed the type 2 immune bias and attenuated the tumor-induced inhibition of T-cell proliferation in tumor-bearing hosts. Further investigation revealed that tumor burden upregulated Treg cell populations and stimulated the production of the immunosuppressive cytokines transforming growth factor (TGF)-beta and IL-10 in these cells. Curcumin, however, inhibited the suppressive activity of Treg cells by downregulating the production of TGF-beta and IL-10 in these cells. More importantly, curcumin treatment enhanced the ability of effector T cells to kill cancer cells. Overall, our observations suggest that the unique properties of curcumin may be exploited for successful attenuation of tumor-induced suppression of cell-mediated immune responses.

Meeting Disorders.

PubMed

Yager, Joel; Katzman, Jeffrey W

2017-12-01

Although meetings are central to organizational work, considerable time devoted to meetings in Academic Health Centers appears to be unproductively spent. The primary purposes of this article are to delineate and describe Meeting Disorders, pathological processes resulting in these inefficient and ineffective scenarios, and Meeting Fatigue Disorder (MFD), a clinical syndrome. The paper also offers preliminary approaches to remedies. The authors integrate observations made during tens of thousands of hours in administrative meetings in academic medical settings with information in the literature regarding the nature, causes and potential interventions for dysfunctional groups and meetings. Meeting Disorders, resulting from distinct pathologies of leadership and organization, constitute prevalent subgroups of the bureaucrapathologies, pathological conditions caused by dysfunctional bureaucratic processes that generate excesses of wasted time, effort, and other resources. These disorders also generate frustration and demoralization among participants, contributing to professional burnout. Meeting Fatigue Disorder (MFD) is a subjective condition that develops in individuals who overdose on these experiences and may reflect one manifestation of burnout. Meeting disorders and Meeting Fatigue Disorder occur commonly in bureaucratic life. Resources and potential remedies are available to help ameliorate their more deleterious effects.

Central fatigue in multiple sclerosis: a review of the literature

PubMed Central

Newland, Pamela; Starkweather, Angela; Sorenson, Matthew

2016-01-01

Concept Fatigue is a major concern for patients with multiple sclerosis (MS). A clear definition of MS-related fatigue is a prerequisite for appropriate instruments for fatigue assessment. In turn, accurate assessment of fatigue in MS will enhance exploration of plausible mechanisms underlying this common and distressing symptom. Content/Objectives To provide an integrative review of the current literature on theoretical models used to study fatigue in MS, instruments used to assess fatigue and other factors that impact fatigue during the various phases of MS. Methods Data sources: PUBMED, OVID, Ovid Health Star, Ovid MEDINE, CINAHL, Health and Psychosocial Instruments (HaPI), and PsycINFO. Seventeen articles fit the inclusion criteria and were included in the review. Results Definitions of MS-related fatigue are reviewed. Several studies found a link with neurotransmitter dysfunction, circadian rhythm, and the timing of fatigue. Central fatigue in MS is associated with neurotransmitters disruptions as well as circadian rhythm disorders, but the evidence is not strong. Perceptions of fatigue or fatigability may arise as either a primary or secondary manifestation of disease. Based on findings from the literature review, a theoretical model of fatigue in MS is proposed. Conclusion Future research on MS-related fatigue may consider a longitudinal design with a carefully selected self-report instrument to advance understanding of the underlying pathological mechanisms. PMID:27146427

Extracellular vesicles are key intercellular mediators in the development of immune dysfunction to allergens in the airways.

PubMed

Shin, T-S; Kim, J H; Kim, Y-S; Jeon, S G; Zhu, Z; Gho, Yong Song; Kim, Yoon-Keun

2010-10-01

Previous evidence indicates that inhalation of lipopolysaccharide (LPS)-containing with allergens induced mixed Th1 and Th17 cell responses in the airways. Extracellular vesicles (EVs) are nanometer-sized spherical, lipid-bilayered structures and are recently in the public eye as an intercellular communicator in immune responses. To evaluate the role of EVs secreted by LPS inhalation in the development of airway immune dysfunction in response to allergens. Extracellular vesicles in bronchoalveolar lavage fluids of BALB/c mice were isolated and characterized 24 h after applications to the airway of 10 μg of LPS for 3 days. To evaluate the role of LPS-induced EVs on the development of airway immune dysfunction, in vivo and in vitro experiments were performed using the isolated LPS-induced EVs. The inhalation of LPS enhanced EVs release into the BAL fluid, when compared to the application of PBS. Airway sensitization with allergens and LPS-induced EVs resulted in a mixed Th1 and Th17 cell responses, although that with allergens and PBS-induced EVs induced immune tolerance. In addition, LPS-induced EVs enhanced the production of Th1- and Th17-polarizing cytokines (IL-12p70 and IL-6, respectively) by lung dendritic cells. Moreover, the immune responses induced by the LPS-induced EVs were blocked by denaturation of the EV-bearing proteins. These data suggest that EVs (especially, the protein components) secreted by LPS inhalation are a key intercellular communicator in the development of airway immune dysfunction to inhaled LPS-containing allergens.

Extracellular vesicles are key intercellular mediators in the development of immune dysfunction to allergens in the airways

PubMed Central

Shin, T-S; Kim, J H; Kim, Y-S; Jeon, S G; Zhu, Z; Gho, Y S; Kim, Y-K

2010-01-01

Background Previous evidence indicates that inhalation of lipopolysaccharide (LPS)-containing with allergens induced mixed Th1 and Th17 cell responses in the airways. Extracellular vesicles (EVs) are nanometer-sized spherical, lipid-bilayered structures and are recently in the public eye as an intercellular communicator in immune responses. Objective To evaluate the role of EVs secreted by LPS inhalation in the development of airway immune dysfunction in response to allergens. Methods Extracellular vesicles in bronchoalveolar lavage fluids of BALB/c mice were isolated and characterized 24 h after applications to the airway of 10 μg of LPS for 3 days. To evaluate the role of LPS-induced EVs on the development of airway immune dysfunction, in vivo and in vitro experiments were performed using the isolated LPS-induced EVs. Results The inhalation of LPS enhanced EVs release into the BAL fluid, when compared to the application of PBS. Airway sensitization with allergens and LPS-induced EVs resulted in a mixed Th1 and Th17 cell responses, although that with allergens and PBS-induced EVs induced immune tolerance. In addition, LPS-induced EVs enhanced the production of Th1- and Th17-polarizing cytokines (IL-12p70 and IL-6, respectively) by lung dendritic cells. Moreover, the immune responses induced by the LPS-induced EVs were blocked by denaturation of the EV-bearing proteins. Conclusion These data suggest that EVs (especially, the protein components) secreted by LPS inhalation are a key intercellular communicator in the development of airway immune dysfunction to inhaled LPS-containing allergens. PMID:20337607

Role of MicroRNAs in Obesity-Induced Metabolic Disorder and Immune Response.

PubMed

Zhong, Hong; Ma, Minjuan; Liang, Tingming; Guo, Li

2018-01-01

In all living organisms, metabolic homeostasis and the immune system are the most fundamental requirements for survival. Recently, obesity has become a global public health issue, which is the cardinal risk factor for metabolic disorder. Many diseases emanating from obesity-induced metabolic dysfunction are responsible for the activated immune system, including innate and adaptive responses. Of note, inflammation is the manifest accountant signal. Deeply studied microRNAs (miRNAs) have participated in many pathways involved in metabolism and immune responses to protect cells from multiple harmful stimulants, and they play an important role in determining the progress through targeting different inflammatory pathways. Thus, immune response and metabolic regulation are highly integrated with miRNAs. Collectively, miRNAs are the new targets for therapy in immune dysfunction.

Mitochondrial dysfunction as a trigger of innate immune responses and inflammation.

PubMed

West, A Phillip

2017-11-01

A growing literature indicates that mitochondria are key participants in innate immune pathways, functioning as both signaling platforms and contributing to effector responses. In addition to regulating antiviral signaling and antibacterial immunity, mitochondria are also important drivers of inflammation caused by sterile injury. Much research on mitochondrial control of immunity now centers on understanding how mitochondrial constituents released during cellular damage simulate the innate immune system. When mitochondrial integrity is compromised, mitochondrial damage-associated molecular patterns engage pattern recognition receptors, trigger inflammation, and promote pathology in an expanding list of diseases. Here, I review the emerging knowledge of mitochondrial dysfunction in innate immune responses and discuss how environmental exposures may induce mitochondrial damage to potentiate inflammation and human disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Role of MicroRNAs in Obesity-Induced Metabolic Disorder and Immune Response

PubMed Central

Zhong, Hong; Ma, Minjuan

2018-01-01

In all living organisms, metabolic homeostasis and the immune system are the most fundamental requirements for survival. Recently, obesity has become a global public health issue, which is the cardinal risk factor for metabolic disorder. Many diseases emanating from obesity-induced metabolic dysfunction are responsible for the activated immune system, including innate and adaptive responses. Of note, inflammation is the manifest accountant signal. Deeply studied microRNAs (miRNAs) have participated in many pathways involved in metabolism and immune responses to protect cells from multiple harmful stimulants, and they play an important role in determining the progress through targeting different inflammatory pathways. Thus, immune response and metabolic regulation are highly integrated with miRNAs. Collectively, miRNAs are the new targets for therapy in immune dysfunction. PMID:29484304

Experiences of living with myasthenia gravis: a qualitative study with Taiwanese people.

PubMed

Chen, Yu Tai; Shih, Fu Jin; Hayter, Mark; Hou, Chang Chiu; Yeh, Jiann Horng

2013-04-01

Myasthenia gravis (MG) is an auto-immune, neuromuscular disorder, which presents with symptoms of fluctuating muscle fatigue because of a dysfunction of the neuromuscular junction. This study explores the illness experience of patients with MG, their experiences of illness, its challenges, and their coping and support strategies. In-depth interviews were undertaken with nine participants with MG (six for a generalized type of MG, three for ocular type). Data were subjected to inductive content and thematic analysis. Four themes emerged from MG patients with associated subthemes. They were "perceptions of MG," "challenges of MG, "social support," and "adapting and adjusting to MG." The study reveals the way in which individuals respond to and cope with their diagnosis. The importance of social and peer support is a key factor as well as the development of psychological strategies to live with MG. The recognition that there was a need to recognize the role of Western medicine in controlling their disease was also an important finding.

Sleep quality and correlates of poor sleep in patients with rheumatoid arthritis.

PubMed

Løppenthin, K; Esbensen, B A; Jennum, P; Østergaard, M; Tolver, A; Thomsen, T; Midtgaard, J

2015-12-01

The objective of this study is to examine sleep quality and correlates of poor sleep in patients with rheumatoid arthritis (RA). Five hundred patients with RA were recruited from a rheumatology outpatient clinic and included in this cross-sectional study. Sleep quality and disturbances were assessed using the Pittsburgh Sleep Quality Index (PSQI). Other instruments included the Multidimensional Fatigue Inventory, the Epworth Sleepiness Scale, and the Health Assessment Questionnaire. Disease activity was assessed according to disease activity score DAS28-CRP-based. Complete scores on PSQI were obtained from 384 patients (77 %). In those, the prevalence of poor sleep (PSQI >5) was 61 %, and the mean global PSQI score was 7.54 (SD 4.17). A linear association was found between poor sleep and mental fatigue, reduced activity related to fatigue, physical fatigue, and general fatigue. Mental fatigue and general fatigue were independently associated with sleep quality, sleep latency, sleep duration, sleep efficiency, and daytime dysfunction. However, in the linear multivariate analysis, only general fatigue 1.06 (95 % CI 1.03-1.09) and mental fatigue 1.03 (95 % CI 1.01-1.05) were found to be significant correlates for reporting poor sleep. This study shows that a majority of patients with RA experience poor sleep and that general fatigue and mental fatigue are associated with poor sleep.

The Immune System’s Role in Sepsis Progression, Resolution and Long-Term Outcome

PubMed Central

Delano, Matthew J.; Ward, Peter A.

2016-01-01

SUMMARY Sepsis occurs when an infection exceeds local tissue containment and induces a series of dysregulated physiologic responses that result in organ dysfunction. A subset of patients with sepsis progress to septic shock, defined by profound circulatory, cellular, and metabolic abnormalities, and associated with a greater mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the complex interplay between the initial inflammatory and later anti-inflammatory responses. With advances in intensive care medicine and goal-directed interventions, early 30-day sepsis mortality has diminished, only to steadily escalate long after “recovery” from acute events. Since so many sepsis survivors succumb later to persistent, recurrent, nosocomial and secondary infections, many investigators have turned their attention to the long-term sepsis-induced alterations in cellular immune function. Sepsis clearly alters the innate and adaptive immune responses for sustained periods of time after clinical recovery, with immune suppression, chronic inflammation, and persistence of bacterial representing such alterations. Understanding that sepsis-associated immune cell defects correlate with long-term mortality, more investigations have centered on the potential for immune modulatory therapy to improve long term patient outcomes. These efforts are focused on more clearly defining and effectively reversing the persistent immune cell dysfunction associated with long-term sepsis mortality. PMID:27782333

The association of fatigue, pain, depression and anxiety with work and activity impairment in immune mediated inflammatory diseases.

PubMed

Enns, Murray W; Bernstein, Charles N; Kroeker, Kristine; Graff, Lesley; Walker, John R; Lix, Lisa M; Hitchon, Carol A; El-Gabalawy, Renée; Fisk, John D; Marrie, Ruth Ann

2018-01-01

Impairment in work function is a frequent outcome in patients with chronic conditions such as immune-mediated inflammatory diseases (IMID), depression and anxiety disorders. The personal and economic costs of work impairment in these disorders are immense. Symptoms of pain, fatigue, depression and anxiety are potentially remediable forms of distress that may contribute to work impairment in chronic health conditions such as IMID. The present study evaluated the association between pain [Medical Outcomes Study Pain Effects Scale], fatigue [Daily Fatigue Impact Scale], depression and anxiety [Hospital Anxiety and Depression Scale] and work impairment [Work Productivity and Activity Impairment Scale] in four patient populations: multiple sclerosis (n = 255), inflammatory bowel disease (n = 248, rheumatoid arthritis (n = 154) and a depression and anxiety group (n = 307), using quantile regression, controlling for the effects of sociodemographic factors, physical disability, and cognitive deficits. Each of pain, depression symptoms, anxiety symptoms, and fatigue individually showed significant associations with work absenteeism, presenteeism, and general activity impairment (quantile regression standardized estimates ranging from 0.3 to 1.0). When the distress variables were entered concurrently into the regression models, fatigue was a significant predictor of work and activity impairment in all models (quantile regression standardized estimates ranging from 0.2 to 0.5). These findings have important clinical implications for understanding the determinants of work impairment and for improving work-related outcomes in chronic disease.

Neuroinflamm-aging and neurodegenerative diseases: an overview.

PubMed

Pizza, Vincenzo; Agresta, Anella; D'Acunto, Cosimo W; Festa, Michela; Capasso, Anna

2011-08-01

Neuroinflammation is considered a chronic activation of the immune response in the central nervous system (CNS) in response to different injuries. This brain immune activation results in various events: circulating immune cells infiltrate the CNS; resident cells are activated; and pro-inflammatory mediators produced and released induce neuroinflammatory brain disease. The effect of immune diffusible mediators on synaptic plasticity might result in CNS dysfunction during neuroinflammatory brain diseases. The CNS dysfunction may induce several human pathological conditions associated with both cognitive impairment and a variable degree of neuroinflammation. Furthermore, age has a powerful effect on enhanced susceptibility to neurodegenerative diseases and age-dependent enhanced neuroinflammatory processes may play an important role in toxin generation that causes death or dysfunction of neurons in neurodegenerative diseases This review will address current understanding of the relationship between ageing, neuroinflammation and neurodegenerative disease by focusing on the principal mechanisms by which the immune system influences the brain plastic phenomena. Also, the present review considers the principal human neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis and psychiatric disorders caused by aging and neuroinflammation.

Metabolic regulation of inflammation.

PubMed

Gaber, Timo; Strehl, Cindy; Buttgereit, Frank

2017-05-01

Immune cells constantly patrol the body via the bloodstream and migrate into multiple tissues where they face variable and sometimes demanding environmental conditions. Nutrient and oxygen availability can vary during homeostasis, and especially during the course of an immune response, creating a demand for immune cells that are highly metabolically dynamic. As an evolutionary response, immune cells have developed different metabolic programmes to supply them with cellular energy and biomolecules, enabling them to cope with changing and challenging metabolic conditions. In the past 5 years, it has become clear that cellular metabolism affects immune cell function and differentiation, and that disease-specific metabolic configurations might provide an explanation for the dysfunctional immune responses seen in rheumatic diseases. This Review outlines the metabolic challenges faced by immune cells in states of homeostasis and inflammation, as well as the variety of metabolic configurations utilized by immune cells during differentiation and activation. Changes in cellular metabolism that contribute towards the dysfunctional immune responses seen in rheumatic diseases are also briefly discussed.

Dysfunctional beliefs, stress and sleep disturbance in fibromyalgia.

PubMed

Theadom, Alice; Cropley, Mark

2008-05-01

To explore sleep-related dysfunctional beliefs, stress levels and sleep quality in patients with fibromyalgia in comparison to healthy controls. One hundred sixty-six participants (83 patients with fibromyalgia and 83 healthy controls) completed self-report measures exploring beliefs and attitudes about sleep, perceived stress, sleep quality and levels of pain and fatigue. Relative to healthy controls, patients with fibromyalgia revealed significantly higher levels of dysfunctional beliefs and attitudes about sleep and perceived stress. High dysfunctional beliefs were significantly associated with poorer sleep quality and high perceived stress was significantly related to higher sleep disturbances and daytime dysfunction. Beliefs about sleep and perceived stress play a significant role in the sleep quality of patients with fibromyalgia. Interventions to improve sleep quality for people with fibromyalgia need to identify and address dysfunctional beliefs about sleep and incorporate stress management approaches.

Graded versus Intermittent Exercise Effects on Lymphocytes in Chronic Fatigue Syndrome.

PubMed

Broadbent, Suzanne; Coutts, Rosanne

2016-09-01

There is increasing evidence of immune system dysfunction in chronic fatigue syndrome (CFS), but little is known of the regular exercise effects on immune cell parameters. This pilot study investigated the effects of graded and intermittent exercise on CD4 lymphocyte subset counts and activation compared with usual care. Twenty-four CFS patients (50.2 ± 10 yr) were randomized to graded exercise (GE), intermittent exercise (IE), or usual care (UC) groups; 18 sedentary non-CFS participants (50.6 ± 10 yr) were controls (CTL) for blood and immunological comparisons. Outcome measures were pre- and postintervention flow cytometric analyses of circulating lymphocyte subset cell counts; expression of CD3, CD4, CD25, and CD134; full blood counts; and V˙O2peak. Preintervention, CD3 cell counts, and expression of CD4, CD25, CD134, and CD4CD25CD134 were significantly lower in GE, IE, and UC compared with CTL (P < 0.05). Total lymphocyte concentration was significantly lower in GE and IE groups compared with CTL. There were significant postintervention increases in i) expression of CD4 and CD4CD25CD134 for GE and IE, but CD25 and CD134 for IE only; ii) circulating counts of CD3 and CD4 for GE, and CD3, CD4, CD8, CD3CD4CD8, CD3CD16CD56, CD19, and CD45 for IE; iii) neutrophil concentration for GE; and iv) V˙O2peak and elapsed test time for IE and GE, V˙Epeak for IE. Twelve weeks of GE and IE training significantly improved CD4 lymphocyte activation and aerobic capacity without exacerbating CFS symptoms. IE may be a more effective exercise modality with regard to enhanced CD4 activation in CFS patients.

Necrotizing herpetic retinopathies. A spectrum of herpes virus-induced diseases determined by the immune state of the host.

PubMed

Guex-Crosier, Y; Rochat, C; Herbort, C P

1997-12-01

Necrotizing herpetic retinopathies (NHR), a new spectrum of diseases induced by viruses of the herpes family (herpes simplex virus, varicella-zoster virus and cytomegalovirus), includes acute retinal necrosis (ARN) occurring in apparently immunocompetent patients and progressive outer retinal necrosis (PORN) described in severely immuno-compromised patients. Signs of impaired cellular immunity were seen in 16% of ARN patients in a review of 216 reported cases, indicating that immune dysfunction is not only at the origin of PORN but might also be at the origin of ARN. The aim of this study was to correlate clinical findings in NHR patients with their immunologic parameters. Charts from patients with the diagnosis of ARN or PORN seen from 1990 to 1995 were reviewed. Clinical characteristics and disease patterns were correlated with immunological parameters taking into account CD4 lymphocyte rate in AIDS patients and blood-lymphocyte subpopulation determination by flow cytometry, cutaneous delayed type hypersensitivity testing and lymphocytic proliferation rate to seven antigens in HIV-negative patients. During the period considered, 11 patients and 7 patients fulfilled the criteria of ARN and PORN respectively. Immune dysfunctions were identified in most patients. Mild type of ARN and classical ARN were associated with discrete immune dysfunctions, ARN with features of PORN was seen in more immunodepressed patients and classical PORN was always seen in severely immunodepressed HIV patients. Our findings suggest that NHR is a continuous spectrum of diseases induced by herpes viruses, whose clinical expression depends on the immune state of the host going from mild or classical ARN at one end in patients with non-detectable or slight immune dysfunction to PORN in severely immunodepressed patients at the other end and with intermediary forms between these extremes.

Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin.

PubMed

Maes, Michael; Twisk, Frank N M; Kubera, Marta; Ringel, Karl

2012-02-01

There is evidence that inflammatory pathways and cell-mediated immunity (CMI) play an important role in the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Activation of inflammatory and CMI pathways, including increased levels of cytokines, is known to induce fatigue and somatic symptoms. Given the broad spectrum inflammatory state in ME/CFS, the aim of this study was to examine whether inflammatory and CMI biomarkers are increased in individuals with ME/CFS. In this study we therefore measured plasma interleukin-(IL)1, tumor necrosis factor (TNF)α, and PMN-elastase, and serum neopterin and lysozyme in 107 patients with ME/CFS, 37 patients with chronic fatigue (CF), and 20 normal controls. The severity of ME/CFS was measured with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale. Serum IL-1, TNFα, neopterin and lysozyme are significantly higher in patients with ME/CFS than in controls and CF patients. Plasma PMN-elastase is significantly higher in patients with ME/CFS than in controls and CF patients and higher in the latter than in controls. Increased IL-1 and TNFα are significantly correlated with fatigue, sadness, autonomic symptoms, and a flu-like malaise; neopterin is correlated with fatigue, autonomic symptoms, and a flu-like malaise; and increased PMN-elastase is correlated with concentration difficulties, failing memory and a subjective experience of infection. The findings show that ME/CFS is characterized by low-grade inflammation and activation of CMI. The results suggest that characteristic symptoms of ME/CFS, such as fatigue, autonomic symptoms and a flu-like malaise, may be caused by inflammatory mediators, e.g. IL-1 and TNFα. Copyright © 2011 Elsevier B.V. All rights reserved.

Reversal in fatigued athletes of a defect in interferon gamma secretion after administration of Lactobacillus acidophilus.

PubMed

Clancy, R L; Gleeson, M; Cox, A; Callister, R; Dorrington, M; D'Este, C; Pang, G; Pyne, D; Fricker, P; Henriksson, A

2006-04-01

Fatigue and impaired performance in athletes is well recognised and has been loosely linked to "overtraining". Reduced concentration of IgA in the saliva and increased shedding of Epstein Barr virus (EBV) have been associated with intense training in elite athletes. To determine whether athletes presenting with fatigue and impaired performance had an immune defect relevant to defective containment of EBV infection, and whether a probiotic preparation (Lactobacillus acidophilus) shown to enhance mucosal immunity in animal models could reverse any detected abnormality. The fatigued athletes had clinical characteristics consistent with re-activation of EBV infection and significantly (p = 0.02) less secretion of interferon (IFN) gamma from blood CD4 positive T cells. After one month of daily capsules containing 2 x 10(10) colony forming units of L acidophilus, secretion of IFNgamma from T cells had increased significantly (p = 0.01) to levels found in healthy control athletes. A significant (p = 0.03) increase in salivary IFNgamma concentrations in healthy control athletes after the one month course of L acidophilus demonstrated in man the capacity for this probiotic to enhance the mucosal IFNgamma concentration. This is the first evidence of a T cell defect in fatigued athletes, and of its reversal following probiotic therapy.

Polysaccharide of radix pseudostellariae improves chronic fatigue syndrome induced by poly I:C in mice.

PubMed

Sheng, Rong; Xu, Xianxiang; Tang, Qin; Bian, Difei; Li, Ying; Qian, Cheng; He, Xin; Gao, Xinghua; Pan, Rong; Wang, Chong; Luo, Yubin; Xia, Yufeng; Dai, Yue

2011-01-01

Radix Pseudostellariae is used as a tonic drug in traditional Chinese medicine with immunomodulating and anti-fatigue activities, and the polysaccharide is considered as the main active component. The purpose of this study is to examine the effect of the polysaccharide isolated from Radix Pseudostellariae (PRP) on mouse chronic fatigue syndrome (CFS) induced by intraperitoneal injection of polyriboinosinic:polyribocytidylic acid (poly I:C), a double-stranded synthetic RNA. It has shown that the fatigue symptom of mice lasted at least 1 week as evaluated by forced swimming time. PRP (100, 200, 400 mg kg(-1)), orally administered 3 days before poly I:C injection, showed dose-dependent anti-fatigue effects. In addition, poly I:C led to evident alternations in neuroendocrine and immune systems of mice, such as reduced spontaneous activity and learning ability, declined serum level of corticosterone, increased weight indexes and T lymphocyte numbers in thymuses and spleens, and increased CD4(+)/CD8(+) ratio but decreased proliferation ability of T lymphocytes in spleens. PRP alleviated the abnormalities caused by poly I:C, and restored the function of hosts to normal conditions. The findings suggest that PRP is beneficial to CFS, and the underlying mechanisms of action involve neuroendocrine and immune systems.

Chronic fatigue syndrome: an update focusing on phenomenology and pathophysiology.

PubMed

Cho, Hyong Jin; Skowera, Anna; Cleare, Anthony; Wessely, Simon

2006-01-01

Chronic fatigue syndrome is a controversial condition especially concerning its clinical definition and aetiopathogenesis. Most recent research progress has been made in phenomenology and pathophysiology and we focused our review on these two areas. The phenomenology research supports the notion of a discrete fatigue syndrome which can be distinguished from depression and anxiety. The current case definition, however, may need an improvement based on empirical data. Recent advances in understanding the pathophysiology of chronic fatigue syndrome continue to demonstrate the involvement of the central nervous system. Hyperserotonergic state and hypoactivity of the hypothalamic-pituitary-adrenal axis constitute other findings, but the question of whether these alterations are a cause or consequence of chronic fatigue syndrome still remains unanswered. Immune system involvement in the pathogenesis seems certain but the findings on the specific mechanisms are still inconsistent. Genetic studies provide some evidence of the syndrome being a partly genetic condition, but environmental effects seem to be still predominant and identification of specific genes is still at a very early stage. The recent findings suggest that further research is needed in improving the current case definition; investigating overlaps and boundaries among various functional somatic syndromes; answering the question of whether the pathophysiologic findings are a cause or consequence; and elucidating the involvement of the central nervous system, immune system and genetic factors.

Muscle Dysfunction in Androgen Deprivation: Role of Ryanodine Receptor

DTIC Science & Technology

2016-11-01

undergoing ORX have reduced muscle specific force due to calcium leak through RyR1, which is caused by high levels of TGFβ released from the bone during... leak could be causing long-term effects, such as decreased muscle mass, body weight and forelimb grip strength. 15. SUBJECT TERMS Prostate Cancer...calcium leak and contractile dysfunction in chronic muscle fatigue, heart failure and muscular dystrophy (13-16). RyR1 is the skeletal muscle

Exhaustive submaximal endurance and resistance exercises induce temporary immunosuppression via physical and oxidative stress

PubMed Central

Jin, Chan-Ho; Paik, Il-Young; Kwak, Yi-Sub; Jee, Yong-Seok; Kim, Joo-Young

2015-01-01

Regular running and strength training are the best ways to improve aerobic capacity and develop the size of skeletal muscles. However, uncontrolled physical activities can often lead to an undertraining or over-training syndrome. In particular, overtraining causes persistent fatigue and reduces physical performance due to changes in the various physiological and immunological factors. In this study, we gave an exhaustive submaximal endurance or resistance exercise to participants and investigated the relationship between physical stress (cortisol level in blood), oxidative stress (intracellular ROS accumulation), and adaptive immune response (CD4:CD8 ratio). Materials and Methods Ten male volunteers were recruited, and performed a submaximal endurance or resistance exercise with 85% of VO2max or 1-repetition maximum until exhaustion. Blood samples were collected at rest, and at 0 and 30 min after the exercise. Cortisol levels, oxidative stress, and immune cell phenotypes in peripheral blood were evaluated. Cortisol levels in the sera increased after the exhaustive endurance and resistance exercises and such increments were maintained through the recovery. Intra-cellular ROS levels also increased after the exhaustive endurance and resistance exercises. The ratio of CD4+ T cells to CD8+ T cells after each type of submaximal exercise decreased compared with that at the resting stage, and returned to the resting level at 30 min after the exercise. In this study, an exhaustive endurance or a resistance exercise with submaximal intensity caused excessive physical stress, intra-cellular oxidative stress, and post-exercise immunosuppression. This result suggests that excessive physical stress induced temporary immune dysfunction via physical and oxidative stress. PMID:26331134

The impact of subjective cognitive fatigue and depression on cognitive function in patients with multiple sclerosis.

PubMed

Golan, Daniel; Doniger, Glen M; Wissemann, Karl; Zarif, Myassar; Bumstead, Barbara; Buhse, Marijean; Fafard, Lori; Lavi, Idit; Wilken, Jeffrey; Gudesblatt, Mark

2018-02-01

The association between subjective cognitive fatigue and objective cognitive dysfunction in patients with multiple sclerosis (PwMS) has been studied, with conflicting results. To explore the impact of fatigue on cognitive function, while controlling for the influence of depression, disability, comorbidities, and psychotropic medications. PwMS completed a computerized cognitive testing battery with age- and education-adjusted cognitive domain scores. Disability (Expanded Disability Status Scale (EDSS)), cognitive fatigue, and depression were concurrently evaluated. In all, 699 PwMS were included. Both cognitive fatigue and depression were significantly and negatively correlated with the same cognitive domains: information processing speed, executive function, attention, motor function, and memory (-0.15 ⩽ r ⩽ -0.14 for cognitive fatigue; -0.24 ⩽ r ⩽ -0.19 for depression). Multivariate analysis revealed significant but small independent correlations only between depression and neuropsychological test results, while cognitive fatigue had no independent correlation with objective cognitive function except for a trend toward impaired motor function in highly fatigued PwMS. Depression and cognitive fatigue accounted for no more than 6% of the variance in objective cognitive domain scores. Cognitive fatigue is not independently related to objective cognitive impairment. Depression may influence cognitive function of PwMS primarily when it is severe. Cognitive impairment in PwMS should not be ascribed to fatigue or mild depression.

Fatigue and neuromuscular diseases.

PubMed

Féasson, L; Camdessanché, J-P; El Mandhi, L; Calmels, P; Millet, G-Y

2006-07-01

To identify the role of fatigue, its evaluation and its causes in the pathophysiology context of acquired or hereditary neuromuscular diseases of the spinal anterior horn cell, peripheral nerve, neuromuscular junction and muscle. A literature review has been done on Medline with the following keywords: neuromuscular disease, peripheral neuropathy, myopathy, fatigue assessment, exercise intolerance, force assessment, fatigue scale and questionnaire, then with the terms: Fatigue Severity Scale, Chalder Fatigue Scale, Fatigue Questionnaire, Piper Fatigue Scale, electromyography and the combination of the word Fatigue with the following terms: Amyotrophic Lateral Sclerosis (ALS), Post-Polio Syndrome (PPS), Guillain-Barre Syndrome, Immune Neuropathy, Charcot-Marie-Tooth Disease, Myasthenia Gravis (MG), Metabolic Myopathy, Mitochondrial Myopathy, Muscular Dystrophy, Facioscapulohumeral Dystrophy, Myotonic Dystrophy. Fatigue is a symptom very frequently reported by patients. Fatigue is mainly evaluated by strength loss after an exercise, by change in electromyographic activity during a given exercise and by questionnaires that takes into account the subjective (psychological) part of fatigue. Due to the large diversity of motor disorders, there are multiple clinical expressions of fatigue that differ in their presentation, consequences and therapeutic approach. This review shows that fatigue has to be taken into account in patients with neuromuscular diseases. In this context, pathophysiology of fatigue often implies the motor component but the disease evolution and the physical obligates of daily life also induce an important psychological component.

The Environment-Immune Route to Chronic Disease

EPA Science Inventory

Specific environmental factors including chemicals, drugs, microbes and both physical and psychological factors can affect the immune system producing dysfunction and, ultimately, an increased risk ofchronic disease. Several different types of immune alterations can result from e...

Severe fatigue after treatment of ductal carcinoma in situ: A comparison with age-matched breast cancer survivors and healthy controls.

PubMed

Abrahams, H J G; Smits, L; Lugt, M de; Roos, W K de; Kamm, Y; Heins, M J; Verhagen, C A H H V M; Gielissen, M F M; Knoop, H

2017-02-01

Severe fatigue after treatment of ductal carcinoma in situ (DCIS) has not been studied before. The current study examined (i) the prevalence of severe fatigue in DCIS patients versus breast cancer survivors (BCS) and healthy controls (HC), (ii) quality of life and functioning of severely versus non-severely fatigued DCIS patients and BCS, and (iii) the association of fatigue with psychosocial and behavioral factors in DCIS patients. 89 patients treated for DCIS were matched on age and gender to 67 BCS and 178 HC (ratio 1:1:2). Fatigue was measured with the Fatigue Severity subscale of the Checklist Individual Strength. 23% of DCIS patients, 25% of BCS, and 6% of HC were severely fatigued (DCIS versus HC: p < 0.001). Severely fatigued DCIS patients had a lower quality of life and were more impaired in all domains of functioning than non-severely fatigued DCIS patients. Sleep problems, dysfunctional cognitions regarding fatigue, avoidance of activities, all-or-nothing behavior, perceived lack of social support, DCIS-related coping problems, and fear of future cancer occurrence were related to fatigue. The prevalence of severe fatigue in DCIS patients was similar to BCS, but higher than in HC. Severely fatigued DCIS patients had a lower quality of life and more functional impairments. The psychosocial and behavioral fatigue-related factors in DCIS patients are known to perpetuate fatigue in BCS. These factors can be targeted in interventions for cancer-related fatigue. Our findings suggest that the same treatment elements might be applicable to severely fatigued DCIS patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cytosolic nucleic acid sensors and innate immune regulation.

PubMed

Ori, Daisuke; Murase, Motoya; Kawai, Taro

2017-03-04

During viral and bacterial infections, pathogen-derived cytosolic nucleic acids are recognized by the intracellular RNA sensors retinoic acid-inducible gene I and melanoma-differentiated gene 5 and intracellular DNA sensors, including cyclic-di-GMP-AMP synthase, absent in melanoma 2, interferon (IFN)-gamma inducible protein 16, polymerase III, and so on. Binding of intracellular nucleic acids to these sensors activates downstream signaling cascades, resulting in the production of type I IFNs and pro-inflammatory cytokines to induce appropriate systematic immune responses. While these sensors also recognize endogenous nucleic acids and activate immune responses, they can discriminate between self- and non-self-nucleic acids. However, dysfunction of these sensors or failure of regulatory mechanisms causes aberrant activation of immune response and autoimmune disorders. In this review, we focus on how intracellular immune sensors recognize exogenous nucleic acids and activate the innate immune system, and furthermore, how autoimmune diseases result from dysfunction of these sensors.

New York City social workers after 9/11: their attachment, resiliency, and compassion fatigue.

PubMed

Tosone, Carol; Bettmann, Joanna E; Minami, Takuya; Jasperson, Rachael A

2010-01-01

This study examines the relationship between attachment classification, resiliency, and compassion fatigue in New York social workers following 9/11. We used single occasion, quasi-random sampling, surveying 481 social workers living in Manhattan. Hierarchical regression analyses revealed that secure attachment is predictive of the ability to cope with secondary traumatic stress as well as capacity for resilience, explaining approximately 7% of the variance in both compassion fatigue and resiliency. These findings suggest that secure attachment may serve as a source of resilience for social workers, immunizing them from significant compassion fatigue. Such findings have significant implications for clinicians working with traumatized populations.

Chronic Lung Allograft Dysfunction: A Systematic Review of Mechanisms.

PubMed

Royer, Pierre-Joseph; Olivera-Botello, Gustavo; Koutsokera, Angela; Aubert, John-David; Bernasconi, Eric; Tissot, Adrien; Pison, Christophe; Nicod, Laurent; Boissel, Jean-Pierre; Magnan, Antoine

2016-09-01

Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. Chronic lung allograft dysfunction manifests as bronchiolitis obliterans syndrome or the recently described restrictive allograft syndrome. Although numerous risk factors have been identified so far, the physiopathological mechanisms of CLAD remain poorly understood. We investigate here the immune mechanisms involved in the development of CLAD after lung transplantation. We explore the innate or adaptive immune reactions induced by the allograft itself or by the environment and how they lead to allograft dysfunction. Because current literature suggests bronchiolitis obliterans syndrome and restrictive allograft syndrome as 2 distinct entities, we focus on the specific factors behind one or the other syndromes. Chronic lung allograft dysfunction is a multifactorial disease that remains irreversible and unpredictable so far. We thus finally discuss the potential of systems-biology approach to predict its occurrence and to better understand its underlying mechanisms.

Type 2 responses at the interface between immunity and fat metabolism.

PubMed

Odegaard, Justin I; Chawla, Ajay

2015-10-01

Adipose tissue resident leukocytes are often cast solely as the effectors of obesity and its attendant pathologies; however, recent observations have demonstrated that these cells support and effect 'healthy' physiologic function as well as pathologic dysfunction. Importantly, these two disparate outcomes are underpinned by similarly disparate immune programs; type 2 responses instruct and promote metabolic normalcy, while type 1 responses drive tissue dysfunction. In this Review, we summarize the literature regarding type 2 immunity's role in adipose tissue physiology and allude to its potential therapeutic implications. Copyright © 2015 Elsevier Ltd. All rights reserved.

Longitudinal peripheral blood transcriptional analysis of a patient with severe Ebola virus disease.

PubMed

Kash, John C; Walters, Kathie-Anne; Kindrachuk, Jason; Baxter, David; Scherler, Kelsey; Janosko, Krisztina B; Adams, Rick D; Herbert, Andrew S; James, Rebekah M; Stonier, Spencer W; Memoli, Matthew J; Dye, John M; Davey, Richard T; Chertow, Daniel S; Taubenberger, Jeffery K

2017-04-12

The 2013-2015 outbreak of Ebola virus disease in Guinea, Liberia, and Sierra Leone was unprecedented in the number of documented cases, but there have been few published reports on immune responses in clinical cases and their relationships with the course of illness and severity of Ebola virus disease. Symptoms of Ebola virus disease can include severe headache, myalgia, asthenia, fever, fatigue, diarrhea, vomiting, abdominal pain, and hemorrhage. Although experimental treatments are in development, there are no current U.S. Food and Drug Administration-approved vaccines or therapies. We report a detailed study of host gene expression as measured by microarray in daily peripheral blood samples collected from a patient with severe Ebola virus disease. This individual was provided with supportive care without experimental therapies at the National Institutes of Health Clinical Center from before onset of critical illness to recovery. Pearson analysis of daily gene expression signatures revealed marked gene expression changes in peripheral blood leukocytes that correlated with changes in serum and peripheral blood leukocytes, viral load, antibody responses, coagulopathy, multiple organ dysfunction, and then recovery. This study revealed marked shifts in immune and antiviral responses that preceded changes in medical condition, indicating that clearance of replicating Ebola virus from peripheral blood leukocytes is likely important for systemic viral clearance. Copyright © 2017, American Association for the Advancement of Science.

Losartan treatment attenuates tumor-induced myocardial dysfunction

PubMed Central

Stevens, Sarah CW; Velten, Markus; Youtz, Dane J.; Clark, Yvonne; Jing, Runfeng; Reiser, Peter J.; Bicer, Sabahattin; Devine, Raymond; McCarthy, Donna O.; Wold, Loren E.

2015-01-01

Fatigue and muscle wasting are common symptoms experienced by cancer patients. Data from animal models demonstrate that angiotensin is involved in tumor-induced muscle wasting, and that tumor growth can independently affect myocardial function, which could contribute to fatigue in cancer patients. In clinical studies, inhibitors of angiotensin converting enzyme (ACE) can prevent the development of chemotherapy-induced cardiovascular dysfunction, suggesting a mechanistic role for the renin-angiotensin-aldosterone system (RAAS). In the present study, we investigated whether an angiotensin (AT)1-receptor antagonist could prevent the development of tumor-associated myocardial dysfunction. Methods and Results: Colon26 adenocarcinoma (c26) cells were implanted into female CD2F1 mice at 8 weeks of age. Simultaneously, mice were administered Losartan (10 mg/kg) daily via their drinking water. In vivo echocardiography, blood pressure, in vitro cardiomyocyte function, cell proliferation assays, and measures of systemic inflammation and myocardial protein degradation were performed 19 days following tumor cell injection. Losartan treatment prevented tumor-induced loss of muscle mass and in vitro c26 cell proliferation, decreased tumor weight, and attenuated myocardial expression of interleukin-6. Furthermore, Losartan treatment mitigated tumor-associated alterations in calcium signaling in cardiomyocytes, which was associated with improved myocyte contraction velocity, systolic function, and blood pressures in the hearts of tumor-bearing mice. Conclusions: These data suggest that Losartan may mitigate tumor-induced myocardial dysfunction and inflammation. PMID:25988231

Losartan treatment attenuates tumor-induced myocardial dysfunction.

PubMed

Stevens, Sarah C W; Velten, Markus; Youtz, Dane J; Clark, Yvonne; Jing, Runfeng; Reiser, Peter J; Bicer, Sabahattin; Devine, Raymond D; McCarthy, Donna O; Wold, Loren E

2015-08-01

Fatigue and muscle wasting are common symptoms experienced by cancer patients. Data from animal models demonstrate that angiotensin is involved in tumor-induced muscle wasting, and that tumor growth can independently affect myocardial function, which could contribute to fatigue in cancer patients. In clinical studies, inhibitors of angiotensin converting enzyme (ACE) can prevent the development of chemotherapy-induced cardiovascular dysfunction, suggesting a mechanistic role for the renin-angiotensin-aldosterone system (RAAS). In the present study, we investigated whether an angiotensin (AT) 1-receptor antagonist could prevent the development of tumor-associated myocardial dysfunction. Colon26 adenocarcinoma (c26) cells were implanted into female CD2F1 mice at 8weeks of age. Simultaneously, mice were administered Losartan (10mg/kg) daily via their drinking water. In vivo echocardiography, blood pressure, in vitro cardiomyocyte function, cell proliferation assays, and measures of systemic inflammation and myocardial protein degradation were performed 19days following tumor cell injection. Losartan treatment prevented tumor-induced loss of muscle mass and in vitro c26 cell proliferation, decreased tumor weight, and attenuated myocardial expression of interleukin-6. Furthermore, Losartan treatment mitigated tumor-associated alterations in calcium signaling in cardiomyocytes, which was associated with improved myocyte contraction velocity, systolic function, and blood pressures in the hearts of tumor-bearing mice. These data suggest that Losartan may mitigate tumor-induced myocardial dysfunction and inflammation. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Chronic Fatigue Syndrome (CFS) severity score based on case designation criteria.

PubMed

Baraniuk, James N; Adewuyi, Oluwatoyin; Merck, Samantha Jean; Ali, Mushtaq; Ravindran, Murugan K; Timbol, Christian R; Rayhan, Rakib; Zheng, Yin; Le, Uyenphuong; Esteitie, Rania; Petrie, Kristina N

2013-01-01

Chronic Fatigue Syndrome case designation criteria are scored as physicians' subjective, nominal interpretations of patient fatigue, pain (headaches, myalgia, arthralgia, sore throat and lymph nodes), cognitive dysfunction, sleep and exertional exhaustion. Subjects self-reported symptoms using an anchored ordinal scale of 0 (no symptom), 1 (trivial complaints), 2 (mild), 3 (moderate), and 4 (severe). Fatigue of 3 or 4 distinguished "Fatigued" from "Not Fatigued" subjects. The sum of the 8(Sum8) ancillary criteria was tested as a proxy for fatigue. All subjects had history and physical examinations to exclude medical fatigue, and ensure categorization as healthy or CFS subjects. Fatigued subjects were divided into CFS with ≥4 symptoms or Chronic Idiopathic Fatigue (CIF) with ≤3 symptoms. ROC of Sum8 for CFS and Not Fatigued subjects generated a threshold of 14 (specificity=0.934; sensitivity=0.928). CFS (n=256) and CIF (n=55) criteria were refined to include Sum8≥14 and ≤13, respectively. Not Fatigued subjects had highly skewed Sum8 responses. Healthy Controls (HC; n=269) were defined by fatigue≤2 and Sum8≤13. Those with Sum8≥14 were defined as CFS-Like With Insufficient Fatigue Syndrome (CFSLWIFS; n=20). Sum8 and Fatigue were highly correlated (R(2)=0.977; Cronbach's alpha=0.924) indicating an intimate relationship between symptom constructs. Cluster analysis suggested 4 clades each in CFS and HC. Translational utility was inferred from the clustering of proteomics from cerebrospinal fluid. Plotting Fatigue severity versus Sum8 produced an internally consistent classifying system. This is a necessary step for translating symptom profiles into fatigue phenotypes and their pathophysiological mechanisms.

Dendritic cells modulate lung response to Pseudomonas aeruginosa in a murine model of sepsis-induced immune dysfunction.

PubMed

Pène, Frédéric; Zuber, Benjamin; Courtine, Emilie; Rousseau, Christophe; Ouaaz, Fatah; Toubiana, Julie; Tazi, Asmaa; Mira, Jean-Paul; Chiche, Jean-Daniel

2008-12-15

Host infection by pathogens triggers an innate immune response leading to a systemic inflammatory response, often followed by an immune dysfunction which can favor the emergence of secondary infections. Dendritic cells (DCs) link innate and adaptive immunity and may be centrally involved in the regulation of sepsis-induced immune dysfunction. We assessed the contribution of DCs to lung defense in a murine model of sublethal polymicrobial sepsis (cecal ligature and puncture, CLP). In this model, bone marrow-derived DCs (BMDCs) retained an immature phenotype, associated with decreased capacity of IL-12p70 release and impaired priming of T cell lymphocytes. Eight days after CLP surgery, we induced a secondary pulmonary infection through intratracheal instillation of 5 x 10(6) CFUs of Pseudomonas aeruginosa. Whereas all sham-operated mice survived, 80% of post-CLP mice died after secondary pneumonia. Post-CLP mice exhibited marked lung damage with early recruitment of neutrophils, cytokine imbalance with decreased IL-12p70 production, and increased IL-10 release, but no defective bacterial lung clearance, while systemic bacterial dissemination was almost constant. Concomitant intrapulmonary administration of exogenous BMDCs into post-CLP mice challenged with P. aeruginosa dramatically improved survival. BMDCs did not improve bacterial lung clearance, but delayed neutrophil recruitment, strongly attenuated the early peak of TNF-alpha and restored an adequate Il-12p70/IL-10 balance in post-CLP mice. Thus, adoptive transfer of BMDCs reversed sepsis-induced immune dysfunction in a relevant model of secondary P. aeruginosa pneumonia. Unexpectedly, the mechanism of action of BMDCs did not involve enhanced antibacterial activity, but occurred by dampening the pulmonary inflammatory response.

Anti-fatigue and vasoprotective effects of quercetin-3-O-gentiobiose on oxidative stress and vascular endothelial dysfunction induced by endurance swimming in rats.

PubMed

Lin, Yin; Liu, Hua-Liang; Fang, Jie; Yu, Chen-Huan; Xiong, Yao-Kang; Yuan, Ke

2014-06-01

Chronic fatigue accumulation increases the incidence of cardiovascular disease while the treatment of antioxidants could prevent this development. We have previously shown that quercetin-3-O-gentiobiose (QG), a flavonoid isolated from tonic herb Okra, possesses anti-oxidative properties. In the present study, the protective effects of QG were evaluated in a rat model of load-induced endurance swimming. Oral administration of QG at the doses of 25-75mg/kg could significantly improve the endurance capability of rats to fatigue along with decrease serum lactic acid and blood urea nitrogen levels were decreased. Moreover, QG could alleviate vascular impairments, enhance the activities of antioxidant enzymes and attenuate the levels of inflammatory cytokines (MCP-1, IL-6 and TNF-α). The results indicated that QG had anti-fatigue and vasoprotective effects and represented a potential agent for the treatment of aortic pathology involved with fatigue- and related syndrome. Copyright © 2014 Elsevier Ltd. All rights reserved.

Muscle fatigue in fibromyalgia is in the brain, not in the muscles: a case-control study of perceived versus objective muscle fatigue.

PubMed

Bandak, Elisabeth; Amris, Kirstine; Bliddal, Henning; Danneskiold-Samsøe, Bente; Henriksen, Marius

2013-06-01

To investigate relationships between perceived and objectively measured muscle fatigue during exhausting muscle contractions in women with fibromyalgia (FM) compared with healthy controls (HC). Women with FM and HC completed an isometric muscle exhaustion task at 90° shoulder abduction. Surface electromyographic (EMG) activity in the deltoid muscle was recorded together with self-reported level of muscle fatigue. 25 participants with FM and 23 HC were included. Average time to exhaustion was 254 s shorter in participants with FM than in HC. Participants with FM did not exhibit the same level of objective signs of muscle fatigue, seen as fewer changes in the EMG activity, as the HC during the exhaustion task. The task did not provoke pain in the HC, while participants with FM reported a doubling of pain. Women with FM had shorter exhaustion times and showed fewer objective signs of muscle fatigue during an exhausting isometric shoulder abduction compared with younger HC. This indicates that perceived muscle fatigue may be of central origin and supports the notion of central nervous dysfunction as basic pathological changes in FM.

Molecular Signatures of Peripheral Blood Mononuclear Cells during Chronic Interferon-alpha Treatment: Relationship with Depression and Fatigue

PubMed Central

Felger, Jennifer C.; Cole, Steve W.; Pace, Thaddeus W. W.; Hu, Fang; Woolwine, Bobbi J.; Doho, Gregory H.; Raison, Charles L.; Miller, Andrew H.

2012-01-01

Background Interferon (IFN)-alpha treatment for infectious disease and cancer causes high rates of depression and fatigue, and has been used to investigate the impact of inflammatory cytokines on brain and behavior. However, little is known about the transcriptional impact of chronic IFN-alpha on immune cells in vivo and its relationship to IFN-alpha-induced behavioral changes. Methods Genome-wide transcriptional profiling was performed on peripheral blood mononuclear cells from 21 patients with chronic hepatitis C either awaiting IFN-alpha therapy (n=10) or at 12 weeks of IFN-alpha treatment (n=11). Results Significance analysis of microarray data identified 252 up-regulated and 116 down-regulated gene transcripts. Of up-regulated genes, 2'-5'-oligoadenylate synthetase 2 (OAS2), a gene linked to chronic fatigue syndrome (CFS), was the only gene that was differentially expressed in patients with IFN-alpha-induced depression/fatigue, and correlated with depression and fatigue scores at 12 weeks (r=0.80, p=0.003 and r=0.70, p=0.017, respectively). Promoter-based bioinformatic analyses linked IFN-alpha-related transcriptional alterations to transcription factors involved in myeloid differentiation, IFN-alpha signaling, AP1 and CREB/ATF pathways, which were derived primarily from monocytes and plasmacytoid dendritic cells. IFN-alpha-treated patients with high depression/fatigue scores demonstrated up-regulation of genes bearing promoter motifs for transcription factors involved in myeloid differentiation, IFN-alpha and AP1 signaling, and reduced prevalence of motifs for CREB/ATF, which has been implicated in major depression. Conclusions Depression and fatigue during chronic IFN-alpha administration were associated with alterations in the expression (OAS2) and transcriptional control (CREB/ATF) of genes linked to behavioral disorders including CFS and major depression, further supporting an immune contribution to these diseases. PMID:22152193

T Follicular Helper Cells and B Cell Dysfunction in Aging and HIV-1 Infection

PubMed Central

Pallikkuth, Suresh; de Armas, Lesley; Rinaldi, Stefano; Pahwa, Savita

2017-01-01

T follicular helper (Tfh) cells are a subset of CD4 T cells that provide critical signals to antigen-primed B cells in germinal centers to undergo proliferation, isotype switching, and somatic hypermutation to generate long-lived plasma cells and memory B cells during an immune response. The quantity and quality of Tfh cells therefore must be tightly controlled to prevent immune dysfunction in the form of autoimmunity and, on the other hand, immune deficiency. Both Tfh and B cell perturbations appear during HIV infection resulting in impaired antibody responses to vaccines such as seasonal trivalent influenza vaccine, also seen in biologic aging. Although many of the HIV-associated defects improve with antiretroviral therapy (ART), excess immune activation and antigen-specific B and T cell responses including Tfh function are still impaired in virologically controlled HIV-infected persons on ART. Interestingly, HIV infected individuals experience increased risk of age-associated pathologies. This review will discuss Tfh and B cell dysfunction in HIV infection and highlight the impact of chronic HIV infection and aging on Tfh–B cell interactions. PMID:29109730

T Follicular Helper Cells and B Cell Dysfunction in Aging and HIV-1 Infection.

PubMed

Pallikkuth, Suresh; de Armas, Lesley; Rinaldi, Stefano; Pahwa, Savita

2017-01-01

T follicular helper (Tfh) cells are a subset of CD4 T cells that provide critical signals to antigen-primed B cells in germinal centers to undergo proliferation, isotype switching, and somatic hypermutation to generate long-lived plasma cells and memory B cells during an immune response. The quantity and quality of Tfh cells therefore must be tightly controlled to prevent immune dysfunction in the form of autoimmunity and, on the other hand, immune deficiency. Both Tfh and B cell perturbations appear during HIV infection resulting in impaired antibody responses to vaccines such as seasonal trivalent influenza vaccine, also seen in biologic aging. Although many of the HIV-associated defects improve with antiretroviral therapy (ART), excess immune activation and antigen-specific B and T cell responses including Tfh function are still impaired in virologically controlled HIV-infected persons on ART. Interestingly, HIV infected individuals experience increased risk of age-associated pathologies. This review will discuss Tfh and B cell dysfunction in HIV infection and highlight the impact of chronic HIV infection and aging on Tfh-B cell interactions.

Non-celiac gluten sensitivity triggers gut dysbiosis, neuroinflammation, gut-brain axis dysfunction, and vulnerability for dementia.

PubMed

Daulatzai, Mak Adam

2015-01-01

The non-celiac gluten sensitivity (NCGS) is a chronic functional gastrointestinal disorder which is very common world wide. The human gut harbors microbiota which has a wide variety of microbial organisms; they are mainly symbiotic and important for well being. However, "dysbiosis" - i.e. an alteration in normal commensal gut microbiome with an increase in pathogenic microbes, impacts homeostasis/health. Dysbiosis in NCGS causes gut inflammation, diarrhea, constipation, visceral hypersensitivity, abdominal pain, dysfunctional metabolic state, and peripheral immune and neuro-immune communication. Thus, immune-mediated gut and extra-gut dysfunctions, due to gluten sensitivity with comorbid diarrhea, may last for decades. A significant proportion of NCGS patients may chronically consume alcohol, non-steroidal anti-inflammatory drugs, and fatty diet, as well as suffer from various comorbid disorders. The above pathophysiological substrate and dysbiosis are underpinned by dysfunctional bidirectional "Gut-Brain Axis" pathway. Pathogenic gut microbiota is known to upregulate gut- and systemic inflammation (due to lipopolysaccharide from pathogenic bacteria and synthesis of pro-inflammatory cytokines); they enhance energy harvest, cause obesity, insulin resistance, and dysfunctional vago-vagal gut-brain axis. Conceivably, the above cascade of pathology may promote various pathophysiological mechanisms, neuroinflammation, and cognitive dysfunction. Hence, dysbiosis, gut inflammation, and chronic dyshomeostasis are of great clinical relevance. It is argued here that we need to be aware of NCGS and its chronic pathophysiological impact. Therapeutic measures including probiotics, vagus nerve stimulation, antioxidants, alpha 7 nicotinic receptor agonists, and corticotropin-releasing factor receptor 1 antagonist may ameliorate neuroinflammation and oxidative stress in NCGS; they may therefore, prevent cognitive dysfunction and vulnerability to Alzheimer's disease.

Heat shock proteins and chronic fatigue in primary Sjögren's syndrome.

PubMed

Bårdsen, Kjetil; Nilsen, Mari Mæland; Kvaløy, Jan Terje; Norheim, Katrine Brække; Jonsson, Grete; Omdal, Roald

2016-04-01

Fatigue occurs frequently in patients with cancer, neurological diseases and chronic inflammatory diseases, but the biological mechanisms that lead to and regulate fatigue are largely unknown. When the innate immune system is activated, heat shock proteins (HSPs) are produced to protect cells. Some extracellular HSPs appear to recognize cellular targets in the brain, and we hypothesize that fatigue may be generated by specific HSPs signalling through neuronal or glial cells in the central nervous system. From a cohort of patients with primary Sjögren's syndrome, 20 patients with high and 20 patients with low fatigue were selected. Fatigue was evaluated with a fatigue visual analogue scale. Plasma concentrations of HSP32, HSP60, HSP72 and HSP90α were measured and analysed to determine if there were associations with the level of fatigue. Plasma concentrations of HSP90α were significantly higher in patients with high fatigue compared with those with low fatigue, and there was a tendency to higher concentrations of HSP72 in patients with high fatigue compared with patients with low fatigue. There were no differences in concentrations of HSP32 and HSP60 between the high- and low-fatigue groups. Thus, extracellular HSPs, particularly HSP90α, may signal fatigue in chronic inflammation. This supports the hypothesis that fatigue is generated by cellular defence mechanisms. © The Author(s) 2016.

The fatigue experience for women with human immunodeficiency virus.

PubMed

Lee, K A; Portillo, C J; Miramontes, H

1999-01-01

To examine fatigue as a symptom experienced by women with human immunodeficiency virus (HIV). A convenience sample of 100 women with HIV. Independent sample t-tests were used to test for mean differences in fatigue related to variables in the women's sociocultural and home environment (ethnicity, employment, marital status, and parenting). Pearson product moment correlations were used to examine significant relationships between fatigue and physiologic variables (age, CD4 cell count, and sleep). Lower CD4 cell counts were related to more daytime sleep, higher evening fatigue, and higher morning fatigue. Morning fatigue was related to duration of wake episodes during the night, napping, and perception of sleep disturbance during the past week. The number of awakenings during the first night predicted the severity of fatigue the next evening. To understand the fatigue experienced by women with HIV, researchers and clinicians must focus on the relative contributions of sociocultural, home, and physiologic environments within which these women live. Additional research is ongoing to identify the strategies these women use to manage daily activities such that gender-relevant and culturally relevant interventions for alleviating fatigue can be tested in women with a variety of chronic illnesses, including HIV and acquired immune deficiency syndrome.

Decoupling activation and exhaustion of B cells in spontaneous controllers of HIV infection

PubMed Central

Sciaranghella, Gaia; Tong, Neath; Mahan, Alison E.; Suscovich, Todd J.; Alter, Galit

2013-01-01

Objective To define the impact of chronic viremia and associated immune activation on B-cell exhaustion in HIV infection. Design Progressive HIV infection is marked by B-cell anergy and exhaustion coupled with dramatic hypergammaglobulinemia. Although both upregulation of CD95 and loss of CD21 have been used as markers of infection-associated B-cell dysfunction, little is known regarding the specific profiles of dysfunctional B cells and whether persistent viral replication and its associated immune activation play a central role in driving B-cell dysfunction. Methods Multiparameter flow cytometry was used to define the profile of dysfunctional B cells. The changes in the expression of CD21 and CD95 were tracked on B-cell subpopulations in patients with differential control of viral replication. Results Although the emergence of exhausted, CD21low tissue-like memory B cells followed similar patterns in both progressors and controllers, the frequency of CD21low activated memory B cells was lower in spontaneous controllers. Conclusion Our results suggest that the loss of CD21 and the upregulation of CD95 occur as separate events during the development of B-cell dysfunction. The loss of CD21 is a marker of B-cell exhaustion induced in the absence of appreciable viral replication, whereas the upregulation of CD95 is tightly linked to persistent viral replication and its associated immune activation. Thus, these dysfunctional profiles potentially represent two functionally distinct states within the B-cell compartment. PMID:23135171

A mechanism for trauma induced muscle wasting and immune dysfunction

NASA Astrophysics Data System (ADS)

Madihally, S.; Toner, M.; Yarmush, M.; Mitchell, R.

A diverse physiological conditions lead to a hypercatabolic state marked by the loss of proteins, primarily derived from skeletal muscle. The sustained loss of proteins results in loss of muscle mass and strength, poor healing, and long-term hospitalization. These problems are further compounded by the deterioration of immunity to infection which is a leading cause of morbidity and mortality of traumatic patients. In an attempt to understand the signal propagation mechanism(s), we tested the role of Interferon-? (IFN-? ) in an animal burn injury model; IFN-? is best conceptualized as a macrophage activating protein and known to modulate a variety of intracellular processes potentially relevant to muscle wasting and immune dysfunction. Mice congenitally -deficient in IFN-? , and IFN-? -Receptor, and wild type (WT) animals treated with IFN-? neutralizing antibody received either a 20% total body surface area burn or a control sham treatment. At days 1, 2, and 7 following treatment, skeletal muscle, peripheral blood, and spleen were harvested from both groups. Overall body weight, protein turnovers, changes in the lymphocyte subpopulations and alterations in the major histocompatibility complex I expression (MHC I) and proliferation capacity of lymphocytes was measured using mixed lymphocyte reaction (MLR). These results indicate that we can prevent both muscle wasting and immune dysfunction. Based on these observations and our previous other animal model results (using insulin therapy), a novel mechanism of interactions leading to muscle wasting and immune dysfunction will be discussed. Further, implications of these findings on future research and clinical therapies will be discussed in detail.

Hyperexcitability to electrical stimulation and accelerated muscle fatiguability of taut bands in rats.

PubMed

Wang, Yong-Hui; Yin, Ming-Jing; Fan, Zhen-Zhen; Arendt-Nielsen, Lars; Ge, Hong-You; Yue, Shou-Wei

2014-04-01

Myofascial trigger points contribute significantly to musculoskeletal pain and motor dysfunction and may be associated with accelerated muscle fatiguability. The aim of this study was to investigate the electrically induced force and fatigue characteristics of muscle taut bands in rats. Muscle taut bands were dissected out and subjected to trains of electrical stimulation. The electrical threshold intensity for muscle contraction and maximum contraction force (MCF), electrical intensity dependent fatigue and electrical frequency dependent fatigue characteristics were assessed in three different sessions (n=10 each) and compared with non-taut bands in the biceps femoris muscle. The threshold intensity for muscle contraction and MCF at the 10th, 15th and 20th intensity dependent fatigue stimuli of taut bands were significantly lower than those of non-taut bands (all p<0.05). The MCF at the 15th and 20th intensity dependent fatigue stimuli of taut bands were significantly lower than those at the 1st and 5th stimuli (all p<0.01). The MCF in the frequency dependent fatigue test was significantly higher and the stimulus frequency that induced MCF was significantly lower for taut bands than for non-taut bands (both p<0.01). The present study demonstrates that the muscle taut band itself was more excitable to electrical stimulation and significantly less fatigue resistant than normal muscle fibres.

[Integrated Chinese and Western medical treatment on postoperative fatigue syndrome in patients with gastric cancer].

PubMed

Dong, Qian-Tong; Zhang, Xiao-Dong; Yu, Zhen

2010-10-01

To evaluate the effect of the combined use of Shenmai Injection (SMI) and enteral nutrition on postoperative fatigue syndrome (POFS) in patients with gastric cancer (GC). Fifty-eight GC patients were randomized into the parenteral nutrition group (PNG, 19 cases), enteral nutrition group (ENG, 19 cases) and combined treatment group (CTG, 20 cases). The post-operative recovery in patients was observed; patients' conditions of fatigue, mood and sleep were evaluated respectively by visual analogue scale of fatigue, profile of mood states (POMS) and Pittsburgh sleep quality index (PSQI). Meanwhile, nutritional variables, such as serum contents of total protein, albumin, pre-albumin, were measured at different time points: before operation (d0) and the 1st, 5th, and 9th day (d1, d5 and d9) after operation. Immune variables such as subsets of lymphocytes (CD3, CD4, CD8), serum immunoglobulins (IgG, IgM, IgA) were also determined. Conditions of recovery, POMS and PSQI were better and the postoperative fatigue reduced more significantly in CTG than those in the other two groups (P < 0.05). On d9, levels of pre-albumin, CD3, CD4, CD4/CD8 in CTG were significantly higher than those in the PNG and ENG (P < 0.05), meantime, levels of albumin and IgA were higher in CTG than those in PNG (P < 0.05). Combined treatment of SMI and enteral nutrition can regulate mood and sleep to some extents, and reduce the postoperative fatigue through improving nutritional status and immune function, thus speeding up the recovery of patients.

Increased Incidence of Fatigue in Patients with Primary Immunodeficiency Disorders: Prevalence and Associations Within the US Immunodeficiency Network Registry.

PubMed

Hajjar, Joud; Guffey, Danielle; Minard, Charles G; Orange, Jordan S

2017-02-01

Patients with primary immunodeficiency (PID) often report fatigue, yet this symptom has not been studied in PID. Fatigue affects 6-7.5% of healthy adults. The goal of this study is to estimate the prevalence of fatigue in patients with PID and investigate its associated factors. We analyzed 2537 PID patients registered in USIDNET to determine responses to the field "fatigue" in the core registry form. Demographics, immune phenotypes, and comorbid conditions were compared between fatigued and non-fatigued patients to identify relevant associations and potential drivers. A focused analysis was performed for patients with predominantly antibody deficiency disorders (PADs). Fatigue was reported in 25.9% (95% CI 23.7-28.3) of PAD patients, compared to 6.4% (95% CI 4.9-8.2) of non-PAD. Patients with common variable immunodeficiency (CVID) had the highest prevalence of fatigue (p < 0.001) among all PID diagnoses. Other factors that were associated with a higher rate of fatigue among PAD patients included female sex, higher BMI, depression, bronchiectasis, and autoimmunity. Additionally, fatigued PAD patients had lower absolute lymphocyte, CD3, CD4, and CD8 counts compared to non-fatigued patients. Our findings suggest that fatigue is overrepresented in PAD patients. Prospective studies to estimate prevalence, risk factors, and fatigue etiology in PID are warranted, so therapeutic interventions can be considered.

The choreography of neuroinflammation in Huntington’s disease

PubMed Central

Crotti, Andrea; Glass, Christopher K.

2016-01-01

Currently, the concept of ‘neuroinflammation’ includes inflammation associated with neurodegenerative diseases, in which there is little or no infiltration of blood-derived immune cells into the brain. The roles of brain-resident and peripheral immune cells in these inflammatory settings are poorly understood, and it is unclear whether neuroinflammation results from immune reaction to neuronal dysfunction/degeneration, and/or represents cell-autonomous phenotypes of dysfunctional immune cells. Here, we review recent studies examining these questions in the context of Huntington’s disease (HD), where mutant Huntingtin (HTT) is expressed in both neurons and glia. Insights into the cellular and molecular mechanisms underlying neuroinflammation in HD may provide a better understanding of inflammation in more complex neurodegenerative disorders, and of the contribution of the neuroinflammatory component to neurodegenerative disease pathogenesis. PMID:26001312

A Chronic Fatigue Syndrome (CFS) severity score based on case designation criteria

PubMed Central

Baraniuk, James N; Adewuyi, Oluwatoyin; Merck, Samantha Jean; Ali, Mushtaq; Ravindran, Murugan K; Timbol, Christian R; Rayhan, Rakib; Zheng, Yin; Le, Uyenphuong; Esteitie, Rania; Petrie, Kristina N

2013-01-01

Background: Chronic Fatigue Syndrome case designation criteria are scored as physicians’ subjective, nominal interpretations of patient fatigue, pain (headaches, myalgia, arthralgia, sore throat and lymph nodes), cognitive dysfunction, sleep and exertional exhaustion. Methods: Subjects self-reported symptoms using an anchored ordinal scale of 0 (no symptom), 1 (trivial complaints), 2 (mild), 3 (moderate), and 4 (severe). Fatigue of 3 or 4 distinguished “Fatigued” from “Not Fatigued” subjects. The sum of the 8(Sum8) ancillary criteria was tested as a proxy for fatigue. All subjects had history and physical examinations to exclude medical fatigue, and ensure categorization as healthy or CFS subjects. Results: Fatigued subjects were divided into CFS with ≥4 symptoms or Chronic Idiopathic Fatigue (CIF) with ≤3 symptoms. ROC of Sum8 for CFS and Not Fatigued subjects generated a threshold of 14 (specificity=0.934; sensitivity=0.928). CFS (n=256) and CIF (n=55) criteria were refined to include Sum8≥14 and ≤13, respectively. Not Fatigued subjects had highly skewed Sum8 responses. Healthy Controls (HC; n=269) were defined by fatigue≤2 and Sum8≤13. Those with Sum8≥14 were defined as CFS–Like With Insufficient Fatigue Syndrome (CFSLWIFS; n=20). Sum8 and Fatigue were highly correlated (R2=0.977; Cronbach’s alpha=0.924) indicating an intimate relationship between symptom constructs. Cluster analysis suggested 4 clades each in CFS and HC. Translational utility was inferred from the clustering of proteomics from cerebrospinal fluid. Conclusions: Plotting Fatigue severity versus Sum8 produced an internally consistent classifying system. This is a necessary step for translating symptom profiles into fatigue phenotypes and their pathophysiological mechanisms. PMID:23390566

Relationship of Mitochondrial Enzymes to Fatigue Intensity in Men With Prostate Cancer Receiving External Beam Radiation Therapy

PubMed Central

Filler, Kristin; Lyon, Debra; McCain, Nancy; Bennett, James; Fernández-Martínez, Juan Luis; deAndrés-Galiana, Enrique Juan; Elswick, R. K.; Lukkahatai, Nada; Saligan, Leorey

2015-01-01

Purpose: Mitochondrial dysfunction is a plausible biological mechanism for cancer-related fatigue. Specific aims of this study were to (1) describe the levels of mitochondrial oxidative phosphorylation complex (MOPC) enzymes, fatigue, and health-related quality of life (HRQOL) before and at completion of external beam radiation therapy (EBRT) in men with nonmetastatic prostate cancer (PC); (2) examine relationships over time among levels of MOPC enzymes, fatigue, and HRQOL; and (3) compare levels of MOPC enzymes in men with clinically significant and nonsignificant fatigue intensification during EBRT. Methods: Fatigue was measured by the revised Piper Fatigue Scale and the Functional Assessment of Cancer Therapy–Fatigue subscale (FACT-F). MOPC enzymes (Complexes I–V) and mitochondrial antioxidant superoxide dismutase 2 were measured in peripheral blood using enzyme-linked immunosorbent assay at baseline and completion of EBRT. Participants were categorized into high or low fatigue (HF vs. LF) intensification groups based on amount of change in FACT-F scores during EBRT. Results: Fatigue reported by the 22 participants with PC significantly worsened and HRQOL significantly declined from baseline to EBRT completion. The HF group comprised 12 men with clinically significant change in fatigue (HF) during EBRT. Although no significant changes were observed in MOPC enzymes from baseline to EBRT completion, there were important differences in the patterns in the levels of MOPC enzymes between HF and LF groups. Conclusion: Distinct patterns of changes in the absorbance of MOPC enzymes delineated fatigue intensification among participants. Further investigation using a larger sample is warranted. PMID:26584846

Gut epithelial barrier dysfunction in human immunodeficiency virus-hepatitis C virus coinfected patients: Influence on innate and acquired immunity.

PubMed

Márquez, Mercedes; Fernández Gutiérrez del Álamo, Clotilde; Girón-González, José Antonio

2016-01-28

Even in cases where viral replication has been controlled by antiretroviral therapy for long periods of time, human immunodeficiency virus (HIV)-infected patients have several non-acquired immunodeficiency syndrome (AIDS) related co-morbidities, including liver disease, cardiovascular disease and neurocognitive decline, which have a clear impact on survival. It has been considered that persistent innate and acquired immune activation contributes to the pathogenesis of these non-AIDS related diseases. Immune activation has been related with several conditions, remarkably with the bacterial translocation related with the intestinal barrier damage by the HIV or by hepatitis C virus (HCV)-related liver cirrhosis. Consequently, increased morbidity and mortality must be expected in HIV-HCV coinfected patients. Disrupted gut barrier lead to an increased passage of microbial products and to an activation of the mucosal immune system and secretion of inflammatory mediators, which in turn might increase barrier dysfunction. In the present review, the intestinal barrier structure, measures of intestinal barrier dysfunction and the modifications of them in HIV monoinfection and in HIV-HCV coinfection will be considered. Both pathogenesis and the consequences for the progression of liver disease secondary to gut microbial fragment leakage and immune activation will be assessed.

Integrated Immune Experiment

NASA Technical Reports Server (NTRS)

Crucian, Brian

2009-01-01

This viewgraph presentation reviews NASA's Integrated Immune Experiment. The objectives include: 1) Address significant lack of data regarding immune status during flight; 2) Replace several recent immune studies with one comprehensive study that will include in-flight sampling; 3) Determine the in-flight status of immunity, physiological stress, viral immunity/reactivation; 4) Determine the clinical risk related to immune dysregulation for exploration class spaceflight; and 5) Determine the appropriate monitoring strategy for spaceflight-associated immune dysfunction, that could be used for the evaluation of countermeasures.

Double-blind, randomized study of the effects of influenza vaccination on the specific antibody response and clinical course of patients with chronic fatigue syndrome

PubMed Central

Sleigh, Kenna M; Danforth, Donelda G; Hall, Raymond T; Fleming, Jonathan A; Stiver, H Grant

2000-01-01

OBJECTIVE: To determine whether influenza immunization is associated with early side effects, a deleterious impact on the illness course and depressed antibody response in patients with chronic fatigue syndrome (CFS). DESIGN: Prospective, randomized, double-blind, placebo controlled trial. CFS patients and healthy volunteers filled out a questionnaire on immunization side effects and had hemagglutination-inhibiting (HI) antibody titres measured pre- and three weeks after immunization. CFS patients completed symptom and function questionnaires before and during the six-week, postimmunization period. SETTING: Ambulatory care. POPULATION STUDIED: Convenience sample of 40 CFS patients fulfilling the Centers for Disease Control and Prevention criteria and 21 demographically matched healthy volunteers. INTERVENTIONS: CFS patients were randomly selected to receive commercially available whole virus influenza vaccine (n=19) or an injection of saline placebo (n=21). Healthy volunteers received vaccine only. MAIN RESULTS: As a group, immunized CFS patients had lower geometric mean HI antibody rises than healthy volunteers (P<0.001). However, there was no difference in the rates of fourfold titre rises, and immunization did achieve a probably protective titre (1:32 or greater) in most CFS patients. No difference could be detected between immunized and placebo CFS patients in immunization side effects, although CFS patients as a group reported four times as many side effects as healthy volunteers. Further, in the six weeks following immunization, placebo and immunized CFS patients did not demonstrate any differences in terms of functioning, symptom severity and sleep disturbance. CONCLUSIONS: In patients with CFS, influenza immunization is safe, not associated with any excess early reactions, and stimulates an immunizing response comparable with that of healthy volunteers. PMID:18159300

Immune Abnormalities in Autism Spectrum Disorder-Could They Hold Promise for Causative Treatment?

PubMed

Gładysz, Dominika; Krzywdzińska, Amanda; Hozyasz, Kamil K

2018-01-06

Autism spectrum disorders (ASD) are characterized by impairments in language and communication development, social behavior, and the occurrence of stereotypic patterns of behavior and interests. Despite substantial speculation about causes of ASD, its exact etiology remains unknown. Recent studies highlight a link between immune dysfunction and behavioral traits. Various immune anomalies, including humoral and cellular immunity along with abnormalities at the molecular level, have been reported. There is evidence of altered immune function both in cerebrospinal fluid and peripheral blood. Several studies hypothesize a role for neuroinflammation in ASD and are supported by brain tissue and cerebrospinal fluid analysis, as well as evidence of microglial activation. It has been shown that immune abnormalities occur in a substantial number of individuals with ASD. Identifying subgroups with immune system dysregulation and linking specific cellular immunophenotypes to different symptoms would be key to defining a group of patients with immune abnormalities as a major etiology underlying behavioral symptoms. These determinations would provide the opportunity to investigate causative treatments for a defined patient group that may specifically benefit from such an approach. This review summarizes recent insights into immune system dysfunction in individuals with ASD and discusses the potential implications for future therapies.

Ginseng and obesity: observations and understanding in cultured cells, animals and humans.

PubMed

Zhang, Longyun; Virgous, Carlos; Si, Hongwei

2017-06-01

Ginseng, a traditional medical herb, has been reported having beneficial effects in fatigue, heart diseases, diabetes, immune function and erectile dysfunction. In recent years, increasing investigations have been conducted on ginseng in preventing and treating of obesity, one of the major worldwide escalating public health concerns. However, the effect and the relevant mechanisms behind how ginseng works as an antiobesity treatment are still controversial. In this review, we briefly discussed the chemical structures, metabolism and pharmacokinetics of ginseng and its major bioactive components ginsenosides. The major focus is on the antiobesity effects and the physiological, cellular and molecular mechanisms of ginseng and its ginsenosides in cultured cells, animal models and humans. We particularly compared the ginsenosides profiles, the antiobesity effects and the mechanisms between Asian ginseng (Panax ginseng) and American ginseng (Panax quinquefolius), the two major ginseng species having opposite medical effects in traditional Chinese medicine. Our unpublished data on the ginseng antiobesity in cultured cells and mice were also included. We further addressed the current problems and future directions of the ginseng antiobesity research. Copyright © 2016 Elsevier Inc. All rights reserved.

Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways.

PubMed

Morris, Gerwyn; Anderson, George; Maes, Michael

2017-11-01

There is evidence that immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways play a role in the pathophysiology of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). There is also evidence that these neuroimmune diseases are accompanied by hypothalamic-pituitary-adrenal (HPA) axis hypoactivity as indicated by lowered baseline glucocorticoid levels. This paper aims to review the bidirectional communications between immune-inflammatory and O&NS pathways and HPA axis hypoactivity in ME/CFS, considering two possibilities: (a) Activation of immune-inflammatory pathways is secondary to HPA axis hypofunction via attenuated negative feedback mechanisms, or (b) chronic activated immune-inflammatory and O&NS pathways play a causative role in HPA axis hypoactivity. Electronic databases, i.e., PUBMED, Scopus, and Google Scholar, were used as sources for this narrative review by using keywords CFS, ME, cortisol, ACTH, CRH, HPA axis, glucocorticoid receptor, cytokines, immune, immunity, inflammation, and O&NS. Findings show that activation of immune-inflammatory and O&NS pathways in ME/CFS are probably not secondary to HPA axis hypoactivity and that activation of these pathways may underpin HPA axis hypofunction in ME/CFS. Mechanistic explanations comprise increased levels of tumor necrosis factor-α, T regulatory responses with elevated levels of interleukin-10 and transforming growth factor-β, elevated levels of nitric oxide, and viral/bacterial-mediated mechanisms. HPA axis hypoactivity in ME/CFS is most likely a consequence and not a cause of a wide variety of activated immune-inflammatory and O&NS pathways in that illness.

Evaluation of anti-fatigue and immunomodulating effects of quercetin in strenuous exercise mice

NASA Astrophysics Data System (ADS)

Zhang, Wei-qiang

2017-04-01

The purpose of the present study was to investigate the anti-fatigue and immunomodulating effects of quercetin in strenuous exercise mice. Mice were given orally either corn oil or quercetin (20, 40 and 60 mg/kg body weight suspended in corn oil) by gavage once a day for 28 day. All mice were sacrificed after rotarod test and the major biochemical parameters were analyzed in serum and liver. The results indicated that quercetin possessed anti-fatigue effects by prolonging retention times, decreasing levels of blood lactate and serum urea nitrogen, and increasing levels of blood glucose, tissue glycogen and serum glucagon. Furthermore, quercetin could improve the immune function of fatigue mice by decreasing tumor necrosis factor-α levels, and elevated interleukin-10 levels. Quercetin possessed anti-fatigue effects may be related to its immunomodulating effects.

Integrated Immune

NASA Technical Reports Server (NTRS)

Crucian, Brian; Mehta, Satish; Stowe, Raymond; Uchakin, Peter; Quiriarte, Heather; Pierson, Duane; Sams, Clarnece

2010-01-01

This slide presentation reviews the program to replace several recent studies about astronaut immune systems with one comprehensive study that will include in-flight sampling. The study will address lack of in-flight data to determine the inflight status of immune systems, physiological stress, viral immunity, to determine the clinical risk related to immune dysregulation for exploration class spaceflight, and to determine the appropriate monitoring strategy for spaceflight-associated immune dysfunction, that could be used for the evaluation of countermeasures.

Effects of acupuncturing Pishu combined with Ginsenoside Rg3 on the immune function of rats with chronic fatigue.

PubMed

Zhang, Wenjing; Zhang, Yue; Ma, Xiande; Chen, Yiguo

2015-01-01

This study was designed to investigate the effects of acupuncturing Pishu combined with Ginsenoside Rg3 on the immune function of rats with chronic fatigue. Forty male SD rats were equally randomized into control group, chronic fatigue system group (CFS), Ginsenoside Rg3 (Rg3) group, acupuncture group and acupuncture combined with Ginsenoside Rg3 (A+Rg3) group. Rats with chronic fatigue were established by bounding and forced swimming in cold water once daily for 21 days except control group, then the rats in the acupuncture and A+Rg3 group were treated by manual acupuncture stimulation of bilateral "Pishu" once daily for 7 days. Ginsenoside Rg3 was administered by intravenous to the rats of the A+Rg3 and Rg3 group for 7 days in dosages of 2 mg/kg body weight, and two markers of physical fatigue were evaluated: body weight and blood lactic acid (LA). The percentages of CD3(+) lymphocytes, CD4(+) lymphocytes, and CD8(+) lymphocytes in the spleens of the rats were evaluated using flow cytometric analysis. Serum IFN-gamma (IFN-γ) and IL-4 contents were detected by ELISA. Increased body weight and reduced blood LA concentrations were found in the rat of Rg3 group and A+Rg3 group than that in CFS group. The rat of Rg3 group and A+Rg3 group also showed a significant increase in the percentage of CD4(+) lymphocytes and a significant decrease in the percentage of CD8(+) lymphocytes and correct CD4(+)/CD8(+) ratio. Compared with the CFS group, the level of IFN-γ in the Rg3, acupuncture and A+Rg3 groups was reduced and IL-4 was increased. Acupuncture and Rg3 can improve the immune system activity of CFS rats and acupuncturing Pishu combined with Rg3 was significantly superior compared with Rg3 and acupuncture, respectively.

Reversal of Refractory Ulcerative Colitis and Severe Chronic Fatigue Syndrome Symptoms Arising from Immune Disturbance in an HLADR/DQ Genetically Susceptible Individual with Multiple Biotoxin Exposures

PubMed Central

Gunn, Shelly R.; Gibson Gunn, G.; Mueller, Francis W.

2016-01-01

Patient: Male, 25 Final Diagnosis: Ulcerative colitis and chronic fatigue syndrome Symptoms: Colitis • profound fatigue • multi-joint pain • cognitive impairment • corneal keratitis Medication: — Clinical Procedure: VIP replacement therapy Specialty: Family Medicine Objective: Unusual clinical course Background: Patients with multisymptom chronic conditions, such as refractory ulcerative colitis (RUC) and chronic fatigue syndrome (CFS), present diagnostic and management challenges for clinicians, as well as the opportunity to recognize and treat emerging disease entities. In the current case we report reversal of co-existing RUC and CFS symptoms arising from biotoxin exposures in a genetically susceptible individual. Case Report: A 25-year-old previously healthy male with new-onset refractory ulcerative colitis (RUC) and chronic fatigue syndrome (CFS) tested negative for autoimmune disease biomarkers. However, urine mycotoxin panel testing was positive for trichothecene group and air filter testing from the patient’s water-damaged rental house identified the toxic mold Stachybotrys chartarum. HLA-DR/DQ testing revealed a multisusceptible haplotype for development of chronic inflammation, and serum chronic inflammatory response syndrome (CIRS) biomarker testing was positive for highly elevated TGF-beta and a clinically undetectable level of vasoactive intestinal peptide (VIP). Following elimination of biotoxin exposures, VIP replacement therapy, dental extractions, and implementation of a mind body intervention-relaxation response (MBI-RR) program, the patient’s symptoms resolved. He is off medications, back to work, and resuming normal exercise. Conclusions: This constellation of RUC and CFS symptoms in an HLA-DR/DQ genetically susceptible individual with biotoxin exposures is consistent with the recently described CIRS disease pathophysiology. Chronic immune disturbance (turbatio immuno) can be identified with clinically available CIRS biomarkers and may represent a treatable underlying disease etiology in a subset of genetically susceptible patients with RUC, CFS, and other immune disorders. PMID:27165859

Cancer pain, fatigue, distress, and insomnia in cancer patients.

PubMed

Theobald, Dale E

2004-01-01

Insomnia is common among cancer patients, occurring in approximately 30% to 50% of the cancer population. The interactions between cancer pain, insomnia, fatigue, and depression/anxiety are complex, warranting treatment plans that focus not only on the relief of specific symptoms to improve quality of life but also on the impact of treatment on other related symptoms. Pain is one of the most common symptoms experienced by cancer patients and is one of the primary factors that precipitate insomnia in this population. Fatigue is also commonly reported by cancer patients, with a prevalence of nearly 80% in some tumor types. Cancer-related fatigue occurs most often after surgery, chemotherapy, radiotherapy, or immunotherapy and has been reported by cancer patients to be the major obstacle to normal functioning and a good quality of life. Insomnia in cancer patients often occurs in association with psychological disorders such as depression or anxiety. Sleep disturbances are associated with aberrant patterns of cortisol secretion, such as those found in insomnia, which are known to significantly depress the immune system, particularly the cells of the immune system responsible for mounting a defense against tumors. Evidence suggests that management of insomnia through a combination of pharmacologic and nonpharmacologic means can have a positive impact not only on insomnia but also on related symptoms and, consequently, on overall health and quality of life. Although the treatment of insomnia in cancer patients can improve cancer-related fatigue, immune functioning, and overall quality of life, insomnia in the context of cancer is still undertreated. Physicians should use hypnotic agents appropriately and be aware of the reduced potential for producing tolerance and dependence with the nonbenzodiazepine hypnotic agents. The management of insomnia in cancer patients should include a global treatment plan designed to address not only the underlying sleep disturbance but also the related symptoms that may contribute to insomnia or occur as a result of it.

BP180 dysfunction triggers spontaneous skin inflammation in mice.

PubMed

Zhang, Yang; Hwang, Bin-Jin; Liu, Zhen; Li, Ning; Lough, Kendall; Williams, Scott E; Chen, Jinbo; Burette, Susan W; Diaz, Luis A; Su, Maureen A; Xiao, Shengxiang; Liu, Zhi

2018-06-04

BP180, also known as collagen XVII, is a hemidesmosomal component and plays a key role in maintaining skin dermal/epidermal adhesion. Dysfunction of BP180, either through genetic mutations in junctional epidermolysis bullosa (JEB) or autoantibody insult in bullous pemphigoid (BP), leads to subepidermal blistering accompanied by skin inflammation. However, whether BP180 is involved in skin inflammation remains unknown. To address this question, we generated a BP180-dysfunctional mouse strain and found that mice lacking functional BP180 (termed Δ NC16A ) developed spontaneous skin inflammatory disease, characterized by severe itch, defective skin barrier, infiltrating immune cells, elevated serum IgE levels, and increased expression of thymic stromal lymphopoietin (TSLP). Severe itch is independent of adaptive immunity and histamine, but dependent on increased expression of TSLP by keratinocytes. In addition, a high TSLP expression is detected in BP patients. Our data provide direct evidence showing that BP180 regulates skin inflammation independently of adaptive immunity, and BP180 dysfunction leads to a TSLP-mediated itch. The newly developed mouse strain could be a model for elucidation of disease mechanisms and development of novel therapeutic strategies for skin inflammation and BP180-related skin conditions.

Innate Immune Signalling Genetics of Pain, Cognitive Dysfunction and Sickness Symptoms in Cancer Pain Patients Treated with Transdermal Fentanyl

PubMed Central

Barratt, Daniel T.; Klepstad, Pål; Dale, Ola; Kaasa, Stein; Somogyi, Andrew A.

2015-01-01

Common adverse symptoms of cancer and chemotherapy are a major health burden; chief among these is pain, with opioids including transdermal fentanyl the mainstay of treatment. Innate immune activation has been implicated generally in pain, opioid analgesia, cognitive dysfunction, and sickness type symptoms reported by cancer patients. We aimed to determine if genetic polymorphisms in neuroimmune activation pathways alter the serum fentanyl concentration-response relationships for pain control, cognitive dysfunction, and other adverse symptoms, in cancer pain patients. Cancer pain patients (468) receiving transdermal fentanyl were genotyped for 31 single nucleotide polymorphisms in 19 genes: CASP1, BDNF, CRP, LY96, IL6, IL1B, TGFB1, TNF, IL10, IL2, TLR2, TLR4, MYD88, IL6R, OPRM1, ARRB2, COMT, STAT6 and ABCB1. Lasso and backward stepwise generalised linear regression were used to identify non-genetic and genetic predictors, respectively, of pain control (average Brief Pain Inventory < 4), cognitive dysfunction (Mini-Mental State Examination ≤ 23), sickness response and opioid adverse event complaint. Serum fentanyl concentrations did not predict between-patient variability in these outcomes, nor did genetic factors predict pain control, sickness response or opioid adverse event complaint. Carriers of the MYD88 rs6853 variant were half as likely to have cognitive dysfunction (11/111) than wild-type patients (69/325), with a relative risk of 0.45 (95% CI: 0.27 to 0.76) when accounting for major non-genetic predictors (age, Karnofsky functional score). This supports the involvement of innate immune signalling in cognitive dysfunction, and identifies MyD88 signalling pathways as a potential focus for predicting and reducing the burden of cognitive dysfunction in cancer pain patients. PMID:26332828

Central nervous system abnormalities in fibromyalgia and chronic fatigue syndrome: new concepts in treatment.

PubMed

Gur, Ali; Oktayoglu, Pelin

2008-01-01

Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are poorly understood disorders that share similar demographic and clinical characteristics. The etiology and pathophysiology of these diseases remain unclear. Because of the similarities between both disorders it was suggested that they share a common pathophysiological mechanisms, namely, central nervous system (CNS) dysfunction. Current hypotheses center on atypical sensory processing in the CNS and dysfunction of skeletal muscle nociception and the hypothalamic-pituitary-adrenal (HPA) axis. Researches suggest that the (CNS) is primarily involved in both disorders in regard to the pain, fatigue and sleep disturbances. Many patients experience difficulty with concentration and memory and many others have mood disturbance, including depression and anxiety. Although fibromyalgia is common and associated with substantial morbidity and disability, there are no US Food and Drug Administration (FDA)-approved treatments except pregabalin. Recent pharmacological treatment studies about fibromyalgia have focused on selective serotonin and norepinephrine (NE) reuptake inhibitors, which enhance serotonin and NE neurotransmission in the descending pain pathways and lack many of the adverse side effects associated with tricyclic medications. CFS is a descriptive term used to define a recognisable pattern of symptoms that cannot be attributed to any alternative condition. The symptoms are currently believed to be the result of disturbed brain function. To date, no pharmacological agent has been reliably shown to be effective treatment for CFS. Management strategies are therefore primarily directed at relief of symptoms and minimising impediments to recovery. This chapter presents data demonstrating CFS, abnormal pain processing and autonomic nervous system (ANS) dysfunction in FM and CFS and concludes by reviewing the new concepts in treatments in CFS and FM.

Chemotherapy Necessitates Increased Immune Control of HHVs: A Cause of Persistent Inflammation Enabling Protracted Fatigue in Breast Cancer Survivors

DTIC Science & Technology

2015-06-01

Hypothesis: This work hypothesizes that chemotherapy can permanently alter the balance between the immune system and chronic herpesvirus ...States. PloS one 6, e16103, doi:10.1371/journal.pone.0016103 (2011). 3 Bennett, J. M. et al. Inflammation and reactivation of latent herpesviruses in

Methods for the assessment of peripheral muscle fatigue and its energy and metabolic determinants in COPD.

PubMed

Rondelli, Rafaella Rezende; Dal Corso, Simone; Simões, Alexandre; Malaguti, Carla

2009-11-01

It has been well established that, in addition to the pulmonary involvement, COPD has systemic consequences that can lead to peripheral muscle dysfunction, with greater muscle fatigue, lower exercise tolerance and lower survival in these patients. In view of the negative repercussions of early muscle fatigue in COPD, the objective of this review was to discuss the principal findings in the literature on the metabolic and bioenergy determinants of muscle fatigue, its functional repercussions, as well as the methods for its identification and quantification. The anatomical and functional substrate of higher muscle fatigue in COPD appears to include lower levels of high-energy phosphates, lower mitochondrial density, early lactacidemia, higher serum ammonia and reduced muscle perfusion. These alterations can be revealed by contraction failure, decreased firing rates of motor units and increased recruitment of motor units in a given activity, which can be functionally detected by a reduction in muscle strength, power and endurance. This review article also shows that various types of muscle contraction regimens and protocols have been used in order to detect muscle fatigue in this population. With this understanding, rehabilitation strategies can be developed in order to improve the resistance to muscle fatigue in this population.

Does Oral Coenzyme Q10 Plus NADH Supplementation Improve Fatigue and Biochemical Parameters in Chronic Fatigue Syndrome?

PubMed Central

Cordero, Mario D.; Segundo, María José; Sáez-Francàs, Naia; Calvo, Natalia; Román-Malo, Lourdes; Aliste, Luisa; Fernández de Sevilla, Tomás; Alegre, José

2015-01-01

Abstract Chronic fatigue syndrome (CFS) is a chronic and extremely debilitating illness characterized by prolonged fatigue and multiple symptoms with unknown cause, diagnostic test, or universally effective treatment. Inflammation, oxidative stress, mitochondrial dysfunction, and CoQ10 deficiency have been well documented in CFS. We conducted an 8-week, randomized, double-blind placebo-controlled trial to evaluate the benefits of oral CoQ10 (200 mg/day) plus NADH (20 mg/day) supplementation on fatigue and biochemical parameters in 73 Spanish CFS patients. This study was registered in ClinicalTrials.gov (NCT02063126). A significant improvement of fatigue showing a reduction in fatigue impact scale total score (p<0.05) was reported in treated group versus placebo. In addition, a recovery of the biochemical parameters was also reported. NAD+/NADH (p<0.001), CoQ10 (p<0.05), ATP (p<0.05), and citrate synthase (p<0.05) were significantly higher, and lipoperoxides (p<0.05) were significantly lower in blood mononuclear cells of the treated group. These observations lead to the hypothesis that the oral CoQ10 plus NADH supplementation could confer potential therapeutic benefits on fatigue and biochemical parameters in CFS. Larger sample trials are warranted to confirm these findings. Antioxid. Redox Signal. 22, 679–685. PMID:25386668

Impact of Dietary Antioxidants on Sport Performance: A Review.

PubMed

Braakhuis, Andrea J; Hopkins, Will G

2015-07-01

Many athletes supplement with antioxidants in the belief this will reduce muscle damage, immune dysfunction and fatigue, and will thus improve performance, while some evidence suggests it impairs training adaptations. Here we review the effect of a range of dietary antioxidants and their effects on sport performance, including vitamin E, quercetin, resveratrol, beetroot juice, other food-derived polyphenols, spirulina and N-acetylcysteine (NAC). Older studies suggest vitamin E improves performance at altitude, with possible harmful effects on sea-level performance. Acute intake of vitamin E is worthy of further consideration, if plasma levels can be elevated sufficiently. Quercetin has a small beneficial effect for exercise of longer duration (>100 min), but it is unclear whether this benefits athletes. Resveratrol benefits trained rodents; more research is needed in athletes. Meta-analysis of beetroot juice studies has revealed that the nitrate component of beetroot juice had a substantial but unclear effect on performance when averaged across athletes, non-athletes and modes of exercise (single dose 1.4 ± 2.0%, double dose 0.5 ± 1.9%). The effect of addition of polyphenols and other components to beetroot juice was trivial but unclear (single dose 0.4 ± 3.2%, double dose -0.5 ± 3.3%). Other food-derived polyphenols indicate a range of performance outcomes from a large improvement to moderate impairment. Limited evidence suggests spirulina enhances endurance performance. Intravenous NAC improved endurance cycling performance and reduced muscle fatigue. On the basis of vitamin E and NAC studies, acute intake of antioxidants is likely to be beneficial. However, chronic intakes of most antioxidants have a harmful effect on performance.

A chronic fatigue syndrome – related proteome in human cerebrospinal fluid

PubMed Central

Baraniuk, James N; Casado, Begona; Maibach, Hilda; Clauw, Daniel J; Pannell, Lewis K; Hess S, Sonja

2005-01-01

Background Chronic Fatigue Syndrome (CFS), Persian Gulf War Illness (PGI), and fibromyalgia are overlapping symptom complexes without objective markers or known pathophysiology. Neurological dysfunction is common. We assessed cerebrospinal fluid to find proteins that were differentially expressed in this CFS-spectrum of illnesses compared to control subjects. Methods Cerebrospinal fluid specimens from 10 CFS, 10 PGI, and 10 control subjects (50 μl/subject) were pooled into one sample per group (cohort 1). Cohort 2 of 12 control and 9 CFS subjects had their fluids (200 μl/subject) assessed individually. After trypsin digestion, peptides were analyzed by capillary chromatography, quadrupole-time-of-flight mass spectrometry, peptide sequencing, bioinformatic protein identification, and statistical analysis. Results Pooled CFS and PGI samples shared 20 proteins that were not detectable in the pooled control sample (cohort 1 CFS-related proteome). Multilogistic regression analysis (GLM) of cohort 2 detected 10 proteins that were shared by CFS individuals and the cohort 1 CFS-related proteome, but were not detected in control samples. Detection of ≥1 of a select set of 5 CFS-related proteins predicted CFS status with 80% concordance (logistic model). The proteins were α-1-macroglobulin, amyloid precursor-like protein 1, keratin 16, orosomucoid 2 and pigment epithelium-derived factor. Overall, 62 of 115 proteins were newly described. Conclusion This pilot study detected an identical set of central nervous system, innate immune and amyloidogenic proteins in cerebrospinal fluids from two independent cohorts of subjects with overlapping CFS, PGI and fibromyalgia. Although syndrome names and definitions were different, the proteome and presumed pathological mechanism(s) may be shared. PMID:16321154

Inflammatory responses to psychological stress in fatigued breast cancer survivors: relationship to glucocorticoids.

PubMed

Bower, Julienne E; Ganz, Patricia A; Aziz, Najib; Olmstead, Richard; Irwin, Michael R; Cole, Steve W

2007-03-01

Fatigue is a common problem following cancer treatment and our previous studies suggest that a chronic inflammatory process might contribute to cancer-related fatigue. However, immune responses to challenge have not yet been evaluated among individuals with cancer-related fatigue, and it is not known what mechanisms drive increased levels of inflammatory markers in fatigued cancer survivors. We have previously reported that fatigued breast cancer survivors show a blunted cortisol response to an experimental psychological stressor. In this report, we focus on inflammatory responses to this stressor and their relationship to circulating glucocorticoids and cellular sensitivity to glucocorticoid inhibition. Relative to non-fatigued control survivors, participants experiencing persistent fatigue showed significantly greater increases in LPS-stimulated production of IL-1beta and IL-6 following the stressor (Group x Time interaction: p<.05). Fatigued participants did not show any difference in cellular sensitivity to cortisol inhibition of cytokine production, but they did show significantly less salivary cortisol increase in the aftermath of the stressor. Moreover, blunted cortisol responses were associated with significantly increased production of IL-6 in response to LPS stimulation (p<.05). These data provide further evidence of enhanced inflammatory processes in fatigued breast cancer survivors and suggest that these processes may stem in part from decreased glucocorticoid response to stress.

Energy Dissipation-Based Method for Fatigue Life Prediction of Rock Salt

NASA Astrophysics Data System (ADS)

He, Mingming; Huang, Bingqian; Zhu, Caihui; Chen, Yunsheng; Li, Ning

2018-05-01

The fatigue test for rock salt is conducted under different stress amplitudes, loading frequencies, confining pressures and loading rates, from which the evaluation rule of the dissipated energy is revealed and analysed. The evolution of energy dissipation under fatigue loading is divided into three stages: the initial stage, the second stage and the acceleration stage. In the second stage, the energy dissipation per cycle remains stable and shows an exponential relation with the stress amplitude; the failure dissipated energy only depends on the mechanical behaviour of the rock salt and confining pressure, but it is immune to the loading conditions. The energy dissipation of fatigued rock salt is discussed, and a novel model for fatigue life prediction is proposed on the basis of energy dissipation. A simple model for evolution of the accumulative dissipated energy is established. Its prediction results are compared with the test results, and the proposed model is validated.

Measurement of fatigue in industries.

PubMed

Saito, K

1999-04-01

Fatigue of workers is a complex phenomenon resulting from various factors in technically innovated modern industries, and it appears as a feeling of exhaustion, lowering of physiological functions, breakdown of autonomic nervous balance, and decrease in work efficiency. On the other hand industrial fatigue is caused by excessive workload, remarkable alteration in working posture and diurnal and nocturnal rhythms in daily life. Working modes in modern industries have changed from work with the whole body into that with the hands, arms, legs and/or eyes which are parts of the body, and from physical work to mental work. Visual display terminal (VDT) work is one of the most characteristic jobs in the various kinds of workplaces. A large number of fatigue tests have already been adopted, but it is still hard to draw a generalized conclusion as to the method of selecting the most appropriate test battery for a given work load. As apparatus for fatigue measurement of VDT work we have developed VRT (Visual Reaction Test) and the Portable Fatigue Meter. Furthermore, we have presented immune parameters of peripheral blood and splenic T cells for physical fatigue.

Immunologic alterations and the pathogenesis of organ failure in the ICU.

PubMed

Opal, Steven M

2011-10-01

Rapid and marked alterations of innate and adaptive immunity typify the host response to systemic infection and acute inflammatory states. Immune dysfunction contributes to the development of organ failure in most patients with critical illness. The molecular mechanisms by which microbial pathogens and tissue injury activate myeloid cells and prime cellular and humoral immunity are increasingly understood. An early and effective immune response to microbial invasion is essential to mount an effective antimicrobial response. However, unchecked and nonresolving inflammation can induce diffuse vasodilation, increased capillary permeability, microvascular damage, coagulation activation, and organ dysfunction. Control of the inflammatory response to limit tissue damage, yet retain the antimicrobial responses in critically ill patients with severe infection, has been sought for decades. Anti-inflammatory approaches might be beneficial in some patients but detrimental in others. It is now clear that a state of sepsis-induced immune suppression can follow the immune activation phase of sepsis. In carefully selected patients, a better therapeutic strategy might be to provide immunoadjuvants to reconstitute immune function in intensive care unit (ICU) patients. Proresolving agents are also in development to terminate acute inflammatory reactions without immune suppression. This brief review summarizes the current understanding of the fundamental immune alterations in critical illness that lead to organ failure in critical illness. © Thieme Medical Publishers.

Increased T Cell Immunosenescence and Accelerated Maturation Phenotypes in Older Kidney Transplant Recipients.

PubMed

Schaenman, J M; Rossetti, M; Sidwell, T; Groysberg, V; Sunga, G; Korin, Y; Liang, E; Zhou, X; Abdallah, B; Lum, E; Bunnapradist, S; Pham, T; Danovitch, G; Reed, E F

2018-06-15

Older kidney transplant recipients experience increased rates of infection and death, and less rejection, compared with younger patients. However, little is known about immune dysfunction in older compared with younger kidney transplant recipients and whether it is associated with infection. We evaluated T cell phenotypes including maturation, immune senescence, and exhaustion in a novel investigation into differences in older compared with younger patients receiving identical immune suppression regimens. We evaluated PBMC from 60 kidney transplant recipients (23 older and 37 matched younger patients) by multiparameter immune phenotyping. Older kidney transplant recipients demonstrated decreased frequency of naïve CD4+ and CD8+ T cells, and increased frequency of terminally differentiated, immune senescent, and NK T cells expressing KLRG1. There was a trend towards increased frequency of T cell immune senescence in patients experiencing infection in the first year after transplantation, which reached statistical significance in a multivariate analysis. This pilot study reveals immune dysfunction in older compared with younger transplant recipients, and suggests a likely mechanism for increased vulnerability to infection. The ability to assess T cell maturation and immune senescence in transplant recipients offers the potential for risk stratification and customization of immune suppression to prevent infection and rejection after transplantation. Copyright © 2018. Published by Elsevier Inc.

Scapular kinematic and shoulder muscle activity alterations after serratus anterior muscle fatigue.

PubMed

Umehara, Jun; Kusano, Ken; Nakamura, Masatoshi; Morishita, Katsuyuki; Nishishita, Satoru; Tanaka, Hiroki; Shimizu, Itsuroh; Ichihashi, Noriaki

2018-02-23

Although the serratus anterior muscle has an important role in scapular movement, no study to date has investigated the effect of serratus anterior fatigue on scapular kinematics and shoulder muscle activity. The purpose of this study was to clarify the effect of serratus anterior fatigue on scapular movement and shoulder muscle activity. The study participants were 16 healthy men. Electrical muscle stimulation was used to fatigue the serratus anterior muscle. Shoulder muscle strength and endurance, scapular movement, and muscle activity were measured before and after the fatigue task. The muscle activity of the serratus anterior, upper and lower trapezius, anterior and middle deltoid, and infraspinatus muscles was recorded, and the median power frequency of these muscles was calculated to examine the degree of muscle fatigue. The muscle endurance and median power frequency of the serratus anterior muscle decreased after the fatigue tasks, whereas the muscle activities of the serratus anterior, upper trapezius, and infraspinatus muscles increased. External rotation of the scapula at the shoulder elevated position increased after the fatigue task. Selective serratus anterior fatigue due to electric muscle stimulation decreased the serratus anterior endurance at the flexed shoulder position. Furthermore, the muscle activities of the serratus anterior, upper trapezius, and infraspinatus increased and the scapular external rotation was greater after serratus anterior fatigue. These results suggest that the rotator cuff and scapular muscle compensated to avoid the increase in internal rotation of the scapula caused by the dysfunction of the serratus anterior muscle. Copyright © 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Increased Incidence of Fatigue in Patients with Primary Immunodeficiency Disorders: Prevalence and Associations Within the US Immunodeficiency Network Registry

PubMed Central

Guffey, Danielle; Minard, Charles G.; Orange, Jordan S.

2017-01-01

Introduction Patients with primary immunodeficiency (PID) often report fatigue, yet this symptom has not been studied in PID. Fatigue affects 6–7.5% of healthy adults. The goal of this study is to estimate the prevalence of fatigue in patients with PID and investigate its associated factors. Methods We analyzed 2537 PID patients registered in USIDNET to determine responses to the field “fatigue” in the core registry form. Demographics, immune phenotypes, and comorbid conditions were compared between fatigued and non-fatigued patients to identify relevant associations and potential drivers. A focused analysis was performed for patients with predominantly antibody deficiency disorders (PADs). Results Fatigue was reported in 25.9%(95% CI 23.7–28.3) of PAD patients, compared to 6.4% (95% CI 4.9–8.2) of non-PAD. Patients with common variable immunodeficiency (CVID) had the highest prevalence of fatigue (p < 0.001) among all PID diagnoses. Other factors that were associated with a higher rate of fatigue among PAD patients included female sex, higher BMI, depression, bronchiectasis, and autoimmunity. Additionally, fatigued PAD patients had lower absolute lymphocyte, CD3, CD4, and CD8 counts compared to non-fatigued patients. Conclusion Our findings suggest that fatigue is overrepresented in PAD patients. Prospective studies to estimate prevalence, risk factors, and fatigue etiology in PID are warranted, so therapeutic interventions can be considered. PMID:28124237

Dietary nucleotides prevent decrease in cellular immunity in ground-based microgravity analog

NASA Technical Reports Server (NTRS)

Yamauchi, Keiko; Hales, Nathan W.; Robinson, Sandra M.; Niehoff, Michael L.; Ramesh, Vani; Pellis, Neal R.; Kulkarni, Anil D.

2002-01-01

Microgravity and stress of spaceflights result in immune dysfunction. The role of nutrition, especially nucleotide supplementation, has become an area of intensive research and significant interest in immunomodulation for maintenance of cellular immune responses. The studies presented here evaluate the plausibility of administering nucleotides to obviate immune dysfunction in an Earth-based in vivo analog of microgravity as studied in anti-orthostatic tail suspension (AOS) of mice. Mice were divided into three housing groups: group, isolation, and AOS. Mice were fed either control chow diet (CD), or RNA-, adenine-, or uracil-supplemented CD for the 1-wk duration of the experiments. In AOS mice, supplemental nucleotides significantly increased in vivo lymph node proliferation and ex vivo lymphoproliferation response to alloantigen and mitogens, respectively, and interleukin-2 and interferon-gamma production. A lower corticosterone level was observed in uracil-supplemented CD compared with CD. These results suggest that exogenous nucleotide supplementation, especially uracil, of normal diet is beneficial in the maintenance and restoration of the immune response during the microgravity analog conditions.

Consideration of sleep dysfunction in rehabilitation.

PubMed

Valenza, Marie Carmen; Rodenstein, Daniel O; Fernández-de-las-Peñas, César

2011-07-01

The physiology of sleep is not completely understood but it is widely accepted that sleep is important to the human body in the recovery of metabolic and neurological processes. This paper summarizes the effects of sleep dysfunction on different systems and considers implications in the context of rehabilitation. When sleep is experimentally completely or partially curtailed important brain functions are impacted leading to psychological and neurological disturbances. Increased cortisol levels, reduction of glucose tolerance, and increased sympathetic nervous system activity have also been identified in healthy subjects under such conditions. Several studies show that 50-80% of patients with chronic pain suffer from sleep dysfunction. It has been suggested that on the one hand pain can cause sleep dysfunction and on the other hand that sleep dysfunction can aggravate pain. The physiologic mechanism behind this interaction is not completely clear; although most authors describe the relationship between pain and sleep dysfunction as aberrant processing of tactile-cutaneous sensory inputs at the meso-encephalic level and in the trigeminal nucleus both when asleep and awake. Decreased duration of sleep also increases heart rate, blood pressure and sympathetic activity magnifying the individual's response to stressful stimuli. Possible causal mechanisms for the established connection between short sleep cycles and coronary pathology include sympathetic nervous system hyperactivity, increased blood pressure increase or reduced glucose tolerance. Finally, sleep and fatigue have traditionally been linked. Fatigue can have a physical etiology but is also associated with depression. Sleep alterations are also considered an important risk factor for psychological dysfunction and also mental illness. However, despite the noted repercussions of sleep dysfunction, studies investigating interventions to improve sleep have been limited in number. Benefits of exercise programs on sleep habits have been controversial with some have finding positive effects, whereas others did not find any significant effect. It is possible that the dose or intensity of exercise programs may have an important influence in the outcomes. It is our opinion that based on the multi-system repercussions of different sleep dysfunctions, evaluation of sleep habits should be considered fundamental in the context of rehabilitation and should be included as part of the clinical history of each patient attending physical therapy. Copyright © 2010 Elsevier Ltd. All rights reserved.

Astrocyte atrophy and immune dysfunction in self-harming macaques.

PubMed

Lee, Kim M; Chiu, Kevin B; Sansing, Hope A; Inglis, Fiona M; Baker, Kate C; MacLean, Andrew G

2013-01-01

Self-injurious behavior (SIB) is a complex condition that exhibits a spectrum of abnormal neuropsychological and locomotor behaviors. Mechanisms for neuropathogenesis could include irregular immune activation, host soluble factors, and astrocyte dysfunction. We examined the role of astrocytes as modulators of immune function in macaques with SIB. We measured changes in astrocyte morphology and function. Paraffin sections of frontal cortices from rhesus macaques identified with SIB were stained for glial fibrillary acidic protein (GFAP) and Toll-like receptor 2 (TLR2). Morphologic features of astrocytes were determined using computer-assisted camera lucida. There was atrophy of white matter astrocyte cell bodies, decreased arbor length in both white and gray matter astrocytes, and decreased bifurcations and tips on astrocytes in animals with SIB. This was combined with a five-fold increase in the proportion of astrocytes immunopositive for TLR2. These results provide direct evidence that SIB induces immune activation of astrocytes concomitant with quantifiably different morphology.

Pomegranate extract and exercise provide additive benefits on improvement of immune function by inhibiting inflammation and oxidative stress in high-fat-diet-induced obesity in rats.

PubMed

Zhao, Fei; Pang, Wentao; Zhang, Ziyi; Zhao, Jialong; Wang, Xin; Liu, Ye; Wang, Xun; Feng, Zhihui; Zhang, Yong; Sun, Wenyan; Liu, Jiankang

2016-06-01

Obesity is reported to be associated with immune dysfunction and a state of low-grade, chronic inflammation. Either pomegranate extract (PomE) or exercise (Ex) has been shown to have antiobesity, anti-inflammatory and antioxidant effects. Nevertheless, no study has addressed the additive benefits of PomE and Ex on the restoration of obesity-induced immune defects. The present work aims to study the effect of PomE and Ex as a combined intervention on immune function and the underlying mechanism involved in inflammation and oxidative stress in rats with high-fat-diet (HFD)-induced obesity. Our results demonstrate that the combination of PomE and Ex showed additive benefits on inhibition of HFD-induced body weight increase and improvement of HFD-induced immune dysfunction, including (a) attenuating the abnormality of histomorphology of the spleen, (b) increasing the ratio of the CD4+:CD8+ T cell subpopulations in splenocytes and peripheral blood mononuclear cells (PBMC), (c) inhibition of apoptosis in splenocytes and PBMC, (d) normalizing peritoneal macrophage phenotypes and (e) restoring immunomodulating factors in serum. We also find that immune dysfunction in HFD-fed rats was associated with increased inflammatory cytokine secretion and oxidative stress biomarkers, and that the combination of PomE and Ex effectively inhibited the inflammatory response and decreased oxidative damage. The effect of PomE and Ex as a combined intervention is greater than the effect of either PomE or Ex alone, showing that PomE and Ex may be additively effective in improving immune function in HFD-fed rats by inhibiting inflammation and decreasing oxidative stress. Copyright © 2016 Elsevier Inc. All rights reserved.

Kv1.1 knock-in ataxic mice exhibit spontaneous myokymic activity exacerbated by fatigue, ischemia and low temperature

PubMed Central

Brunetti, Orazio; Imbrici, Paola; Botti, Fabio Massimo; Pettorossi, Vito Enrico; D'Adamo, Maria Cristina; Valentino, Mario; Zammit, Christian; Mora, Marina; Gibertini, Sara; Di Giovanni, Giuseppe; Muscat, Richard; Pessia, Mauro

2012-01-01

Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder characterized by myokymia and attacks of ataxic gait often precipitated by stress. Several genetic mutations have been identified in the Shaker-like K+ channel Kv1.1 (KCNA1) of EA1 individuals, including V408A, which result in remarkable channel dysfunction. By inserting the heterozygous V408A, mutation in one Kv1.1 allele, a mouse model of EA1 has been generated (Kv1.1V408A/+). Here, we investigated the neuromuscular transmission of Kv1.1V408A/+ ataxic mice and their susceptibility to physiologically relevant stressors. By using in vivo preparations of lateral gastrocnemius (LG) nerve–muscle from Kv1.1+/+ and Kv1.1V408A/+ mice, we show that the mutant animals exhibit spontaneous myokymic discharges consisting of repeated singlets, duplets or multiplets, despite motor nerve axotomy. Two-photon laser scanning microscopy from the motor nerve, ex vivo, revealed spontaneous Ca2 + signals that occurred abnormally only in preparations dissected from Kv1.1V408A/+ mice. Spontaneous bursting activity, as well as that evoked by sciatic nerve stimulation, was exacerbated by muscle fatigue, ischemia and low temperatures. These stressors also increased the amplitude of compound muscle action potential. Such abnormal neuromuscular transmission did not alter fiber type composition, neuromuscular junction and vascularization of LG muscle, analyzed by light and electron microscopy. Taken together these findings provide direct evidence that identifies the motor nerve as an important generator of myokymic activity, that dysfunction of Kv1.1 channels alters Ca2 + homeostasis in motor axons, and also strongly suggest that muscle fatigue contributes more than PNS fatigue to exacerbate the myokymia/neuromyotonia phenotype. More broadly, this study points out that juxtaparanodal K+ channels composed of Kv1.1 subunits exert an important role in dampening the excitability of motor nerve axons during fatigue or ischemic insult. PMID:22609489

Fatigue is not associated with impaired function of regulatory T cells in untreated patients with multiple sclerosis.

PubMed

Yaldizli, Ozguer; Kumar, Manoj; Vago, Susanne; Kreuzfelder, Erich; Limmroth, Volker; Putzki, Norman

2009-01-01

The pathophysiology of multiple sclerosis (MS)-associated fatigue is poorly understood. Immunological mechanisms may play a role. Alterations in immunological profile indicate a chronic immune activation in MS patients with fatigue. T-regulatory (Treg) cells seem to play a key role in coordinating autoimmune mechanisms in MS. This is the first study investigating the relationship between Treg cell function and fatigue in MS patients. In this cross-sectional in vitro, ex vivo study, we isolated peripheral blood mononuclear cells (PBMCs) from 20 MS patients with fatigue, determined lymphocyte subsets by flow cytometry and suppressive function of Treg cells in PBMC cultures with antigen stimulation. Forkhead box protein 3 expression was evaluated by PCR. Results were compared with 20 MS patients without fatigue and with 19 healthy controls. Leukocytes and lymphocyte subsets including Treg cell frequency did not differ in patients with and without fatigue. Co-culturing of Treg cells with CD4+CD25- cells did not lead to a significant suppression of myelin basic protein- and pokeweed mitogen-induced proliferation in MS patients in contrast to healthy controls. There were no statistical differences between MS patients with and without fatigue regarding this suppression activity. Fatigue seems not to be associated with impaired function of Treg cells in untreated MS patients.

Investigations Concerning Cavitation and Frost Fatigue in Clonal 84K Poplar Using High-Resolution Cavitron Measurements1[OPEN

PubMed Central

Feng, Feng; Ding, Fei; Tyree, Melvin T.

2015-01-01

Both drought and freezing-thawing of stems induce a loss of hydraulic conductivity (percentage loss of conductivity [PLC]) in woody plants. Drought-induced PLC is often accompanied by physical damage to pit membranes, causing a shift in vulnerability curves (cavitation fatigue). Hence, if cavitated stems are flushed to remove embolisms, the next vulnerability curve is different (shifted to lower tensions). The 84K poplar (Populus alba × Populus glandulosa) clone has small vessels that should be immune from frost-induced PLC, but results demonstrated that freezing-thawing in combination with tension synergistically increased PLC. Frost fatigue has already been defined, which is similar to cavitation fatigue but induced by freezing. Frost fatigue caused a transition from a single to a dual Weibull curve, but drought-fatigued stems had single Weibull curves shifted to lower tensions. Studying the combined impact of tension plus freezing on fatigue provided evidence that the mechanism of frost fatigue may be the extra water tension induced by freezing or thawing while spinning stems in a centrifuge rather than direct ice damage. A hypothesis is advanced that tension is enhanced as ice crystals grow or melt during the freeze or thaw event, respectively, causing a nearly identical fatigue event to that induced by drought. PMID:25786827

Symptom Severity and Quality of Life Among Long-term Colorectal Cancer Survivors Compared With Matched Control Subjects: A Population-Based Study.

PubMed

Hart, Tae L; Charles, Susan T; Gunaratne, Mekhala; Baxter, Nancy N; Cotterchio, Michelle; Cohen, Zane; Gallinger, Steven

2018-03-01

Data are lacking regarding physical functioning, psychological well-being, and quality of life among colorectal cancer survivors >10 years postdiagnosis. The purpose of this study was to examine self-reported physical functioning, quality of life, and psychological well-being in long-term colorectal cancer survivors compared with age- and sex-matched unaffected control subjects. Participants completed a cross-sectional survey. The colorectal cancer survivors and unaffected control subjects were recruited from the Ontario Familial Colorectal Cancer Registry. A population-based sample of colorectal cancer survivors (N = 296) and their age- and sex-matched unaffected control subjects (N = 255) were included. Survivors were, on average, 15 years postdiagnosis. Quality of life was measured with the Functional Assessment of Cancer Therapy-General scale, bowel dysfunction with the Memorial Sloan-Kettering Cancer Center scale, urinary dysfunction with the International Consultation on Incontinence Questionnaire-Short Form, fatigue with the Functional Assessment of Chronic Illness Therapy-Fatigue scale, and depression with the Center for Epidemiologic Studies-Depression scale. In linear mixed-model analyses adjusting for income, education, race, and comorbid medical conditions, survivors reported good emotional, functional, physical, and overall quality of life, comparable to control subjects. Fatigue and urinary functioning did not differ significantly between survivors and control subjects. Survivors reported significantly higher social quality of life and lower depression compared with unaffected control subjects. The only area where survivors reported significantly worse deficits was in bowel dysfunction, but the magnitude of differences was relatively small. Generalizability is limited by moderately low participation rates. Findings are likely biased toward healthy participants. No baseline assessment was available to examine change in outcomes over time. Long-term colorectal cancer survivors appear to have comparable quality of life and, in some areas, better well-being than their unaffected peers. Bowel dysfunction may continue to be an ongoing issue even 15 years after colorectal cancer diagnosis. Overall quality of life can be expected to be good in this group of older survivors. See Video Abstract at http://links.lww.com/DCR/A476.

[Researches in immunological responses after burn injury in China].

PubMed

Peng, Dai-zhi

2008-10-01

For five decades it has been recognized that severe burn injury may precipitate in marked alterations in immune function, resulting in life-threatening systemic infections, sepsis, multiple organ failure, and even death. Extensive and deep burns exert widespread and profound impacts on various cells and molecules of the immune system. The general characteristics of abnormal immune responses following major burns are hyperinflammatory response and hypoimmune response of innate and adaptive immunity. These are recognized as postburn immune dysfunction (PID). The stress reaction, massive necrotic tissue, shock, infection, malnutrition and various therapeutic procedures after burns alter the microenvironment of the immune cells and molecules in which they reside, and consequently result in the changes in immune cells and their secretions in quantity and/or activity, and also aberrant signal transduction in different immune cells. These events constitute the cellular and molecular bases in the pathogenesis of PID. The main clinical consequences of PID include tissue damages and increased susceptibility to opportunistic pathogens caused by refractory inflammation and suppressed adaptive immunity. In order to decrease the morbidity of these lethal complications, efforts to improve the immune dysfunction after burn injury have been made not only at the integral level of etiological factors, but also at the cellular and molecular levels of its mechanisms. In this review, all these above-mentioned aspects of PID are comprehensively discussed.

Wind Turbines Make Waves: Why Some Residents near Wind Turbines Become Ill

ERIC Educational Resources Information Center

Havas, Magda; Colling, David

2011-01-01

People who live near wind turbines complain of symptoms that include some combination of the following: difficulty sleeping, fatigue, depression, irritability, aggressiveness, cognitive dysfunction, chest pain/pressure, headaches, joint pain, skin irritations, nausea, dizziness, tinnitus, and stress. These symptoms have been attributed to the…

Factors associated with current and severe physical side-effects after prostate cancer treatment: What men report.

PubMed

Steentjes, L; Siesling, S; Drummond, F J; van Manen, J G; Sharp, L; Gavin, A

2018-01-01

We identified patient and disease characteristics associated with (1) "current" physical side-effects of any severity; and (2) "severe" physical side-effects "ever" experienced by 3,348 (54%) prostate cancer (PCa) survivors in Ireland diagnosed 2-18 years previously. Postal questionnaires collected symptoms at diagnosis, post-biopsy complications, comorbidities, primary treatments and physical side-effects post-treatment (urinary incontinence, erectile dysfunction, libido loss, bowel problems, breast changes, hot flushes, and fatigue, "ever" and "current" at time of questionnaire completion). Men were grouped by "early" (localised) and "late" (locally advanced/advanced) disease at diagnosis. Multivariable logistic regression analysis identified patient and disease-related factors associated with post-treatment side-effects. Complications post-biopsy were associated with higher risk of "current" libido loss and impotence. Radical prostatectomy was associated with higher risk of "current" and "severe" incontinence, libido loss and impotence in both early and late disease. In early disease, brachytherapy was associated with lower risk of "current" fatigue and "severe" impotence. Comorbidities were associated with higher risk of "current" experience of four side-effects (incontinence, libido loss, bowel problems, fatigue). Men on active surveillance/watchful-waiting reported lower risk of sexual dysfunction. These findings could inform development of tailored information on side-effects, which, in turn, could inform treatment decision-making and post-treatment monitoring. © 2016 John Wiley & Sons Ltd.

Zinc in Infection and Inflammation

PubMed Central

Gammoh, Nour Zahi; Rink, Lothar

2017-01-01

Micronutrient homeostasis is a key factor in maintaining a healthy immune system. Zinc is an essential micronutrient that is involved in the regulation of the innate and adaptive immune responses. The main cause of zinc deficiency is malnutrition. Zinc deficiency leads to cell-mediated immune dysfunctions among other manifestations. Consequently, such dysfunctions lead to a worse outcome in the response towards bacterial infection and sepsis. For instance, zinc is an essential component of the pathogen-eliminating signal transduction pathways leading to neutrophil extracellular traps (NET) formation, as well as inducing cell-mediated immunity over humoral immunity by regulating specific factors of differentiation. Additionally, zinc deficiency plays a role in inflammation, mainly elevating inflammatory response as well as damage to host tissue. Zinc is involved in the modulation of the proinflammatory response by targeting Nuclear Factor Kappa B (NF-κB), a transcription factor that is the master regulator of proinflammatory responses. It is also involved in controlling oxidative stress and regulating inflammatory cytokines. Zinc plays an intricate function during an immune response and its homeostasis is critical for sustaining proper immune function. This review will summarize the latest findings concerning the role of this micronutrient during the course of infections and inflammatory response and how the immune system modulates zinc depending on different stimuli. PMID:28629136

Zinc in Infection and Inflammation.

PubMed

Gammoh, Nour Zahi; Rink, Lothar

2017-06-17

Micronutrient homeostasis is a key factor in maintaining a healthy immune system. Zinc is an essential micronutrient that is involved in the regulation of the innate and adaptive immune responses. The main cause of zinc deficiency is malnutrition. Zinc deficiency leads to cell-mediated immune dysfunctions among other manifestations. Consequently, such dysfunctions lead to a worse outcome in the response towards bacterial infection and sepsis. For instance, zinc is an essential component of the pathogen-eliminating signal transduction pathways leading to neutrophil extracellular traps (NET) formation, as well as inducing cell-mediated immunity over humoral immunity by regulating specific factors of differentiation. Additionally, zinc deficiency plays a role in inflammation, mainly elevating inflammatory response as well as damage to host tissue. Zinc is involved in the modulation of the proinflammatory response by targeting Nuclear Factor Kappa B (NF-κB), a transcription factor that is the master regulator of proinflammatory responses. It is also involved in controlling oxidative stress and regulating inflammatory cytokines. Zinc plays an intricate function during an immune response and its homeostasis is critical for sustaining proper immune function. This review will summarize the latest findings concerning the role of this micronutrient during the course of infections and inflammatory response and how the immune system modulates zinc depending on different stimuli.

Elevated liver stiffness is linked to increased biomarkers of inflammation and immune activation in HIV/hepatitis C virus-coinfected patients.

PubMed

Medrano, Luz M; Garcia-Broncano, Pilar; Berenguer, Juan; González-García, Juan; Jiménez-Sousa, Ma Ángeles; Guardiola, Josep M; Crespo, Manuel; Quereda, Carmen; Sanz, José; Canorea, Isabel; Carrero, Ana; Hontañón, Victor; Muñoz-Fernández, Ma Ángeles; Resino, Salvador

2018-06-01

Immune dysregulation is a hallmark of HIV and hepatitis C virus (HCV) infections. We aimed to evaluate the relationship between liver stiffness measurement (LSM) and biomarkers of T-cell activation, bacterial translocation, inflammation, endothelial dysfunction, and coagulopathy in HIV/HCV-coinfected patients. Cross-sectional study. We studied 238 HIV/HCV-coinfected patients, 32 healthy controls, and 39 HIV-monoinfected patients. Patients were stratified according to LSM into four groups: less than 12.5, 12.5-25, 25-40, and more than 40 kPa. T-cell subsets were measured using flow cytometry and plasma biomarkers using immunoassays. HIV/HCV-coinfected patients had higher biomarker levels of immune activation in peripheral blood [T-cell activation (CD4CD38 and CD8CD38), bacterial translocation (soluble CD14), inflammation [IL-1b, IL-6, IL-8, IL-18, IFN-γ-inducible protein 10 (IP-10)] endothelial dysfunction [soluble vascular cell adhesion molecule 1 (sVCAM1), soluble intercellular cell adhesion molecule 1 (sICAM1), and soluble tumor necrosis factor receptor 1 (sTNFR1)], and coagulopathy (plasminogen activator inhibitor-1)] than healthy controls and HIV-monoinfected patients. Moreover, in HIV/HCV-coinfected patients, a direct relationship between LSM and immune activation [T-cell activation (CD8CD38 bacterial translocation (lipopolysaccharide), inflammation (IL-8, IP-10), endothelial dysfunction (sVCAM1, sICAM1, and sTNFR1), and coagulopathy (D-dimer)] was found. Subsequently, patients were stratified into different fibrosis stages, finding that patients with cirrhosis who had LSM at least 40 kPa showed higher biomarker values of immune activation [T-cell activation (CD4CD38 and CD8CD38), bacterial translocation (lipopolysaccharide), inflammation (IL-8, IL-6, IP-10), endothelial dysfunction (sVCAM1, sICAM1, and sTNFR1), and coagulopathy (D-dimer)] than patients from the other three groups (<12.5, 12.5-25, and 25-40 kPa). T-cell activation, bacterial translocation, inflammation, endothelial dysfunction, and coagulopathy increased with the severity of liver fibrosis in HIV/HCV-coinfected patients, particularly in patients who had LSM at least 40 kPa.

Applications of the FIV Model to Study HIV Pathogenesis

PubMed Central

Abdo, Zaid; Ericsson, Aaron; Elder, John; VandeWoude, Sue

2018-01-01

Feline immunodeficiency virus (FIV) is a naturally-occurring retrovirus that infects domestic and non-domestic feline species, producing progressive immune depletion that results in an acquired immunodeficiency syndrome (AIDS). Much has been learned about FIV since it was first described in 1987, particularly in regard to its application as a model to study the closely related lentivirus, human immunodeficiency virus (HIV). In particular, FIV and HIV share remarkable structure and sequence organization, utilize parallel modes of receptor-mediated entry, and result in a similar spectrum of immunodeficiency-related diseases due to analogous modes of immune dysfunction. This review summarizes current knowledge of FIV infection kinetics and the mechanisms of immune dysfunction in relation to opportunistic disease, specifically in regard to studying HIV pathogenesis. Furthermore, we present data that highlight changes in the oral microbiota and oral immune system during FIV infection, and outline the potential for the feline model of oral AIDS manifestations to elucidate pathogenic mechanisms of HIV-induced oral disease. Finally, we discuss advances in molecular biology, vaccine development, neurologic dysfunction, and the ability to apply pharmacologic interventions and sophisticated imaging technologies to study experimental and naturally occurring FIV, which provide an excellent, but often overlooked, resource for advancing therapies and the management of HIV/AIDS. PMID:29677122

Cognitive impairments associated with CFS and POTS.

PubMed

Shanks, Lindzi; Jason, Leonard A; Evans, Meredyth; Brown, Abigail

2013-01-01

Chronic fatigue syndrome (CFS) is characterized by fatigue, sleep dysfunction, and cognitive deficits (Fukuda et al., 1994). Research surrounding cognitive functioning among patients with CFS has found difficulty with memory, attention, and information processing. A similar disorder, postural tachycardia syndrome (POTS), is characterized by increased heart rate, fatigue, and mental cloudiness (Raj et al., 2009). Potential implications of cognitive deficits for patients with CFS and/or POTS are discussed, including difficulties with school and/or employment. A few biological theories (i.e., kindling, impairments in the central nervous system, and difficulty with blood flow) have emerged as potential explanations for the cognitive deficits reported in both CFS and POTS Future research should continue to examine possible explanations for cognitive impairments in CFS and POTS, and ultimately use this information to try and reduce cognitive impairments for these patients.

Cancer cachexia decreases specific force and accelerates fatigue in limb muscle

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roberts, B.M.; Frye, G.S.; Ahn, B.

Highlights: •C-26 cancer cachexia causes a significant decrease in limb muscle absolute force. •C-26 cancer cachexia causes a significant decrease in limb muscle specific force. •C-26 cancer cachexia decreases fatigue resistance in the soleus muscle. •C-26 cancer cachexia prolongs time to peak twitch tension in limb muscle. •C-26 cancer cachexia prolongs one half twitch relaxation time in limb muscle. -- Abstract: Cancer cachexia is a complex metabolic syndrome that is characterized by the loss of skeletal muscle mass and weakness, which compromises physical function, reduces quality of life, and ultimately can lead to mortality. Experimental models of cancer cachexia havemore » recapitulated this skeletal muscle atrophy and consequent decline in muscle force generating capacity. However, more recently, we provided evidence that during severe cancer cachexia muscle weakness in the diaphragm muscle cannot be entirely accounted for by the muscle atrophy. This indicates that muscle weakness is not just a consequence of muscle atrophy but that there is also significant contractile dysfunction. The current study aimed to determine whether contractile dysfunction is also present in limb muscles during severe Colon-26 (C26) carcinoma cachexia by studying the glycolytic extensor digitorum longus (EDL) muscle and the oxidative soleus muscle, which has an activity pattern that more closely resembles the diaphragm. Severe C-26 cancer cachexia caused significant muscle fiber atrophy and a reduction in maximum absolute force in both the EDL and soleus muscles. However, normalization to muscle cross sectional area further demonstrated a 13% decrease in maximum isometric specific force in the EDL and an even greater decrease (17%) in maximum isometric specific force in the soleus. Time to peak tension and half relaxation time were also significantly slowed in both the EDL and the solei from C-26 mice compared to controls. Since, in addition to postural control, the oxidative soleus is also important for normal locomotion, we further performed a fatigue trial in the soleus and found that the decrease in relative force was greater and more rapid in solei from C-26 mice compared to controls. These data demonstrate that severe cancer cachexia causes profound muscle weakness that is not entirely explained by the muscle atrophy. In addition, cancer cachexia decreases the fatigue resistance of the soleus muscle, a postural muscle typically resistant to fatigue. Thus, specifically targeting contractile dysfunction represents an additional means to counter muscle weakness in cancer cachexia, in addition to targeting the prevention of muscle atrophy.« less

Integrated Immunomodulatory Mechanisms through which Long-Chain n-3 Polyunsaturated Fatty Acids Attenuate Obese Adipose Tissue Dysfunction

PubMed Central

Liddle, Danyelle M.; Wellings, Hannah R.; Power, Krista A.; Robinson, Lindsay E.; Monk, Jennifer M.

2017-01-01

Obesity is a global health concern with rising prevalence that increases the risk of developing other chronic diseases. A causal link connecting overnutrition, the development of obesity and obesity-associated co-morbidities is visceral adipose tissue (AT) dysfunction, characterized by changes in the cellularity of various immune cell populations, altered production of inflammatory adipokines that sustain a chronic state of low-grade inflammation and, ultimately, dysregulated AT metabolic function. Therefore, dietary intervention strategies aimed to halt the progression of obese AT dysfunction through any of the aforementioned processes represent an important active area of research. In this connection, fish oil-derived dietary long-chain n-3 polyunsaturated fatty acids (PUFA) in the form of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been demonstrated to attenuate obese AT dysfunction through multiple mechanisms, ultimately affecting AT immune cellularity and function, adipokine production, and metabolic signaling pathways, all of which will be discussed herein. PMID:29186929

Brain-Immune Interactions as the Basis of Gulf War Illness: Gulf War Illness Consortium (GWIC)

DTIC Science & Technology

2014-10-01

neuroinflammation as an end result of initial glial activation and subsequent priming of glial responses that cause a chronic activation loop of...infection, or physical trauma—that mobilizes CNS defense systems via activation of glia, the brain’s primary immune response cells, and release of...oligodendrocytes Microglial Activation (cytokine signaling) Behavioral Effects (fatigue, pain, cognitive problems) Astrocyte Activation (cytokine signaling

Stress, depression, and cardiovascular dysregulation: A review of neurobiological mechanisms and the integration of research from preclinical disease models

PubMed Central

Grippo, Angela J.; Johnson, Alan Kim

2008-01-01

A bidirectional association between mood disorders such as depression, and cardiovascular diseases such as myocardial infarction and congestive heart failure, has been described; however, the precise neurobiological mechanisms that underlie these associations have not been fully elucidated. This review is focused on the neurobiological processes and mediators that are common to both mood and cardiovascular disorders, with an emphasis on the role of exogenous stressors in addition to: (a) neuroendocrine and neurohumoral changes involving dysfunction of the hypothalamic-pituitary-adrenal axis and activation of the renin-angiotensin-aldosterone system, (b) immune alterations including activation of pro-inflammatory cytokines, (c) autonomic and cardiovascular dysregulation including increased sympathetic drive, withdrawal of parasympathetic tone, cardiac rate and rhythm disturbances, and altered baroreceptor reflex function, (d) central neurotransmitter system dysfunction including dopamine, norepinephrine and serotonin, and (e) behavioral changes including fatigue and physical inactivity. We also focus specifically on experimental investigations with preclinical disease models, conducted to elucidate the neurobiological mechanisms underlying the link between mood disorders and cardiovascular disease. These include: (a) the chronic mild stress model of depression, (b) a model of congestive heart failure, a model of cardiovascular deconditioning, (d) pharmacological manipulations of body fluid and sodium balance, and (e) pharmacological manipulations of the central serotonergic system. In combination with the extensive literature describing findings from human research, the investigation of mechanisms underlying mood and cardiovascular regulation using animal models will enhance our understanding of the association of depression and cardiovascular disease, and can promote the development of better treatments and interventions for individuals with these co-morbid conditions. PMID:19116888

Camel whey protein protects lymphocytes from apoptosis via the PI3K/AKT, NF-κB, ATF-3 and HSP-70 signaling pathways in heat-stressed male mice.

PubMed

Badr, Gamal; Ramadan, Nancy K; Abdel-Tawab, Hanem S; Ahmed, Samia F; Mahmoud, Mohamed H

2017-11-22

Heat stress (HS) is an environmental factor that depresses the immune systems mediating dysfunctional immune cells. Camel whey protein (CWP) can scavenge free radicals and enhance immunity. The present study investigated the impact of dietary supplementation with CWP on immune dysfunction induced by exposure to HS. Male mice (n = 45) were divided into three groups: control group; HS group; and HS mice that were orally administered CWP (HS+CWP group). The HS group exhibited elevated levels of reactive oxygen species (ROS) and pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) as well as a significant reduction in the IL-2 and IL-4 levels. Exposure to HS resulted in impaired AKT and IκB-α phosphorylation; increased ATF-3 and HSP70 expression; and aberrant distribution of CD3+ T cells and CD20+ B cells in the thymus and spleen. Interestingly, HS mice treated with CWP presented significantly restored levels of ROS and pro-inflammatory cytokines near the levels observed in control mice. Furthermore, supplementation of HS mice with CWP enhanced the phosphorylation of AKT and IκB-α; attenuated the expression of ATF-3, HSP70 and HSP90; and improved T and B cell distributions in the thymus and spleen. Our findings reveal a potential immunomodulatory effect of CWP in attenuating immune dysfunction induced by exposure to thermal stress.

[Endothelial dysfunction and nonspecific immune reactions in development and progression of osteoarthrosis in women engaged into manual work].

PubMed

Maliutina, N N; Nevzorova, M S

2015-01-01

The article considers mechanisms of development and progression of osteoarthrosis as an occupationally conditioned disease in women of manual work. Women working in physical overstrain conditions are under occupational risk with dysfunction of many body systems. The authors set a hypothesis on association of endothelial dysfunction markers dysbalance and structural remodelling of cartilage matrix as a proof of degenerative changes.

Chronic lymphocytic leukemia and infection risk in the era of targeted therapies: Linking mechanisms with infections.

PubMed

Hilal, Talal; Gea Banacloche, Juan C; Leis, Jose F

2018-03-16

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the world. Patient with CLL are at particular risk for infections due to inherent disease-related immune dysfunction in addition to the effect of certain systemic therapies on the immune system. The advent of B-cell receptor (BCR) inhibitors such as ibrutinib and idelalisib has led to a practice change that utilizes these targeted agents in the treatment of CLL, either in place of chemoimmunotherapy (CIT) or in later line settings. In this paper, we review the pathophysiology of immune dysfunction in CLL, the spectrum of immunodeficiency with the various therapeutic agents along with prevention strategies with a focus on targeted therapies. Copyright © 2018 Elsevier Ltd. All rights reserved.

Increased brain white matter axial diffusivity associated with fatigue, pain and hyperalgesia in Gulf War illness.

PubMed

Rayhan, Rakib U; Stevens, Benson W; Timbol, Christian R; Adewuyi, Oluwatoyin; Walitt, Brian; VanMeter, John W; Baraniuk, James N

2013-01-01

Gulf War exposures in 1990 and 1991 have caused 25% to 30% of deployed personnel to develop a syndrome of chronic fatigue, pain, hyperalgesia, cognitive and affective dysfunction. Gulf War veterans (n = 31) and sedentary veteran and civilian controls (n = 20) completed fMRI scans for diffusion tensor imaging. A combination of dolorimetry, subjective reports of pain and fatigue were correlated to white matter diffusivity properties to identify tracts associated with symptom constructs. Gulf War Illness subjects had significantly correlated fatigue, pain, hyperalgesia, and increased axial diffusivity in the right inferior fronto-occipital fasciculus. ROC generated thresholds and subsequent binary regression analysis predicted CMI classification based upon axial diffusivity in the right inferior fronto-occipital fasciculus. These correlates were absent for controls in dichotomous regression analysis. The right inferior fronto-occipital fasciculus may be a potential biomarker for Gulf War Illness. This tract links cortical regions involved in fatigue, pain, emotional and reward processing, and the right ventral attention network in cognition. The axonal neuropathological mechanism(s) explaining increased axial diffusivity may account for the most prominent symptoms of Gulf War Illness.

Mechanisms Explaining Muscle Fatigue and Muscle Pain in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a Review of Recent Findings.

PubMed

Gerwyn, Morris; Maes, Michael

2017-01-01

Here, we review potential causes of muscle dysfunction seen in many patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) such as the effects of oxidative and nitrosative stress (O&NS) and mitochondrial impairments together with reduced heat shock protein production and a range of metabolic abnormalities. Several studies published in the last few years have highlighted the existence of chronic O&NS, inflammation, impaired mitochondrial function and reduced heat shock protein production in many patients with ME/CFS. These studies have also highlighted the detrimental effects of chronically elevated O&NS on muscle functions such as reducing the time to muscle fatigue during exercise and impairing muscle contractility. Mechanisms have also been revealed by which chronic O&NS and or impaired heat shock production may impair muscle repair following exercise and indeed the adaptive responses in the striated muscle to acute and chronic increases in physical activity. The presence of chronic O&NS, low-grade inflammation and impaired heat shock protein production may well explain the objective findings of increased muscle fatigue, impaired contractility and multiple dimensions of exercise intolerance in many patients with ME/CFS.

Investigation of the Plausibility of 5-Alpha-Reductase Inhibitor Syndrome

PubMed Central

Fertig, Raymond; Shapiro, Jerry; Bergfeld, Wilma; Tosti, Antonella

2017-01-01

Postfinasteride syndrome (PFS) is a term recently coined to characterize a constellation of reported undesirable side effects described in postmarketing reports and small uncontrolled studies that developed during or after stopping finasteride treatment, and persisted after drug discontinuation. Symptoms included decreased libido, erectile dysfunction, sexual anhedonia, decreased sperm count, gynecomastia, skin changes, cognitive impairment, fatigue, anxiety, depression, and suicidal ideation. The aim of this study is to review the existing medical literature for evidence-based research of permanent sexual dysfunction and mood changes during treatment with 5-alpha-reductase inhibitors including finasteride and dutasteride. PMID:28232919

Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination

NASA Astrophysics Data System (ADS)

de Santo, Carmela; Serafini, Paolo; Marigo, Ilaria; Dolcetti, Luigi; Bolla, Manlio; del Soldato, Piero; Melani, Cecilia; Guiducci, Cristiana; Colombo, Mario P.; Iezzi, Manuela; Musiani, Piero; Zanovello, Paola; Bronte, Vincenzo

2005-03-01

Active suppression of tumor-specific T lymphocytes can limit the immune-mediated destruction of cancer cells. Of the various strategies used by tumors to counteract immune attacks, myeloid suppressors recruited by growing cancers are particularly efficient, often resulting in the induction of systemic T lymphocyte dysfunction. We have previously shown that the mechanism by which myeloid cells from tumor-bearing hosts block immune defense strategies involves two enzymes that metabolize L-arginine: arginase and nitric oxide (NO) synthase. NO-releasing aspirin is a classic aspirin molecule covalently linked to a NO donor group. NO aspirin does not possess direct antitumor activity. However, by interfering with the inhibitory enzymatic activities of myeloid cells, orally administered NO aspirin normalized the immune status of tumor-bearing hosts, increased the number and function of tumor-antigen-specific T lymphocytes, and enhanced the preventive and therapeutic effectiveness of the antitumor immunity elicited by cancer vaccination. Because cancer vaccines and NO aspirin are currently being investigated in independent phase I/II clinical trials, these findings offer a rationale to combine these treatments in subjects with advanced neoplastic diseases. arginase | immunosuppression | myeloid cells | nitric oxide | immunotherapy

High levels of type 2 cytokine-producing cells in chronic fatigue syndrome.

PubMed

Skowera, A; Cleare, A; Blair, D; Bevis, L; Wessely, S C; Peakman, M

2004-02-01

The aetiology of chronic fatigue syndrome (CFS) is not known. However, it has been suggested that CFS may be associated with underlying immune activation resulting in a Th2-type response. We measured intracellular production of interferon (IFN)-gamma and interleukin (IL)-2; type 1 cytokines), IL-4 (type 2) and IL-10 (regulatory) by both polyclonally stimulated and non-stimulated CD4 and CD8 lymphocytes from patients with CFS and control subjects by flow cytometry. After polyclonal activation we found evidence of a significant bias towards Th2- and Tc2-type immune responses in CFS compared to controls. In contrast, levels of IFN-gamma, IL-2 and IL-10-producing cells were similar in both study groups. Non-stimulated cultures revealed significantly higher levels of T cells producing IFN-gamma or IL-4 in CFS patients. Concluding, we show evidence for an effector memory cell bias towards type 2 responsiveness in patients with CFS, as well as ongoing type 0 immune activation in unstimulated cultures of peripheral blood cells.

High levels of type 2 cytokine-producing cells in chronic fatigue syndrome

PubMed Central

SKOWERA, A; CLEARE, A; BLAIR, D; BEVIS, L; WESSELY, S C; PEAKMAN, M

2004-01-01

The aetiology of chronic fatigue syndrome (CFS) is not known. However, it has been suggested that CFS may be associated with underlying immune activation resulting in a Th2-type response. We measured intracellular production of interferon (IFN)-γ and interleukin (IL)-2; type 1 cytokines), IL-4 (type 2) and IL-10 (regulatory) by both polyclonally stimulated and non-stimulated CD4 and CD8 lymphocytes from patients with CFS and control subjects by flow cytometry. After polyclonal activation we found evidence of a significant bias towards Th2- and Tc2-type immune responses in CFS compared to controls. In contrast, levels of IFN-γ, IL-2 and IL-10-producing cells were similar in both study groups. Non-stimulated cultures revealed significantly higher levels of T cells producing IFN-γ or IL-4 in CFS patients. Concluding, we show evidence for an effector memory cell bias towards type 2 responsiveness in patients with CFS, as well as ongoing type 0 immune activation in unstimulated cultures of peripheral blood cells. PMID:14738459

Dysfunctional brain-bone marrow communication: a paradigm shift in the pathophysiology of hypertension.

PubMed

Santisteban, Monica M; Zubcevic, Jasenka; Baekey, David M; Raizada, Mohan K

2013-08-01

It is widely accepted that the pathophysiology of hypertension involves autonomic nervous system dysfunction, as well as a multitude of immune responses. However, the close interplay of these systems in the development and establishment of high blood pressure and its associated pathophysiology remains elusive and is the subject of extensive investigation. It has been proposed that an imbalance of the neuro-immune systems is a result of an enhancement of the "proinflammatory sympathetic" arm in conjunction with dampening of the "anti-inflammatory parasympathetic" arm of the autonomic nervous system. In addition to the neuronal modulation of the immune system, it is proposed that key inflammatory responses are relayed back to the central nervous system and alter the neuronal communication to the periphery. The overall objective of this review is to critically discuss recent advances in the understanding of autonomic immune modulation, and propose a unifying hypothesis underlying the mechanisms leading to the development and maintenance of hypertension, with particular emphasis on the bone marrow, as it is a crucial meeting point for neural, immune, and vascular networks.

Dysfunctional brain-bone marrow communication: A paradigm shift in the pathophysiology of hypertension

PubMed Central

Santisteban, Monica M.; Zubcevic, Jasenka; Baekey, David M.; Raizada, Mohan K.

2013-01-01

It is widely accepted that the pathophysiology of hypertension involves autonomic nervous system dysfunction, as well as a multitude of immune responses. However, the close interplay of these systems in the development and establishment of high blood pressure and its associated pathophysiology remains elusive and is the subject of extensive investigation. It has been proposed that an imbalance of the neuro-immune systems is a result of an enhancement of the “pro-inflammatory sympathetic” arm in conjunction with dampening of the “anti-inflammatory parasympathetic” arm of the autonomic nervous system. In addition to the neuronal modulation of the immune system, it is proposed that key inflammatory responses are relayed back to the central nervous system and alter the neuronal communication to the periphery. The overall objective of this review is to critically discuss recent advances in the understanding of autonomic immune modulation, and propose a unifying hypothesis underlying the mechanisms leading to the development and maintenance of hypertension, with particular emphasis on the bone marrow, as it is a crucial meeting point for neural, immune, and vascular networks. PMID:23715920

Jet fuel-induced immunotoxicity.

PubMed

Harris, D T; Sakiestewa, D; Titone, D; Robledo, R F; Young, R S; Witten, M

2000-09-01

Chronic exposure to jet fuel has been shown to cause human liver dysfunction, emotional dysfunction, abnormal electroencephalograms, shortened attention spans, and to decrease sensorimotor speed (3-5). Exposure to potential environmental toxicants such as jet fuel may have significant effects on host systems beyond those readily visible (e.g., physiology, cardiology, respiratory, etc.), e.g., the immune system. Significant changes in immune function, even if short-lived, may have serious consequences for the exposed host that may impinge affect susceptibility to infectious agents. Major alterations in immune function that are long lasting may result in an increased likelihood of development and/or progression of cancer, as well as autoimmune diseases. In the current study mice were exposed 1 h/day for 7 days to a 1000-mg/m3 concentration of aerosolized jet fuel obtained from various sources (JP-8, JP-8+100 and Jet A1) and of differing compositions to simulate occupational exposures. Twenty-four hours after the last exposure the mice were analyzed for effects on the immune system. It was observed that exposure to all jet fuel sources examined had detrimental effects on the immune system. Decreases in viable immune cell numbers and immune organ weights were found. Jet fuel exposure resulted in differential losses of immune cell populations in the thymus. Further, jet fuel exposure resulted in significantly decreased immune function, as analyzed by mitogenesis assays. Suppressed immune function could not be overcome by the addition of exogenous growth factors known to stimulate immune function. Thus, short-term, low-concentration exposure of mice to aerosolized jet fuel, regardless of source or composition, caused significant deleterious effects on the immune system.

Oxidative Stress in HIV Infection and Alcohol Use: Role of Redox Signals in Modulation of Lipid Rafts and ATP-Binding Cassette Transporters.

PubMed

Thangavel, Samikkannu; Mulet, Carmen T; Atluri, Venkata S R; Agudelo, Marisela; Rosenberg, Rhonda; Devieux, Jessy G; Nair, Madhavan P N

2018-02-01

Human immunodeficiency virus (HIV) infection induces oxidative stress and alcohol use accelerates disease progression, subsequently causing immune dysfunction. However, HIV and alcohol impact on lipid rafts-mediated immune dysfunction remains unknown. In this study, we investigate the modulation by which oxidative stress induces reactive oxygen species (ROS) affecting redox expression, lipid rafts caveiloin-1, ATP-binding cassette (ABC) transporters, and transcriptional sterol regulatory element-binding protein (SREBP) gene and protein modification and how these mechanisms are associated with arachidonic acid (AA) metabolites in HIV positive alcohol users, and how they escalate immune dysfunction. In both alcohol using HIV-positive human subjects and in vitro studies of alcohol with HIV-1 gp120 protein in peripheral blood mononuclear cells, increased ROS production significantly affected redox expression in glutathione synthetase (GSS), super oxide dismutase (SOD), and glutathione peroxidase (GPx), and subsequently impacted lipid rafts Cav-1, ABC transporters ABCA1, ABCG1, ABCB1, and ABCG4, and SREBP transcription. The increased level of rate-limiting enzyme 3-hydroxy-3-methylglutaryl HMG-CoA reductase (HMGCR), subsequently, inhibited 7-dehydrocholesterol reductase (DHCR-7). Moreover, the expression of cyclooxygenase-2 (COX-2) and lipoxygenase-5 (5-LOX) mRNA and protein modification tentatively increased the levels of prostaglandin E2 synthases (PGE 2 ) in plasma when compared with either HIV or alcohol alone. This article suggests for the first time that the redox inhibition affects lipid rafts, ABC-transporter, and SREBP transcription and modulates AA metabolites, serving as an important intermediate signaling network during immune cell dysfunction in HIV-positive alcohol users. These findings indicate that HIV infection induces oxidative stress and redox inhibition, affecting lipid rafts and ABC transports, subsequently upregulating AA metabolites and leading to immune toxicity, and further exacerbation with alcohol use. Antioxid. Redox Signal. 28, 324-337.

Periodontal disease as a potential factor of migraine chronification.

PubMed

Ameijeira, Pablo; Leira, Yago; Blanco, Juan; Leira, Rogelio

2017-05-01

Migraine is a hereditary constitutional base disorder, which is characterized by recurrent episodes of headache pulsatile characteristics associated with photophobia/phonophobia, nausea and/or vomiting. The main complication in migraine is the chronicity of the process, now recognized as a chronic migraine. Although pathogenic mechanisms that may influence the pathophysiology of migraine and its possible chronicity are not fully understood, previous studies have shown in patients with migraine molecular alterations of systemic inflammation, neurogenic inflammation, endothelial dysfunction, innate immunity, dysfunction of matrix proteases and blood-brain barrier. Periodontal disease is an inflammatory lesion caused by bacteria. After the bacterial infection begins, an immune response that will be responsible for individual susceptibility appears. More advanced forms of periodontitis have demonstrated molecular alterations of inflammation, endothelial dysfunction, dysfunction of matrix proteases and innate immunity, similar to those observed in migraine. Furthermore, the main molecular mediators of neurogenic inflammation related to activation of the trigeminovascular system, which are characteristic of migraine, are overexpressed in gingival crevicular fluid and mucosa in patients with periodontal disease. Hypertension, hypercholesterolemia, insulin resistance, stroke or coronary artery disease are comorbidities that periodontal disease and migraine could share. Therefore, several mechanisms and hypotheses could explain the possible association between both diseases. However, epidemiological and molecular studies will be necessary to provide a better understanding of this potential association, which could be implicated in the chronification of migraine. Copyright © 2017 Elsevier Ltd. All rights reserved.

Parallels in Immunometabolic Adipose Tissue Dysfunction with Ageing and Obesity

PubMed Central

Trim, William; Turner, James E.; Thompson, Dylan

2018-01-01

Ageing, like obesity, is often associated with alterations in metabolic and inflammatory processes resulting in morbidity from diseases characterised by poor metabolic control, insulin insensitivity, and inflammation. Ageing populations also exhibit a decline in immune competence referred to as immunosenescence, which contributes to, or might be driven by chronic, low-grade inflammation termed “inflammageing”. In recent years, animal and human studies have started to uncover a role for immune cells within the stromal fraction of adipose tissue in driving the health complications that come with obesity, but relatively little work has been conducted in the context of immunometabolic adipose function in ageing. It is now clear that aberrant immune function within adipose tissue in obesity—including an accumulation of pro-inflammatory immune cell populations—plays a major role in the development of systemic chronic, low-grade inflammation, and limiting the function of adipocytes leading to an impaired fat handling capacity. As a consequence, these changes increase the chance of multiorgan dysfunction and disease onset. Considering the important role of the immune system in obesity-associated metabolic and inflammatory diseases, it is critically important to further understand the interplay between immunological processes and adipose tissue function, establishing whether this interaction contributes to age-associated immunometabolic dysfunction and inflammation. Therefore, the aim of this article is to summarise how the interaction between adipose tissue and the immune system changes with ageing, likely contributing to the age-associated increase in inflammatory activity and loss of metabolic control. To understand the potential mechanisms involved, parallels will be drawn to the current knowledge derived from investigations in obesity. We also highlight gaps in research and propose potential future directions based on the current evidence. PMID:29479350

Myasthenia gravis in a patient affected by glycogen storage disease type Ib: a further manifestation of an increased risk for autoimmune disorders?

PubMed

Melis, D; Balivo, F; Della Casa, R; Romano, A; Taurisano, R; Capaldo, B; Riccardi, G; Monsurrò, M R; Parenti, G; Andria, G

2008-12-01

Glycogen storage disease type Ib (GSD Ib, OMIM 232220) is an inborn disorder of glucose metabolism, caused by mutations in the G6PT gene, encoding a glucose 6-phosphate transporter (G6PT). GSD Ib is mainly associated with fasting hypoglycaemia and hepatomegaly. Most GSD Ib patients also show neutropenia and neutrophil dysfunction and therefore are at risk of developing severe infections and inflammatory bowel disease (IBD). An increased risk for autoimmune disorders, such as thyroid autoimmunity and Crohn-like disease, has also been demonstrated, but no systematic study on the prevalence of autoimmune disorders in GSD Ib patients has ever been performed. We describe a 25-year-old patient affected by GSD Ib who developed 'seronegative' myasthenia gravis (MG), presenting with bilateral eyelid ptosis, diplopia, dysarthria, severe dysphagia, dyspnoea and fatigue. The repetitive stimulation of peripheral nerves test showed signs of exhaustion of neuromuscular transmission, particularly evident in the cranial area. Even in the absence of identifiable anti-acetylcholine receptor antibodies, seronegative MG is considered an autoimmune disorder and may be related to the disturbed immune function observed in GSD Ib patients.

Aluminum adjuvants of vaccines injected into the muscle: Normal fate, pathology and associated disease.

PubMed

Gherardi, R K; Aouizerate, J; Cadusseau, J; Yara, S; Authier, F J

2016-06-01

Aluminum oxyhydroxide (Alhydrogel(®)) is a nano-crystalline compound forming aggregates that has been introduced in vaccine for its immunologic adjuvant effect in 1926. It is the most commonly used adjuvant in human and veterinary vaccines but mechanisms by which it stimulates immune responses remain ill-defined. Although generally well tolerated on the short term, it has been suspected to occasionally cause delayed neurologic problems in susceptible individuals. In particular, the long-term persistence of aluminic granuloma also termed macrophagic myofasciitis is associated with chronic arthromyalgias and fatigue and cognitive dysfunction. Safety concerns largely depend on the long biopersistence time inherent to this adjuvant, which may be related to its quick withdrawal from the interstitial fluid by avid cellular uptake; and the capacity of adjuvant particles to migrate and slowly accumulate in lymphoid organs and the brain, a phenomenon documented in animal models and resulting from MCP1/CCL2-dependant translocation of adjuvant-loaded monocyte-lineage cells (Trojan horse phenomenon). These novel insights strongly suggest that serious re-evaluation of long-term aluminum adjuvant phamacokinetics and safety should be carried out. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Liver-brain interactions in inflammatory liver diseases: implications for fatigue and mood disorders.

PubMed

D'Mello, Charlotte; Swain, Mark G

2014-01-01

Chronic inflammatory liver diseases are often accompanied by behavior alterations including fatigue, mood disorders, cognitive dysfunction and sleep disturbances. These altered behaviors can adversely affect patient quality of life. The communication pathways between the inflamed liver and the brain that mediate changes in central neural activity leading to behavior alterations during liver inflammation are poorly understood. Neural and humoral communication pathways have been most commonly implicated as driving peripheral inflammation to brain signaling. Classically, the cytokines TNFα, IL-1β and IL-6 have received the greatest scientific attention as potential mediators of this communication pathway. In mice with liver inflammation we have identified a novel immune-mediated liver-to-brain communication pathway whereby CCR2(+) monocytes found within the peripheral circulation transmigrate into the brain parenchyma in response to MCP-1/CCL2 expressing activated microglia. Inhibition of cerebral monocyte infiltration in these mice significantly improved liver inflammation associated sickness behaviors. Importantly, in recent work we have found that at an earlier time point, when cerebral monocyte infiltration is not evident in mice with liver inflammation, increased monocyte:cerebral endothelial cell adhesive interactions are observed using intravital microscopy of the brain. These monocyte:cerebral endothelial cell adhesive interactions are P-selectin mediated, and inhibition of these interactions attenuated microglial activation and sickness behavior development. Delineating the pathways that the periphery uses to communicate with the brain during inflammatory liver diseases, and the central neurotransmitter systems that are altered through these communication pathways (e.g., serotonin, corticotrophin releasing hormone) to give rise to liver inflammation-associated sickness behaviors, will allow for the identification of novel therapeutic targets to decrease the burden of debilitating symptoms in these patients. Copyright © 2013 Elsevier Inc. All rights reserved.

Efficacy of a Home-Based Exercise Program After Thyroidectomy for Thyroid Cancer Patients.

PubMed

Kim, Kyunghee; Gu, Mee Ock; Jung, Jung Hwa; Hahm, Jong Ryeal; Kim, Soo Kyoung; Kim, Jin Hyun; Woo, Seung Hoon

2018-02-01

The objective of this study was to determine the effect of a home-based exercise program on fatigue, anxiety, quality of life (QoL), and immune function of thyroid cancer patients taking thyroid hormone replacement after thyroidectomy. This quasi-experimental study with a non-equivalent control group included 43 outpatients taking thyroid hormone replacement after thyroidectomy (22 in the experimental group and 21 in the control group). After education about the home-based exercise program, subjects in the experimental group underwent 12 weeks of aerobic, resistance, and flexibility exercise. A comparative analysis was conducted between the two groups. Patients in the experimental group were significantly less fatigued or anxious (p < 0.01). They reported significantly improved QoL (p < 0.05) compared to those in the control group. Natural killer cell activity was significantly higher in the exercise group compared to that in the control group (p < 0.05). A home-based exercise program is effective in reducing fatigue and anxiety, improving QoL, and increasing immune function in patients taking thyroid hormone replacement after thyroidectomy. Therefore, such a home-based exercise program can be used as an intervention for patients who are taking thyroid hormone replacement after thyroidectomy.

How Does Optimism Suppress Immunity? Evaluation of Three Affective Pathways

PubMed Central

Segerstrom, Suzanne C.

2005-01-01

Studies have linked optimism to poorer immunity during difficult stressors. In the present report, when first-year law students (N = 46) relocated to attend law school, reducing conflict among curricular and extracurricular goals, optimism predicted larger delayed type hypersensitivity responses, indicating more robust in vivo cellular immunity. However, when students did not relocate, increasing goal conflict, optimism predicted smaller responses. Although this effect has been attributed to negative affect when difficult stressors violate optimistic expectancies, distress did not mediate optimism’s effects on immunity. Alternative affective mediators related to engagement – engaged affect and fatigue – likewise failed to mediate optimism’s effects, although all three types of affect independently influenced in vivo immunity. Alternative pathways include effort or self-regulatory depletion. PMID:17014284

Increased risk of organic erectile dysfunction in patients with chronic fatigue syndrome: a nationwide population-based cohort study.

PubMed

Chao, C-H; Chen, H-J; Wang, H-Y; Li, T-C; Kao, C-H

2015-07-01

Chronic fatigue syndrome (CFS) is a complex disorder characterized by profound and persistent fatigue and several comorbidities. CFS was previously reported to be associated with female sexual dysfunction. We propose that CFS might also be associated with organic erectile dysfunction (organic ED). We conducted a retrospective cohort study by using data from the National Health Insurance (NHI) Research Database. We identified 2156 male patients who were newly diagnosed with CFS between January 1, 2003 and December 31, 2006. After excluding those younger than 20 years and prevalent cases, 1976 patients were subjected to analysis, and 7904 people served as healthy controls. All study subjects were followed up from the index date to the date of organic ED diagnosis, withdrawal from the NHI program, or the end of 2011. Compared with the non-CFS cohort, the incidence density rate of organic ED was 1.88-fold higher than that in the CFS cohort (3.23 vs. 1.73 per 1000 person-years) with an adjusted hazard ratio (HR) of 1.88 (95% CI = 1.26-2.81) when adjusting for sex and comorbidities. The combined impacts of patients with CFS and cardiovascular disease (CVD), diabetes mellitus (DM), chronic kidney disease (CKD), depression, and anxiety showed a significant by joint association with organic ED risk compared with patients with no CFS and no counterpart comorbidity. The greatest magnitude of adjusted HR of ED for CFS was observed in individuals without any comorbidity (3.87, 1.95-7.66). The incidence of organic ED is higher among males aged 40 years and over for both CFS and non-CFS cohorts. As the number of comorbidity increases, the incidence of organic ED increases in males without CFS. Higher incidence of organic ED was observed in males with CVD, DM, CKD, depression, or anxiety for both CFS and non-CFS cohorts. © 2015 American Society of Andrology and European Academy of Andrology.

Long-term pain, fatigue, and impairment in neuralgic amyotrophy.

PubMed

van Alfen, Nens; van der Werf, Sieberen P; van Engelen, Baziel G

2009-03-01

Recently, it has become clear that neuralgic amyotrophy (NA; idiopathic and hereditary brachial plexus neuropathy) has a less optimistic prognosis than usually assumed. To optimize treatment and management of these patients, one needs to know the residual symptoms and impairments they suffer. Therefore, the objective of this study was to describe the prevalence of pain, psychologic symptoms, fatigue, functional status, and quality of life in patients with NA. Neurology outpatient department of an academic teaching hospital. NA patients (N=89) were studied, and clinical details were recorded. Self-report data were on average collected 2 years after the onset of the last NA episode. Pain was assessed with the McGill Pain Questionnaire, fatigue with the Checklist Individual Strength, and psychologic distress with the Symptom Checklist 90. Functional status and handicap were assessed with the modified Rankin Scale and Medical Outcomes Study 36-Item Short-Form Health Survey. Pain was usually localized in the right shoulder and upper arm, matching the clinical predilection site for paresis in NA. About a quarter to a third of the patients reported significant long-term pain and fatigue, and half to two thirds still experienced impairments in daily life. Over one third of the individual patients suffered from severe fatigue. The group did not fulfill the criteria of chronic fatigue or major psychologic distress. There was no correlation of pain or fatigue with the level of residual paresis on a Medical Research Council scale, but patients with a comorbid condition fared worse than patients without. A significant number of NA patients suffer from persistent pain and fatigue, leading to impairment. Symptoms were not correlated with psychologic distress. This makes it likely that they are caused by residual shoulder or arm dysfunction but not as part of a chronic pain or fatigue syndrome in these patients.

Current insights into the innate immune system dysfunction in irritable bowel syndrome.

PubMed

Lazaridis, Nikolaos; Germanidis, Georgios

2018-01-01

Irritable bowel syndrome (IBS) is a functional bowel disorder associated with abdominal pain and alterations in bowel habits. The presence of IBS greatly impairs patients' quality of life and imposes a high economic burden on the community; thus, there is intense pressure to reveal its elusive pathogenesis. Many etiological mechanisms have been implicated, but the pathophysiology of the syndrome remains unclear. As a result, novel drug development has been slow and no pharmacological intervention is universally accepted. A growing evidence implicates the role of low-grade inflammation and innate immune system dysfunction, although contradictory results have frequently been presented. Mast cells (MC), eosinophils and other key immune cells together with their mediators seem to play an important role, at least in subgroups of IBS patients. Cytokine imbalance in the systematic circulation and in the intestinal mucosa may also characterize IBS presentation. Toll-like receptors and their emerging role in pathogen recognition have also been highlighted recently, as dysregulation has been reported to occur in patients with IBS. This review summarizes the current knowledge regarding the involvement of any immunological alteration in the development of IBS. There is substantial evidence to support innate immune system dysfunction in several IBS phenotypes, but additional studies are required to better clarify the underlying pathogenetic pathways. IBS heterogeneity could potentially be attributed to multiple causes that lead to different disease phenotypes, thus explaining the variability found between study results.

The Impact of Exercising During Haemodialysis on Blood Pressure, Markers of Cardiac Injury and Systemic Inflammation--Preliminary Results of a Pilot Study.

PubMed

Dungey, Maurice; Bishop, Nicolette C; Young, Hannah M L; Burton, James O; Smith, Alice C

2015-01-01

Patients requiring haemodialysis have cardiovascular and immune dysfunction. Little is known about the acute effects of exercise during haemodialysis. Exercise has numerous health benefits but in other populations has a profound impact upon blood pressure, inflammation and immune function; therefore having the potential to exacerbate cardiovascular and immune dysfunction in this vulnerable population. Fifteen patients took part in a randomised-crossover study investigating the effect of a 30-min bout of exercise during haemodialysis compared to resting haemodialysis. We assessed blood pressure, plasma markers of cardiac injury and systemic inflammation and neutrophil degranulation. Exercise increased blood pressure immediately post-exercise; however, 1 hour after exercise blood pressure was lower than resting levels (106±22 vs. 117±25 mm Hg). No differences in h-FABP, cTnI, myoglobin or CKMB were observed between trial arms. Exercise did not alter circulating concentrations of IL-6, TNF-α or IL-1ra nor clearly suppress neutrophil function. This study demonstrates fluctuations in blood pressure during haemodialysis in response to exercise. However, since the fall in blood pressure occurred without evidence of cardiac injury, we regard it as a normal response to exercise superimposed onto the haemodynamic response to haemodialysis. Importantly, exercise did not exacerbate systemic inflammation or immune dysfunction; intradialytic exercise was well tolerated. © 2015 The Author(s) Published by S. Karger AG, Basel.

Ascending caudal medullary catecholamine pathways drive sickness-induced deficits in exploratory behavior: brain substrates for fatigue?

PubMed

Gaykema, Ronald P A; Goehler, Lisa E

2011-03-01

Immune challenges can lead to marked behavioral changes, including fatigue, reduced social interest, anorexia, and somnolence, but the precise neuronal mechanisms that underlie sickness behavior remain elusive. Part of the neurocircuitry influencing behavior associated with illness likely includes viscerosensory nuclei located in the caudal brainstem, based on findings that inactivation of the dorsal vagal complex (DVC) can prevent social withdrawal. These brainstem nuclei contribute multiple neuronal projections that target different components of autonomic and stress-related neurocircuitry. In particular, catecholaminergic neurons in the ventrolateral medulla (VLM) and DVC target the hypothalamus and drive neuroendocrine responses to immune challenge, but their particular role in sickness behavior is not known. To test whether this catecholamine pathway also mediates sickness behavior, we compared effects of DVC inactivation with targeted lesion of the catecholamine pathway on exploratory behavior, which provides an index of motivation and fatigue, and associated patterns of brain activation assessed by immunohistochemical detection of c-Fos protein. LPS treatment dramatically reduced exploratory behavior, and produced a pattern of increased c-Fos expression in brain regions associated with stress and autonomic adjustments paraventricular hypothalamus (PVN), bed nucleus of the stria terminalis (BST), central amygdala (CEA), whereas activation was reduced in regions involved in exploratory behavior (hippocampus, dorsal striatum, ventral tuberomammillary nucleus, and ventral tegmental area). Both DVC inactivation and catecholamine lesion prevented reductions in exploratory behavior and completely blocked the inhibitory LPS effects on c-Fos expression in the behavior-associated regions. In contrast, LPS-induced activation in the CEA and BST was inhibited by DVC inactivation but not by catecholamine lesion. The findings support the idea that parallel pathways from immune-sensory caudal brainstem sources target distinct populations of forebrain neurons that likely mediate different aspects of sickness. The caudal medullary catecholaminergic projections to the hypothalamus may significantly contribute to brain mechanisms that induce behavioral "fatigue" in the context of physiological stressors. Copyright © 2010 Elsevier Inc. All rights reserved.

Protection from JP-8 jet fuel induced immunotoxicity by administration of aerosolized substance P.

PubMed

Harris, D T; Sakiestewa, D; Robledo, R F; Witten, M

1997-01-01

Chronic exposure to jet fuel has been shown to cause human liver dysfunction, emotional dysfunction, abnormal electroencephalograms, shortened attention spans, and decreased sensorimotor speed. The United States Air Force has decided to implement the widespread use of JP-8 jet fuel in its operations, although a thorough understanding of its potential effects upon exposed personnel is unclear. Exposure to potential environment toxicants such as JP-8 may have significant effects on host physiology. Previous studies in mice have shown that short-term, low concentration JP-8 exposure had significant effects on the immune system; e.g., decreased viable immune cell numbers, decreased immune organ weights, and loss on immune function that persisted for extended periods of time (i.e., up to 4 weeks post-exposure). Previous studies have shown that JP-8 induced pulmonary dysfunction was associated with a decrease in levels of the neuropeptide substance P (SP) in lung lavage fluids. It was found that administration of aerosolized SP was able to protect exposed animals from such JP-8 induced pulmonary changes. In the current study, aerosolized SP was analyzed for its effects on JP-i induced immunotoxicity in exposed mice. It was observed that SP administration could protect JP-8 exposed animals from losses of viable immune cell numbers, but not losses in immune organ weights. Further, exposure of animals to SP inhibitors generally increased the immunotoxicity of JP-8 exposure. SP appeared to act on all immune cell populations equally as analyzed by flow cytometry, as no one immune cell population appeared to be preferentially protected by SP. Also, SP administration was capable of protecting JP-8 exposed animals from loss of immune function at all concentrations of JP-8 utilized (250-2500 mg/m3). Significantly, SP only needed to be administered for 15 minutes after JP-8 exposure, and was active at both 1 microM and 1 nM concentrations. Thus, SP administration appears to be a relatively simple and efficient means to reverse the immunotoxicity due to hydrocarbon exposure.

Orthostatic intolerance and postural tachycardia syndrome as suspected adverse effects of vaccination against human papilloma virus.

PubMed

Brinth, Louise S; Pors, Kirsten; Theibel, Ann C; Mehlsen, Jesper

2015-05-21

Infections with human papilloma virus (HPV) can result in cervical, oropharyngeal, anal, and penile cancer and vaccination programs have been launched in many countries as a preventive measure. We report the characteristics of a number of patients with a syndrome of orthostatic intolerance, headache, fatigue, cognitive dysfunction, and neuropathic pain starting in close relation to HPV vaccination. Patients were referred for orthostatic intolerance following HPV vaccination. Symptoms of autonomic dysfunction were quantified by standardised questionnaire. The diagnosis of postural orthostatic tachycardia syndrome (POTS) rested on finding a sustained heart rate increment of >30 min(-1) (>40 min(-1) in adolescents) or to levels >120 min(-1) during orthostatic challenge. 35 women aged 23.3 ± 7.1 years participated. Twenty-five had a high level of physical activity before vaccination and irregular periods were reported by all patients not on treatment with oral contraception. Serum bilirubin was below the lower detection limit in 17 patients. Twenty-one of the referred patients fulfilled the criteria for a diagnosis of POTS (60%, 95%CI 43-77%). All patients had orthostatic intolerance, 94% nausea, 82% chronic headache, 82% fatigue, 77% cognitive dysfunction, 72% segmental dystonia, 68% neuropathic pain. In a population referred for symptoms of orthostatic intolerance and other symptoms consistent with autonomic dysfunction that began in close temporal association with a quadrivalent HPV vaccination, we identified a 60% prevalence of POTS. Further work is urgently needed to elucidate the potential for a causal link between the vaccine and circulatory abnormalities and to establish targeted treatment options for the affected patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

Association between White Matter Lesions and Non-Motor Symptoms in Parkinson Disease.

PubMed

Lee, Jeong-Yoon; Kim, Ji Sun; Jang, Wooyoung; Park, Jinse; Oh, Eungseok; Youn, Jinyoung; Park, Suyeon; Cho, Jin Whan

2018-06-05

There are only few studies exploring the relationship between white matter lesions (WMLs) and non-motor symptoms in Parkinson disease (PD). This study aimed to investigate the association between WMLs and the severity of non-motor symptoms in PD. The severity of motor dysfunction, cognitive impairment, and non-motor symptoms was assessed by various scales in 105 PD patients. We used a visual semiquantitative rating scale and divided the subjects into four groups: no, mild, moderate, and severe WMLs. We compared the means of all scores between the four groups and analyzed the association between the severity of WMLs and the specific domain of non-motor symptoms. The non-motor symptoms as assessed by the Non-Motor Symptoms Scale, Parkinson's Disease Questionnaire (PDQ-39), Parkinson's Disease Sleep Scale, Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Neuropsychiatric Inventory (NPI), and Parkinson Fatigue Scale (PFS) were significantly worse in the patients with moderate and severe WMLs than in those without WMLs. Compared with the no WML group, the scores for motor dysfunction were significantly higher in the mild, moderate, and severe WML groups. The scores for cognitive dysfunction were significantly higher in the patients with severe WMLs than in those without WMLs. The severity of WMLs showed linear associations with PFS, BDI, BAI, NPI, and PDQ-39 scores. The severity of WMLs also correlated linearly with scores for motor and cognitive dysfunction. Among the non-motor symptoms, fatigue, depression, anxiety, and quality of life were significantly affected by WMLs in PD. Confirmation of the possible role of WMLs in non-motor symptoms associated with PD in a prospective manner may be crucial not only for understanding non-motor symptoms but also for the development of treatment strategies. © 2018 S. Karger AG, Basel.

Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: immunity interruptus

PubMed Central

Behar, Samuel M.; Carpenter, Stephen M.; Booty, Matthew G.; Barber, Daniel L.; Jayaraman, Pushpa

2014-01-01

Despite the introduction almost a century ago of Mycobacterium bovis BCG (BCG), an attenuated form of M. bovis that is used as a vaccine against Mycobacterium tuberculosis, tuberculosis remains a global health threat and kills more than 1.5 million people each year. This is mostly because BCG fails to prevent pulmonary disease – the contagious form of tuberculosis. Although there have been significant advances in understanding how the immune system responds to infection, the qualities that define protective immunity against M. tuberculosis remain poorly characterized. The ability to predict who will maintain control over the infection and who will succumb to clinical disease would revolutionize our approach to surveillance, control, and treatment. Here we review the current understanding of pulmonary T cell responses following M. tuberculosis infection. While infection elicits a strong immune response that contains infection, M. tuberculosis evades eradication. Traditionally, its intracellular lifestyle and alteration of macrophage function are viewed as the dominant mechanisms of evasion. Now we appreciate that chronic inflammation leads to T cell dysfunction. While this may arise as the host balances the goals of bacterial sterilization and avoidance of tissue damage, it is becoming clear that T cell dysfunction impairs host resistance. Defining the mechanisms that lead to T cell dysfunction is crucial as memory T cell responses are likely to be subject to the same subject to the same pressures. Thus, success of T cell based vaccines is predicated on memory T cells avoiding exhaustion while at the same time not promoting overt tissue damage. PMID:25311810

Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: immunity interruptus.

PubMed

Behar, Samuel M; Carpenter, Stephen M; Booty, Matthew G; Barber, Daniel L; Jayaraman, Pushpa

2014-12-01

Despite the introduction almost a century ago of Mycobacterium bovis BCG (BCG), an attenuated form of M. bovis that is used as a vaccine against Mycobacterium tuberculosis, tuberculosis remains a global health threat and kills more than 1.5 million people each year. This is mostly because BCG fails to prevent pulmonary disease--the contagious form of tuberculosis. Although there have been significant advances in understanding how the immune system responds to infection, the qualities that define protective immunity against M. tuberculosis remain poorly characterized. The ability to predict who will maintain control over the infection and who will succumb to clinical disease would revolutionize our approach to surveillance, control, and treatment. Here we review the current understanding of pulmonary T cell responses following M. tuberculosis infection. While infection elicits a strong immune response that contains infection, M. tuberculosis evades eradication. Traditionally, its intracellular lifestyle and alteration of macrophage function are viewed as the dominant mechanisms of evasion. Now we appreciate that chronic inflammation leads to T cell dysfunction. While this may arise as the host balances the goals of bacterial sterilization and avoidance of tissue damage, it is becoming clear that T cell dysfunction impairs host resistance. Defining the mechanisms that lead to T cell dysfunction is crucial as memory T cell responses are likely to be subject to the same subject to the same pressures. Thus, success of T cell based vaccines is predicated on memory T cells avoiding exhaustion while at the same time not promoting overt tissue damage. Copyright © 2014 Elsevier Ltd. All rights reserved.

Learning and cognitive fatigue trajectories in multiple sclerosis defined using a burst measurement design.

PubMed

Holtzer, Roee; Foley, Frederick; D'Orio, Vanessa; Spat, Jessica; Shuman, Melissa; Wang, Cuiling

2013-10-01

Compromised learning and cognitive fatigue are critical clinical features in multiple sclerosis. This study was designed to determine the effect of repeated exposures within and across study visits on performance measures of learning and cognitive fatigue in relapsing-remitting multiple sclerosis (RRMS). Thirty patients with RRMS and 30 controls were recruited. Using a burst measurement design (i.e. repeated assessments within and across study visits) the oral version of the Symbol Digit Modalities Test (SDMT) was administered three times during the baseline and two consecutive monthly follow-up visits for a total of nine test administrations. Learning was assessed within and across study visits whereas cognitive fatigue was assessed during the course of each test administration that was divided into three 30-second intervals. Linear mixed-effect models revealed compromised learning within (95% CI: 2.6355 to 3.9867) and across (95% CI: 1.3250 to 3.1861) visits and worse cognitive fatigue (95% CI: -2.1761 to -0.1720) in patients with RRMS compared with controls. Among patients with RRMS, worse self-rated cognitive dysfunction predicted poor learning within (95% CI: -0.1112 to -0.0020) and across (95% CI: -0.0724 to -0.0106) visits. Burst design is optimal to study learning and cognitive fatigue. This methodology, using the SDMT or other time-efficient tests as outcome measures, can be successfully implemented in longitudinal studies and clinical trials.

Rituximab is Ineffective for Treatment of Fatigue in Primary Biliary Cholangitis: A phase-2 Randomised Controlled Trial.

PubMed

Khanna, Amardeep; Jopson, Laura; Howel, Denise; Bryant, Andrew; Blamire, Andrew; Newton, Julia L; Jones, David E

2018-05-23

Primary Biliary Cholangitis (PBC) is a chronic cholestatic liver disease. Half of patients experience debilitating fatigue which is currently untreatable. Previous studies have shown muscle bioenergetic abnormalities in PBC, including increased muscle acidosis with exercise linked to the anti-mitochondrial antibody (AMA) diagnostic of the disease, and reduced anaerobic threshold. In this study we addressed the hypothesis that fatigue in PBC is driven by muscle bioenergetic abnormality related to AMA, and that AMA reduction with B-cell depletion therapy will improve fatigue. In our single-centred Phase II randomised controlled trial (RCT) 57 participants aged ≥18 years with PBC and moderate or severe fatigue were randomized to receive 2 doses of either rituximab (1000mg) or saline (placebo). The primary outcome measure was fatigue severity assessed using the PBC-40 fatigue domain at 3 months. Secondary outcomes measures included patient-reported outcomes, immunological and bioenergetics disease parameters. Experimental outcomes included biochemical markers of disease severity. Improvement in fatigue score at 3 months was seen in both arms, with no significant difference (adjusted mean difference -0.9 95%CI -4.6 to 3.1). Little difference was observed in other patient reported outcomes or physical activity. Significant anaerobic threshold improvement was seen in the Rituximab group only but this was not associated with fatigue improvement. No treatment-emergent SAEs were seen. Rituximab was safe over the 12 month study period but showed no evidence of effectiveness for the treatment of fatigue in PBC. Anaerobic threshold improvement was seen; potentially linking AMA with muscle bioenergetics dysfunction, however, this was not related to improvement in fatigue. Rituximab had some evidence of a beneficial effect on alkaline phosphatase levels in this largely UDCA-responding, early disease stage cohort. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

Cancer and Cancer-Related Fatigue and the Interrelationships With Depression, Stress, and Inflammation

PubMed Central

Weber, Daniel; O’Brien, Kylie

2016-01-01

Cancer-related fatigue (CRF) is a common symptom experienced in cancer patients. Depression, anxiety, and stress are associated with cancer. Depression and anxiety are also associated with CRF. At the cellular level, much is known about the impact of stress on the body generally, and its potential role in cancer. Stress, anxiety, and depression have been found to depress the immune system. Depression and stress have also been found to create inflammatory changes in the body and there is emerging evidence that inflammation is involved in cancer pathogenesis and in CRF. This article examines the relationships between stress, anxiety, depression, and cancer; relationships between anxiety and depression and CRF; and what happens at the cellular level, including impact on the immune system and emerging evidence of the role of inflammation in CRF. It also reports on research in relation to some Chinese herbal medicines that may be used to treat CRF.

Prevalence and Predictors of Thyroid Dysfunction in Patients with HIV Infection and Acquired Immunodeficiency Syndrome: An Indian Perspective.

PubMed

Sharma, Neera; Sharma, Lokesh Kumar; Dutta, Deep; Gadpayle, Adesh Kisanji; Anand, Atul; Gaurav, Kumar; Mukherjee, Sabyasachi; Bansal, Rahul

2015-01-01

Background. Predictors of thyroid dysfunction in HIV are not well determined. This study aimed to determine the prevalence and predictors of thyroid dysfunction in HIV infected Indians. Methods. Consecutive HIV patients, 18-70 years of age, without any severe comorbid state, having at least 1-year follow-up at the antiretroviral therapy clinic, underwent clinical assessment and hormone assays. Results. From initially screened 527 patients, 359 patients (61.44 ± 39.42 months' disease duration), having good immune function [CD4 count >200 cell/mm(3): 90.25%; highly active antiretroviral therapy (HAART): 88.58%], were analyzed. Subclinical hypothyroidism (ScH) was the commonest thyroid dysfunction (14.76%) followed by sick euthyroid syndrome (SES) (5.29%) and isolated low TSH (3.1%). Anti-TPO antibody (TPOAb) was positive in 3.90%. Baseline CD4 count had inverse correlation with TPOAb after adjusting for age and body mass index. Stepwise linear regression revealed baseline CD4 count, TPOAb, and tuberculosis to be best predictors of ScH after adjusting for age, weight, duration of HIV, and history of opportunistic fungal and viral infections. Conclusion. Burden of thyroid dysfunction in chronic HIV infection with stable immune function is lower compared to pre-HAART era. Thyroid dysfunction is primarily of nonautoimmune origin, predominantly ScH. Severe immunodeficiency at disease onset, TPOAb positivity, and tuberculosis were best predictors of ScH.

Altered resting brain connectivity in persistent cancer related fatigue

PubMed Central

Hampson, Johnson P.; Zick, Suzanna M.; Khabir, Tohfa; Wright, Benjamin D.; Harris, Richard E.

2015-01-01

There is an estimated 3 million women in the US living as breast cancer survivors and persistent cancer related fatigue (PCRF) disrupts the lives of an estimated 30% of these women. PCRF is associated with decreased quality of life, decreased sleep quality, impaired cognition and depression. The mechanisms of cancer related fatigue are not well understood; however, preliminary findings indicate dysfunctional activity in the brain as a potential factor. Here we investigate the relationship between PCRF on intrinsic resting state connectivity in this population. Twenty-three age matched breast cancer survivors (15 fatigued and 8 non-fatigued) who completed all cancer-related treatments at least 12 weeks prior to the study, were recruited to undergo functional connectivity magnetic resonance imaging (fcMRI). Intrinsic resting state networks were examined with both seed based and independent component analysis methods. Comparisons of brain connectivity patterns between groups as well as correlations with self-reported fatigue symptoms were performed. Fatigued patients displayed greater left inferior parietal lobule to superior frontal gyrus connectivity as compared to non-fatigued patients (P < 0.05 FDR corrected). This enhanced connectivity was associated with increased physical fatigue (P = 0.04, r = 0.52) and poor sleep quality (P = 0.04, r = 0.52) in the fatigued group. In contrast greater connectivity in the non-fatigued group was found between the right precuneus to the periaqueductal gray as well as the left IPL to subgenual cortex (P < 0.05 FDR corrected). Mental fatigue scores were associated with greater default mode network (DMN) connectivity to the superior frontal gyrus (P = 0.05 FDR corrected) among fatigued subjects (r = 0.82) and less connectivity in the non-fatigued group (r = −0.88). These findings indicate that there is enhanced intrinsic DMN connectivity to the frontal gyrus in breast cancer survivors with persistent fatigue. As the DMN is a network involved in self-referential thinking we speculate that enhanced connectivity between the DMN and the frontal gyrus may be related to mental fatigue and poor sleep quality. In contrast, enhanced connectivity between the DMN and regions in the subgenual cingulate and brainstem may serve a protective function in the non-fatigued group. PMID:26106555

Altered resting brain connectivity in persistent cancer related fatigue.

PubMed

Hampson, Johnson P; Zick, Suzanna M; Khabir, Tohfa; Wright, Benjamin D; Harris, Richard E

2015-01-01

There is an estimated 3 million women in the US living as breast cancer survivors and persistent cancer related fatigue (PCRF) disrupts the lives of an estimated 30% of these women. PCRF is associated with decreased quality of life, decreased sleep quality, impaired cognition and depression. The mechanisms of cancer related fatigue are not well understood; however, preliminary findings indicate dysfunctional activity in the brain as a potential factor. Here we investigate the relationship between PCRF on intrinsic resting state connectivity in this population. Twenty-three age matched breast cancer survivors (15 fatigued and 8 non-fatigued) who completed all cancer-related treatments at least 12 weeks prior to the study, were recruited to undergo functional connectivity magnetic resonance imaging (fcMRI). Intrinsic resting state networks were examined with both seed based and independent component analysis methods. Comparisons of brain connectivity patterns between groups as well as correlations with self-reported fatigue symptoms were performed. Fatigued patients displayed greater left inferior parietal lobule to superior frontal gyrus connectivity as compared to non-fatigued patients (P < 0.05 FDR corrected). This enhanced connectivity was associated with increased physical fatigue (P = 0.04, r = 0.52) and poor sleep quality (P = 0.04, r = 0.52) in the fatigued group. In contrast greater connectivity in the non-fatigued group was found between the right precuneus to the periaqueductal gray as well as the left IPL to subgenual cortex (P < 0.05 FDR corrected). Mental fatigue scores were associated with greater default mode network (DMN) connectivity to the superior frontal gyrus (P = 0.05 FDR corrected) among fatigued subjects (r = 0.82) and less connectivity in the non-fatigued group (r = -0.88). These findings indicate that there is enhanced intrinsic DMN connectivity to the frontal gyrus in breast cancer survivors with persistent fatigue. As the DMN is a network involved in self-referential thinking we speculate that enhanced connectivity between the DMN and the frontal gyrus may be related to mental fatigue and poor sleep quality. In contrast, enhanced connectivity between the DMN and regions in the subgenual cingulate and brainstem may serve a protective function in the non-fatigued group.

RNA-Binding Proteins in Female Reproductive Pathologies.

PubMed

Khalaj, Kasra; Miller, Jessica E; Fenn, Christian R; Ahn, SooHyun; Luna, Rayana L; Symons, Lindsey; Monsanto, Stephany P; Koti, Madhuri; Tayade, Chandrakant

2017-06-01

RNA-binding proteins are key regulatory molecules involved primarily in post-transcriptional gene regulation of RNAs. Post-transcriptional gene regulation is critical for adequate cellular growth and survival. Recent reports have shown key interactions between these RNA-binding proteins and other regulatory elements, such as miRNAs and long noncoding RNAs, either enhancing or diminishing their response to RNA stabilization. Many RNA-binding proteins have been reported to play a functional role in mediation of cytokines involved in inflammation and immune dysfunction, and some have been classified as global post-transcriptional regulators of inflammation. The ubiquitous expression of RNA-binding proteins in a wide variety of cell types and their unique mechanisms of degradative action provide evidence that they are involved in reproductive tract pathologies. Aberrant inflammation and immune dysfunction are major contributors to the pathogenesis and disease pathophysiology of many reproductive pathologies, including ovarian and endometrial cancers in the female reproductive tract. Herein, we discuss various RNA-binding proteins and their unique contributions to female reproductive pathologies with a focus on those mediated by aberrant inflammation and immune dysfunction. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

The Representation of Inflammatory Signals in the Brain – A Model for Subjective Fatigue in Multiple Sclerosis

PubMed Central

Hanken, Katrin; Eling, Paul; Hildebrandt, Helmut

2014-01-01

In multiple sclerosis (MS) patients, fatigue is rated as one of the most common and disabling symptoms. However, the pathophysiology underlying this fatigue is not yet clear. Several lines of evidence suggest that immunological factors, such as elevated levels of pro-inflammatory cytokines, may contribute to subjective fatigue in MS patients. Pro-inflammatory cytokines represent primary mediators of immune-to-brain-communication, modulating changes in the neurophysiology of the central nervous system. Recently, we proposed a model arguing that fatigue in MS patients is a subjective feeling, which is related to inflammation. Moreover, it implies that fatigue can be measured behaviorally only by applying specific cognitive tasks related to alertness and vigilance. In the present review, we focus on the subjective feeling of MS-related fatigue. We examine the hypothesis that the subjective feeling of MS-related fatigue may be a variant of inflammation-induced sickness behavior, resulting from cytokine-mediated activity changes within brain areas involved in interoception and homeostasis including the insula, the anterior cingulate, and the hypothalamus. We first present studies demonstrating a relationship between pro-inflammatory cytokines and subjective fatigue in healthy individuals, in people with inflammatory disorders, and particularly in MS patients. Subsequently, we discuss studies analyzing the impact of anti-inflammatory treatment on fatigue. In the next part of this review, we present studies on the transmission and neural representation of inflammatory signals, with a special focus on possible neural concomitants of inflammation-induced fatigue. We also present two of our studies on the relationship between local gray and white matter atrophy and fatigue in MS patients. Finally, we discuss some implications of our findings and future perspectives. PMID:25566171

Pharmaceutical composition and drug effect of synthetic Bacopa monnieri L. health promoting agent from the perspective of resistance fatigue.

PubMed

Chen, Zhidan; Yan, Yanqin

2017-09-01

Bacopa monnieri has effect on the nervous system, digestive system and blood circulation systems. In this paper, the authors conducted pharmacological analysis on Bacopa monniera and its innovative pharmaceutical preparation of promote motor function. The extract of the drug has some effect on relieving the fatigue and providing the movement function. By analyzing the composition and efficacy of Chinese herbal extracts, it can be seen that these drugs have obvious effect on improving immunity. Experimental results show that the agent can increase the liver glycogen energy reserves, reduce Bla and BUN levels, balance and energy metabolism of muscle cells in the environment, it plays a positive role to improve the exercise capacity and exercise fatigue.

T-cell homeostasis in breast cancer survivors with persistent fatigue.

PubMed

Bower, Julienne E; Ganz, Patricia A; Aziz, Najib; Fahey, John L; Cole, Steve W

2003-08-06

Approximately 30% of women successfully treated for breast cancer suffer persistent fatigue of unknown origin. Recent studies linking inflammatory processes to central nervous system-mediated fatigue led us to examine cellular immune system status in 20 fatigued breast cancer survivors and 19 matched non-fatigued breast cancer survivors. Fatigued survivors, compared with non-fatigued survivors, had statistically significantly increased numbers of circulating T lymphocytes (mean 31% increase, 95% confidence interval [CI] = 6% to 56%; P =.015 by two-sided analysis of variance [ANOVA]), with pronounced elevation in the numbers of CD4+ T lymphocytes (mean 41% increase, 95% CI = 15% to 68%; P =.003 by two-sided ANOVA) and CD56+ effector T lymphocytes (mean 52% increase, 95% CI = 4% to 99%; P =.027 by two-sided ANOVA). These changes were independent of patient demographic and treatment characteristics. Absolute numbers of B cells, natural killer cells, granulocytes, and monocytes were not altered. The increased numbers of circulating T cells correlated with elevations in the level of serum interleukin 1 receptor antagonist (for CD3+ cells, r =.56 and P =.001; for CD3+/CD4+ cells, r =.68 and P<.001, by Spearman rank correlation). Results of this study suggest that persistent fatigue in breast cancer survivors might be associated with a chronic inflammatory process involving the T-cell compartment. These results require confirmation in a larger study that is specifically designed to address this hypothesis.

Classifying Patients with Chronic Pelvic Pain into Levels of Biopsychosocial Dysfunction Using Latent Class Modeling of Patient Reported Outcome Measures

PubMed Central

Fenton, Bradford W.; Grey, Scott F.; Tossone, Krystel; McCarroll, Michele; Von Gruenigen, Vivian E.

2015-01-01

Chronic pelvic pain affects multiple aspects of a patient's physical, social, and emotional functioning. Latent class analysis (LCA) of Patient Reported Outcome Measures Information System (PROMIS) domains has the potential to improve clinical insight into these patients' pain. Based on the 11 PROMIS domains applied to n=613 patients referred for evaluation in a chronic pelvic pain specialty center, exploratory factor analysis (EFA) was used to identify unidimensional superdomains. Latent profile analysis (LPA) was performed to identify the number of homogeneous classes present and to further define the pain classification system. The EFA combined the 11 PROMIS domains into four unidimensional superdomains of biopsychosocial dysfunction: Pain, Negative Affect, Fatigue, and Social Function. Based on multiple fit criteria, a latent class model revealed four distinct classes of CPP: No dysfunction (3.2%); Low Dysfunction (17.8%); Moderate Dysfunction (53.2%); and High Dysfunction (25.8%). This study is the first description of a novel approach to the complex disease process such as chronic pelvic pain and was validated by demographic, medical, and psychosocial variables. In addition to an essentially normal class, three classes of increasing biopsychosocial dysfunction were identified. The LCA approach has the potential for application to other complex multifactorial disease processes. PMID:26355825

A Systematic Review of the Association between Immunogenomic Markers and Cancer-Related Fatigue

PubMed Central

Saligan, LN; Kim, HS

2012-01-01

Fatigue, which is one of the most commonly reported symptoms in cancer, can negatively impact the functional status and the health-related quality of life of individuals. This paper systematically reviews 34 studies to determine patterns of associations between immunogenomic markers and levels of cancer-related fatigue (CRF). Findings from the longitudinal studies revealed that elevated fatigue symptoms especially of women with early stages of breast cancer were associated with high levels of neutrophil/monocyte, IL-1ra, and IL-6 during radiation therapy; high levels of CD4+, IL-1β, and IL-6 with stressing stimuli; high levels of IL-1β during chemotherapy; low NK cell levels after chemotherapy; and presence of homozygous IL-6 and TNF alleles. In the cross-sectional studies, associations between levels of fatigue and immune/inflammatory markers were not consistently found, especially when covariates such as BMI, ethnicity, menopausal status, and educational level were controlled in the statistical analyses. However, a number of genomic markers were observed to be elevated mostly in fatigued breast cancer survivors in the cross-sectional studies. Gaps in knowledge and recommendations for future research are discussed. PMID:22595751

A systematic review of the association between immunogenomic markers and cancer-related fatigue.

PubMed

Saligan, L N; Kim, H S

2012-08-01

Fatigue, which is one of the most commonly reported symptoms in cancer, can negatively impact the functional status and the health-related quality of life of individuals. This paper systematically reviews 34 studies to determine patterns of associations between immunogenomic markers and levels of cancer-related fatigue (CRF). Findings from the longitudinal studies revealed that elevated fatigue symptoms especially of women with early stages of breast cancer were associated with high levels of neutrophil/monocyte, IL-1ra, and IL-6 during radiation therapy; high levels of CD4+, IL-1β, and IL-6 with stressing stimuli; high levels of IL-1β during chemotherapy; low NK cell levels after chemotherapy; and presence of homozygous IL-6 and TNF alleles. In the cross-sectional studies, associations between levels of fatigue and immune/inflammatory markers were not consistently found, especially when covariates such as BMI, ethnicity, menopausal status, and educational level were controlled in the statistical analyses. However, a number of genomic markers were observed to be elevated mostly in fatigued breast cancer survivors in the cross-sectional studies. Gaps in knowledge and recommendations for future research are discussed. Copyright © 2012 Elsevier Inc. All rights reserved.

Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

PubMed

Brenu, Ekua W; van Driel, Mieke L; Staines, Don R; Ashton, Kevin J; Ramos, Sandra B; Keane, James; Klimas, Nancy G; Marshall-Gradisnik, Sonya M

2011-05-28

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is characterised by severe prolonged fatigue, and decreases in cognition and other physiological functions, resulting in severe loss of quality of life, difficult clinical management and high costs to the health care system. To date there is no proven pathomechanism to satisfactorily explain this disorder. Studies have identified abnormalities in immune function but these data are inconsistent. We investigated the profile of markers of immune function (including novel markers) in CFS/ME patients. We included 95 CFS/ME patients and 50 healthy controls. All participants were assessed on natural killer (NK) and CD8(+) T cell cytotoxic activities, Th1 and Th2 cytokine profile of CD4(+) T cells, expression of vasoactive intestinal peptide receptor 2 (VPACR2), levels of NK phenotypes (CD56(bright) and CD56(dim)) and regulatory T cells expressing FoxP3 transcription factor. Compared to healthy individuals, CFS/ME patients displayed significant increases in IL-10, IFN-γ, TNF-α, CD4(+)CD25(+) T cells, FoxP3 and VPACR2 expression. Cytotoxic activity of NK and CD8(+) T cells and NK phenotypes, in particular the CD56(bright) NK cells were significantly decreased in CFS/ME patients. Additionally granzyme A and granzyme K expression were reduced while expression levels of perforin were significantly increased in the CFS/ME population relative to the control population. These data suggest significant dysregulation of the immune system in CFS/ME patients. Our study found immunological abnormalities which may serve as biomarkers in CFS/ME patients with potential for an application as a diagnostic tool.

Immune System Dysfunction in the Elderly.

PubMed

Fuentes, Eduardo; Fuentes, Manuel; Alarcón, Marcelo; Palomo, Iván

2017-01-01

Human aging is characterized by both physical and physiological frailty that profoundly affects the immune system. In this context aging is associated with declines in adaptive and innate immunity established as immunosenescence. Immunosenescence is a new concept that reflects the age-associated restructuring changes of innate and adaptive immune functions. Thus elderly individuals usually present chronic low-level inflammation, higher infection rates and chronic diseases. A study of alterations in the immune system during aging could provide a potentially useful biomarker for the evaluation of immune senescence treatment. The immune system is the result of the interplay between innate and adaptive immunity, yet the impact of aging on this function is unclear. In this article the function of the immune system during aging is explored.

Kv1.1 knock-in ataxic mice exhibit spontaneous myokymic activity exacerbated by fatigue, ischemia and low temperature.

PubMed

Brunetti, Orazio; Imbrici, Paola; Botti, Fabio Massimo; Pettorossi, Vito Enrico; D'Adamo, Maria Cristina; Valentino, Mario; Zammit, Christian; Mora, Marina; Gibertini, Sara; Di Giovanni, Giuseppe; Muscat, Richard; Pessia, Mauro

2012-09-01

Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder characterized by myokymia and attacks of ataxic gait often precipitated by stress. Several genetic mutations have been identified in the Shaker-like K(+) channel Kv1.1 (KCNA1) of EA1 individuals, including V408A, which result in remarkable channel dysfunction. By inserting the heterozygous V408A, mutation in one Kv1.1 allele, a mouse model of EA1 has been generated (Kv1.1(V408A/+)). Here, we investigated the neuromuscular transmission of Kv1.1(V408A/+) ataxic mice and their susceptibility to physiologically relevant stressors. By using in vivo preparations of lateral gastrocnemius (LG) nerve-muscle from Kv1.1(+/+) and Kv1.1(V408A/+) mice, we show that the mutant animals exhibit spontaneous myokymic discharges consisting of repeated singlets, duplets or multiplets, despite motor nerve axotomy. Two-photon laser scanning microscopy from the motor nerve, ex vivo, revealed spontaneous Ca(2+) signals that occurred abnormally only in preparations dissected from Kv1.1(V408A/+) mice. Spontaneous bursting activity, as well as that evoked by sciatic nerve stimulation, was exacerbated by muscle fatigue, ischemia and low temperatures. These stressors also increased the amplitude of compound muscle action potential. Such abnormal neuromuscular transmission did not alter fiber type composition, neuromuscular junction and vascularization of LG muscle, analyzed by light and electron microscopy. Taken together these findings provide direct evidence that identifies the motor nerve as an important generator of myokymic activity, that dysfunction of Kv1.1 channels alters Ca(2+) homeostasis in motor axons, and also strongly suggest that muscle fatigue contributes more than PNS fatigue to exacerbate the myokymia/neuromyotonia phenotype. More broadly, this study points out that juxtaparanodal K(+) channels composed of Kv1.1 subunits exert an important role in dampening the excitability of motor nerve axons during fatigue or ischemic insult. Copyright © 2012 Elsevier Inc. All rights reserved.

Triactome: neuro-immune-adipose interactions. Implication in vascular biology.

PubMed

Chaldakov, George Nikov; Fiore, Marco; Ghenev, Peter I; Beltowski, Jerzy; Ranćić, Gorana; Tunçel, Neşe; Aloe, Luigi

2014-01-01

Understanding how the precise interactions of nerves, immune cells, and adipose tissue account for cardiovascular and metabolic biology is a central aim of biomedical research at present. A long standing paradigm holds that the vascular wall is composed of three concentric tissue coats (tunicae): intima, media, and adventitia. However, large- and medium-sized arteries, where usually atherosclerotic lesions develop, are consistently surrounded by periadventitial adipose tissue (PAAT), we recently designated tunica adiposa (in brief, adiposa like intima, media, and adventitia). Today, atherosclerosis is considered an immune-mediated inflammatory disease featured by endothelial dysfunction/intimal thickening, medial atrophy, and adventitial lesions associated with adipose dysfunction, whereas hypertension is characterized by hyperinnervation-associated medial thickening due to smooth muscle cell hypertrophy/hyperplasia. PAAT expansion is associated with increased infiltration of immune cells, both adipocytes and immunocytes secreting pro-inflammatory and anti-inflammatory (metabotrophic) signaling proteins collectively dubbed adipokines. However, the role of vascular nerves and their interactions with immune cells and paracrine adipose tissue is not yet evaluated in such an integrated way. The present review attempts to briefly highlight the findings in basic and translational sciences in this area focusing on neuro-immune-adipose interactions, herein referred to as triactome. Triactome-targeted pharmacology may provide a novel therapeutic approach in cardiovascular disease.

Effects of Astragalus Polysaccharides on Dysfunction of Mitochondrial Dynamics Induced by Oxidative Stress.

PubMed

Huang, Yan-Feng; Lu, Lu; Zhu, Da-Jian; Wang, Ming; Yin, Yi; Chen, De-Xiu; Wei, Lian-Bo

2016-01-01

This paper studied the chronic fatigue induced by excessive exercise and the restoration effects of Astragalus polysaccharides (APS) on mitochondria. In vivo, we found that excessive exercise could cause oxidative stress statue which led to morphological and functional changes of mitochondria. The changes, including imbalance between mitochondria fusion-fission processes, activation of mitophagy, and decrease of PGC-1α expression, could be restored by APS. We further confirmed in vitro, and what is more, we found that APS may ameliorate mitochondrial dysfunction through Sirt1 pathway. Based on the results, we may figure out part of the molecular mechanism of mitochondrial amelioration by APS.

Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs.

PubMed

Cheng, Liang; Ma, Jianping; Li, Jingyun; Li, Dan; Li, Guangming; Li, Feng; Zhang, Qing; Yu, Haisheng; Yasui, Fumihiko; Ye, Chaobaihui; Tsao, Li-Chung; Hu, Zhiyuan; Su, Lishan; Zhang, Liguo

2017-01-03

Despite the efficient suppression of HIV-1 replication that can be achieved with combined antiretroviral therapy (cART), low levels of type I interferon (IFN-I) signaling persist in some individuals. This sustained signaling may impede immune recovery and foster viral persistence. Here we report studies using a monoclonal antibody to block IFN-α/β receptor (IFNAR) signaling in humanized mice (hu-mice) that were persistently infected with HIV-1. We discovered that effective cART restored the number of human immune cells in HIV-1-infected hu-mice but did not rescue their immune hyperactivation and dysfunction. IFNAR blockade fully reversed HIV-1-induced immune hyperactivation and rescued anti-HIV-1 immune responses in T cells from HIV-1-infected hu-mice. Finally, we found that IFNAR blockade in the presence of cART reduced the size of HIV-1 reservoirs in lymphoid tissues and delayed HIV-1 rebound after cART cessation in the HIV-1-infected hu-mice. We conclude that low levels of IFN-I signaling contribute to HIV-1-associated immune dysfunction and foster HIV-1 persistence in cART-treated hosts. Our results suggest that blocking IFNAR may provide a potential strategy to enhance immune recovery and reduce HIV-1 reservoirs in individuals with sustained elevations in IFN-I signaling during suppressive cART.

The Role of the Immune System in Autism Spectrum Disorder

PubMed Central

Meltzer, Amory; Van de Water, Judy

2017-01-01

Autism is a neurodevelopmental disorder characterized by deficits in communication and social skills as well as repetitive and stereotypical behaviors. While much effort has focused on the identification of genes associated with autism, research emerging within the past two decades suggests that immune dysfunction is a viable risk factor contributing to the neurodevelopmental deficits observed in autism spectrum disorders (ASD). Further, it is the heterogeneity within this disorder that has brought to light much of the current thinking regarding the subphenotypes within ASD and how the immune system is associated with these distinctions. This review will focus on the two main axes of immune involvement in ASD, namely dysfunction in the prenatal and postnatal periods. During gestation, prenatal insults including maternal infection and subsequent immunological activation may increase the risk of autism in the child. Similarly, the presence of maternally derived anti-brain autoantibodies found in ~20% of mothers whose children are at risk for developing autism has defined an additional subphenotype of ASD. The postnatal environment, on the other hand, is characterized by related but distinct profiles of immune dysregulation, inflammation, and endogenous autoantibodies that all persist within the affected individual. Further definition of the role of immune dysregulation in ASD thus necessitates a deeper understanding of the interaction between both maternal and child immune systems, and the role they have in diagnosis and treatment. PMID:27534269

Impact of pediatric epilepsy on sleep patterns and behaviors in children and parents.

PubMed

Larson, Anna M; Ryther, Robin C C; Jennesson, Melanie; Geffrey, Alexandra L; Bruno, Patricia L; Anagnos, Christina J; Shoeb, Ali H; Thibert, Ronald L; Thiele, Elizabeth A

2012-07-01

Disrupted sleep patterns in children with epilepsy and their parents are commonly described clinically. A number of studies have shown increased frequency of sleep disorders among pediatric epilepsy patients; however, few have characterized the association between epilepsy and parental sleep quality and household sleeping arrangements. The purpose of this study was to explore the effect of pediatric epilepsy on child sleep, parental sleep and fatigue, and parent-child sleeping arrangements, including room sharing and cosleeping. Parents of children 2 to 10 years of age with and without epilepsy completed written questionnaires assessing seizure history, child and parent sleep, and household sleeping arrangements. Children's Sleep Habits Questionnaire (CSHQ) scores were used to evaluate sleep disturbances for the child. The Pittsburgh Sleep Quality Index (PSQI) and the Iowa Fatigue Scale (IFS) were used to evaluate parental sleep and fatigue, respectively. The Early Childhood Epilepsy Severity Scale (E-Chess) was used to assess epilepsy severity. One hundred five households with a child with epilepsy and 79 controls participated in this study. Households with a child with epilepsy reported increased rates of both parent-child room sharing (p < 0.001) and cosleeping (p = 0.005) compared to controls. Children with epilepsy were found to have greater sleep disturbance by total CSHQ score (p < 0.001) and the following subscores: parasomnias (p < 0.001), night wakings (p < 0.001), sleep duration (p < 0.001), daytime sleepiness (<0.001), sleep onset delay (p = 0.009), and bedtime resistance (p = 0.023). Parents of children with epilepsy had increased sleep dysfunction (p = 0.005) and were more fatigued (p < 0.001). Severity of epilepsy correlated positively with degree of child sleep dysfunction (0.192, p = 0.049), parental sleep dysfunction (0.273, p = 0.005), and parental fatigue (0.324, p = 0.001). Antiepileptic drug polytherapy was predictive of greater childhood sleep disturbances. Nocturnal seizures were associated with parental sleep problems, whereas room sharing and cosleeping behavior were associated with child sleep problems. Within the epilepsy cohort, 69% of parents felt concerned about night seizures and 44% reported feeling rested rarely or never. Finally, 62% of parents described decreased sleep quality and/or quantity with cosleeping. Pediatric epilepsy can significantly affect sleep patterns for both the affected child and his or her parents. Parents frequently room share or cosleep with their child, adaptations which may have detrimental effects for many households. Clinicians must not only be attentive to the sleep issues occurring in pediatric patients with epilepsy, but also for the household as a whole. These data provide evidence of a profound clinical need for improved epilepsy therapeutics and the development of nocturnal seizure monitoring technologies. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Therapeutic Role of Hematopoietic Stem Cells in Autism Spectrum Disorder-Related Inflammation

PubMed Central

Siniscalco, Dario; Bradstreet, James Jeffrey; Antonucci, Nicola

2013-01-01

Autism and autism spectrum disorders (ASDs) are heterogeneous, severe neuro-developmental disorders with core symptoms of dysfunctions in social interactions and communication skills, restricted interests, repetitive – stereotypic verbal and non-verbal behaviors. Biomolecular evidence points to complex gene-environmental interactions in ASDs. Several biochemical processes are associated with ASDs: oxidative stress (including endoplasmic reticulum stress), decreased methylation capacity, limited production of glutathione; mitochondrial dysfunction, intestinal dysbiosis, increased toxic metal burden, and various immune abnormalities. The known immunological disorders include: T-lymphocyte populations and function, gene expression changes in monocytes, several autoimmune-related findings, high levels of N-acetylgalactosaminidase (which precludes macrophage activation), and primary immune deficiencies. These immunological observations may result in minicolumn structural changes in the brain, as well as, abnormal immune mediation of synaptic functions. Equally, these immune dysregulations serve as the rationale for immune-directed interventions such as hematopoietic stem cells (HSCs), which are pivotal in controlling chronic inflammation and in the restoration of immunological balance. These properties make them intriguing potential agents for ASD treatments. This prospective review will focus on the current state-of-the-art knowledge and challenges intrinsic in the application of HSCs for ASD-related immunological disorders. PMID:23772227

[Immunopathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)].

PubMed

Yamamura, Takashi; Ono, Hirohiko; Sato, Wakiro

2018-01-01

A recent study on the pathogenesis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has revealed an elevation of inflammatory and anti-inflammatory cytokines in the sera and cerebrospinal fluids of the patients and presence of autoantibodies in subgroups of ME/CFS patients. Furthermore, investigator-initiated clinical trials have proved the efficacy of anti-CD20 antibody (rituximab), that eliminate B cells, in the treatment of ME/CFS. Based on these findings, we hypothesize that immune abnormalities, such as enhanced autoimmune responses, may play an essential role in the neuroinflammatory pathogenesis of ME/CFS.

Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome.

PubMed

Sheedy, John R; Wettenhall, Richard E H; Scanlon, Denis; Gooley, Paul R; Lewis, Donald P; McGregor, Neil; Stapleton, David I; Butt, Henry L; DE Meirleir, Kenny L

2009-01-01

Patients with chronic fatigue syndrome (CFS) are affected by symptoms of cognitive dysfunction and neurological impairment, the cause of which has yet to be elucidated. However, these symptoms are strikingly similar to those of patients presented with D-lactic acidosis. A significant increase of Gram positive facultative anaerobic faecal microorganisms in 108 CFS patients as compared to 177 control subjects (p<0.01) is presented in this report. The viable count of D-lactic acid producing Enterococcus and Streptococcus spp. in the faecal samples from the CFS group (3.5 x 10(7) cfu/L and 9.8 x 10(7) cfu/L respectively) were significantly higher than those for the control group (5.0 x 10(6) cfu/L and 8.9 x 10(4) cfu/L respectively). Analysis of exometabolic profiles of Enterococcus faecalis and Streptococcus sanguinis, representatives of Enterococcus and Streptococcus spp. respectively, by NMR and HPLC showed that these organisms produced significantly more lactic acid (p<0.01) from (13)C-labeled glucose, than the Gram negative Escherichia coli. Further, both E. faecalis and S. sanguinis secrete more D-lactic acid than E. coli. This study suggests a probable link between intestinal colonization of Gram positive facultative anaerobic D-lactic acid bacteria and symptom expressions in a subgroup of patients with CFS. Given the fact that this might explain not only neurocognitive dysfunction in CFS patients but also mitochondrial dysfunction, these findings may have important clinical implications.

Role of Dendritic Cells in Immune Dysfunction

NASA Technical Reports Server (NTRS)

Savary, Cherylyn A.

1998-01-01

The specific aims of the project were: (1) Application of the NASA bioreactor to enhance cytokine-regulated proliferation and maturation of dendritic cells (DC). (2) Compare the frequency and function of DC in normal donors and immunocompromised cancer patients. (3) Analyze the effectiveness of cytokine therapy and DC-assisted immunotherapy (using bioreactor-expanded DC) in a murine model of experimental fungal disease. Our investigations have provided new insight into DC immunobiology and have led to the development of methodology to evaluate DC in blood of normal donors and patients. Information gained from these studies has broadened our understanding of possible mechanisms involved in the immune dysfunction of space travelers and earth-bound cancer patients, and could contribute to the design of novel therapies to restore/preserve immunity in these individuals. Several new avenues of investigation were also revealed. The results of studies completed during Round 2 are summarized.

Immune System Dysregulation and Herpesvirus Reactivation Persist During Long-Duration Spaceflight

NASA Technical Reports Server (NTRS)

Crucian, B. E.; Mehta, S.; Stowe, R. P.; Uchakin, P.; Quiriarte, H.; Pierson, D.; Sams, C. F.

2011-01-01

This poster presentation reviews a study that is designed to address immune system dysregulation and the risk to crewmembers in long duration exploration class missions. This study will address these objectives: (1) Determine the status of adaptive immunity physiological stress, viral immunity, latent herpesvirus reactivation in astronauts during 6 month missions to the International Space Station; (2) determine the clinical risk related to immune dysregulation for exploration class spaceflight; and (3) determine an appropriate monitoring strategy for spaceflight-associated immune dysfunction that could be used for the evaluation of countermeasures. The study anticipates 17 subjects, and for this presentation, (midpoint study data) 10 subjects are reviewed.

Immune System Dysregulation, Viral Reactivation and Stress During Short-Duration Space Flight

NASA Technical Reports Server (NTRS)

Crucian, Brian; Mehta, Satish; Stowe, Raymond; Uchakin, Peter; Quiriarte, Heather; Pierson, Duane; Sams, Clarence

2010-01-01

This slide presentation reviews a study that was conducted to ascertain if the immune system dysregulation, viral reactivation and stress from short duration space flight were a result of the stress of landing and readjustment to gravity. The objectives of the study were to replace several recent immune studies with one comprehensive study that will include in-flight sampling; address lack of in-flight data: (i.e., determine the in-flight status of immunity, physiological stress, viral immunity/reactivation); determine the clinical risk related to immune dysregulation for exploration class spaceflight; and determine the appropriate monitoring strategy for spaceflight-associated immune dysfunction, that could be used for the evaluation of countermeasures.

Pharmacological treatments for fatigue in patients with multiple sclerosis: A systematic review and meta-analysis.

PubMed

Yang, Ting-Ting; Wang, Li; Deng, Xiao-Yang; Yu, Gang

2017-09-15

Multiple sclerosis (MS) is a chronic immune-mediated inflammatory disease. Fatigue is the most common symptom of MS patients, affecting >80% subjects. Medical treatment is an important method for managing fatigue. Currently, although many drugs have been tested in treatment of MS fatigue, the efficacy of these drugs remain largely unclear. We researched available literatures in PubMed, Embase, Medline, Google Scholar, Cochrane Library (August 31, 2016). Search terms included multiple sclerosis, fatigue, medication treatments, amantadine, modafinil, aspirin, acetyl-l-carnitine, pemoline, 4-aminopyridine and randomized controlled trial (RCT). Two researchers were required to independently assess the quality of literatures, and finish data extraction. Meta-analysis was conducted using RevMan 5.3 software. A total of 11 RCTs involving 723 patients were included. The therapeutic effects were quantified by different scales, such as Modified Fatigue Impact Scale (MFIS) or Fatigue Severity Scale (FSS). Here, meta-analysis suggested that amantadine, not modafinil, was effective for treating the fatigue in MS. Moreover, two studies implied that l-carnitine might have similar therapeutic effect with amantadine. However, the reliability of this finding was greatly weakened by the limited sample sizes. Additionally, current data could not answer whether treatment of MS fatigue using aspirin or 4-aminopyridine was beneficial. Finally, we found that all drugs except pemoline were relatively safe for treating MS fatigue. Current limited data suggest that amantadine may be the only drug that has relatively sufficient evidences in treatment of fatigue symptoms in MS. Further RCT studies recruiting larger samples sizes are required to validate the therapeutic effect of these candidate drugs. Copyright © 2017. Published by Elsevier B.V.

Overexpression of antioxidant enzymes in diaphragm muscle does not alter contraction-induced fatigue or recovery

PubMed Central

McClung, Joseph M.; DeRuisseau, Keith C.; Whidden, Melissa A.; Van Remmen, Holly; Richardson, Arlan; Song, Wook; Vrabas, Ioannis S.; Powers, Scott K.

2010-01-01

Low levels of reactive oxygen species (ROS) production are necessary to optimize muscle force production in unfatigued muscle. In contrast, sustained high levels of ROS production have been linked to impaired muscle force production and contraction-induced skeletal muscle fatigue. Using genetically engineered mice, we tested the hypothesis that the independent transgenic overexpression of catalase (CAT), copper/zinc superoxide dismutase (CuZnSOD; SOD1) or manganese superoxide dismutase (MnSOD; SOD2) antioxidant enzymes would negatively affect force production in unfatigued diaphragm muscle but would delay the development of muscle fatigue and enhance force recovery after fatiguing contractions. Diaphragm muscle from wild-type littermates (WT) and from CAT, SOD1 and SOD2 overexpressing mice were subjected to an in vitro contractile protocol to investigate the force–frequency characteristics, the fatigue properties and the time course of recovery from fatigue. The CAT, SOD1 and SOD2 overexpressors produced less specific force (in N cm−2) at stimulation frequencies of 20–300 Hz and produced lower maximal tetanic force than WT littermates. The relative development of muscle fatigue and recovery from fatigue were not influenced by transgenic overexpression of any antioxidant enzyme. Morphologically, the mean cross-sectional area (in μm2) of diaphragm myofibres expressing myosin heavy chain type IIA was decreased in both CAT and SOD2 transgenic animals, and the percentage of non-contractile tissue increased in diaphragms from all transgenic mice. In conclusion, our results do not support the hypothesis that overexpression of independent antioxidant enzymes protects diaphragm muscle from contraction-induced fatigue or improves recovery from fatigue. Moreover, our data are consistent with the concept that a basal level of ROS is important to optimize muscle force production, since transgenic overexpression of major cellular antioxidants is associated with contractile dysfunction. Finally, the transgenic overexpression of independent endogenous antioxidants alters diaphragm skeletal muscle morphology, and these changes may also contribute to the diminished specific force production observed in these animals. PMID:19783618

Chronic retinal necrosis: cytomegalovirus necrotizing retinitis associated with panretinal vasculopathy in non-HIV patients.

PubMed

Schneider, Eric W; Elner, Susan G; van Kuijk, Frederik J; Goldberg, Naomi; Lieberman, Ronni M; Eliott, Dean; Johnson, Mark W

2013-10-01

To characterize a unique cytomegalovirus (CMV)-associated retinopathy in patients with limited immune dysfunction. Retrospective observational case series. CMV was confirmed as the pathogenic agent via polymerase chain reaction analysis of aqueous or vitreous humor samples or via immunohistochemical analysis of retinal biopsy specimens. Five non-HIV patients with granular necrotizing retinitis, vitritis, and severe occlusive vasculopathy were identified. Patient histories all suggested a basis for limited immune dysfunction including advanced age (n = 4), diabetes mellitus (n = 4), and noncytotoxic immunotherapy (n = 3). Diagnosis of CMV retinitis was delayed in all cases and patients received either no antiviral therapy (n = 2) or incorrect antiviral therapy (n = 3) for presumed herpes simplex/varicella zoster-related acute retinal necrosis. Retinitis subsequently regressed in all cases with introduction of systemic ganciclovir/valganciclovir (n = 5) and/or intravitreal foscarnet (n = 2). Four of five patients developed neovascularization because of extensive retinal ischemia. The clinical expression of CMV-associated retinopathy is strongly related to immune status. In patients with limited immune dysfunction, a mixed clinical picture of intraocular inflammation with panretinal occlusive vasculopathy, more characteristic of acute retinal necrosis, and peripheral slowly progressive granular retinitis, more characteristic of classic CMV retinitis, is observed. Recognition of this atypical clinical presentation, which the authors term chronic retinal necrosis, should prompt molecular testing for CMV to determine the appropriate antiviral therapy. Consideration should also be given to prophylactic panretinal photocoagulation in such eyes, given the high risk of neovascular complications.

Current insights into the innate immune system dysfunction in irritable bowel syndrome

PubMed Central

Lazaridis, Nikolaos; Germanidis, Georgios

2018-01-01

Irritable bowel syndrome (IBS) is a functional bowel disorder associated with abdominal pain and alterations in bowel habits. The presence of IBS greatly impairs patients’ quality of life and imposes a high economic burden on the community; thus, there is intense pressure to reveal its elusive pathogenesis. Many etiological mechanisms have been implicated, but the pathophysiology of the syndrome remains unclear. As a result, novel drug development has been slow and no pharmacological intervention is universally accepted. A growing evidence implicates the role of low-grade inflammation and innate immune system dysfunction, although contradictory results have frequently been presented. Mast cells (MC), eosinophils and other key immune cells together with their mediators seem to play an important role, at least in subgroups of IBS patients. Cytokine imbalance in the systematic circulation and in the intestinal mucosa may also characterize IBS presentation. Toll-like receptors and their emerging role in pathogen recognition have also been highlighted recently, as dysregulation has been reported to occur in patients with IBS. This review summarizes the current knowledge regarding the involvement of any immunological alteration in the development of IBS. There is substantial evidence to support innate immune system dysfunction in several IBS phenotypes, but additional studies are required to better clarify the underlying pathogenetic pathways. IBS heterogeneity could potentially be attributed to multiple causes that lead to different disease phenotypes, thus explaining the variability found between study results. PMID:29507464

Portable Immune-Assessment System

NASA Technical Reports Server (NTRS)

Pierson, Duane L.; Stowe, Raymond P.; Mishra, Saroj K.

1995-01-01

Portable immune-assessment system developed for use in rapidly identifying infections or contaminated environment. System combines few specific fluorescent reagents for identifying immune-cell dysfunction, toxic substances, buildup of microbial antigens or microbial growth, and potential identification of pathogenic microorganisms using fluorescent microplate reader linked to laptop computer. By using few specific dyes for cell metabolism, DNA/RNA conjugation, specific enzyme activity, or cell constituents, one makes immediate, onsite determination of person's health or of contamination of environment.

Immunotherapy for glioblastoma: playing chess, not checkers.

PubMed

Jackson, Christopher M; Lim, Michael

2018-04-24

Patients with glioblastoma (GBM) exhibit a complex state of immune dysfunction involving multiple mechanisms of local, regional, and systemic immune suppression and tolerance. These pathways are now being identified and their relative contributions explored. Delineating how these pathways are interrelated is paramount to effectively implementing immunotherapy for GBM. Copyright ©2018, American Association for Cancer Research.

Oral Human Immunoglobulin for Children with Autism and Gastrointestinal Dysfunction: A Prospective, Open-Label Study

ERIC Educational Resources Information Center

Schneider, Cindy K.; Melmed, Raun D.; Barstow, Leon E.; Enriquez, F. Javier; Ranger-Moore, James; Ostrem, James A.

2006-01-01

Immunoglobulin secretion onto mucosal surfaces is a major component of the mucosal immune system. We hypothesized that chronic gastrointestinal (GI) disturbances associated with autistic disorder (AD) may be due to an underlying deficiency in mucosal immunity, and that orally administered immunoglobulin would be effective in alleviating chronic GI…

Dietary rice bran supplementation prevents salmonella colonization differentially across varieties and by priming intestinal immunity

USDA-ARS?s Scientific Manuscript database

The global burden of enteric dysfunction and diarrhoeal disease remains a formidable problem that requires novel interventions. This study investigated the immune-modulatory capacity of bran across rice varieties with phytochemical differences. 129SvEvTac mice were fed a 10% rice bran or control die...

Decreased Numbers of CD57+CD3- Cells Identify Potential Innate Immune Differences in Patients with Autism Spectrum Disorder.

PubMed

Siniscalco, Dario; Mijatovic, Tatjana; Bosmans, Eugene; Cirillo, Alessandra; Kruzliak, Peter; Lombardi, Vincent C; De Meirleir, Kenny; Antonucci, Nicola

2016-01-01

Autism spectrum disorders (ASD) are complex, and severe heterogeneous neurodevelopmental pathologies with accepted but complex immune system abnormalities. Additional knowledge regarding potential immune dysfunctions may provide a greater understanding of this malady. The aim of this study was to evaluate the CD57(+)CD3(-) mature lymphocyte subpopulation of natural killer cells as a marker of immune dysfunction in ASD. Three-color flow cytometry-based analysis of fresh peripheral blood samples from children with autism was utilized to measure CD57(+)CD3(-) lymphocytes. A reduction of CD57(+)CD3(-) lymphocyte count was recorded in a significant number of patients with autism. We demonstrated that the number of peripheral CD57(+)CD3(-) cells in children with autism often falls below the clinically accepted normal range. This implies that a defect in the counter-regulatory functions necessary for balancing pro-inflammatory cytokines exists, thus opening the way to chronic inflammatory conditions associated with ASD. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Evidence for neuroinflammation and neuroprotection in HCV infection-associated encephalopathy.

PubMed

Bokemeyer, M; Ding, X-Q; Goldbecker, A; Raab, P; Heeren, M; Arvanitis, D; Tillmann, H L; Lanfermann, H; Weissenborn, K

2011-03-01

Fatigue, mood disturbances and cognitive dysfunction are frequent in patients infected with hepatitis C virus (HCV) who have mild liver disease. The reason is still unclear. The present study aims to gain more insight into the pathomechanism by combining an extensive neuropsychological examination with magnetic resonance spectroscopy in four different brain regions in a patient group covering the whole spectrum of neuropsychiatric findings in patients afflicted with HCV who have only mild liver disease. 53 HCV-positive patients with only mild liver disease and differing degrees of neuropsychiatric symptoms were studied with single-voxel MRS of the parietal white matter, occipital grey matter, basal ganglia and pons. Brain metabolite concentrations were quantitatively analysed by using LCmodel. MRS data were compared to those of 23 healthy controls adjusted for age, and analysed for relationships with the extent of neuropsychiatric symptoms. Choline (p=0.02), creatine (p=0.047) and N-acetyl-aspartate plus N-acetyl-aspartyl-glutamate (NN, p=0.02) concentrations in the basal ganglia and choline concentrations in the white matter (p=0.045) were significantly higher in the patients than in controls. Interestingly, the difference was most evident for the patients with low fatigue scores (eg, white matter: choline: p=0.001, creatine: p=0.003, NN: p=0.031). Myo-inositol differed significantly between groups in the white (p=0.001) and grey matter (p=0.003). Fatigue correlated negatively with white matter NN, choline and creatine and myo-inositol levels in white and grey matter and basal ganglia (p<0.01). As the increase of choline, creatine and myo-inositol are usually interpreted to indicate glial activation and macrophage infiltration in chronic inflammation and slow virus infections of the brain the present data endorse the hypothesis, that HCV infection may induce neuroinflammation and brain dysfunction. The concomitant increase of NN and the negative correlation to the extent of fatigue suggest a cerebral compensatory process after HCV infection.

Tryptophan circuit in fatigue: From blood to brain and cognition.

PubMed

Yamashita, Masatoshi; Yamamoto, Takanobu

2017-11-15

Brain tryptophan and its neuroactive metabolites play key roles in central fatigue. However, previous brain function analysis targets may have included both glia and neurons together. Here, we clarified the fatigue-cognitive circuit of the central-peripheral linkage, including the role of glial-neuronal interaction in cognition. Using a rat model of central fatigue induced by chronic sleep disorder (CFSD), we isolated presynaptic terminals and oligodendrocytes. Results showed that compared to control group, presynaptic levels of tryptophan, kynurenine, and kynurenic acid, but not serotonin, in the CFSD group were higher in the hypothalamus and hippocampus. Moreover, CFSD group had higher oligodendrocytic levels of tryptophan, and impaired spatial cognitive memory accuracy and increased hyperactivity and impulsivity. These findings suggest that dynamic change in glial-neuronal interactions within the hypothalamus-hippocampal circuit causes central fatigue, and increased tryptophan-kynurenic acid pathway activity in this circuit causes reduced cognitive function. Additionally, CFSD group had 1.5 times higher plasma levels of tryptophan and kynurenine. Furthermore, in rats undergoing intraperitoneal administration of kynurenine (100mg/kg) versus vehicle, kynurenine-treated rats showed enhanced production of kynurenic acid in the hippocampus, with suppressed recall of retained spatial cognitive memory. The study revealed that uptake of periphery-derived kynurenine and tryptophan into the brain enhances kynurenic acid production in the brain, and the three factors produce amplification effect involved in the role of central-peripheral linkage in central fatigue, triggering cognitive dysfunction. Copyright © 2017 Elsevier B.V. All rights reserved.

Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study.

PubMed

Dass, S; Bowman, S J; Vital, E M; Ikeda, K; Pease, C T; Hamburger, J; Richards, A; Rauz, S; Emery, P

2008-11-01

Primary Sjögren syndrome (pSS) causes significant systemic symptoms including fatigue as well as glandular dysfunction. There are currently no effective systemic therapies; however, open label series have suggested that rituximab may be beneficial for systemic and glandular manifestations. Therefore, we performed a double blind, placebo-controlled, randomised pilot study of the efficacy of rituximab in reducing fatigue in pSS. A total of 17 patients with pSS and a score on fatigue visual analogue scale (VAS) >50 were randomised to receive either 2 infusions of rituximab 1 g or placebo; patients also received oral and intravenous steroids. Outcome measures included: the proportion of patients with >20% reduction in fatigue VAS, changes in pSS related symptoms, health related quality of life and immunological parameters of pSS. These were measured 6 months after therapy. There was significant improvement from baseline in fatigue VAS in the rituximab group (p<0.001) in contrast to the placebo group (p = 0.147). There was a significant difference between the groups at 6 months in the social functioning score of SF-36 (p = 0.01) and a trend to significant difference in the mental health domain score of SF-36 (p = 0.06). There was one episode of serum sickness in the rituximab treated group. This is the first double blind study of rituximab in pSS to show benefit; further studies are justified.

HIV-associated fatigue in the era of highly active antiretroviral therapy: novel biological mechanisms?

PubMed

Payne, B A I; Hateley, C L; Ong, E L C; Premchand, N; Schmid, M L; Schwab, U; Newton, J L; Price, D A

2013-04-01

The aim of the study was to determine the prevalence and risk factors for HIV-associated fatigue in the era of highly active antiretroviral therapy (HAART). A cross-sectional survey of 100 stable HIV-infected out-patients was carried out. Severity of fatigue was measured using the Fatigue Impact Scale (FIS). Symptoms of orthostatic intolerance (dysautonomia) were evaluated using the Orthostatic Grading Scale (OGS). Data for HIV-infected patients were compared with those for 166 uninfected controls and 74 patients with chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (encephalopathy) (ME). Ninety-one per cent of HIV-infected patients were on HAART and 78% had suppressed plasma HIV viral load (≤ 40 HIV-1 RNA copies/mL). Fifty-one per cent of HIV-infected patients reported excessive symptomatic fatigue (FIS ≥ 40), and 28% reported severe fatigue symptoms (FIS ≥ 80). The mean FIS score among HIV-infected patients was 50.8 [standard deviation (SD) 41.9] compared with 13.0 (SD 17.6) in uninfected control subjects, and 92.9 (SD 29.0) in CFS patients (P < 0.001 for comparison of HIV-infected patients and uninfected controls). Among HIV-infected patients, fatigue severity was not significantly associated with current or nadir CD4 lymphocyte count, HIV plasma viral load, or whether on HAART. Prior dideoxynucleoside analogue (d-drug) exposure (P = 0.016) and the presence of clinical lipodystrophy syndrome (P = 0.011) were associated with fatigue. Additionally, fatigue severity correlated strongly with symptomatic orthostatic intolerance (r = 0.65; P < 0.001). Fatigue is very common and often severe in HIV-infected out-patients, despite viral suppression and good immune function. In a subgroup of patients, prior d-drug exposure may contribute to fatigue, suggesting a metabolic basis. Dysautonomia may also drive fatigue associated with HIV infection, as in other chronic diseases, and CFS/ME, and should be further evaluated with the potential for a shared therapeutic approach. © 2012 British HIV Association.

Myeloid dendritic cells frequencies are increased in children with autism spectrum disorder and associated with amygdala volume and repetitive behaviors

PubMed Central

Breece, Elizabeth; Paciotti, Brian; Nordahl, Christine Wu; Ozonoff, Sally; Van de Water, Judy A.; Rogers, Sally J.; Amaral, David; Ashwood, Paul

2012-01-01

The pathophysiology of Autism Spectrum Disorder (ASD) is not yet known; however, studies suggest that dysfunction of the immune system affects many children with ASD. Increasing evidence points to dysfunction of the innate immune system including activation of microglia and perivascular macrophages, increases in inflammatory cytokines/chemokines in brain tissue and CSF, and abnormal peripheral monocyte cell function. Dendritic cells are major players in innate immunity and have important functions in the phagocytosis of pathogens or debris, antigen presentation, activation of naïve T cells, induction of tolerance and cytokine/chemokine production. In this study, we assessed circulating frequencies of myeloid dendritic cells (defined as Lin-1−BDCA1+CD11c+ and Lin-1−BDCA3+CD123−) and plasmacytoid dendritic cells (Lin-1− BDCA2+CD123+ or Lin-1−BDCA4+ CD11c−) in 57 children with ASD, and 29 typically developing controls of the same age, all of who were enrolled as part of the Autism Phenome Project (APP). The frequencies of dendritic cells and associations with behavioral assessment and MRI measurements of amygdala volume were compared in the same participants. The frequencies of myeloid dendritic cells were significantly increased in children with ASD compared to typically developing controls (p < 0.03). Elevated frequencies of myeloid dendritic cells were positively associated with abnormal right and left amygdala enlargement, severity of gastrointestinal symptoms and increased repetitive behaviors. The frequencies of plasmacytoid dendritic cells were also associated with amygdala volumes as well as developmental regression in children with ASD. Dendritic cells play key roles in modulating immune responses and differences in frequencies or functions of these cells may result in immune dysfunction in children with ASD. These data further implicate innate immune cells in the complex pathophysiology of ASD. PMID:23063420

The Prevalence of Compassion Fatigue among Veterinary Students in Australia and the Associated Psychological Factors.

PubMed

McArthur, Michelle L; Andrews, Jena R; Brand, Conor; Hazel, Susan J

Compassion fatigue, compassion satisfaction, and other characteristics such as mindfulness and mental health stigma have not been investigated in veterinary students. The aims of this study were twofold: first to determine the prevalence of compassion, satisfaction, burnout, and secondary traumatic stress among Australian veterinary students and second to investigate the association between these factors and self-stigma, coping, empathy, and mindfulness. A cross-sectional online survey consisting of demographic questions and four validated psychological measures sampled 828 students, with a response rate of 31% (255/828). We obtained a usable sample of completed surveys from 193 of 828 (23%) veterinary students from six of the seven Australian veterinary schools. Bivariate correlations and multiple regression analyses were used to examine associations between the psychological predictors and the outcome variables. Approximately 30% of veterinary students were at high risk of burnout, 24% were at high risk of secondary traumatic stress, and 21% reported low compassion satisfaction. High empathic concern, low personal distress, female gender, and employment history at a veterinary clinic were associated with high compassion satisfaction. High dysfunctional coping, low nonjudgmental and acting-with-awareness mindfulness, and lack of previous employment at a veterinary clinic were associated with high burnout. High dysfunctional coping, low acting-with-awareness mindfulness, high self-stigma, and high personal distress were associated with high secondary traumatic stress. As a result of these findings, certain emotional characteristics can be identified as targets for intervention to minimize the frequency and potentially negative impact of compassion fatigue and burnout in veterinary students.

Sexual Dysfunctions in Men and Women with Inflammatory Bowel Disease: The Influence of IBD-Related Clinical Factors and Depression on Sexual Function.

PubMed

Bel, Linda G J; Vollebregt, Anna M; Van der Meulen-de Jong, Andrea E; Fidder, Herma H; Ten Hove, Willem R; Vliet-Vlieland, Cornelia W; Ter Kuile, Moniek M; de Groot, Helena E; Both, Stephanie

2015-07-01

Inflammatory bowel disease (IBD) is likely to have an impact on sexual function because of its symptoms, like diarrhea, fatigue, and abdominal pain. Depression is commonly reported in IBD and is also related to impaired sexual function. This study aimed to evaluate sexual function and its association with depression among patients with IBD compared with controls. IBD patients registered at two hospitals participated. The control group consisted of a general practitioner practice population. The web-based questionnaire included the Female Sexual Function Index (FSFI) for women and the International Index of Erectile Function (IIEF) for men. Other variables evaluated were depression, disease activity, IBD-related quality of life, body image, and fatigue. In total, 168 female and 119 male patients were available for analysis (response rate 24%). Overall, patients with IBD did not significantly differ in prevalence of sexual dysfunctions from controls: female patients 52%, female controls 44%, male patients and male controls both 25%. However, men and women with an active disease scored significantly lower than patients in remission and controls, indicating impaired sexual functioning during disease activity. Significant associations were found between active disease, fatigue, depressive mood, quality of life, and sexual function for both male and female patients. The association between disease activity and sexual function was totally mediated by depression. Male and female IBD patients with an active disease show impaired sexual function relative to patients in remission and controls. Depression is the most important determinant for impaired sexual function in IBD. © 2015 International Society for Sexual Medicine.

A Randomized Trial Comparing Live and Telemedicine Delivery of an Imagery-based Behavioral Intervention for Breast Cancer Survivors: Reducing Symptoms and Barriers to Care

PubMed Central

Freeman, Lyn W.; White, Rebecca; Ratcliff, Chelsea G.; Sutton, Sue; Stewart, Mary; Palmer, J. Lynn; Link, Judith; Cohen, Lorenzo

2015-01-01

Objective This multi-site randomized trial evaluates the quality of life (QOL) benefits of an imagery-based group intervention titled “Envision the Rhythms of Life” (ERL). Methods Breast cancer survivors >6 weeks post-treatment were randomized to attend five weekly 4-hour group sessions at a community center with therapist present (live-delivery; LD, n=48); therapist streamed via telemedicine (telemedicine-delivery; TD, n=23); or to a waitlist control group (WL, n=47). Weekly individual phone calls to encourage at-home practice began at session one and continued until the 3-month follow-up. Seven self-report measures of QOL were examined at baseline, 1 and 3 months post-treatment including health-related and breast cancer-specific QOL, fatigue, cognitive function, spirituality, distress, and sleep. Results The Bonferroni method was used to correct for multiple comparisons, and alpha was adjusted to 0.01. LMM analyses revealed less fatigue, cognitive dysfunction, and sleep disturbance for LD and TD compared to WL across the follow-up (p’s <0.01). Changes in fatigue, cognitive dysfunction, sleep disturbance, and health-related and breast cancer-related QOL were clinically significant. There were no differences between LD and TD. Conclusions Both the live and telemedicine delivered ERL intervention resulted in improvements in multiple QOL domains for breast cancer survivors compared to a waitlist control. Further, there were no significant differences between live- and telemedicine-delivery, suggesting telemedicine delivered ERL intervention may represent an effective and viable option for cancer survivors in remote areas. PMID:25146413

Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles, decreases beta-amyloid plaque load, and rescues impaired long-term potentiation in 5xFAD mice.

PubMed

MacPherson, Kathryn P; Sompol, Pradoldej; Kannarkat, George T; Chang, Jianjun; Sniffen, Lindsey; Wildner, Mary E; Norris, Christopher M; Tansey, Malú G

2017-06-01

Clinical and animal model studies have implicated inflammation and peripheral immune cell responses in the pathophysiology of Alzheimer's disease (AD). Peripheral immune cells including T cells circulate in the cerebrospinal fluid (CSF) of healthy adults and are found in the brains of AD patients and AD rodent models. Blocking entry of peripheral macrophages into the CNS was reported to increase amyloid burden in an AD mouse model. To assess inflammation in the 5xFAD (Tg) mouse model, we first quantified central and immune cell profiles in the deep cervical lymph nodes and spleen. In the brains of Tg mice, activated (MHCII + , CD45 high , and Ly6C high ) myeloid-derived CD11b + immune cells are decreased while CD3 + T cells are increased as a function of age relative to non-Tg mice. These immunological changes along with evidence of increased mRNA levels for several cytokines suggest that immune regulation and trafficking patterns are altered in Tg mice. Levels of soluble Tumor Necrosis Factor (sTNF) modulate blood-brain barrier (BBB) permeability and are increased in CSF and brain parenchyma post-mortem in AD subjects and Tg mice. We report here that in vivo peripheral administration of XPro1595, a novel biologic that sequesters sTNF into inactive heterotrimers, reduced the age-dependent increase in activated immune cells in Tg mice, while decreasing the overall number of CD4 + T cells. In addition, XPro1595 treatment in vivo rescued impaired long-term potentiation (LTP) measured in brain slices in association with decreased Aβ plaques in the subiculum. Selective targeting of sTNF may modulate brain immune cell infiltration, and prevent or delay neuronal dysfunction in AD. Immune cells and cytokines perform specialized functions inside and outside the brain to maintain optimal brain health; but the extent to which their activities change in response to neuronal dysfunction and degeneration is not well understood. Our findings indicate that neutralization of sTNF reduced the age-dependent increase in activated immune cells in Tg mice, while decreasing the overall number of CD4 + T cells. In addition, impaired long-term potentiation (LTP) was rescued by XPro1595 in association with decreased hippocampal Aβ plaques. Selective targeting of sTNF holds translational potential to modulate brain immune cell infiltration, dampen neuroinflammation, and prevent or delay neuronal dysfunction in AD. Copyright © 2017 Elsevier Inc. All rights reserved.

Protein tyrosine phosphatase non-receptor type 2 and inflammatory bowel disease.

PubMed

Spalinger, Marianne R; McCole, Declan F; Rogler, Gerhard; Scharl, Michael

2016-01-21

Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) with the onset of inflammatory bowel disease (IBD) and other inflammatory disorders. Expression of PTPN2 is enhanced in actively inflamed intestinal tissue featuring a marked up-regulation in intestinal epithelial cells. PTPN2 deficient mice suffer from severe intestinal and systemic inflammation and display aberrant innate and adaptive immune responses. In particular, PTPN2 is involved in the regulation of inflammatory signalling cascades, and critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses, and finally for maintaining intestinal homeostasis. On one hand, dysfunction of PTPN2 has drastic effects on innate host defence mechanisms, including increased secretion of pro-inflammatory cytokines, limited autophagosome formation in response to invading pathogens, and disruption of the intestinal epithelial barrier. On the other hand, PTPN2 function is crucial for controlling adaptive immune functions, by regulating T cell proliferation and differentiation as well as maintaining T cell tolerance. In this way, dysfunction of PTPN2 contributes to the manifestation of IBD. The aim of this review is to present an overview of recent findings on the role of PTPN2 in intestinal homeostasis and the impact of dysfunctional PTPN2 on intestinal inflammation.

Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology.

PubMed

Stringer, Elizabeth Ann; Baker, Katharine Susanne; Carroll, Ian R; Montoya, Jose G; Chu, Lily; Maecker, Holden T; Younger, Jarred W

2013-04-09

Chronic fatigue syndrome (CFS) is a debilitating disorder characterized by persistent fatigue that is not alleviated by rest. The lack of a clearly identified underlying mechanism has hindered the development of effective treatments. Studies have demonstrated elevated levels of inflammatory factors in patients with CFS, but findings are contradictory across studies and no biomarkers have been consistently supported. Single time-point approaches potentially overlook important features of CFS, such as fluctuations in fatigue severity. We have observed that individuals with CFS demonstrate significant day-to-day variability in their fatigue severity. Therefore, to complement previous studies, we implemented a novel longitudinal study design to investigate the role of cytokines in CFS pathophysiology. Ten women meeting the Fukuda diagnostic criteria for CFS and ten healthy age- and body mass index (BMI)-matched women underwent 25 consecutive days of blood draws and self-reporting of symptom severity. A 51-plex cytokine panel via Luminex was performed for each of the 500 serum samples collected. Our primary hypothesis was that daily fatigue severity would be significantly correlated with the inflammatory adipokine leptin, in the women with CFS and not in the healthy control women. As a post-hoc analysis, a machine learning algorithm using all 51 cytokines was implemented to determine whether immune factors could distinguish high from low fatigue days. Self-reported fatigue severity was significantly correlated with leptin levels in six of the participants with CFS and one healthy control, supporting our primary hypothesis. The machine learning algorithm distinguished high from low fatigue days in the CFS group with 78.3% accuracy. Our results support the role of cytokines in the pathophysiology of CFS.

Understanding the origin of non-immune cell-mediated weakness in the idiopathic inflammatory myopathies - potential role of ER stress pathways.

PubMed

Lightfoot, Adam P; Nagaraju, Kanneboyina; McArdle, Anne; Cooper, Robert G

2015-11-01

Discussion of endoplasmic reticulum (ER) stress pathway activation in idiopathic inflammatory myopathies (IIM), and downstream mechanisms causative of muscle weakness. In IIM, ER stress is an important pathogenic process, but how it causes muscle dysfunction is unknown. We discuss relevant pathways modified in response to ER stress in IIM: reactive oxygen species (ROS) generation and mitochondrial dysfunction, and muscle cytokine (myokine) generation. First, ER stress pathway activation can induce changes in mitochondrial bioenergetics and ROS production. ROS can oxidize cellular components, causing muscle contractile dysfunction and energy deficits. Novel compounds targeting ROS generation and/or mitochondrial dysfunction can improve muscle function in several myopathologies. Second, recent research has demonstrated that skeletal muscle produces multiple myokines. It is suggested that these play a role in causing muscle weakness. Myokines are capable of immune cell recruitment, thus contributing to perturbed muscle function. A characterization of myokines in IIM would clarify their pathogenic role, and so identify new therapeutic targets. ER stress pathway activation is clearly of etiological relevance in IIM. Research to better understand mechanisms of weakness downstream of ER stress is now required, and which may discover new therapeutic targets for nonimmune cell-mediated weakness.

Measuring the executive regulation of emotion with self-rating scales in a nonclinical population.

PubMed

Spinella, Marcello

2007-01-01

Prefrontal systems play an important role in the regulation of emotion as evidenced by clinical neuroimaging studies. Both subjective and objective neuropsychological tests provide functional evidence of executive dysfunction in emotional deregulation. The present authors evaluated these relationships here in a nonclinical community sample using the Frontal Systems Behavior Scale, Profile of Mood States (POMS), and Depression Anxiety Stress Scales (DASS). Positive correlations uniformly emerged between prefrontal system dysfunction and negative emotional states (anger, depression, anxiety, stress, confusion, and fatigue), whereas positive emotion (vigor) showed a modest inverse correlation with prefrontal system dysfunction, even after control for demographic influences. These relationships may result from cognitive strategies for managing emotion mediated by reciprocal connections between prefrontal systems and the limbic system. The findings corroborated those of other methodologies, supporting the Frontal Systems Behavior Scale (FrSBe) as a valid tool to measure prefrontal function in nonclinical populations.

Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles

PubMed Central

Yamano, Emi; Sugimoto, Masahiro; Hirayama, Akiyoshi; Kume, Satoshi; Yamato, Masanori; Jin, Guanghua; Tajima, Seiki; Goda, Nobuhito; Iwai, Kazuhiro; Fukuda, Sanae; Yamaguti, Kouzi; Kuratsune, Hirohiko; Soga, Tomoyoshi; Watanabe, Yasuyoshi; Kataoka, Yosky

2016-01-01

Chronic fatigue syndrome (CFS) is a persistent and unexplained pathological state characterized by exertional and severely debilitating fatigue, with/without infectious or neuropsychiatric symptoms, lasting at least 6 consecutive months. Its pathogenesis remains incompletely understood. Here, we performed comprehensive metabolomic analyses of 133 plasma samples obtained from CFS patients and healthy controls to establish an objective diagnosis of CFS. CFS patients exhibited significant differences in intermediate metabolite concentrations in the tricarboxylic acid (TCA) and urea cycles. The combination of ornithine/citrulline and pyruvate/isocitrate ratios discriminated CFS patients from healthy controls, yielding area under the receiver operating characteristic curve values of 0.801 (95% confidential interval [CI]: 0.711–0.890, P < 0.0001) and 0.750 (95% CI: 0.584–0.916, P = 0.0069) for training (n = 93) and validation (n = 40) datasets, respectively. These findings provide compelling evidence that a clinical diagnostic tool could be developed for CFS based on the ratios of metabolites in plasma. PMID:27725700

Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

PubMed Central

2011-01-01

Background Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is characterised by severe prolonged fatigue, and decreases in cognition and other physiological functions, resulting in severe loss of quality of life, difficult clinical management and high costs to the health care system. To date there is no proven pathomechanism to satisfactorily explain this disorder. Studies have identified abnormalities in immune function but these data are inconsistent. We investigated the profile of markers of immune function (including novel markers) in CFS/ME patients. Methods We included 95 CFS/ME patients and 50 healthy controls. All participants were assessed on natural killer (NK) and CD8+T cell cytotoxic activities, Th1 and Th2 cytokine profile of CD4+T cells, expression of vasoactive intestinal peptide receptor 2 (VPACR2), levels of NK phenotypes (CD56bright and CD56dim) and regulatory T cells expressing FoxP3 transcription factor. Results Compared to healthy individuals, CFS/ME patients displayed significant increases in IL-10, IFN-γ, TNF-α, CD4+CD25+ T cells, FoxP3 and VPACR2 expression. Cytotoxic activity of NK and CD8+T cells and NK phenotypes, in particular the CD56bright NK cells were significantly decreased in CFS/ME patients. Additionally granzyme A and granzyme K expression were reduced while expression levels of perforin were significantly increased in the CFS/ME population relative to the control population. These data suggest significant dysregulation of the immune system in CFS/ME patients. Conclusions Our study found immunological abnormalities which may serve as biomarkers in CFS/ME patients with potential for an application as a diagnostic tool. PMID:21619669

Characterization and implications of thyroid dysfunction induced by immune checkpoint inhibitors in real-life clinical practice: a long-term prospective study from a referral institution.

PubMed

Guaraldi, F; La Selva, R; Samà, M T; D'Angelo, V; Gori, D; Fava, P; Fierro, M T; Savoia, P; Arvat, E

2018-05-01

Autoimmune diseases are typically associated with immune checkpoints blockade. This study aims at assessing, in real-life clinical practice, the prevalence and impact of thyroid disorders induced by immune checkpoint inhibitors. 52 patients (30 F; age 61 ± 13 years) with advanced melanoma treated with ipilimumab (3 mg/kg i.v./3 weeks; 4 doses) were included. For disease progression, 29 (16 F) of them received nivolumab (3 mg/kg i.v./2 weeks) or pembrolizumab (2 mg/kg i.v./3 weeks). Thyroid function and autoimmunity were assessed before, after 6 weeks, at the end of ipilimumab, as well as before and every 3 months during nivolumab/pembrolizumab treatment. During ipilimumab, 7 (4 F) patients developed thyroid dysfunction (4 thyroiditis, 1 associated with hypothyroidism; 2 thyrotoxicosis in a previously euthyroid multinodular goiter; 1 hypothyroidism worsened). During PD1 inhibitors, 7 patients (3 F) developed hypothyroidism with severe manifestations in 6 of them; 3 patients suffered from euthyroid autoimmune thyroiditis from baseline, one after ipilimumab; 2 patients developed after transient thyrotoxicosis. Mean follow-up after anti-CTLA4 inhibitors treatment was 36 ± 28 months. Thyroid disorders occurred 45.1 ± 20.8 and 151 ± 67 days after the initiation of CTLA4 and PD1 inhibitors, respectively. Autoimmune disorders and BRAF mutation were associated with a better clinical response to CTLA4 followed by PD1 treatment. Immune checkpoint blockade is burdened by a high incidence of autoimmune thyroid dysfunction, which is often severe. Therefore, early and careful monitoring and, eventually, treatment are crucial to prevent the negative impact of thyroid dysfunction on the clinical outcome.

Bilateral Vestibular Dysfunction Associated With Chronic Exposure to Military Jet Propellant Type-Eight Jet Fuel

PubMed Central

Fife, Terry D.; Robb, Michael J. A.; Steenerson, Kristen K.; Saha, Kamala C.

2018-01-01

We describe three patients diagnosed with bilateral vestibular dysfunction associated with the jet propellant type-eight (JP-8) fuel exposure. Chronic exposure to aromatic and aliphatic hydrocarbons, which are the main constituents of JP-8 military aircraft jet fuel, occurred over 3–5 years’ duration while working on or near the flight line. Exposure to toxic hydrocarbons was substantiated by the presence of JP-8 metabolite n-hexane in the blood of one of the cases. The presenting symptoms were dizziness, headache, fatigue, and imbalance. Rotational chair testing confirmed bilateral vestibular dysfunction in all the three patients. Vestibular function improved over time once the exposure was removed. Bilateral vestibular dysfunction has been associated with hydrocarbon exposure in humans, but only recently has emphasis been placed specifically on the detrimental effects of JP-8 jet fuel and its numerous hydrocarbon constituents. Data are limited on the mechanism of JP-8-induced vestibular dysfunction or ototoxicity. Early recognition of JP-8 toxicity risk, cessation of exposure, and customized vestibular therapy offer the best chance for improved balance. Bilateral vestibular impairment is under-recognized in those chronically exposed to all forms of jet fuel. PMID:29867750

Bilateral Vestibular Dysfunction Associated With Chronic Exposure to Military Jet Propellant Type-Eight Jet Fuel.

PubMed

Fife, Terry D; Robb, Michael J A; Steenerson, Kristen K; Saha, Kamala C

2018-01-01

We describe three patients diagnosed with bilateral vestibular dysfunction associated with the jet propellant type-eight (JP-8) fuel exposure. Chronic exposure to aromatic and aliphatic hydrocarbons, which are the main constituents of JP-8 military aircraft jet fuel, occurred over 3-5 years' duration while working on or near the flight line. Exposure to toxic hydrocarbons was substantiated by the presence of JP-8 metabolite n -hexane in the blood of one of the cases. The presenting symptoms were dizziness, headache, fatigue, and imbalance. Rotational chair testing confirmed bilateral vestibular dysfunction in all the three patients. Vestibular function improved over time once the exposure was removed. Bilateral vestibular dysfunction has been associated with hydrocarbon exposure in humans, but only recently has emphasis been placed specifically on the detrimental effects of JP-8 jet fuel and its numerous hydrocarbon constituents. Data are limited on the mechanism of JP-8-induced vestibular dysfunction or ototoxicity. Early recognition of JP-8 toxicity risk, cessation of exposure, and customized vestibular therapy offer the best chance for improved balance. Bilateral vestibular impairment is under-recognized in those chronically exposed to all forms of jet fuel.

A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures

PubMed Central

Rossignol, D A; Frye, R E

2012-01-01

Recent studies have implicated physiological and metabolic abnormalities in autism spectrum disorders (ASD) and other psychiatric disorders, particularly immune dysregulation or inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures (‘four major areas'). The aim of this study was to determine trends in the literature on these topics with respect to ASD. A comprehensive literature search from 1971 to 2010 was performed in these four major areas in ASD with three objectives. First, publications were divided by several criteria, including whether or not they implicated an association between the physiological abnormality and ASD. A large percentage of publications implicated an association between ASD and immune dysregulation/inflammation (416 out of 437 publications, 95%), oxidative stress (all 115), mitochondrial dysfunction (145 of 153, 95%) and toxicant exposures (170 of 190, 89%). Second, the strength of evidence for publications in each area was computed using a validated scale. The strongest evidence was for immune dysregulation/inflammation and oxidative stress, followed by toxicant exposures and mitochondrial dysfunction. In all areas, at least 45% of the publications were rated as providing strong evidence for an association between the physiological abnormalities and ASD. Third, the time trends in the four major areas were compared with trends in neuroimaging, neuropathology, theory of mind and genetics (‘four comparison areas'). The number of publications per 5-year block in all eight areas was calculated in order to identify significant changes in trends. Prior to 1986, only 12 publications were identified in the four major areas and 51 in the four comparison areas (42 for genetics). For each 5-year period, the total number of publications in the eight combined areas increased progressively. Most publications (552 of 895, 62%) in the four major areas were published in the last 5 years (2006–2010). Evaluation of trends between the four major areas and the four comparison areas demonstrated that the largest relative growth was in immune dysregulation/inflammation, oxidative stress, toxicant exposures, genetics and neuroimaging. Research on mitochondrial dysfunction started growing in the last 5 years. Theory of mind and neuropathology research has declined in recent years. Although most publications implicated an association between the four major areas and ASD, publication bias may have led to an overestimation of this association. Further research into these physiological areas may provide insight into general or subset-specific processes that could contribute to the development of ASD and other psychiatric disorders. PMID:22143005

Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa.

PubMed

Dantzer, Robert

2018-01-01

Because of the compartmentalization of disciplines that shaped the academic landscape of biology and biomedical sciences in the past, physiological systems have long been studied in isolation from each other. This has particularly been the case for the immune system. As a consequence of its ties with pathology and microbiology, immunology as a discipline has largely grown independently of physiology. Accordingly, it has taken a long time for immunologists to accept the concept that the immune system is not self-regulated but functions in close association with the nervous system. These associations are present at different levels of organization. At the local level, there is clear evidence for the production and use of immune factors by the central nervous system and for the production and use of neuroendocrine mediators by the immune system. Short-range interactions between immune cells and peripheral nerve endings innervating immune organs allow the immune system to recruit local neuronal elements for fine tuning of the immune response. Reciprocally, immune cells and mediators play a regulatory role in the nervous system and participate in the elimination and plasticity of synapses during development as well as in synaptic plasticity at adulthood. At the whole organism level, long-range interactions between immune cells and the central nervous system allow the immune system to engage the rest of the body in the fight against infection from pathogenic microorganisms and permit the nervous system to regulate immune functioning. Alterations in communication pathways between the immune system and the nervous system can account for many pathological conditions that were initially attributed to strict organ dysfunction. This applies in particular to psychiatric disorders and several immune-mediated diseases. This review will show how our understanding of this balance between long-range and short-range interactions between the immune system and the central nervous system has evolved over time, since the first demonstrations of immune influences on brain functions. The necessary complementarity of these two modes of communication will then be discussed. Finally, a few examples will illustrate how dysfunction in these communication pathways results in what was formerly considered in psychiatry and immunology to be strict organ pathologies.

Immune Dysfunction in Transition Dairy Cows: Pharmacologic and Dietary Immune Modulation

USDA-ARS?s Scientific Manuscript database

With a $40.5 billion Gross Domestic Value for milk produced in the U.S. during 2013, the dairy industry was the third largest sector of the 2013 U.S. animal agriculture economic engine. The value of milk produced in 2013 represented 24% of the total value of animal agriculture production; this figu...

Immune dysfunction in periparturient dairy cows: Insight into pharmacologic and dietary immune treatments

USDA-ARS?s Scientific Manuscript database

With a $40.5 billion Gross Domestic Value for milk produced in the U.S. during 2013, the dairy industry was the third largest sector of the 2013 U.S. animal agriculture economic engine. The value of milk produced in 2013 represented 24% of the total value of animal agriculture production; this figu...

Transcriptional Regulation of Brain-Derived Neurotrophic Factor (BDNF) by Methyl CpG Binding Protein 2 (MeCP2): a Novel Mechanism for Re-Myelination and/or Myelin Repair Involved in the Treatment of Multiple Sclerosis (MS).

PubMed

KhorshidAhmad, Tina; Acosta, Crystal; Cortes, Claudia; Lakowski, Ted M; Gangadaran, Surendiran; Namaka, Michael

2016-03-01

Multiple sclerosis (MS) is a chronic progressive, neurological disease characterized by the targeted immune system-mediated destruction of central nervous system (CNS) myelin. Autoreactive CD4+ T helper cells have a key role in orchestrating MS-induced myelin damage. Once activated, circulating Th1-cells secrete a variety of inflammatory cytokines that foster the breakdown of blood-brain barrier (BBB) eventually infiltrating into the CNS. Inside the CNS, they become reactivated upon exposure to the myelin structural proteins and continue to produce inflammatory cytokines such as tumor necrosis factor α (TNFα) that leads to direct activation of antibodies and macrophages that are involved in the phagocytosis of myelin. Proliferating oligodendrocyte precursors (OPs) migrating to the lesion sites are capable of acute remyelination but unable to completely repair or restore the immune system-mediated myelin damage. This results in various permanent clinical neurological disabilities such as cognitive dysfunction, fatigue, bowel/bladder abnormalities, and neuropathic pain. At present, there is no cure for MS. Recent remyelination and/or myelin repair strategies have focused on the role of the neurotrophin brain-derived neurotrophic factor (BDNF) and its upstream transcriptional repressor methyl CpG binding protein (MeCP2). Research in the field of epigenetic therapeutics involving histone deacetylase (HDAC) inhibitors and lysine acetyl transferase (KAT) inhibitors is being explored to repress the detrimental effects of MeCP2. This review will address the role of MeCP2 and BDNF in remyelination and/or myelin repair and the potential of HDAC and KAT inhibitors as novel therapeutic interventions for MS.

Concurrent, but not sequential, PD-1 blockade with a DNA vaccine elicits anti-tumor responses in patients with metastatic, castration-resistant prostate cancer.

PubMed

McNeel, Douglas G; Eickhoff, Jens C; Wargowski, Ellen; Zahm, Christopher; Staab, Mary Jane; Straus, Jane; Liu, Glenn

2018-05-22

T-cell checkpoint inhibitors have demonstrated dramatic clinical activity against multiple cancer types, however little activity in patients with prostate cancer. Conversely, an anti-tumor vaccine was approved for the treatment of prostate cancer, having demonstrated an improvement in overall survival, despite few objective disease responses. In murine studies, we found that PD-1 expression on CD8+ T cells increased following anti-tumor vaccination, and that PD-1/PD-L1 blockade at the time of immunization elicited greater anti-tumor responses. Based on these data we initiated a pilot trial evaluating the immunological and clinical efficacy of a DNA encoding prostatic acid phosphatase (PAP) when delivered in combination with pembrolizumab. 26 patients were treated for 12 weeks with vaccine and received pembrolizumab either during this time or during the subsequent 12 weeks. Adverse events included grade 2 and 3 fatigue, diarrhea, thyroid dysfunction, and hepatitis. Median time to radiographic progression was not different between study arms. 8/13 (62%) of patients treated concurrently, and 1/12 (8%, p=0.01) of patients treated sequentially, experienced PSA declines from baseline. Of these, two were over 50% and one was a complete PSA response. No confirmed CR or PR were observed, however 4/5 patients treated concurrently had measurable decreases in tumor volume at 12 weeks. PSA declines were associated with the development of PAP-specific Th1-biased T cell immunity and CD8+ T cell infiltration in metastatic tumor biopsy specimens. These data are the first report of a clinical trial demonstrating that the efficacy of an anti-tumor vaccine can be augmented by concurrent PD-1 blockade.

Potential immunotoxic effects of trichloroethylene-induced IV allergic reaction in renal impairment

PubMed Central

Yu, Jun-Feng; Feng, Yan-Yan

2017-01-01

Trichloroethylene (TCE) is known to induce allergic contact dermatitis and subsequent occupational medicamentosa-like dermatitis (OMLD) with multi-system injuries, including liver, kidney, and skin injuries. However, the mechanisms underlying immune system dysfunction that result in organ injury have not yet been clearly elucidated. In the present study, we measured the levels of secreted cytokines by effect or T cells in TCE-treated guinea pigs to better understand the contribution of allergic disorders in renal injuries. We immunized guinea pigs with trichloroethylene using the Guinea Pig Maximization Test (GPMT) and scored the inflammation on the guinea pigs’ skin. The kidney function and ultra-structural changes in the kidneys were detected using biochemical methods and electron microscopy. The deposition of cytokines was determined using immunohistochemistry. The sensitization rate was 63.16% in the TCE-sensitized groups. The electron microscopy results showed tubular epithelial cell mitochondrial swelling, vacuolar degeneration, and atrophy of the microvillus in the sensitized groups. A high degree of cytokine deposition was observed in the renal tubular proximal epithelial cells in the TCE-sensitized groups. As observed in this study, the variation in the level of immune system activation not only indicates that TCE can largely magnify the immune reaction but also suggests a potential role of immune dysfunction in renal impairment. PMID:28867961

Sleep Tips for Sjogren's Patients

MedlinePlus

... important for those with Sjögren’s syndrome, saying that sleep deprivation exacerbates daytime fatigue and can affect the immune system. Make sure the bedroom is comfortable, secure, dark, and quiet. Try to maintain good “sleep hygiene:” Get out of bed at the same ...

Head and Neck Carcinoma Immunotherapy: Facts and Hopes.

PubMed

Whiteside, Theresa L

2018-01-01

Cancer of the head and neck (HNC) is a heterogeneous disease of the upper aerodigestive tract, encompassing distinct histologic types, different anatomic sites, and human papillomavirus (HPV)-positive as well as HPV-negative cancers. Advanced/recurrent HNCs have poor prognosis with low survival rates. Tumor-mediated inhibition of antitumor immune responses and a high mutational burden are common features of HNCs. Both are responsible for the successful escape of these tumors from the host immune system. HNCs evolve numerous mechanisms of evasion from immune destruction. These mechanisms are linked to genetic aberrations, so that HNCs with a high mutational load are also highly immunosuppressive. The tumor microenvironment of these cancers is populated by immune cells that are dysfunctional, inhibitory cytokines, and exosomes carrying suppressive ligands. Dysfunctional immune cells in patients with recurrent/metastatic HNC can be made effective by the delivery of immunotherapies in combination with conventional treatments. With many promising immune-based strategies available, the future of immune therapies in HNC is encouraging, especially as methods for genetic profiling and mapping the immune landscape of the tumor are being integrated into a personalized approach. Efficiency of immune therapies is expected to rapidly improve with the possibility for patients' selection based on personal immunogenomic profiles. Noninvasive biomarkers of response to therapy will be emerging as a better understanding of the various molecular signals co-opted by the tumors is gained. The emerging role of immunotherapy as a potentially beneficial addition to standard treatments for recurrent/metastatic HNC offers hope to the patients for whom no other therapeutic options exist. Clin Cancer Res; 24(1); 6-13. ©2017 AACR . ©2017 American Association for Cancer Research.

Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross-sectional study suggesting altered B cell differentiation and survival.

PubMed

Nguyen, Chinh Bkrong; Alsøe, Lene; Lindvall, Jessica M; Sulheim, Dag; Fagermoen, Even; Winger, Anette; Kaarbø, Mari; Nilsen, Hilde; Wyller, Vegard Bruun

2017-05-11

Chronic fatigue syndrome (CFS) is a prevalent and disabling condition affecting adolescents. The pathophysiology is poorly understood, but immune alterations might be an important component. This study compared whole blood gene expression in adolescent CFS patients and healthy controls, and explored associations between gene expression and neuroendocrine markers, immune markers and clinical markers within the CFS group. CFS patients (12-18 years old) were recruited nation-wide to a single referral center as part of the NorCAPITAL project. A broad case definition of CFS was applied, requiring 3 months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Healthy controls having comparable distribution of gender and age were recruited from local schools. Whole blood samples were subjected to RNA sequencing. Immune markers were blood leukocyte counts, plasma cytokines, serum C-reactive protein and immunoglobulins. Neuroendocrine markers encompassed plasma and urine levels of catecholamines and cortisol, as well as heart rate variability indices. Clinical markers consisted of questionnaire scores for symptoms of post-exertional malaise, inflammation, fatigue, depression and trait anxiety, as well as activity recordings. A total of 29 CFS patients and 18 healthy controls were included. We identified 176 genes as differentially expressed in patients compared to controls, adjusting for age and gender factors. Gene set enrichment analyses suggested impairment of B cell differentiation and survival, as well as enhancement of innate antiviral responses and inflammation in the CFS group. A pattern of co-expression could be identified, and this pattern, as well as single gene transcripts, was significantly associated with indices of autonomic nervous activity, plasma cortisol, and blood monocyte and eosinophil counts. Also, an association with symptoms of post-exertional malaise was demonstrated. Adolescent CFS is characterized by differential gene expression pattern in whole blood suggestive of impaired B cell differentiation and survival, and enhanced innate antiviral responses and inflammation. This expression pattern is associated with neuroendocrine markers of altered HPA axis and autonomic nervous activity, and with symptoms of post-exertional malaise. Trial registration Clinical Trials NCT01040429.

Quant. PCR and bDNA - the search for the truth continues as high viral load are linked to high beta 2 microglobulin levels.

PubMed

1998-01-01

Controversy exists over whether numbers obtained from Quant. PCR & bDNA tests actually represent the HIV virus; however, a researcher is collecting evidence to determine whether both tests have the same prognostic value as the beta 2 microglobulin tests. There is enough evidence to show that beta 2 microglobulin levels correlate directly with high viral loads. The researcher speculates that Quant. PCR or bDNA measures the combined effects of both HIV and HHV-6A infection in destroying cells. To help resolve this and other issues, volunteers with Chronic Fatigue Immune Dysfunction Syndrome (CFIDS) and active HHV-6A infection are being sought. Volunteers will be asked to use Norvir after which its effectiveness against HHV-6A infection will be determined. CFIDS patients will show a viral load for HIV even though they do not have the virus; the research speculates that if the PCR test for HIV is non-detectable in HHV-6A related cases, it will prove that Quant PCR is not measuring HHV-6A titers in persons with AIDS. Other diagnostic tests are available to patients. Five of these tests are briefly summarized and responses to patient questions regarding viral load issues and therapy are included.

Gulf War Illness Inflammation Reduction Trial

DTIC Science & Technology

2015-10-01

study comparing blood samples from Gulf War veterans with and without multiple symptoms of pain, fatigue, and cognitive dysfunction. The goal of the...pilot study was to identify a potential therapeutic target for the treatment of GWI. Examination to the peripheral blood revealed the biomarker...understood. Therefore, we performed a pilot study comparing blood samples from Gulf War veterans who very GWI- with blood 6 from veterans who were

Designing a Successful Acupuncture Treatment Program for Gulf War Illness

DTIC Science & Technology

2016-10-01

Deployment psychology . Washington, DC: American Psychological Association. 2 Saab PG, et al. ENRICHD Investigators.(2009). The impact of cognitive ...1) Joe Chang Lic Ac, an acupuncturist with experience working in military settings; (2) Marc Goldstein MD, a physician at the VA in Boston MA who...War Illness (GWI) is a complex illness with multiple symptoms, including fatigue, sleep and mood disturbances, cognitive dysfunction and

Mechanisms of Mitochondrial Defects in Gulf War Syndrome

DTIC Science & Technology

2012-08-01

oxidized; POR: porin; TCA: Tricarboxylic acid cycle ( Kreb cycle ). Page 2 Body: YEAR 1 of research (10/13/2009-7/14/2010) (9 months): Human... mitochondria , fatigue, myalgias 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON...abnormalities in genes that are related to mitochondrial function. Hence, investigation of mitochondrial dysfunction in GWS is a priority. Mitochondria

Cognitive dysfunction in adolescents with chronic fatigue: a cross-sectional study.

PubMed

Sulheim, Dag; Fagermoen, Even; Sivertsen, Øyvind Stople; Winger, Anette; Wyller, Vegard Bruun; Øie, Merete Glenne

2015-09-01

To compare cognitive function in adolescents with chronic fatigue with cognitive function in healthy controls (HC). Cross-sectional study. Paediatric department at Oslo University Hospital, Norway. 120 adolescents with chronic fatigue (average age 15.4 years; range 12-18) and 39 HC (average age 15.2 years; range 12-18). The adolescents completed a neurocognitive test battery measuring processing speed, working memory, cognitive inhibition, cognitive flexibility, verbal learning and verbal memory, and questionnaires addressing demographic data, depression symptoms, anxiety traits, fatigue and sleep problems. Parents completed the Behaviour Rating Inventory of Executive Function (BRIEF), which measures the everyday executive functions of children. Adolescents with chronic fatigue had impaired cognitive function compared to HC regarding processing speed (mean difference 3.3, 95% CI 1.1 to 5.5, p=0.003), working memory (-2.4, -3.7 to -1.1, p<0.001), cognitive inhibition response time (6.2, 0.8 to 11.7, p=0.025) and verbal learning (-1.7, -3.2 to -0.3, p=0.022). The BRIEF results indicated that everyday executive functions were significantly worse in the chronic fatigue group compared to the HC (11.2, 8.2 to 14.3, p<0.001). Group differences remained largely unaffected when adjusted for symptoms of depression, anxiety traits and sleep problems. Adolescents with chronic fatigue had impaired cognitive function of clinical relevance, measured by objective cognitive tests, in comparison to HC. Working memory and processing speed may represent core difficulties. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Poor self-reported sleep quality and health-related quality of life in patients with chronic fatigue syndrome/myalgic encephalomyelitis.

PubMed

Castro-Marrero, Jesús; Zaragozá, Maria C; González-Garcia, Sergio; Aliste, Luisa; Sáez-Francàs, Naia; Romero, Odile; Ferré, Alex; Fernández de Sevilla, Tomás; Alegre, José

2018-05-16

Non-restorative sleep is a hallmark symptom of chronic fatigue syndrome/myalgic encephalomyelitis. However, little is known about self-reported sleep disturbances in these subjects. This study aimed to assess the self-reported sleep quality and its impact on quality of life in a Spanish community-based chronic fatigue syndrome/myalgic encephalomyelitis cohort. A prospective cross-sectional cohort study was conducted in 1,455 Spanish chronic fatigue syndrome/myalgic encephalomyelitis patients. Sleep quality, fatigue, pain, functional capacity impairment, psychopathological status, anxiety/depression and health-related quality of life were assessed using validated subjective measures. The frequencies of muscular, cognitive, neurological, autonomic and immunological symptom clusters were above 80%. High scores were recorded for pain, fatigue, psychopathological status, anxiety/depression, and low scores for functional capacity and quality of life, all of which correlated significantly (all p < 0.01) with quality of sleep as measured by the Pittsburgh Sleep Quality Index. Multivariate regression analysis showed that after adjusting for age and gender, the pain intensity (odds ratio, 1.11; p <0.05), psychopathological status (odds ratio, 1.85; p < 0.001), fibromyalgia (odds ratio, 1.39; p < 0.05), severe autonomic dysfunction (odds ratio, 1.72; p < 0.05), poor functional capacity (odds ratio, 0.98; p < 0.05) and quality of life (odds ratio, 0.96; both p < 0.001) were significantly associated with poor sleep quality. These findings suggest that this large chronic fatigue syndrome/myalgic encephalomyelitis sample presents poor sleep quality, as assessed by the Pittsburgh Sleep Quality Index, and that this poor sleep quality is associated with many aspects of quality of life. © 2018 European Sleep Research Society.

Housebound versus nonhousebound patients with myalgic encephalomyelitis and chronic fatigue syndrome.

PubMed

Pendergrast, Tricia; Brown, Abigail; Sunnquist, Madison; Jantke, Rachel; Newton, Julia L; Strand, Elin Bolle; Jason, Leonard A

2016-12-01

The objective of this study was to examine individuals with myalgic encephalomyelitis and chronic fatigue syndrome who are confined to their homes due to severe symptomatology. The existing literature fails to address differences between this group, and less severe, nonhousebound patient populations. Participants completed the DePaul Symptom Questionnaire, a measure of myalgic encephalomyelitis and chronic fatigue syndrome symptomology, and the SF-36, a measure of health impact on physical/mental functioning. ANOVAs and, where appropriate, MANCOVAS were used to compare housebound and nonhousebound patients with myalgic encephalomyelitis and chronic fatigue syndrome across areas of functioning, symptomatology, and illness onset characteristics. Findings indicated that the housebound group represented one quarter of the sample, and were significantly more impaired with regards to physical functioning, bodily pain, vitality, social functioning, fatigue, postexertional malaise, sleep, pain, neurocognitive, autonomic, neuroendocrine, and immune functioning compared to individuals who were not housebound. Findings indicated that housebound patients have more impairment on functional and symptom outcomes compared to those who were not housebound. Understanding the differences between housebound and not housebound groups holds implications for physicians and researchers as they develop interventions intended for patients who are most severely affected by this chronic illness. © The Author(s) 2016.

The role of cytokines in cancer-related fatigue.

PubMed

Kurzrock, R

2001-09-15

Fatigue is prominent in cancer patients and probably multifactorial in origin. Factors contributing to fatigue include anemia, weight loss, fever, pain, medication, and infection. In cancer patients, many of these factors are influenced by a frequently disrupted balance between endogenous cytokine levels and their natural antagonists. Indeed, cancer cells and the immune system appear to overexpress a range of cytokines in patients with malignancies. Some of these cytokines act as autocrine or paracrine growth factors for the neoplastic tissue while simultaneously causing secondary symptoms related to fatigue. For instance, cancer-associated anemia may be due to a blunted erythropoietin response and/or cytokines (interleukin-1 [IL-1], IL-6, tumor necrosis factor-alpha [TNF-alpha]), which suppress erythropoiesis. Cancerous cachexia, a wasting syndrome and a hallmark of cancer, can be attributed to loss of appetite or enhanced energy expenditure. Several different interleukins, as well as TNF, interferon-gamma, and leukemia inhibitory factor, act as cachectins in animal models. Similarly, fever and night sweats are influenced by pyrogenic cytokines. Recently, molecules that function as cytokine antagonists have been identified. These molecules may be exploitable in combating the components of cancer-related fatigue, and may inhibit tumor growth as well. Copyright 2001 American Cancer Society.

Got worms? Perinatal exposure to helminths prevents persistent immune sensitization and cognitive dysfunction induced by early-life infection.

PubMed

Williamson, Lauren L; McKenney, Erin A; Holzknecht, Zoie E; Belliveau, Christine; Rawls, John F; Poulton, Susan; Parker, William; Bilbo, Staci D

2016-01-01

The incidence of autoimmune and inflammatory diseases has risen dramatically in post-industrial societies. "Biome depletion" - loss of commensal microbial and multicellular organisms such as helminths (intestinal worms) that profoundly modulate the immune system - may contribute to these increases. Hyperimmune-associated disorders also affect the brain, especially neurodevelopment, and increasing evidence links early-life infection to cognitive and neurodevelopmental disorders. We have demonstrated previously that rats infected with bacteria as newborns display life-long vulnerabilities to cognitive dysfunction, a vulnerability that is specifically linked to long-term hypersensitivity of microglial cell function, the resident immune cells of the brain. Here, we demonstrate that helminth colonization of pregnant dams attenuated the exaggerated brain cytokine response of their offspring to bacterial infection, and that combined with post-weaning colonization of offspring with helminths (consistent with their mothers treatment) completely prevented enduring microglial sensitization and cognitive dysfunction in adulthood. Importantly, helminths had no overt impact on adaptive immune cell subsets, whereas exaggerated innate inflammatory responses in splenic macrophages were prevented. Finally, helminths altered the effect of neonatal infection on the gut microbiome; neonatal infection with Escherichia coli caused a shift from genera within the Actinobacteria and Tenericutes phyla to genera in the Bacteroidetes phylum in rats not colonized with helminths, but helminths attenuated this effect. In sum, these data point toward an inter-relatedness of various components of the biome, and suggest potential mechanisms by which this helminth might exert therapeutic benefits in the treatment of neuroinflammatory and cognitive disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

Oxidative stress activates endothelial innate immunity via sterol regulatory element binding protein 2 (SREBP2) transactivation of microRNA-92a.

PubMed

Chen, Zhen; Wen, Liang; Martin, Marcy; Hsu, Chien-Yi; Fang, Longhou; Lin, Feng-Mao; Lin, Ting-Yang; Geary, McKenna J; Geary, Greg G; Zhao, Yongli; Johnson, David A; Chen, Jaw-Wen; Lin, Shing-Jong; Chien, Shu; Huang, Hsien-Da; Miller, Yury I; Huang, Po-Hsun; Shyy, John Y-J

2015-03-03

Oxidative stress activates endothelial innate immunity and disrupts endothelial functions, including endothelial nitric oxide synthase-derived nitric oxide bioavailability. Here, we postulated that oxidative stress induces sterol regulatory element-binding protein 2 (SREBP2) and microRNA-92a (miR-92a), which in turn activate endothelial innate immune response, leading to dysfunctional endothelium. Using cultured endothelial cells challenged by diverse oxidative stresses, hypercholesterolemic zebrafish, and angiotensin II-infused or aged mice, we demonstrated that SREBP2 transactivation of microRNA-92a (miR-92a) is oxidative stress inducible. The SREBP2-induced miR-92a targets key molecules in endothelial homeostasis, including sirtuin 1, Krüppel-like factor 2, and Krüppel-like factor 4, leading to NOD-like receptor family pyrin domain-containing 3 inflammasome activation and endothelial nitric oxide synthase inhibition. In endothelial cell-specific SREBP2 transgenic mice, locked nucleic acid-modified antisense miR-92a attenuates inflammasome, improves vasodilation, and ameliorates angiotensin II-induced and aging-related atherogenesis. In patients with coronary artery disease, the level of circulating miR-92a is inversely correlated with endothelial cell-dependent, flow-mediated vasodilation and is positively correlated with serum level of interleukin-1β. Our findings suggest that SREBP2-miR-92a-inflammasome exacerbates endothelial dysfunction during oxidative stress. Identification of this mechanism may help in the diagnosis or treatment of disorders associated with oxidative stress, innate immune activation, and endothelial dysfunction. © 2014 American Heart Association, Inc.

Dysfunctions of the Iga system: a common link between intestinal and renal diseases

PubMed Central

Papista, Christina; Berthelot, Laureline; Monteiro, Renato C

2011-01-01

Immunoglobulin A (Iga)-isotype antibodies play an important role in immunity owing to their structure, glycosylation, localization and receptor interactions. Dysfunctions in this system can lead to multiple types of pathology. This review describes the characteristics of Iga and discusses the involvement of abnormalities in the Iga system on the development of celiac disease and Iga nephropathy. PMID:21278767

Immune Regulation during Chronic Visceral Leishmaniasis

PubMed Central

Faleiro, Rebecca J.; Kumar, Rajiv; Hafner, Louise M.; Engwerda, Christian R.

2014-01-01

Visceral leishmaniasis is a chronic parasitic disease associated with severe immune dysfunction. Treatment options are limited to relatively toxic drugs, and there is no vaccine for humans available. Hence, there is an urgent need to better understand immune responses following infection with Leishmania species by studying animal models of disease and clinical samples from patients. Here, we review recent discoveries in these areas and highlight shortcomings in our knowledge that need to be addressed if better treatment options are to be developed and effective vaccines designed. PMID:25010815

Acute Radiation Effects Resulting from Exposure to Solar Particle Event-Like Radiation

NASA Astrophysics Data System (ADS)

Kennedy, Ann; Cengel, Keith

2012-07-01

A major solar particle event (SPE) may place astronauts at significant risk for the acute radiation syndrome (ARS), which may be exacerbated when combined with other space flight stressors, such that the mission or crew health may be compromised. The National Space Biomedical Research Institute (NSBRI) Center of Acute Radiation Research (CARR) is focused on the assessment of risks of adverse biological effects related to the ARS in animal models exposed to space flight stressors combined with the types of radiation expected during an SPE. As part of this program, FDA-approved drugs that may prevent and/or mitigate ARS symptoms are being evaluated. The CARR studies are focused on the adverse biological effects resulting from exposure to the types of radiation, at the appropriate energies, doses and dose-rates, present during an SPE (and standard reference radiations, gamma rays or electrons). The ARS is a phased syndrome which often includes vomiting and fatigue. Other acute adverse biologic effects of concern are the loss of hematopoietic cells, which can result in compromised bone marrow and immune cell functions. There is also concern for skin damage from high SPE radiation doses, including burns, and resulting immune system dysfunction. Using 3 separate animal model systems (ferrets, mice and pigs), the major ARS biologic endpoints being evaluated are: 1) vomiting/retching and fatigue, 2) hematologic changes (with focus on white blood cells) and immune system changes resulting from exposure to SPE radiation with and without reduced weightbearing conditions, and 3) skin injury and related immune system functions. In all of these areas of research, statistically significant adverse health effects have been observed in animals exposed to SPE-like radiation. Countermeasures for the management of ARS symptoms are being evaluated. New research findings from the past grant year will be discussed. Acknowledgements: This research is supported by the NSBRI Center of Acute Radiation Research (CARR) grant; NSBRI is funded through NASA NCC 9-58. Recent Publications: [1]Cengel K. A. et al. (2010) Radiat Environ Biophys 49(4): 715-21. [2] Ware J. H. et al. (2010) Radiation Res 174: 325-330. [3] Davis J. G. et al. (2010) Radiation Res 173(3):353-61. [4] Sanzari J.K. et al. (2011) Radiation Res 175(5):650-6. [5] Ni H. et al. (2011) Radiation Res 175(4): 485-92. [6] Mao X. W. et al. (2011) Radiation Res 176: 187-197. [7] Maks C. J. et al. (2011) Radiation Res 176: 170-6. [8] Kennedy A. R. et al. (2011) Radiation Res 176: 62-70. [9] Sanzari J. K. et al. (2011) Int J Radiat Biol 87: 1033-8. [10] Wilson J. M. et al. (2011) Radiation Res 176(5):649-59. [11] Kennedy A. R. and Wan X. S. (2011) Advances in Space Res 48: 1460-1479. [12] Gridley D. S. et al. (2011) Int J Radiat Biol 2011 87(12): 1173-81, [13] York J. M., et al. (2012) Brain Behav Immun 26(2): 218-27,[14] Wilson J. M. et al. (2012) Advances in Space Res 49: 237-248. [15] Krigsfeld, G.S. et al. Int J Radiat Biol 2012 Feb 6 [Epub ahead of print

The innate immune response during urinary tract infection and pyelonephritis

PubMed Central

Spencer, John David; Schwaderer, Andrew L.; Becknell, Brian; Watson, Joshua; Hains, David S.

2013-01-01

Despite its proximity to the fecal flora, the urinary tract is considered sterile. The precise mechanisms by which the urinary tract maintains sterility are not well understood. Host immune responses are critically important in the antimicrobial defense of the urinary tract. During recent years, considerable advances have been made in our understanding of the mechanisms underlying immune homeostasis of the kidney and urinary tract. Dysfunctions in these immune mechanisms may result in acute disease, tissue destruction and overwhelming infection. The objective of this review is to provide an overview of the innate immune response in the urinary tract in response to microbial assault. In doing so, we focus on the role of antimicrobial peptides – a ubiquitous component of the innate immune response. PMID:23732397

The innate immune response during urinary tract infection and pyelonephritis.

PubMed

Spencer, John David; Schwaderer, Andrew L; Becknell, Brian; Watson, Joshua; Hains, David S

2014-07-01

Despite its proximity to the fecal flora, the urinary tract is considered sterile. The precise mechanisms by which the urinary tract maintains sterility are not well understood. Host immune responses are critically important in the antimicrobial defense of the urinary tract. During recent years, considerable advances have been made in our understanding of the mechanisms underlying immune homeostasis of the kidney and urinary tract. Dysfunctions in these immune mechanisms may result in acute disease, tissue destruction and overwhelming infection. The objective of this review is to provide an overview of the innate immune response in the urinary tract in response to microbial assault. In doing so, we focus on the role of antimicrobial peptides-a ubiquitous component of the innate immune response.

Commensal-innate immune miscommunication in IBD pathogenesis.

PubMed

Cario, Elke

2012-01-01

Commensal microbiota plays a key role in the health and disease of the host. The innate immune system comprises an essential functional component of the intestinal mucosal barrier, maintaining hyporesponsiveness to omnipresent harmless commensals in the lumen, but rapidly recognizing and combating invading bacteria through diverse antimicrobial mechanisms. Interactions between commensals and innate immune cells are constant, multidimensional and entirely context-dependent. Environment, genetics and host defense differentially modulate commensal-innate immune effects and functions in the intestinal mucosa. In IBD, dysbiosis, mucus layer disruption, impairment in bacterial clearance, intestinal epithelial cell barrier dysfunction and/or immune cell deregulation may lead to commensal-innate immune miscommunication, which critically drives mucosal inflammation and associated cancer. Copyright © 2012 S. Karger AG, Basel.

Factors associated with remission of post-traumatic brain injury fatigue in the years following traumatic brain injury (TBI): a TBI model systems module study.

PubMed

Lequerica, Anthony H; Botticello, Amanda L; Lengenfelder, Jean; Chiaravalloti, Nancy; Bushnik, Tamara; Dijkers, Marcel P; Hammond, Flora M; Kolakowsky-Hayner, Stephanie A; Rosenthal, Joseph

2017-10-01

Post-traumatic brain injury fatigue (PTBIF) is a major problem in the years after traumatic brain injury (TBI), yet little is known about its persistence and resolution. The objective of the study was to identify factors related to PTBIF remission and resolution. TBI Model System registrants at five centres participated in interviews at either one and two years post-injury (Y1-2 Cohort), or two and five years post-injury (Y2-5 Cohort). Characteristics of participants with PTBIF remission were compared to those with PTBIF persistence. Variables studied included the presence of and changes in disability, sleep dysfunction, mood, and community participation. The Functional Independence Measure did not differ significantly between groups or over time. In the Y1-2 Cohort the Fatigue Resolved group scored significantly better on the Disability Rating Scale and Pittsburgh Sleep Quality Index. In the Y2-5 Cohort the Fatigue Resolved group scored significantly higher on a measure of community participation. It was concluded that fewer than half of the sample in each cohort experienced a remission of PTBIF between time points. Persistence of PTBIF 1-2 years post-injury is associated with disability, sleep disturbance, and depression while persistence of fatigue beyond 2 years post-injury appears to be related to participation level, underscoring the potential impact of effective surveillance, assessment, and treatment of this condition in optimising life after TBI. Differences in fatigue progression may point to the presence of different types of PTBIF.

Self-reported post-exertional fatigue in Gulf War veterans: roles of autonomic testing

PubMed Central

Li, Mian; Xu, Changqing; Yao, Wenguo; Mahan, Clare M.; Kang, Han K.; Sandbrink, Friedhelm; Zhai, Ping; Karasik, Pamela A.

2014-01-01

To determine if objective evidence of autonomic dysfunction exists from a group of Gulf War veterans with self-reported post-exertional fatigue, we evaluated 16 Gulf War ill veterans and 12 Gulf War controls. Participants of the ill group had self- reported, unexplained chronic post-exertional fatigue and the illness symptoms had persisted for years until the current clinical study. The controls had no self-reported post-exertional fatigue either at the time of initial survey nor at the time of the current study. We intended to identify clinical autonomic disorders using autonomic and neurophysiologic testing in the clinical context. We compared the autonomic measures between the 2 groups on cardiovascular function at both baseline and head-up tilt, and sudomotor function. We identified 1 participant with orthostatic hypotension, 1 posture orthostatic tachycardia syndrome, 2 distal small fiber neuropathy, and 1 length dependent distal neuropathy affecting both large and small fiber in the ill group; whereas none of above definable diagnoses was noted in the controls. The ill group had a significantly higher baseline heart rate compared to controls. Compound autonomic scoring scale showed a significant higher score (95% CI of mean: 1.72–2.67) among ill group compared to controls (0.58–1.59). We conclude that objective autonomic testing is necessary for the evaluation of self-reported, unexplained post-exertional fatigue among some Gulf War veterans with multi-symptom illnesses. Our observation that ill veterans with self-reported post-exertional fatigue had objective autonomic measures that were worse than controls warrants validation in a larger clinical series. PMID:24431987

Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus.

PubMed

Vernon, Suzanne D; Whistler, Toni; Cameron, Barbara; Hickie, Ian B; Reeves, William C; Lloyd, Andrew

2006-01-31

Acute infectious diseases are typically accompanied by non-specific symptoms including fever, malaise, irritability and somnolence that usually resolve on recovery. However, in some individuals these symptoms persist in what is commonly termed post-infective fatigue. The objective of this pilot study was to determine the gene expression correlates of post-infective fatigue following acute Epstein Barr virus (EBV) infection. We followed 5 people with acute mononucleosis who developed post-infective fatigue of more than 6 months duration and 5 HLA-matched control subjects who recovered within 3 months. Subjects had peripheral blood mononuclear cell (PBMC) samples collected at varying time points including at diagnosis, then every 2 weeks for 3 months, then every 3 months for a year. Total RNA was extracted from the PBMC samples and hybridized to microarrays spotted with 3,800 oligonucleotides. Those who developed post-infective fatigue had gene expression profiles indicative of an altered host response during acute mononucleosis compared to those who recovered uneventfully. Several genes including ISG20 (interferon stimulated gene), DNAJB2 (DnaJ [Hsp40] homolog and CD99), CDK8 (cyclin-dependent kinase 8), E2F2 (E2F transcription factor 2), CDK8 (cyclin-dependent kinase 8), and ACTN2 (actinin, alpha 2), known to be regulated during EBV infection, were differentially expressed in post-infective fatigue cases. Several of the differentially expressed genes affect mitochondrial functions including fatty acid metabolism and the cell cycle. These preliminary data provide insights into alterations in gene transcripts associated with the varied clinical outcomes from acute infectious mononucleosis.

High-intensity resistance training in multiple sclerosis - An exploratory study of effects on immune markers in blood and cerebrospinal fluid, and on mood, fatigue, health-related quality of life, muscle strength, walking and cognition.

PubMed

Kierkegaard, Marie; Lundberg, Ingrid E; Olsson, Tomas; Johansson, Sverker; Ygberg, Sofia; Opava, Christina; Holmqvist, Lotta Widén; Piehl, Fredrik

2016-03-15

High-intensity resistance training is unexplored in people with multiple sclerosis. To evaluate effects of high-intensity resistance training on immune markers and on measures of mood, fatigue, health-related quality of life, muscle strength, walking and cognition. Further, to describe participants' opinion and perceived changes of the training. Twenty patients with relapsing-remitting multiple sclerosis performed high-intensity resistance training at an intensity of 80% of one-repetition maximum, twice a week for 12 weeks. Blood and optional cerebrospinal fluid samples, and data on secondary outcome measures were collected before and after intervention. A study-specific questionnaire was used for capturing participants' opinion. Seventeen participants completed the study. Plasma cytokine levels of tumor necrosis factor were significantly decreased post-intervention (p=0.001). Exploratory cytokine analyses in cerebrospinal fluid (n=8) did not reveal major changes. Significant and clinically important improvements were found in fatigue (p=0.001) and health-related quality of life (p=0.004). Measures of mood (p=0.002), muscle strength (p ≤ 0.001), walking speed (p=0.013) and cognition (p=0.04) were also improved. A majority of participants evaluated the training as very good and perceived changes to the better. High-intensity resistance training in persons with relapsing remitting multiple sclerosis with low disability had positive effects on peripheral pro-inflammatory cytokine levels, led to clinically relevant improvements in measures of fatigue and health-related quality of life, and was well tolerated. These results provide a basis for a larger randomized trial. Copyright © 2016 Elsevier B.V. All rights reserved.

Associations among human papillomavirus, inflammation, and fatigue in patients with head and neck cancer.

PubMed

Xiao, Canhua; Beitler, Jonathan J; Higgins, Kristin A; Glazer, Toby; Huynh, Linh Kha; Paul, Sudeshna; Felger, Jennifer C; Wommack, Evanthia C; Saba, Nabil F; Shin, Dong M; Bruner, Deborah W; Miller, Andrew H

2018-05-09

Human papillomavirus (HPV) infection has contributed to an increased incidence of squamous cell carcinoma of the head and neck (SCCHN). Fatigue is a major side effect of SCCHN and its treatment. However, to the authors' knowledge, the association between HPV and fatigue has not been examined to date, nor is it known whether HPV influences biological mechanisms of fatigue, including inflammation. Patients with SCCHN who were without distant metastasis were assessed at baseline (pre-radiotherapy) and 1 month and 3 months postradiotherapy. Fatigue was measured using the Multidimensional Fatigue Inventory. Peripheral inflammation was assessed by plasma C-reactive protein (CRP), interleukin 1 receptor antagonist (IL-1ra), soluble tumor necrosis factor receptor 2 (sTNFR2), and IL-6. Mixed effect models were used to examine associations. A total of 94 patients who were newly diagnosed were enrolled; 53% had HPV-related tumors. Patients with HPV-unrelated tumors had higher fatigue and higher plasma CRP, sTNFR2, and IL-6 over time, especially at baseline and 3 months after intensity-modulated radiotherapy compared with those with HPV-related tumors (all P < .05). However, fatigue and plasma sTNFR2 increased more significantly from baseline to 1 month after radiotherapy in the HPV-related group compared with the HPV-unrelated group (both P < .01). Controlling for significant covariates, HPV status and inflammation were found to be independent predictors of fatigue over time. HPV status is an important marker of vulnerability to the behavioral and immune consequences of SCCHN and its treatment, providing support for different symptom management strategies. Special emphasis should be placed on addressing marked persistent fatigue in patients with HPV-unrelated tumors, whereas attention should be paid to the large increases in fatigue during treatment among patients with HPV-related tumors. Cancer 2018. © 2018 American Cancer Society. © 2018 American Cancer Society.

Targeting Microglia to Prevent Post-Traumatic Epilepsy

DTIC Science & Technology

2012-07-01

long-term effects of nigral lipopolysaccharide administration on dopaminergic dysfunction and glial cell activation. Eur J Neurosci 22 :317-330...attenuating damaging effects of hyperexcitability in the brain induced by inflammation resulting from glial cell immune responses to trauma. We are...damaging effects of hyperexcitability in the brain induced by inflammation resulting from glial cell immune responses to trauma. We are exploring two

[Oxidative stress in patients with type I diabetes mellitus and persistent coxsackie virus B infection as the reason of dysfunction of the immune system].

PubMed

Hyrin, V V

2009-01-01

A chronic inflammatory process takes place in patients with diabetes mellitus type 1. Numerous disorders of the immune status and complications testify the present of this process. The presence of chronic inflammation at diabetes mellitus enhances free radical reactions which are accompanied by oxidative stress.

Atypical Skeletal Muscle Profiles in Human Immunodeficiency Virus-Infected Asymptomatic Middle-Aged Adults.

PubMed

Tran, Thanh; Guardigni, Viola; Pencina, Karol M; Amato, Anthony A; Floyd, Michael; Brawley, Brooke; Mozeleski, Brian; McKinnon, Jennifer; Woodbury, Erin; Heckel, Emily; Li, Zhuoying; Storer, Tom; Sax, Paul E; Montano, Monty

2018-06-01

Human immunodeficiency virus (HIV)-infected individuals are at increased risk of age-associated functional impairment, even with effective antiretroviral therapy (ART). A concurrent characterization of skeletal muscle, physical function, and immune phenotype in aviremic middle-aged HIV-infected adults represents a knowledge gap in prognostic biomarker discovery. We undertook a prospective observational study of 170 middle-aged, HIV-infected ambulatory men and women with CD4+ T-cell counts of at least 350/µL and undetectable plasma viremia while on effective ART, and uninfected control participants. We measured biomarkers for inflammation and immune activation, fatigue, the Veterans Aging Cohort Study mortality index, and physical function. A subset also received a skeletal muscle biopsy and computed tomography scan. Compared to the uninfected participants, HIV-infected participants displayed increased immune activation (P < .001), inflammation (P = .001), and fatigue (P = .010), and in a regression model adjusting for age and sex displayed deficits in stair-climb power (P < .001), gait speed (P = .036), and predicted metabolic equivalents (P = .019). Skeletal muscle displayed reduced nuclear peroxisome proliferator-activated receptor-γ coactivator 1α-positive myonuclei (P = .006), and increased internalized myonuclei (P < .001) that correlated with immune activation (P = .003) and leukocyte infiltration (P < .001). Internalized myonuclei improved a model for HIV discrimination, increasing the C-statistic from 0.84 to 0.90. Asymptomatic HIV-infected middle-aged adults display atypical skeletal muscle profiles, subclinical deficits in physical function, and persistent inflammation and immune activation. Identifying biomarker profiles for muscle dysregulation and risk for future functional decline in the HIV-infected population will be key to developing and monitoring preventive interventions. NCT03011957.

Effect of aromatherapy via inhalation on the sleep quality and fatigue level in people undergoing hemodialysis.

PubMed

Muz, Gamze; Taşcı, Sultan

2017-10-01

The most common problems in hemodialysis patients are sleep disorders and fatigue. This randomized-controlled experimental study was conducted to determine the effect of aromatherapy applied by inhalation on sleep quality and fatigue level in hemodialysis patients. The study was completed in five hemodialysis centers settled in two provinces with 27 intervention group patients and 35 controls, being totally 62 patients, recruited with simple randomization. Ethical approval, informed consent from the individuals and institutional permission were obtained. Data were collected with a questionnaire form and Visual Analogue Scale (VAS) for fatigue, Piper fatigue scale, Pittsburgh Sleep Quality Index (PSQI), and follow-up forms for the patient and the researcher. Aromatherapy inhalation (sweet orange and lavender oil) was performed before going to bed every day for one month to the intervention group patients. No other application has been made to the control group patients except for standard hemodialysis treatment. All of the forms were performed at baseline and at follow-up at the end of the four weeks (baseline and last follow-up), VAS and Piper fatigue scale were performed during follow-ups at the end of every week (the first, second and third follow-ups). Data were statistically analyzed with Independent Samples t-test, one way analysis of variance, Pearson correlation analysis, chi-square test, Friedman and Mann Whitney U tests and Bonferroni test. p<0.05 was set as statistically significant in comparisons. Mean total and sub-dimension scores of VAS, Piper fatigue scale and PSQI (except for daytime sleepiness dysfunction sub-dimension) of the intervention and control groups at baseline were not significantly different (p>0.05). It was found that mean total and sub-dimension scores of VAS, Piper fatigue scale and PSQI of the intervention group significantly decreased in other follow-ups compared to the control group (p<0.05). Consequently, it was determined that aromatherapy applied by inhalation improved sleep quality, decreased fatigue level and severity in hemodialysis patients. Accordingly, aromatherapy prepared with sweet orange and lavender oil may be recommended to increase sleep quality and to decrease fatigue level of the hemodialysis patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Phagocyte dysfunction, tissue aging and degeneration

PubMed Central

2013-01-01

Immunologically-silent phagocytosis of apoptotic cells is critical to maintaining tissue homeostasis and innate immune balance. Aged phagocytes reduce their functional activity, leading to accumulation of unphagocytosed debris, chronic sterile inflammation and exacerbation of tissue aging and damage. Macrophage dysfunction plays an important role in immunosenescence. Microglial dysfunction has been linked to age-dependent neurodegenerations. Retinal pigment epithelial (RPE) cell dysfunction has been implicated in the pathogenesis of age-related macular degeneration (AMD). Despite several reports on the characterization of aged phagocytes, the role of phagocyte dysfunction in tissue aging and degeneration is yet to be fully appreciated. Lack of knowledge of molecular mechanisms by which aging reduces phagocyte function has hindered our capability to exploit the therapeutic potentials of phagocytosis for prevention or delay of tissue degeneration. This review summarizes our current knowledge of phagocyte dysfunction in aged tissues and discusses possible links to age-related diseases. We highlight the challenges to decipher the molecular mechanisms, present new research approaches and envisage future strategies to prevent phagocyte dysfunction, tissue aging and degeneration. PMID:23748186

A randomized trial comparing live and telemedicine deliveries of an imagery-based behavioral intervention for breast cancer survivors: reducing symptoms and barriers to care.

PubMed

Freeman, Lyn W; White, Rebecca; Ratcliff, Chelsea G; Sutton, Sue; Stewart, Mary; Palmer, J Lynn; Link, Judith; Cohen, Lorenzo

2015-08-01

This multi-site randomized trial evaluates the quality of life (QOL) benefits of an imagery-based group intervention titled 'Envision the Rhythms of Life'(ERL). Breast cancer survivors >6 weeks post-treatment were randomized to attend five weekly 4-h group sessions at a community center with therapist present (live delivery (LD), n = 48), therapist streamed via telemedicine (telemedicine delivery (TD), n = 23), or to a waitlist control (WL) group (n = 47). Weekly individual phone calls to encourage at-home practice began at session one and continued until the 3-month follow-up. Seven self-report measures of QOL were examined at baseline, 1-month and 3-month post-treatments including health-related and breast cancer-specific QOL, fatigue, cognitive function, spirituality, distress, and sleep. The Bonferroni method was used to correct for multiple comparisons, and alpha was adjusted to 0.01. Linear multilevel modeling analyses revealed less fatigue, cognitive dysfunction, and sleep disturbance for LD and TD compared with WL across the follow-up (p's < 0.01). Changes in fatigue, cognitive dysfunction, sleep disturbance, and health-related and breast cancer-related QOL were clinically significant. There were no differences between LD and TD. Both the live and telemedicine delivered ERL intervention resulted in improvements in multiple QOL domains for breast cancer survivors compared with WL. Further, there were no significant differences between LD and TD, suggesting telemedicine delivered ERL intervention may represent an effective and viable option for cancer survivors in remote areas. Copyright © 2014 John Wiley & Sons, Ltd.

Alteration of Lymphocyte Phenotype and Function in Sickle Cell Anemia: Implications for Vaccine Responses

PubMed Central

Balandya, Emmanuel; Reynolds, Teri; Obaro, Stephen; Makani, Julie

2016-01-01

Individuals with sickle cell anemia (SCA) have increased susceptibility to infections, secondary to impairment of immune function. Besides the described dysfunction in innate immunity, including impaired opsonization and phagocytosis of bacteria, evidence of dysfunction of T and B lymphocytes in SCA has also been reported. This includes reduction in the proportion of circulating CD4+ and CD8+ T cells, reduction of CD4+ helper : CD8+ suppressor T cell ratio, aberrant activation and dysfunction of regulatory T cells (Treg), skewing of CD4+ T cells towards Th2 response and loss of IgM-secreting CD27+IgMhighIgDlow memory B cells. These changes occur on the background of immune activation characterized by predominance of memory CD4+ T cell phenotypes, increased Th17 signaling and elevated levels of C-reactive protein and pro-inflammatory cytokines IL-6 and TNF-α, which may affect the immunogenicity and protective efficacy of vaccines available to prevent infections in SCA. Thus, in order to optimize the use of vaccines in SCA, a thorough understanding of T and B lymphocyte functions and vaccine reactivity among individuals with SCA is needed. Studies should be encouraged of different SCA populations, including sub-Saharan Africa where the burden of SCA is highest. This article summarizes our current understanding of lymphocyte biology in SCA, and highlights areas that warrant future research. PMID:27237467

Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies.

PubMed

Broce, Iris; Karch, Celeste M; Wen, Natalie; Fan, Chun C; Wang, Yunpeng; Tan, Chin Hong; Kouri, Naomi; Ross, Owen A; Höglinger, Günter U; Muller, Ulrich; Hardy, John; Momeni, Parastoo; Hess, Christopher P; Dillon, William P; Miller, Zachary A; Bonham, Luke W; Rabinovici, Gil D; Rosen, Howard J; Schellenberg, Gerard D; Franke, Andre; Karlsen, Tom H; Veldink, Jan H; Ferrari, Raffaele; Yokoyama, Jennifer S; Miller, Bruce L; Andreassen, Ole A; Dale, Anders M; Desikan, Rahul S; Sugrue, Leo P

2018-01-01

Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD-immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.

A multi-ingredient containing carbohydrate, proteins L-glutamine and L-carnitine attenuates fatigue perception with no effect on performance, muscle damage or immunity in soccer players.

PubMed

Naclerio, Fernando; Larumbe-Zabala, Eneko; Cooper, Robert; Allgrove, Judith; Earnest, Conrad P

2015-01-01

We investigated the effects of ingesting a multi-ingredient (53 g carbohydrate, 14.5 g whey protein, 5 g glutamine, 1.5 g L-carnitine-L-tartrate) supplement, carbohydrate only, or placebo on intermittent performance, perception of fatigue, immunity, and functional and metabolic markers of recovery. Sixteen amateur soccer players ingested their respective treatments before, during and after performing a 90-min intermittent repeated sprint test. Primary outcomes included time for a 90-min intermittent repeated sprint test (IRS) followed by eleven 15 m sprints. Measurements included creatine kinase, myoglobin, interleukine-6, Neutrophil; Lymphocytes and Monocyte before (pre), immediately after (post), 1 h and 24 h after exercise testing period. Overall, time for the IRS and 15 m sprints was not different between treatments. However, the perception of fatigue was attenuated (P<0.001) for the multi-ingredient (15.9±1.4) vs. placebo (17.8±1.4) but not for the carbohydrate (17.0±1.9) condition. Several changes in immune/inflammatory indices were noted as creatine kinase peaked at 24 h while Interleukin-6 and myoglobin increased both immediately after and at 1 h compared with baseline (P<0.05) for all three conditions. However, Myoglobin (P<0.05) was lower 1 h post-exercise for the multi-ingredient (241.8±142.6 ng·ml(-1)) and CHO (265.4±187.8 ng·ml(-1)) vs. placebo (518.6±255.2 ng·ml(-1)). Carbohydrate also elicited lower neutrophil concentrations vs. multi-ingredient (3.9±1.5 10(9)/L vs. 4.9±1.8 10(9)/L, P = 0.016) and a reduced (P<0.05) monocytes count (0.36±0.09 10(9)/L) compared to both multi-ingredient (0.42±0.09 10(9)/L) and placebo (0.42±0.12 10(9)/L). In conclusion, multi-ingredient and carbohydrate supplements did not improve intermittent performance, inflammatory or immune function. However, both treatments did attenuate serum myoglobin, while only carbohydrate blunted post-exercise leukocytosis.

A Multi-Ingredient Containing Carbohydrate, Proteins L-Glutamine and L-Carnitine Attenuates Fatigue Perception with No Effect on Performance, Muscle Damage or Immunity in Soccer Players

PubMed Central

Naclerio, Fernando; Larumbe-Zabala, Eneko; Cooper, Robert; Allgrove, Judith; Earnest, Conrad P.

2015-01-01

We investigated the effects of ingesting a multi-ingredient (53g carbohydrate, 14.5g whey protein, 5g glutamine, 1.5g L-carnitine-L-tartrate) supplement, carbohydrate only, or placebo on intermittent performance, perception of fatigue, immunity, and functional and metabolic markers of recovery. Sixteen amateur soccer players ingested their respective treatments before, during and after performing a 90-min intermittent repeated sprint test. Primary outcomes included time for a 90-min intermittent repeated sprint test (IRS) followed by eleven 15 m sprints. Measurements included creatine kinase, myoglobin, interleukine-6, Neutrophil; Lymphocytes and Monocyte before (pre), immediately after (post), 1h and 24h after exercise testing period. Overall, time for the IRS and 15 m sprints was not different between treatments. However, the perception of fatigue was attenuated (P<0.001) for the multi-ingredient (15.9±1.4) vs. placebo (17.8±1.4) but not for the carbohydrate (17.0±1.9) condition. Several changes in immune/inflammatory indices were noted as creatine kinase peaked at 24h while Interleukin-6 and myoglobin increased both immediately after and at 1h compared with baseline (P<0.05) for all three conditions. However, Myoglobin (P<0.05) was lower 1h post-exercise for the multi-ingredient (241.8±142.6 ng·ml-1) and CHO (265.4±187.8 ng·ml-1) vs. placebo (518.6±255.2 ng·ml-1). Carbohydrate also elicited lower neutrophil concentrations vs. multi-ingredient (3.9±1.5 109/L vs. 4.9±1.8 109/L, P = 0.016) and a reduced (P<0.05) monocytes count (0.36±0.09 109/L) compared to both multi-ingredient (0.42±0.09 109/L) and placebo (0.42±0.12 109/L). In conclusion, multi-ingredient and carbohydrate supplements did not improve intermittent performance, inflammatory or immune function. However, both treatments did attenuate serum myoglobin, while only carbohydrate blunted post-exercise leukocytosis. PMID:25915424

Mitochondrial dysfunction in a family with psychosis and chronic fatigue syndrome.

PubMed

Torrell, Helena; Alonso, Yolanda; Garrabou, Glòria; Mulet, David; Catalán, Marc; Valiente-Pallejà, Alba; Carreño-Gago, Lidia; García-Arumí, Elena; Montaña, Elena; Vilella, Elisabet; Martorell, Lourdes

2017-05-01

Mitochondrial impairment is hypothesized to be involved in chronic fatigue syndrome (CFS) and schizophrenia. We performed a clinical, genetic and functional mitochondrial study in a family consisting of a female presenting schizophrenia in addition to CFS symptoms and her mother and older sister, both presenting with CFS. The three family members showed higher blood lactate levels, higher mitochondrial mass, lower mtDNA content and overall lower mitochondrial enzymatic activities and lower oxygen consumption capacities than healthy women. This family presented mtDNA depletion; however, no mutation was identified neither in the mtDNA nor in the nuclear genes related with mtDNA depletion, even though C16179A and T16519A variants should be further studied. Copyright © 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

Physiological Aging: Links Among Adipose Tissue Dysfunction, Diabetes, and Frailty

PubMed Central

Stout, Michael B.; Justice, Jamie N.; Nicklas, Barbara J.; Kirkland, James L.

2016-01-01

Advancing age is associated with progressive declines in physiological function that lead to overt chronic disease, frailty, and eventual mortality. Importantly, age-related physiological changes occur in cellularity, insulin-responsiveness, secretory profiles, and inflammatory status of adipose tissue, leading to adipose tissue dysfunction. Although the mechanisms underlying adipose tissue dysfunction are multifactorial, the consequences result in secretion of proinflammatory cytokines and chemokines, immune cell infiltration, an accumulation of senescent cells, and an increase in senescence-associated secretory phenotype (SASP). These processes synergistically promote chronic sterile inflammation, insulin resistance, and lipid redistribution away from subcutaneous adipose tissue. Without intervention, these effects contribute to age-related systemic metabolic dysfunction, physical limitations, and frailty. Thus adipose tissue dysfunction may be a fundamental contributor to the elevated risk of chronic disease, disability, and adverse health outcomes with advancing age. PMID:27927801

Traditional Chinese medicine and new concepts of predictive, preventive and personalized medicine in diagnosis and treatment of suboptimal health.

PubMed

Wang, Wei; Russell, Alyce; Yan, Yuxiang

2014-02-13

The premise of disease-related phenotypes is the definition of the counterpart normality in medical sciences. Contrary to clinical practices that can be carefully planned according to clinical needs, heterogeneity and uncontrollability is the essence of humans in carrying out health studies. Full characterization of consistent phenotypes that define the general population is the basis to individual difference normalization in personalized medicine. Self-claimed normal status may not represent health because asymptomatic subjects may carry chronic diseases at their early stage, such as cancer, diabetes mellitus and atherosclerosis. Currently, treatments for non-communicable chronic diseases (NCD) are implemented after disease onset, which is a very much delayed approach from the perspective of predictive, preventive and personalized medicine (PPPM). A NCD pandemic will develop and be accompanied by increased global economic burden for healthcare systems throughout both developed and developing countries. This paper examples the characterization of the suboptimal health status (SHS) which represents a new PPPM challenge in a population with ambiguous health complaints such as general weakness, unexplained medical syndrome (UMS), chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS) and chronic fatigue immune dysfunction syndrome (CFIDS). We applied clinical informatic approaches and developed a questionnaire-suboptimal health status questionnaire-25 (SHSQ-25) for measuring SHS. The validity and reliability of this approach were evaluated in a small pilot study and then in a cross-sectional study of 3,405 participants in China. We found a correlation between SHS and systolic blood pressure, diastolic blood pressure, plasma glucose, total cholesterol and high-density lipoprotein (HDL) cholesterol among men, and a correlation between SHS and systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides and HDL cholesterol among women. The SHSQ-25 is a self-rated questionnaire of perceived health complaints, which can be used as a new instrument for PPPM. An ongoing longitudinal SHS cohort survey (China Sub-optimal Health Cohort Study, COACS) consisting of 50,000 participants will provide a powerful health trial to use SHSQ-25 for its application to PPPM through patient stratification and therapy monitoring using innovative technologies of predictive diagnostics and prognosis: an effort of paradigm shift from reactive to predictive medicine.

Implications of immune dysfunction on endometriosis associated infertility

PubMed Central

Miller, Jessica E.; Ahn, Soo Hyun; Monsanto, Stephany P.; Khalaj, Kasra; Koti, Madhuri; Tayade, Chandrakant

2017-01-01

Endometriosis is a complex, inflammatory disease that affects 6-10% of reproductive-aged women. Almost half of the women with endometriosis experience infertility. Despite the excessive prevalence, the pathogenesis of endometriosis and its associated infertility is unknown and a cure is not available. While many theories have been suggested to link endometriosis and infertility, a consensus among investigators has not emerged. In this extensive review of the literature as well as research from our laboratory, we provide potential insights into the role of immune dysfunction in endometriosis associated infertility. We discuss the implication of the peritoneal inflammatory microenvironment on various factors that contribute to infertility such as hormonal imbalance, oxidative stress and how these could further lead to poor oocyte, sperm and embryo quality, impaired receptivity of the endometrium and implantation failure. PMID:27740937

Implications of immune dysfunction on endometriosis associated infertility.

PubMed

Miller, Jessica E; Ahn, Soo Hyun; Monsanto, Stephany P; Khalaj, Kasra; Koti, Madhuri; Tayade, Chandrakant

2017-01-24

Endometriosis is a complex, inflammatory disease that affects 6-10% of reproductive-aged women. Almost half of the women with endometriosis experience infertility. Despite the excessive prevalence, the pathogenesis of endometriosis and its associated infertility is unknown and a cure is not available. While many theories have been suggested to link endometriosis and infertility, a consensus among investigators has not emerged. In this extensive review of the literature as well as research from our laboratory, we provide potential insights into the role of immune dysfunction in endometriosis associated infertility. We discuss the implication of the peritoneal inflammatory microenvironment on various factors that contribute to infertility such as hormonal imbalance, oxidative stress and how these could further lead to poor oocyte, sperm and embryo quality, impaired receptivity of the endometrium and implantation failure.

Maternal stress, nutrition and physical activity: Impact on immune function, CNS development and psychopathology.

PubMed

Marques, Andrea Horvath; Bjørke-Monsen, Anne-Lise; Teixeira, Antônio L; Silverman, Marni N

2015-08-18

Evidence suggests that maternal and fetal immune dysfunction may impact fetal brain development and could play a role in neurodevelopmental disorders, although the definitive pathophysiological mechanisms are still not completely understood. Stress, malnutrition and physical inactivity are three maternal behavioral lifestyle factors that can influence immune and central nervous system (CNS) functions in both the mother and fetus, and may therefore, increase risk for neurodevelopmental/psychiatric disorders. First, we will briefly review some aspects of maternal-fetal immune system interactions and development of immune tolerance. Second, we will discuss the bidirectional communication between the immune system and CNS and the pathways by which immune dysfunction could contribute to neurodevelopmental disorders. Third, we will discuss the effects of prenatal stress and malnutrition (over and undernutrition) on perinatal programming of the CNS and immune system, and how this might influence neurodevelopment. Finally, we will discuss the beneficial impact of physical fitness during pregnancy on the maternal-fetal unit and infant and how regular physical activity and exercise can be an effective buffer against stress- and inflammatory-related disorders. Although regular physical activity has been shown to promote neuroplasticity and an anti-inflammatory state in the adult, there is a paucity of studies evaluating its impact on CNS and immune function during pregnancy. Implementing stress reduction, proper nutrition and ample physical activity during pregnancy and the childbearing period may be an efficient strategy to counteract the impact of maternal stress and malnutrition/obesity on the developing fetus. Such behavioral interventions could have an impact on early development of the CNS and immune system and contribute to the prevention of neurodevelopmental and psychiatric disorders. Further research is needed to elucidate this relationship and the underlying mechanisms of protection. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease. Copyright © 2014 Elsevier B.V. All rights reserved.

The brain and immune system prompt energy shortage in chronic inflammation and ageing.

PubMed

Straub, Rainer H

2017-12-01

Sequelae frequently seen in patients with chronic inflammatory diseases, such as fatigue, depressed mood, sleep alterations, loss of appetite, muscle wasting, cachectic obesity, bone loss and hypertension, can be the result of energy shortages caused by an overactive immune system. These sequelae can also be found in patients with chronic inflammatory diseases that are in remission and in ageing individuals, despite the immune system being less active in these situations. This Perspectives article proposes a new way of understanding situations of chronic inflammation (such as rheumatic diseases) and ageing based on the principles of evolutionary medicine, energy regulation and neuroendocrine-immune crosstalk. A conceptual framework is provided to enable physicians and scientists to better understand the signs and symptoms of chronic inflammatory diseases and long-term disease consequences resulting from physical and mental inactivity.

HIV lipodystrophy etiology and pathogenesis. Body composition and metabolic alterations: etiology and pathogenesis.

PubMed

Kotler, Donald P

2003-04-01

The results of epidemiologic investigations have clearly indicated that the development of lipodystrophy is multifactorial. Factors related to HIV infection, hormonal influences, mitochondrial dysfunction, cytokine activation related to immune reconstitution, and individual genetic predisposition all have been hypothesized as etiologic. Recent studies suggest that immune dysregulation rather than HIV infection per se may be the predominant factor in the development of lipodystrophy.

Sleep quality in fibromyalgia and rheumatoid arthritis: associations with pain, fatigue, depression, and disease activity.

PubMed

Ulus, Y; Akyol, Y; Tander, B; Durmus, D; Bilgici, A; Kuru, O

2011-01-01

The aim of this study was to compare the sleep quality in patients with rheumatoid arthritis (RA) and fibromyalgia syndrome (FMS); and to evaluate the relationship between sleep quality and pain, fatigue, depression, and disease activity in patients with RA and FMS. Forty RA, 40 FMS and 40 healthy controls were enrolled in the study. Disease activity and disease duration were reported in patients. Pain by visual analogue scale (VAS), fatigue by Multidimensional Assesment of Fatigue (MAF), depression by Beck Depression Index (BDI), and sleep quality by Pittsburgh Sleep Quality Index (PSQI) were gathered in all participants. All participants were aged between 20 and 65 years, with a mean age of 42.97±10.75 years. There was no significant difference with respect to demographic characteristics among the three study groups. Patients reported more depression than controls, but BDI scores were similar in FMS and RA patients. VAS pain scores and MAF scores were significantly different in the three groups (p<0.001). FMS and RA patients had poor sleep quality (p<0.001). FMS patients had daytime dysfunction due to sleep disorder and had worse habitual sleep efficiency than RA patients (p<0.05). In patients, positive correlations were found between PSQI and clinic assessment variables except disease duration. FMS and RA may have poor sleep quality when compared to subjects without rheumatologic disorders. The quality of sleep can be impaired by pain, fatigue, depression, and disease activity in such patients.

Immune thrombocytopenia with multi-organ dysfunction syndrome as a rare presentation of scrub typhus: a case report.

PubMed

Ittyachen, Abraham M; Abraham, Saramma P; Krishnamoorthy, Smitha; Vijayan, Anuroopa; Kokkat, Jayamohan

2017-10-06

Scrub typhus is an acute infectious illness caused by Orientia tsutsugamushi. It is endemic to a part of the world known as the "tsutsugamushi triangle". Humans are accidental hosts in this zoonotic disease. About a third of patients admitted with scrub typhus have evidence of multi-organ dysfunction. Multi-organ dysfunction secondary to scrub typhus carries a high mortality rate. We report a 65-year old lady who was admitted in a Tertiary Care Center in the state of Kerala in India, with 7 day history of fever, myalgia and reduced urine output. Head to foot examination revealed the presence of an eschar on her chest. One week prior to the onset of her illness she had gone trekking through a hilly forest area. She was clinically suspected to have scrub typhus, which was later confirmed with laboratory tests. She developed multi-organ dysfunction syndrome secondary to this illness. Though there was an improvement in the multi-organ dysfunction, thrombocytopenia alone failed to improve. Bone marrow study was done which was suggestive of immune thrombocytopenia. Patient was given a course of steroids with which the thrombocytopenia improved. Failure of platelet count to normalize even after there has been a general improvement of other markers of multi-organ dysfunction in scrub typhus should prompt the clinician to consider other potential causes of thrombocytopenia. An unusual finding as this calls for further research to understand the molecular mechanisms behind such an event. Further, considering the close similarity in clinical presentation of several tropical illnesses, meticulous history taking and a detailed physical examination needs to be emphasized.

Characteristics of the sequence effect in Parkinson's disease.

PubMed

Kang, Suk Yun; Wasaka, Toshiaki; Shamim, Ejaz A; Auh, Sungyoung; Ueki, Yoshino; Lopez, Grisel J; Kida, Tetsuo; Jin, Seung-Hyun; Dang, Nguyet; Hallett, Mark

2010-10-15

The sequence effect (SE) in Parkinson's disease (PD) is progressive slowing of sequential movements. It is a feature of bradykinesia, but is separate from a general slowness without deterioration over time. It is commonly seen in PD, but its physiology is unclear. We measured general slowness and the SE separately with a computer-based, modified Purdue pegboard in 11 patients with advanced PD. We conducted a placebo-controlled, four-way crossover study to learn whether levodopa and repetitive transcranial magnetic stimulation (rTMS) could improve general slowness or the SE. We also examined the correlation between the SE and clinical fatigue. Levodopa alone and rTMS alone improved general slowness, but rTMS showed no additive effect on levodopa. Levodopa alone, rTMS alone, and their combination did not alleviate the SE. There was no correlation between the SE and fatigue. This study suggests that dopaminergic dysfunction and abnormal motor cortex excitability are not the relevant mechanisms for the SE. Additionally, the SE is not a component of clinical fatigue. Further work is needed to establish the physiology and clinical relevance of the SE. © 2010 Movement Disorder Society.

Comparison of treatments with the Forsus fatigue resistant device in relation to skeletal maturity: a cephalometric and magnetic resonance imaging study.

PubMed

Aras, Aynur; Ada, Emel; Saracoğlu, Hatice; Gezer, Naciye S; Aras, Isil

2011-11-01

The aim of this study was to compare the dentoskeletal changes and alterations of mandibular condyle-disc-fossa relationships in subjects at the peak and the end of the pubertal growth period treated with the Forsus fatigue resistant device (3M Unitek, Monrovia, Calif). The sample consisted of 29 subjects with Class II Division 1 malocclusions who were classified according to their hand-wrist radiographs. Fifteen patients were at or just before the peak phase of pubertal growth (peak pubertal group). Fourteen patients were near the end of the pubertal growth period (late pubertal group). The study was conducted by using lateral cephalometric radiographs and magnetic resonance images obtained at the beginning and at the end of the application of the Forsus fatigue resistant device. The treatment period was 9 months. The Wilcoxon signed rank test was used to evaluate differences within groups. The changes observed in both groups were compared by using the Mann-Whitney U test. There were statistically significant group differences in mandibular length and ramus length, with significant increases of these parameters in the peak pubertal group (P <0.05). No significant differences were observed between the groups concerning dental parameters (P >0.05), with the exception of mandibular molar vertical movements, which were significantly greater in the peak pubertal group (P <0.05). Analysis of the magnetic resonance images showed no positional changes of the mandibular condyle in relation to the glenoid fossa in either group (P >0.05). Although the articular disc was positioned more anteriorly in the peak pubertal group compared with its pretreatment position (P <0.05), the position of the disc was still within the physiologic range. No significant intergroup difference was observed for disc-condyle relationship (P >0.05). The Forsus fatigue resistant device did not appear to cause significant increases in mandibular dimensions in subjects in late puberty. According to the magnetic resonance image findings, Forsus treatment is not a risk factor for the development of temporomandibular dysfunction in subjects with no signs and clinical symptoms of dysfunction. Copyright © 2011 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

A Formal Analysis of Cytokine Networks in Chronic Fatigue Syndrome

PubMed Central

Broderick, Gordon; Fuite, Jim; Kreitz, Andrea; Vernon, Suzanne D; Klimas, Nancy; Fletcher, Mary Ann

2010-01-01

Chronic Fatigue Syndrome (CFS) is a complex illness affecting 4 million Americans for which no characteristic lesion has been identified. Instead of searching for a deficiency in any single marker, we propose that CFS is associated with a profound imbalance in the regulation of immune function forcing a departure from standard preprogrammed responses. To identify these imbalances we apply network analysis to the co-expression of 16 cytokines in CFS subjects and healthy controls. Concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12, 13, 15, 17 and 23, IFN-γ, lymphotoxin-α (LT-α) and TNF-α were measured in the plasma of 40 female CFS and 59 case-matched controls. Cytokine co-expression networks were constructed from the pair-wise mutual information (MI) patterns found within each subject group. These networks differed in topology significantly more than expected by chance with the CFS network being more hub-like in design. Analysis of local modularity isolated statistically distinct cytokine communities recognizable as pre-programmed immune functional components. These showed highly attenuated Th1 and Th17 immune responses in CFS. High Th2 marker expression but weak interaction patterns pointed to an established Th2 inflammatory milieu. Similarly, altered associations in CFS provided indirect evidence of diminished NK cell responsiveness to IL-12 and LTα stimulus. These observations are consistent with several processes active in latent viral infection and would not have been uncovered by assessing marker expression alone. Furthermore this analysis identifies key subnetworks such as IL-2:IFNγ:TNFα that might be targeted in restoring normal immune function. PMID:20447453

Regulation of immunity and inflammation by hypoxia in immunological niches.

PubMed

Taylor, Cormac T; Colgan, Sean P

2017-12-01

Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.

The biology of cancer-related fatigue: a review of the literature.

PubMed

Saligan, Leorey N; Olson, Karin; Filler, Kristin; Larkin, David; Cramp, Fiona; Yennurajalingam, Sriram; Sriram, Yennu; Escalante, Carmen P; del Giglio, Auro; Kober, Kord M; Kamath, Jayesh; Palesh, Oxana; Mustian, Karen

2015-08-01

Understanding the etiology of cancer-related fatigue (CRF) is critical to identify targets to develop therapies to reduce CRF burden. The goal of this systematic review was to expand on the initial work by the National Cancer Institute CRF Working Group to understand the state of the science related to the biology of CRF and, specifically, to evaluate studies that examined the relationships between biomarkers and CRF and to develop an etiologic model of CRF to guide researchers on pathways to explore or therapeutic targets to investigate. This review was completed by the Multinational Association of Supportive Care in Cancer Fatigue Study Group-Biomarker Working Group. The initial search used three terms (biomarkers, fatigue, cancer), which yielded 11,129 articles. After removing duplicates, 9145 articles remained. Titles were assessed for the keywords "cancer" and "fatigue" resulting in 3811 articles. Articles published before 2010 and those with samples <50 were excluded, leaving 75 articles for full-text review. Of the 75 articles, 28 were further excluded for not investigating the associations of biomarkers and CRF. Of the 47 articles reviewed, 25 were cross-sectional and 22 were longitudinal studies. More than half (about 70 %) were published recently (2010-2013). Almost half (45 %) enrolled breast cancer participants. The majority of studies assessed fatigue using self-report questionnaires, and only two studies used clinical parameters to measure fatigue. The findings from this review suggest that CRF is linked to immune/inflammatory, metabolic, neuroendocrine, and genetic biomarkers. We also identified gaps in knowledge and made recommendations for future research.

Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr Virus

PubMed Central

Vernon, Suzanne D; Whistler, Toni; Cameron, Barbara; Hickie, Ian B; Reeves, William C; Lloyd, Andrew

2006-01-01

Background Acute infectious diseases are typically accompanied by non-specific symptoms including fever, malaise, irritability and somnolence that usually resolve on recovery. However, in some individuals these symptoms persist in what is commonly termed post-infective fatigue. The objective of this pilot study was to determine the gene expression correlates of post-infective fatigue following acute Epstein Barr virus (EBV) infection. Methods We followed 5 people with acute mononucleosis who developed post-infective fatigue of more than 6 months duration and 5 HLA-matched control subjects who recovered within 3 months. Subjects had peripheral blood mononuclear cell (PBMC) samples collected at varying time points including at diagnosis, then every 2 weeks for 3 months, then every 3 months for a year. Total RNA was extracted from the PBMC samples and hybridized to microarrays spotted with 3,800 oligonucleotides. Results Those who developed post-infective fatigue had gene expression profiles indicative of an altered host response during acute mononucleosis compared to those who recovered uneventfully. Several genes including ISG20 (interferon stimulated gene), DNAJB2 (DnaJ [Hsp40] homolog and CD99), CDK8 (cyclin-dependent kinase 8), E2F2 (E2F transcription factor 2), CDK8 (cyclin-dependent kinase 8), and ACTN2 (actinin, alpha 2), known to be regulated during EBV infection, were differentially expressed in post-infective fatigue cases. Several of the differentially expressed genes affect mitochondrial functions including fatty acid metabolism and the cell cycle. Conclusion These preliminary data provide insights into alterations in gene transcripts associated with the varied clinical outcomes from acute infectious mononucleosis. PMID:16448567

Subgrouping Chronic Fatigue Syndrome Patients by Genetic and Immune Profiling

DTIC Science & Technology

2013-10-01

CONTRACTING ORGANIZATION : Stanford University Stanford, CA 94305-2004 REPORT DATE...Rosemary Fernandez 5e. TASK NUMBER E-Mail: gilberto@stanford.edu 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES...8. PERFORMING ORGANIZATION REPORT NUMBER Stanford University Stanford, CA 94305-2004 9. SPONSORING / MONITORING AGENCY NAME

Subacute chlordane poisoning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garrettson, L.K.; Guzelian, P.S.; Blanke, R.V.

A 30 year old female was exposed to chlordane through careless and excessive domestic use over a 1 to 4 week period. Early symptoms included circumoral numbness, anorexia, nausea, and fatigue. Myoclonic jerks occurred after a delay of one month. Malaise and anorexia became the dominant symptoms leading to referral at six months. Dysfunctional bleeding was attributed to hepatic enzyme induction by the chlordane and increased metabolism of contraceptive medication. Cholestyramine increased the stool elimination of chlordane.

Oral administration of hot water extracts of Chlorella vulgaris increases physical stamina in mice.

PubMed

An, Hyo-Jin; Choi, Hyun-Myung; Park, Hyeung-Suk; Han, Jae-Gab; Lee, Eun-Hee; Park, Young-Sig; Um, Jae-Young; Hong, Seung-Heon; Kim, Hyung-Min

2006-01-01

A unicellular algae, Chlorella vulgaris, was used as a biological response modifier. Although hot water extracts of C. vulgaris (CVE) are thought to augment immune responses, the effect of CVE on fatigue and physical stamina has not been studied. In the present study, we investigated the effect of CVE on forced swimming test and blood biochemical parameters related to fatigue, blood urea nitrogen (BUN), creatine kinase (CK), lactic dehydrogenase (LDH), glucose (Glc), and total protein (TP). CVE (0.05-0.15 g/kg/day) was orally administered to mice. After 7 days, the immobility time was decreased in the 0.1- and 0.15-g/kg CVE-treated groups (179 +/- 8.3 and 175 +/- 2.1 s) in comparison with the control group (223 +/- 5.4 s). In addition, the contents of BUN, CK, and LDH in the blood serum were decreased in the CVE-fed group. However, they had no effect on the elevation of Glc and TP level. The results predict a potential benefit of CVE for enhancing immune function and improving physical stamina. Copyright 2006 S. Karger AG, Basel.

Physiological Aging: Links Among Adipose Tissue Dysfunction, Diabetes, and Frailty.

PubMed

Stout, Michael B; Justice, Jamie N; Nicklas, Barbara J; Kirkland, James L

2017-01-01

Advancing age is associated with progressive declines in physiological function that lead to overt chronic disease, frailty, and eventual mortality. Importantly, age-related physiological changes occur in cellularity, insulin-responsiveness, secretory profiles, and inflammatory status of adipose tissue, leading to adipose tissue dysfunction. Although the mechanisms underlying adipose tissue dysfunction are multifactorial, the consequences result in secretion of proinflammatory cytokines and chemokines, immune cell infiltration, an accumulation of senescent cells, and an increase in senescence-associated secretory phenotype (SASP). These processes synergistically promote chronic sterile inflammation, insulin resistance, and lipid redistribution away from subcutaneous adipose tissue. Without intervention, these effects contribute to age-related systemic metabolic dysfunction, physical limitations, and frailty. Thus adipose tissue dysfunction may be a fundamental contributor to the elevated risk of chronic disease, disability, and adverse health outcomes with advancing age. ©2017 Int. Union Physiol. Sci./Am. Physiol. Soc.

A Framework of Care in Multiple Sclerosis, Part 2

PubMed Central

Aliotta, Philip J.; Bainbridge, Jacquelyn; Bennett, Susan E.; Cutter, Gary; Fenton, Kaylan; Lublin, Fred; Northrop, Dorothy; Rintell, David; Walker, Bryan D.; Weigel, Megan; Zackowski, Kathleen; Jones, David E.

2017-01-01

Abstract The Consortium of Multiple Sclerosis Centers (CMSC) convened a Framework Taskforce composed of a multidisciplinary group of clinicians and researchers to examine and evaluate the current models of care in multiple sclerosis (MS). The methodology of this project included analysis of a needs assessment survey and an extensive literature review. The outcome of this work is a two-part continuing education series of articles. Part 1, published previously, covered the updated disease phenotypes of MS along with recommendations for the use of disease-modifying therapies. Part 2, presented herein, reviews the variety of symptoms and potential complications of MS. Mobility impairment, spasticity, pain, fatigue, bladder/bowel/sexual dysfunction, cognitive dysfunction, and neuropsychiatric issues are examined, and both pharmacologic and nonpharmacologic interventions are described. Because bladder and bowel symptoms substantially affect health-related quality of life, detailed information about elimination dysfunction is provided. In addition, a detailed discussion about mental health and cognitive dysfunction in people with MS is presented. Part 2 concludes with a focus on the role of rehabilitation in MS. The goal of this work is to facilitate the highest levels of independence or interdependence, function, and quality of life for people with MS. PMID:28243186

Autoantibodies and an immune-based rat model of inflammatory bowel disease.

PubMed

Esmaily, Hadi; Sanei, Yara; Abdollahi, Mohammad

2013-11-21

The exact causes of inflammatory bowel disease (IBD) are not yet fully defined. From a vast body of literature, we know that the immune response has long been involved in the pathogenesis of IBD, including both ulcerative colitis and Crohn's disease. A variety of specific alterations can lead to immune activation and inflammation directed to the colon, as revealed by some animal models. Current research has focused on the role of antibodies in downstream events and mechanisms of autoimmunity and inflammation. It is not well known whether the production of antibodies is a serologic consequence of IBD, or if it is a result of barrier dysfunction induced by inflammation. Here, we present a new hypothesis to distinguish the complex links between genetic susceptibility, barrier dysfunction, commensal and pathologic microbial factors and inflammatory response (especially autoantibodies) in the pathogenesis of IBD. To ascertain the hypothesis, we developed a pilot model with the concept of the presence of antibodies against enteric bacterial antigens in IBD. Results confirmed our hypothesis. Our hypothesis suggests the possibility of subcutaneous vaccination of animals with administration of all or specific enteric bacterial antigens.

Maternal-Fetal rejection reactions are unconstrained in preeclamptic women.

PubMed

Nguyen, Tina A; Kahn, Daniel A; Loewendorf, Andrea I

2017-01-01

The risk factors for preeclampsia, extremes of maternal age, changing paternity, concomitant maternal autoimmunity, and/or birth intervals greater than 5 years, suggest an underlying immunopathology. We used peripheral blood and lymphocytes from the UteroPlacental Interface (UPI) of 3rd trimester healthy pregnant women in multicolor flow cytometry-and in vitro suppression assays. The major end-point was the characterization of activation markers, and potential effector functions of different CD4-and CD8 subsets as well as T regulatory cells (Treg). We observed a significant shift of peripheral CD4 -and CD8- T cells from naïve to memory phenotype in preeclamptic women compared to healthy pregnant women consistent with long-standing immune activation. While the proportions of the highly suppressive Cytokine and Activated Treg were increased in preeclampsia, Treg tolerance toward fetal antigens was dysfunctional. Thus, our observations indicate a long-standing inflammatory derangement driving immune activation in preeclampsia; in how far the Treg dysfunction is caused by/causes this immune activation in preeclampsia will be the object of future studies.

Triactome: Neuro–Immune–Adipose Interactions. Implication in Vascular Biology

PubMed Central

Chaldakov, George Nikov; Fiore, Marco; Ghenev, Peter I.; Beltowski, Jerzy; Ranćić, Gorana; Tunçel, Neşe; Aloe, Luigi

2014-01-01

Understanding how the precise interactions of nerves, immune cells, and adipose tissue account for cardiovascular and metabolic biology is a central aim of biomedical research at present. A long standing paradigm holds that the vascular wall is composed of three concentric tissue coats (tunicae): intima, media, and adventitia. However, large- and medium-sized arteries, where usually atherosclerotic lesions develop, are consistently surrounded by periadventitial adipose tissue (PAAT), we recently designated tunica adiposa (in brief, adiposa like intima, media, and adventitia). Today, atherosclerosis is considered an immune-mediated inflammatory disease featured by endothelial dysfunction/intimal thickening, medial atrophy, and adventitial lesions associated with adipose dysfunction, whereas hypertension is characterized by hyperinnervation-associated medial thickening due to smooth muscle cell hypertrophy/hyperplasia. PAAT expansion is associated with increased infiltration of immune cells, both adipocytes and immunocytes secreting pro-inflammatory and anti-inflammatory (metabotrophic) signaling proteins collectively dubbed adipokines. However, the role of vascular nerves and their interactions with immune cells and paracrine adipose tissue is not yet evaluated in such an integrated way. The present review attempts to briefly highlight the findings in basic and translational sciences in this area focusing on neuro–immune–adipose interactions, herein referred to as triactome. Triactome-targeted pharmacology may provide a novel therapeutic approach in cardiovascular disease. PMID:24782857

Immune suppression of human lymphoid tissues and cells in rotating suspension culture and onboard the International Space Station

PubMed Central

Fitzgerald, Wendy; Chen, Silvia; Walz, Carl; Zimmerberg, Joshua; Margolis, Leonid

2013-01-01

The immune responses of human lymphoid tissue explants or cells isolated from this tissue were studied quantitatively under normal gravity and microgravity. Microgravity was either modeled by solid body suspension in a rotating, oxygenated culture vessel or was actually achieved on the International Space Station (ISS). Our experiments demonstrate that tissues or cells challenged by recall antigen or by polyclonal activator in modeled microgravity lose all their ability to produce antibodies and cytokines and to increase their metabolic activity. In contrast, if the cells were challenged before being exposed to modeled microgravity suspension culture, they maintained their responses. Similarly, in microgravity in the ISS, lymphoid cells did not respond to antigenic or polyclonal challenge, whereas cells challenged prior to the space flight maintained their antibody and cytokine responses in space. Thus, immune activation of cells of lymphoid tissue is severely blunted both in modeled and true microgravity. This suggests that suspension culture via solid body rotation is sufficient to induce the changes in cellular physiology seen in true microgravity. This phenomenon may reflect immune dysfunction observed in astronauts during space flights. If so, the ex vivo system described above can be used to understand cellular and molecular mechanisms of this dysfunction. PMID:19609626

Regulatory immune cells in regulation of intestinal inflammatory response to microbiota

PubMed Central

Cong, Y; Liu, Z

2015-01-01

The intestinal lumen harbors nearly 100 trillion commensal bacteria that exert crucial function for health. An elaborate balance between immune responses and tolerance to intestinal microbiota is required to maintain intestinal homeostasis. This process depends on diverse regulatory mechanisms, including both innate and adaptive immunity. Dysregulation of the homeostasis between intestinal immune systems and microbiota has been shown to be associated with the development of inflammatory bowel diseases (IBD) in genetically susceptible populations. In this review, we discuss the recent progress reported in studies of distinct types of regulatory immune cells in the gut, including intestinal intraepithelial lymphocytes, Foxp3+ regulatory T cells, regulatory B cells, alternatively activated macrophages, dendritic cells, and innate lymphoid cells, and how dysfunction of this immune regulatory system contributes to intestinal diseases such as IBD. Moreover, we discuss the manipulation of these regulatory immune cells as a potential therapeutic method for management of intestinal inflammatory disorders. PMID:26080708

Regulatory immune cells in regulation of intestinal inflammatory response to microbiota.

PubMed

Sun, M; He, C; Cong, Y; Liu, Z

2015-09-01

The intestinal lumen harbors nearly 100 trillion commensal bacteria that exert crucial function for health. An elaborate balance between immune responses and tolerance to intestinal microbiota is required to maintain intestinal homeostasis. This process depends on diverse regulatory mechanisms, including both innate and adaptive immunity. Dysregulation of the homeostasis between intestinal immune systems and microbiota has been shown to be associated with the development of inflammatory bowel diseases (IBD) in genetically susceptible populations. In this review, we discuss the recent progress reported in studies of distinct types of regulatory immune cells in the gut, including intestinal intraepithelial lymphocytes, Foxp3(+) regulatory T cells, regulatory B cells, alternatively activated macrophages, dendritic cells, and innate lymphoid cells, and how dysfunction of this immune regulatory system contributes to intestinal diseases such as IBD. Moreover, we discuss the manipulation of these regulatory immune cells as a potential therapeutic method for management of intestinal inflammatory disorders.

Ascending caudal medullary catecholamine pathways drive sickness-induced deficits in exploratory behavior: brain substrates for fatigue?

PubMed Central

Gaykema, Ronald P.A.; Goehler, Lisa E.

2010-01-01

Immune challenges can lead to marked behavioral changes, including fatigue, reduced social interest, anorexia, and somnolence, but the precise neuronal mechanisms that underlie sickness behavior remain elusive. Part of the neurocircuitry influencing behavior associated with illness likely includes viscerosensory nuclei located in the caudal brainstem, based on findings that inactivation of the dorsal vagal complex (DVC) can prevent social withdrawal. These brainstem nuclei contribute multiple neuronal projections that target different components of autonomic and stress-related neurocircuitry. In particular, catecholaminergic neurons in the ventrolateral medulla (VLM) and DVC target the hypothalamus and drive neuroendocrine responses to immune challenge, but their particular role in sickness behavior is not known. To test whether this catecholamine pathway also mediates sickness behavior, we compared effects of DVC inactivation with targeted lesion of the catecholamine pathway on exploratory behavior, which provides an index of motivation and fatigue, and associated patterns of brain activation assessed by immunohistochemical detection of c-Fos protein. LPS treatment dramatically reduced exploratory behavior, and produced a pattern of increased c-Fos expression in brain regions associated with stress and autonomic adjustments paraventricular hypothalamus (PVN), bed nucleus of the stria terminalis (BST), central amygdala (CEA), whereas activation was reduced in regions involved in exploratory behavior (hippocampus, dorsal striatum, ventral tuberomammillary nucleus, and ventral tegmental area). Both DVC inactivation and catecholamine lesion prevented reductions in exploratory behavior and completely blocked the inhibitory LPS effects on c-Fos expression in the behavior-associated regions. In contrast, LPS-induced activation in the CEA and BST was inhibited by DVC inactivation but not by catecholamine lesion. The findings support the idea that parallel pathways from immune-sensory caudal brainstem sources target distinct populations of forebrain neurons that likely mediate different aspects of sickness. The caudal medullary catecholaminergic projections to the hypothalamus may significantly contribute to brain mechanisms that induce behavioral “fatigue” in the context of physiological stressors. PMID:21075199

[Effects of branched amino acids in endurance sports: a review].

PubMed

Salinas-García, María Elia; Martínez-Sanz, José Miguel; Urdampilleta, Aritz; Mielgo-Ayuso, Juan; Norte Navarro, Aurora; Ortiz-Moncada, Rocio

2014-11-16

The report issued by the European Food Safety Agency (EFSA) in 2010 on nutrition and health claims, shows that there is no scientific evidence to support supplementation with branched chain amino acids (BCAAs). The aim of this study is to analyze the effects of consumption of BCAAs in endurance sports. A literature review on the current state of the effect of consumption of dietary supplements of BCAAs. We conducted a search in the PubMed database and snowball strategy. Spanish / English randomized clinical trial related to the consumption of BCAAs, leucine, valine and isoleucine in endurance sports and its effects on muscle damage, athletic performance, central fatigue, anabolic signals during recovery and immune system response published in any country until May 2014. Out of 330 studies identified, 14 met the inclusion criteria. The mean of subjects participating in the study was (11.36±7.43). Only two studies included a group of women. The sports that we found in the studies were: run, cycling, combining cycling and running, Olympic distance triathlon and one study included 2 groups of athletes (Olympic distance triathletes and runners). The effects of BCAAs and muscle damage, athletic performance, central fatigue, anabolic signals during recovery period and immune response were studied at different times: before, during and after training or a combination of these. It is observed that there is a lesser degree of pain and muscle damage, less perceived exertion and mental fatigue, greater anabolic response in recovery period and improved immune response when supplemented with BCAAs, notwithstanding its decision before or during physical activity does not improve athletic performance. No consensus was found in the dose and timing of the most effective decision, although it is more effective if there is 2-3/1/1g relationship between leucine / isoleucine and valine amino acids. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Phagocyte dysfunction, tissue aging and degeneration.

PubMed

Li, Wei

2013-09-01

Immunologically-silent phagocytosis of apoptotic cells is critical to maintaining tissue homeostasis and innate immune balance. Aged phagocytes reduce their functional activity, leading to accumulation of unphagocytosed debris, chronic sterile inflammation and exacerbation of tissue aging and damage. Macrophage dysfunction plays an important role in immunosenescence. Microglial dysfunction has been linked to age-dependent neurodegenerations. Retinal pigment epithelial (RPE) cell dysfunction has been implicated in the pathogenesis of age-related macular degeneration (AMD). Despite several reports on the characterization of aged phagocytes, the role of phagocyte dysfunction in tissue aging and degeneration is yet to be fully appreciated. Lack of knowledge of molecular mechanisms by which aging reduces phagocyte function has hindered our capability to exploit the therapeutic potentials of phagocytosis for prevention or delay of tissue degeneration. This review summarizes our current knowledge of phagocyte dysfunction in aged tissues and discusses possible links to age-related diseases. We highlight the challenges to decipher the molecular mechanisms, present new research approaches and envisage future strategies to prevent phagocyte dysfunction, tissue aging and degeneration. Copyright © 2013 Elsevier B.V. All rights reserved.

Diabetes

MedlinePlus

... pain, tingling, a loss of feeling, problems digesting food, and erectile dysfunction Kidney problems , which can lead to kidney failure Weakened immune system, which can lead to more frequent infections Increased chance of having a heart attack or stroke

Associations of Body Mass Index and Physical Activity With Sexual Dysfunction in Breast Cancer Survivors.

PubMed

Paiva, Carlos Eduardo; Rezende, Fabiana Faria; Paiva, Bianca Sakamoto Ribeiro; Mauad, Edmundo Carvalho; Zucca-Matthes, Gustavo; Carneseca, Estela Cristina; Syrjänen, Kari Juhani; Schover, Leslie R

2016-11-01

Sexual dysfunction is a common and distressing consequence of breast cancer (BC) treatment. In the present study, we investigated the sexual functioning of BC patients and its association with women's personal characteristics and cancer treatments. In this cross-sectional study, sexual function was assessed using the Female Sexual Function Index (FSFI). The health-related quality of life (HRQOL) was measured using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and its breast module BR-23. Of the 235 participants approached, 216 participants were included in the study. Of these, 63 patients reported no sexual activity in the last month and thus were analyzed only in relation to the sexual desire domain of FSFI. A total of 154 (71.3 %) patients were classified with hypoactive sexual desire disorder (HSDD). From those patients reporting sexual activity in the last month, 63.3 % (97 out of 153) were classified with sexual dysfunction. Using hierarchical logistic regression, the variance explained (change in R 2 ) by the addition of body mass index (BMI) and mild to moderate physical activity in the prediction models of sexual dysfunction and HSDD were 6.8 and 7.2 %, respectively. Age, BMI, and physical activity were independently associated with sexual dysfunction and HSDD. Additionally, BC patients with sexual dysfunction reported lower scores on global HRQOL, role functioning, and fatigue. Based on our findings, BC survivors should be encouraged to practice regular physical activity and to lose weight in order to avoid sexual dysfunction. However, future clinical trials are needed to confirm these findings.

[The role of immune system in the control of cancer development and growth].

PubMed

Sütő, Gábor

2016-06-01

The role of immune system is the maintenace of the integritiy of the living organism. The elements of the immune system are connected by several ways forming a complex biological network. This network senses the changes of the inner and outer environment and works out the most effective response against infections and tumors. Dysfunction of the immune system leads to the development of cancer development and chronic inflammatory diseases. Modulation of the checkpoints of the immune system opened new perspecitves in the treatment of rheumatological and oncological diseases as well. Beside the potent antiinflammatory activity, new therapies are able to stimulate anticancer activity of the immune system. The result of these recent developments is a better outcome of malignant diseases, which had an unfavorable outcome in the past. Orv. Hetil., 2016, 157(Suppl. 2), 3-8.

MicroRNA-155 attenuates late sepsis-induced cardiac dysfunction through JNK and β-arrestin 2.

PubMed

Zhou, Yu; Song, Yan; Shaikh, Zahir; Li, Hui; Zhang, Haiju; Caudle, Yi; Zheng, Shouhua; Yan, Hui; Hu, Dan; Stuart, Charles; Yin, Deling

2017-07-18

Cardiac dysfunction is correlated with detrimental prognosis of sepsis and contributes to a high risk of mortality. After an initial hyperinflammatory reaction, most patients enter a protracted state of immunosuppression (late sepsis) that alters both innate and adaptive immunity. The changes of cardiac function in late sepsis are not yet known. MicroRNA-155 (miR-155) is previously found to play important roles in both regulations of immune activation and cardiac function. In this study, C57BL/6 mice were operated to develop into early and late sepsis phases, and miR-155 mimic was injected through the tail vein 48 h after cecal ligation and puncture (CLP). The effect of miR-155 on CLP-induced cardiac dysfunction was explored in late sepsis. We found that increased expression of miR-155 in the myocardium protected against cardiac dysfunction in late sepsis evidenced by attenuating sepsis-reduced cardiac output and enhancing left ventricular systolic function. We also observed that miR-155 markedly reduced the infiltration of macrophages and neutrophils into the myocardium and attenuated the inflammatory response via suppression of JNK signaling pathway. Moreover, overexpression of β-arrestin 2 (Arrb2) exacerbated the mice mortality and immunosuppression in late sepsis. Furthermore, transfection of miR-155 mimic reduced Arrb2 expression, and then restored immunocompetence and improved survival in late septic mice. We conclude that increased miR-155 expression through systemic administration of miR-155 mimic attenuates cardiac dysfunction and improves late sepsis survival by targeting JNK associated inflammatory signaling and Arrb2 mediated immunosuppression.

A preliminary prospective study of nutritional, psychological and combined therapies for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in a private care setting.

PubMed

Arroll, Megan Anne; Howard, Alex

2012-01-01

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a condition characterised by severe and persistent fatigue, neurological disturbances, autonomic and endocrine dysfunctions and sleep difficulties that have a pronounced and significant impact on individuals' lives. Current National Institute for Health and Clinical Excellence guidelines within the UK suggest that this condition should be treated with cognitive behavioural therapy and/or graded exercise therapy, where appropriate. There is currently a lack of an evidence base concerning alternative techniques that may be beneficial to those with ME/CFS. This study aimed to investigate whether three modalities of psychology, nutrition and combined treatment influenced symptom report measures in those with ME/CFS over a 3-month time period and whether there were significant differences in these changes between groups. This is a preliminary prospective study with one follow-up point conducted at a private secondary healthcare facility in London, UK. 138 individuals (110 females, 79.7%; 42 participants in psychology, 44 in nutrition and 52 in combined) participated at baseline and 72 participants completed the battery of measures at follow-up (52.17% response rate; 14, 27 and 31 participants in each group, respectively). Self-reported measures of ME/CFS symptoms, functional ability, multidimensional fatigue and perceived control. Baseline comparisons showed those in the combined group had higher levels of fatigue. At follow-up, all groups saw improvements in fatigue, functional ability and symptomatology; those within the psychology group also experienced a shift in perceived control over time. This study provides early evidence that psychological, nutritional and combined techniques for the treatment of ME/CFS may influence symptomatology, fatigue, function and perceived control. However, these results must be viewed with caution as the allocation to groups was not randomised, there was no control group and the study suffered from high drop-out rates.

Acute hypopituitarism associated with periorbital swelling and cardiac dysfunction in a patient with pituitary tumor apoplexy: a case report.

PubMed

Ohara, Nobumasa; Yoneoka, Yuichiro; Seki, Yasuhiro; Akiyama, Katsuhiko; Arita, Masataka; Ohashi, Kazumasa; Suzuki, Kazuo; Takada, Toshinori

2017-08-24

Pituitary tumor apoplexy is a rare clinical syndrome caused by acute hemorrhage or infarction in a preexisting pituitary adenoma. It typically manifests as an acute episode of headache, visual disturbance, mental status changes, cranial nerve palsy, and endocrine pituitary dysfunction. However, not all patients present with classical symptoms, so it is pertinent to appreciate the clinical spectrum of pituitary tumor apoplexy presentation. We report an unusual case of a patient with pituitary tumor apoplexy who presented with periorbital edema associated with hypopituitarism. An 83-year-old Japanese man developed acute anterior hypopituitarism; he showed anorexia, fatigue, lethargy, severe bilateral periorbital edema, and mild cardiac dysfunction in the absence of headache, visual disturbance, altered mental status, and cranial nerve palsy. Magnetic resonance imaging showed a 2.5-cm pituitary tumor containing a mixed pattern of solid and liquid components indicating pituitary tumor apoplexy due to hemorrhage in a preexisting pituitary adenoma. Replacement therapy with oral hydrocortisone and levothyroxine relieved his symptoms of central adrenal insufficiency, central hypothyroidism, periorbital edema, and cardiac dysfunction. Common causes of periorbital edema include infections, inflammation, trauma, allergy, kidney or cardiac dysfunction, and endocrine disorders such as primary hypothyroidism. In the present case, the patient's acute central hypothyroidism was probably involved in the development of both periorbital edema and cardiac dysfunction. The present case highlights the need for physicians to consider periorbital edema as an unusual predominant manifestation of pituitary tumor apoplexy.

[Immune dysfunction and cognitive deficit in stress and physiological aging (Part I): Pathogenesis and risk factors].

PubMed

Pukhal'skiĭ, A L; Shmarina, G V; Aleshkin, V A

2014-01-01

The concept of stressful cognitive dysfunction, which is under consideration in this review, allows picking out several therapeutic targets. The brain, immune and endocrine systems being the principal adaptive systems in the body permanently share information both in the form of neural impulses and soluble mediators. The CNS differs from other organs due to several peculiarities that affect local immune surveillance. The brain cells secluded from the blood flow by a specialized blood-brain-barrier (BBB) can endogenously express pro- and anti-inflammatory cytokines without the intervention of the immune system. In normal brain the cytokine signaling rather contributes to exclusive brain function (e.g. long-term potentiation, synaptic plasticity, adult neurogenesis) than serves as immune communicator. The stress of different origin increases the serum cytokine levels and disrupts BBB. As a result peripheral cytokines penetrate into the brain where they begin to perform new functions. Mass intrusion of biologically active peptides having a lot of specific targets alters the brain work that we can observe both in humans and in animal experiments. In addition owing to BBB disruption dendritic cells and T cells also penetrate into the brain where they take up a perivascular position. The changes observed in stressed subject may accumulate during repeated episodes of stress forming a picture typical of the aging brain. Moreover long-term stress as well as physiological aging result in hormonal and immunological disturbances including hypothalamic-pituitary-adrenal axis depletion, regulatory T-cell accumulation and dehydroepiandrosterone decrease.

Auto-immune hepatitis following delivery.

PubMed

Saini, Vandana; Gupta, Mamta; Mishra, S K

2013-05-01

Auto-immune hepatitis first presenting in the early postpartum period is rare. Immunosuppressive effects of pregnancy result in delayed manifestation of auto-immune hepatitis, and in established cases, the spontaneous improvements are there. Auto-immune hepatitis should be considered in the differential diagnosis of liver dysfunction first presenting in the early postpartum period. A case of postpartum hepatitis of auto-immune aetiology is being presented here. It is disease of unknown aetiology, characterised by inflammation of liver (as evidenced by raised serum transaminases, presence of interface hepatitis on histological examination), hypergammaglobulinaemia (> 1.5 times normal), presence of auto-antibodies [(antinuclear antibodies (ANA)], smooth muscle antibody (SMA) and antibody to liver-kidney microsome type 1 (LKM1) in the absence of viral markers ie, hepatitis B (HBsAg) and C (AntiHCV) and excellent response to corticosteroid therapy.

Radiation-Induced Hemopoietic and Immune Dysfunction

DTIC Science & Technology

1991-06-01

the dog. Culture conditions were studied and optimized, and marrow cells were transplanted into otherwise lethally irradiated dogs to investigate stem ... cell survival in long- term cultures. Engraftment was observed only with short-term marrow cultures.

Genetics Home Reference: Netherton syndrome

MedlinePlus

... stratum corneum. LEKT1 is also involved in normal hair growth, the development of lymphocytes in the thymus, and ... Loss of LEKT1 function also results in abnormal hair growth and immune dysfunction that leads to allergies, asthma, ...

Relationship between stress and pain in work-related upper extremity disorders: the hidden role of chronic multisymptom illnesses.

PubMed

Clauw, Daniel J; Williams, David A

2002-05-01

Pain and fatigue are commonly associated with work-related upper extremity disorders. Occasionally these symptoms persist beyond a reasonable healing period. One potential explanation for prolonged symptom expression is the concurrent development of a stress-mediated illness or CMI (Chronic Multi-Symptom Illness). In such a scenario, the chronic regional pain and other symptoms that the individual is experiencing would be attributable to the CMI rather than to tissue damage or a biomechanical dysfunction of the upper-extremity. This article critically reviews the case definitions of the new class of CMI disorders and evaluates the existing evidence supporting centrally mediated physiological changes (e.g., sensory hypervigilance, dysautonomia) that manifest as symptoms of pain and fatigue in some individuals experiencing chronic stressors. While explanations for prolonged pain and fatigue have historically focused on mechanisms involving peripheral pathology or psychiatric explanations, ample evidences support the role of altered Central Nervous System function in accounting for symptom manifestation in CMI. A model is presented that unites seemingly disparate findings across numerous investigations and provides a framework for understanding how genetics, triggering events, stressors, and early life events can affect CNS activity. Resultant symptom expression (e.g., pain and fatigue) from central dysregulation would be expected to occur in a subset of individuals in the population, including a subset of individuals with work-related upper extremity disorders. Thus when symptoms such as pain and fatigue persist beyond a reasonable period, consideration of CMI and associated assessment and interventions focused on central mechanisms may be worthwhile.

Physical activity in ovarian cancer survivors: associations with fatigue, sleep, and psychosocial functioning.

PubMed

Stevinson, Clare; Steed, Helen; Faught, Wylam; Tonkin, Katia; Vallance, Jeffrey K; Ladha, Aliya B; Schepansky, Alexandra; Capstick, Valerie; Courneya, Kerry S

2009-01-01

Physical activity has been associated with better health-related outcomes in several cancer survivor groups but very few data exist for women with ovarian cancer. The purpose of this study was to investigate the associations between physical activity and health-related outcomes in ovarian cancer survivors and to examine any dose-response relationship. A cross-sectional postal survey of ovarian cancer survivors on and off treatment identified through the Alberta Cancer Registry was performed. Participants completed self-report measures of physical activity, cancer-related fatigue, peripheral neuropathy, depression, anxiety, and happiness, as well as demographic and medical variables. A total of 359 ovarian cancer survivors participated (51.4% response rate) of whom 31.1% were meeting the public health physical activity guidelines of the Centers for Disease Control and Prevention. Those meeting guidelines reported significantly lower fatigue than those not meeting guidelines (mean difference, 7.1; 95% confidence interval, 5.5-8.8; d = 0.87; P < 0.001). Meeting guidelines was also significantly inversely associated with peripheral neuropathy, depression, anxiety, sleep latency, use of sleep medication, and daytime dysfunction and was positively associated with happiness, sleep quality, and sleep efficiency. There was no evidence of a dose-response relationship beyond meeting or not meeting the guidelines for any variables. Ovarian cancer survivors who were meeting physical activity guidelines reported more favorable outcomes of fatigue, peripheral neuropathy, sleep, and psychosocial functioning.

Divergent hydraulic strategies to cope with freezing in co-occurring temperate tree species with special reference to root and stem pressure generation.

PubMed

Yin, Xiao-Han; Sterck, Frank; Hao, Guang-You

2018-04-23

Some temperate tree species mitigate the negative impacts of frost-induced xylem cavitation by restoring impaired hydraulic function via positive pressures, and may therefore be more resistant to frost fatigue (the phenomenon that post-freezing xylem becomes more susceptible to hydraulic dysfunction) than nonpressure-generating species. We test this hypothesis and investigate underlying anatomical/physiological mechanisms. Using a common garden experiment, we studied key hydraulic traits and detailed xylem anatomical characteristics of 18 sympatric tree species. These species belong to three functional groups, that is, one generating both root and stem pressures (RSP), one generating only root pressure (RP), and one unable to generate such pressures (NP). The three functional groups diverged substantially in hydraulic efficiency, resistance to drought-induced cavitation, and frost fatigue resistance. Most notably, RSP and RP were more resistant to frost fatigue than NP, but this was at the cost of reduced hydraulic conductivity for RSP and reduced resistance to drought-induced cavitation for RP. Our results show that, in environments with strong frost stress: these groups diverge in hydraulic functioning following multiple trade-offs between hydraulic efficiency, resistance to drought and resistance to frost fatigue; and how differences in anatomical characteristics drive such divergence across species. © 2018 The Authors. New Phytologist © 2018 New Phytologist Trust.

Ubiquinol reduces muscle wasting but not fatigue in tumor-bearing mice.

PubMed

Clark, Yvonne Y; Wold, Loren E; Szalacha, Laura A; McCarthy, Donna O

2015-05-01

Fatigue is the most common and distressing symptom reported by cancer patients during and after treatment. Tumor growth increases oxidative stress and cytokine production, which causes skeletal muscle wasting and cardiac dysfunction. The purpose of this study was to determine whether treatment with the antioxidant ubiquinol improves muscle mass, cardiac function, and behavioral measures of fatigue in tumor-bearing mice. Adult female mice were inoculated with colon26 tumor cells. Half the control and tumor-bearing mice were administered ubiquinol (500 mg/kg/day) in their drinking water. Voluntary wheel running (i.e., voluntary running activity [VRA]) and grip strength were measured at Days 0, 8, 14, and 17 of tumor growth. Cardiac function was measured using echocardiography on Day 18 or 19. Biomarkers of inflammation, protein degradation, and oxidative stress were measured in serum and heart and gastrocnemius tissue. VRA and grip strength progressively declined in tumor-bearing mice. Muscle mass and myocardial diastolic function were decreased, and expression of proinflammatory cytokines was increased in serum and muscle and heart tissue on Day 19 of tumor growth. Oxidative stress was present only in the heart, while biomarkers of protein degradation were increased only in the gastrocnemius muscle. Ubiquinol increased muscle mass in the tumor-bearing and control animals but had no effect on the expression of biomarkers of inflammation, protein degradation, or oxidative stress or on behavioral measures of fatigue. © The Author(s) 2014.

Reduced Cardiac Vagal Modulation Impacts on Cognitive Performance in Chronic Fatigue Syndrome

PubMed Central

Beaumont, Alison; Burton, Alexander R.; Lemon, Jim; Bennett, Barbara K.; Lloyd, Andrew; Vollmer-Conna, Uté

2012-01-01

Background Cognitive difficulties and autonomic dysfunction have been reported separately in patients with chronic fatigue syndrome (CFS). A role for heart rate variability (HRV) in cognitive flexibility has been demonstrated in healthy individuals, but this relationship has not as yet been examined in CFS. The objective of this study was to examine the relationship between HRV and cognitive performance in patients with CFS. Methods Participants were 30 patients with CFS and 40 healthy controls; the groups were matched for age, sex, education, body mass index, and hours of moderate exercise/week. Questionnaires were used to obtain relevant medical and demographic information, and assess current symptoms and functional impairment. Electrocardiograms, perceived fatigue/effort and performance data were recorded during cognitive tasks. Between–group differences in autonomic reactivity and associations with cognitive performance were analysed. Results Patients with CFS showed no deficits in performance accuracy, but were significantly slower than healthy controls. CFS was further characterized by low and unresponsive HRV; greater heart rate (HR) reactivity and prolonged HR-recovery after cognitive challenge. Fatigue levels, perceived effort and distress did not affect cognitive performance. HRV was consistently associated with performance indices and significantly predicted variance in cognitive outcomes. Conclusions These findings reveal for the first time an association between reduced cardiac vagal tone and cognitive impairment in CFS and confirm previous reports of diminished vagal activity. PMID:23166694

Soluble TNFα Signaling within the Spinal Cord Contributes to the Development of Autonomic Dysreflexia and Ensuing Vascular and Immune Dysfunction after Spinal Cord Injury.

PubMed

Mironets, Eugene; Osei-Owusu, Patrick; Bracchi-Ricard, Valerie; Fischer, Roman; Owens, Elizabeth A; Ricard, Jerome; Wu, Di; Saltos, Tatiana; Collyer, Eileen; Hou, Shaoping; Bethea, John R; Tom, Veronica J

2018-04-25

Cardiovascular disease and susceptibility to infection are leading causes of morbidity and mortality for individuals with spinal cord injury (SCI). A major contributor to these is autonomic dysreflexia (AD), an amplified reaction of the autonomic nervous system (hallmarked by severe hypertension) in response to sensory stimuli below the injury. Maladaptive plasticity of the spinal sympathetic reflex circuit below the SCI results in AD intensification over time. Mechanisms underlying this maladaptive plasticity are poorly understood, restricting the identification of treatments. Thus, no preventative treatments are currently available. Neuroinflammation has been implicated in other pathologies associated with hyperexcitable neural circuits. Specifically, the soluble form of TNFα (sTNFα) is known to play a role in neuroplasticity. We hypothesize that persistent expression of sTNFα in spinal cord underlies AD exacerbation. To test this, we intrathecally administered XPro1595, a biologic that renders sTNFα nonfunctional, after complete, high-level SCI in female rats. This dramatically attenuated the intensification of colorectal distension-induced and naturally occurring AD events. This improvement is mediated via decreased sprouting of nociceptive primary afferents and activation of the spinal sympathetic reflex circuit. We also examined peripheral vascular function using ex vivo pressurized arterial preparations and immune function via flow cytometric analysis of splenocytes. Diminishing AD via pharmacological inhibition of sTNFα mitigated ensuing vascular hypersensitivity and immune dysfunction. This is the first demonstration that neuroinflammation-induced sTNFα is critical for altering the spinal sympathetic reflex circuit, elucidating a novel mechanism for AD. Importantly, we identify the first potential pharmacological, prophylactic treatment for this life-threatening syndrome. SIGNIFICANCE STATEMENT Autonomic dysreflexia (AD), a disorder that develops after spinal cord injury (SCI) and is hallmarked by sudden, extreme hypertension, contributes to cardiovascular disease and susceptibility to infection, respectively, two leading causes of mortality and morbidity in SCI patients. We demonstrate that neuroinflammation-induced expression of soluble TNFα plays a critical role in AD, elucidating a novel underlying mechanism. We found that intrathecal administration after SCI of a biologic that inhibits soluble TNFα signaling dramatically attenuates AD and significantly reduces AD-associated peripheral vascular and immune dysfunction. We identified mechanisms behind diminished plasticity of neuronal populations within the spinal sympathetic reflex circuit. This study is the first to pinpoint a potential pharmacological, prophylactic strategy to attenuate AD and ensuing cardiovascular and immune dysfunction. Copyright © 2018 the authors 0270-6474/18/384147-17$15.00/0.

Beyond infection - Maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders.

PubMed

Bilbo, Staci D; Block, Carina L; Bolton, Jessica L; Hanamsagar, Richa; Tran, Phuong K

2018-01-01

Immune molecules such as cytokines and chemokines and the cells that produce them within the brain, notably microglia, are critical for normal brain development. This recognition has in recent years led to the working hypothesis that inflammatory events during pregnancy, e.g. in response to infection, may disrupt the normal expression of immune molecules during critical stages of neural development and thereby contribute to the risk for neurodevelopmental disorders such as autism spectrum disorder (ASD). This hypothesis has in large part been shepherded by the work of Dr. Paul Patterson and colleagues, which has elegantly demonstrated that a single viral infection or injection of a viral mimetic to pregnant mice significantly and persistently impacts offspring immune and nervous system function, changes that underlie ASD-like behavioral dysfunction including social and communication deficits. Subsequent studies by many labs - in humans and in non-human animal models - have supported the hypothesis that ongoing disrupted immune molecule expression and/or neuroinflammation contributes to at least a significant subset of ASD. The heterogeneous clinical and biological phenotypes observed in ASD strongly suggest that in genetically susceptible individuals, environmental risk factors combine or synergize to create a tipping or threshold point for dysfunction. Importantly, animal studies showing a link between maternal immune activation (MIA) and ASD-like outcomes in offspring involve different species and diverse environmental factors associated with ASD in humans, beyond infection, including toxin exposures, maternal stress, and maternal obesity, all of which impact inflammatory or immune pathways. The goal of this review is to highlight the broader implications of Dr. Patterson's work for the field of autism, with a focus on the impact that MIA by diverse environmental factors has on fetal brain development, immune system development, and the pathophysiology of ASD. Copyright © 2017 Elsevier Inc. All rights reserved.

A randomised controlled trial testing the feasibility and efficacy of a physical activity behavioural change intervention in managing fatigue with gynaecological cancer survivors.

PubMed

Donnelly, C M; Blaney, J M; Lowe-Strong, A; Rankin, J P; Campbell, A; McCrum-Gardner, E; Gracey, J H

2011-09-01

To determine the feasibility and efficacy of a physical activity behavioural change intervention in managing cancer-related fatigue among gynaecological cancer survivors during and post anti-cancer treatments. A two arm, single blind, randomised controlled trial was conducted within the Northern Ireland regional Cancer Centre. Thirty three sedentary gynaecological cancer survivors (stage I-III; ≤3 years post diagnosis), experiencing cancer-related fatigue (mild-severe) took part. Participants were randomly assigned to a behavioural change, moderate intensity physical activity intervention (n=16) or a Contact Control group (n=17). The primary outcome was fatigue (Multidimensional Fatigue Symptom Inventory-Short Form and Functional Assessment in Chronic Illness Therapy-Fatigue subscale). Secondary outcomes included quality of life, physical functioning, positive and negative affect, depression, body composition, sleep dysfunction and self-reported physical activity. Feasibility was assessed based on the recruitment rate, programme and physical activity adherence and participants' programme evaluation, including optional focus groups (n=16). Twenty five percent of eligible women took part (33/134). Participants were 8.7 (SD=9.1) months post diagnosis, with a mean age of 53 (SD=10.3) years. The majority of the sample had a diagnosis of ovarian (n=12) or endometrial cancer (n=11). Significant differences favouring the intervention group were observed for fatigue at 12 weeks and 6 months follow-up (12 week: mean difference=-11.06; 95% confidence interval (CI)=-21.89 to -0.23; effect size (d)=0.13; p=0.046; 6 month: mean difference=-19.48; 95% CI=-19.67 to -19.15; effect size (d)=0.20; p=0.01). A mean of 10 calls (SD=1.2 calls) were delivered to the Physical Activity Group, and 10 (SD=1.6 calls) to the CC group. The intervention was positively perceived based on exit questionnaire and focus group findings. A physical activity behavioural change intervention for gynaecological cancer survivors is feasible in terms of participants' programme adherence and evaluation, and the intervention demonstrates improvements in fatigue. However, confirmation in the form of a larger fully powered RCT is warranted. Copyright © 2011 Elsevier Inc. All rights reserved.

Depressive disorders: Processes leading to neurogeneration and potential novel treatments.

PubMed

Brown, Gregory M; McIntyre, Roger S; Rosenblat, Joshua; Hardeland, Rüdiger

2018-01-03

Mood disorders are wide spread with estimates that one in seven of the population are affected at some time in their life (Kessler et al., 2012). Many of those affected with severe depressive disorders have cognitive deficits which may progress to frank neurodegeneration. There are several peripheral markers shown by patients who have cognitive deficits that could represent causative factors and could potentially serve as guides to the prevention or even treatment of neurodegeneration. Circadian rhythm misalignment, immune dysfunction and oxidative stress are key pathologic processes implicated in neurodegeneration and cognitive dysfunction in depressive disorders. Novel treatments targeting these pathways may therefore potentially improve patient outcomes whereby the primary mechanism of action is outside of the monoaminergic system. Moreover, targeting immune dysfunction, oxidative stress and circadian rhythm misalignment (rather than primarily the monoaminergic system) may hold promise for truly disease modifying treatments that may prevent neurodegeneration rather than simply alleviating symptoms with no curative intent. Further research is required to more comprehensively understand the contributions of these pathways to the pathophysiology of depressive disorders to allow for disease modifying treatments to be discovered. Copyright © 2017 Elsevier Inc. All rights reserved.

Nerve growth factor and diarrhea-predominant irritable bowel syndrome (IBS-D): a potential therapeutic target?

PubMed

Xu, Xiao-juan; Liu, Liang; Yao, Shu-kun

2016-01-01

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by recurrent abdominal pain or discomfort associated with abnormal bowel habits. Diarrhea-predominant IBS (IBS-D) is a major subtype of IBS, the predominant manifestations of which are abdominal pain and diarrhea. The pathogenesis of IBS-D remained unknown until recently. The effects of psychosocial stress, central hypervigilance, neuroendocrine abnormality, disturbed gastrointestinal motility, mucosal immune activation, intestinal barrier dysfunction, visceral hypersensitivity (VH), altered gut flora, and genetic susceptibility may be involved in its development. Recently, increased attention has been placed on the neural-immune-endocrine network mechanism in IBS-D, especially the role of various neuroendocrine mediators. As a member of the neurotrophin family, nerve growth factor (NGF) has diverse biological effects, and participates in the pathogenesis of many diseases. Basic studies have demonstrated that NGF is associated with inflammatory- and stress-related VH, as well as stress-related intestinal barrier dysfunction. The aim of this study is to summarize recent literature and discuss the role of NGF in the pathophysiology of IBS-D, especially in VH and intestinal barrier dysfunction, as well as its potential as a therapeutic target in IBS-D.

Decreased expression of CD69 in chronic fatigue syndrome in relation to inflammatory markers: evidence for a severe disorder in the early activation of T lymphocytes and natural killer cells.

PubMed

Mihaylova, Ivana; DeRuyter, Marcel; Rummens, Jean-Luc; Bosmans, Eugene; Maes, Michael

2007-08-01

There is some evidence that patients with chronic fatigue syndrome (CFS) suffer from immune abnormalities, such as immune activation and decreased immune cell responsivity upon polyclonal stimili. This study was designed to evaluate lymphocyte activation in CFS by using a CD69 expression assay. CD69 acts as a costimulatory molecule for T- and natural killer (NK) cell activation. We collected whole blood from CFS patients, who met CDC criteria, and healthy volunteers. The blood samples were stimulated with mitogens during 18 h and the levels of activated T and NK cells expressing CD69 were measured on a Coulter Epics flow cytometer using a three color immunofluorescence staining protocol. The expression of the CD69 activation marker on T cells (CD3+, CD3+CD4+, and CD3+CD8+) and on NK cells (CD45+CD56+) was significantly lower in CFS patients than in healthy subjects. These differences were significant to the extent that a significant diagnostic performance was obtained, i.e. the area under the ROC curve was around 89%. No differences either in the number of leukocytes or in the number or percentage of lymphocytes, i.e. CD3, CD4, CD8 and CD19, could be found between CFS patients and the controls. Patients with CFS show defects in T- and NK cell activation. Since induction of CD69 surface expression is dependent on the activation of the protein kinase C (PKC) activation pathway, it is suggested that in CFS there is a disorder in the early activation of the immune system involving PKC.

Longitudinal analysis of immune abnormalities in varying severities of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients.

PubMed

Hardcastle, Sharni Lee; Brenu, Ekua Weba; Johnston, Samantha; Nguyen, Thao; Huth, Teilah; Ramos, Sandra; Staines, Donald; Marshall-Gradisnik, Sonya

2015-09-14

Research has identified immunological abnormalities in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), a heterogeneous illness with an unknown cause and absence of diagnostic test. There have been no CFS/ME studies examining innate and adaptive immune cells longitudinally in patients with varying severities. This is the first study to investigate immune cells over 6 months while also examining CFS/ME patients of varying symptom severity. Participants were grouped into 18 healthy controls, 12 moderate and 12 severe CFS/ME patients and flow cytometry was used to examine cell parameters at 0 and 6 months. Over time, iNKT CD62L expression significantly increased in moderate CFS/ME patients and CD56(bright) NK receptors differed in severe CFS/ME. Naïve CD8(+)T cells, CD8(-)CD4(-) and CD56(-)CD16(-) iNKT phenotypes, γδ2T cells and effector memory subsets were significantly increased in severe CFS/ME patients at 6 months. Severe CFS/ME patients were significantly reduced in CD56(bright)CD16(dim) NKG2D, CD56(dim)CD16(-) KIR2DL2/DL3, CD94(-)CD11a(-) γδ1T cells and CD62L(+)CD11a(-) γδ1T cells at 6 months. Severe CFS/ME patients differed from controls and moderate CFS/ME patients over time and expressed significant alterations in iNKT cell phenotypes, CD8(+)T cell markers, NK cell receptors and γδT cells at 6 months. This highlights the importance of further assessing these potential immune biomarkers longitudinally in both moderate and severe CFS/ME patients.

The Immune System and Developmental Programming of Brain and Behavior

PubMed Central

Bilbo, Staci D.; Schwarz, Jaclyn M.

2012-01-01

The brain, endocrine, and immune systems are inextricably linked. Immune molecules have a powerful impact on neuroendocrine function, including hormone-behavior interactions, during health as well as sickness. Similarly, alterations in hormones, such as during stress, can powerfully impact immune function or reactivity. These functional shifts are evolved, adaptive responses that organize changes in behavior and mobilize immune resources, but can also lead to pathology or exacerbate disease if prolonged or exaggerated. The developing brain in particular is exquisitely sensitive to both endogenous and exogenous signals, and increasing evidence suggests the immune system has a critical role in brain development and associated behavioral outcomes for the life of the individual. Indeed, there are associations between many neuropsychiatric disorders and immune dysfunction, with a distinct etiology in neurodevelopment. The goal of this review is to describe the important role of the immune system during brain development, and to discuss some of the many ways in which immune activation during early brain development can affect the later-life outcomes of neural function, immune function, mood and cognition. PMID:22982535

[Thyroid dysfunction in adults infected by human immunodeficiency virus].

PubMed

Abelleira, Erika; De Cross, Graciela A; Pitoia, Fabián

2014-01-01

Patients infected with human immunodeficiency virus (HIV) have a higher prevalence of thyroid dysfunction when compared with the general population. The most frequently observed manifestations are euthyroid sick syndrome, Graves' disease and subclinical hypothyroidism. The relationship between the use of highly active antiretroviral therapy and the increased prevalence of thyroid dysfunction has been demonstrated in several series of patients. Grave's disease is recognized as a consequence of immune restitution syndrome. Besides, several studies have suggested an association between hypothyroidism and the use of nucleoside reverse transcriptase inhibitors, particularly stavudine and non-nucleoside reverse transcriptase inhibitors such as efavirenz. Further studies could provide additional evidence of the need for routine assessment of thyroid function in HIV-infected patients.

Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

PubMed

Maes, Michael; Kubera, Marta; Uytterhoeven, Marc; Vrydags, Nicolas; Bosmans, Eugene

2011-04-01

There is evidence that myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by activation of immune, inflammatory, oxidative and nitrosative stress (IO&NS) pathways. The present study was carried out in order to examine whether ME/CFS is accompanied by increased levels of plasma peroxides and serum oxidized LDL (oxLDL) antibodies, two biomarkers of oxidative stress. Blood was collected from 56 patients with ME/CFS and 37 normal volunteers. Severity of ME/CFS was measured using the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale. Plasma peroxide concentrations were significantly higher in patients with ME/CFS than in normal controls. There was a trend towards significantly higher serum oxLDL antibodies in ME/CFS than in controls. Both biomarkers contributed significantly in discriminating between patients with ME/CFS and normal controls. Plasma peroxide and serum oxLDL antibody levels were both significantly related to one of the FF symptoms. The results show that ME/CFS is characterized by increased oxidative stress.

Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)

PubMed Central

Mitchell, William M

2016-01-01

ABSTRACT Chronic fatigue syndrome/ Myalgic encephalomyelitis (CFS/ME) is a poorly understood seriously debilitating disorder in which disabling fatigue is an universal symptom in combination with a variety of variable symptoms. The only drug in advanced clinical development is rintatolimod, a mismatched double stranded polymer of RNA (dsRNA). Rintatolimod is a restricted Toll-Like Receptor 3 (TLR3) agonist lacking activation of other primary cellular inducers of innate immunity (e.g.- cytosolic helicases). Rintatolimod also activates interferon induced proteins that require dsRNA for activity (e.g.- 2ʹ-5ʹ adenylate synthetase, protein kinase R). Rintatolimod has achieved statistically significant improvements in primary endpoints in Phase II and Phase III double-blind, randomized, placebo-controlled clinical trials with a generally well tolerated safety profile and supported by open-label trials in the United States and Europe. The chemistry, mechanism of action, clinical trial data, and current regulatory status of rintatolimod for CFS/ME including current evidence for etiology of the syndrome are reviewed. PMID:27045557

Anti-Fatigue Effects of the Unique Polysaccharide Marker of Dendrobium officinale on BALB/c Mice.

PubMed

Wei, Wei; Li, Zhi-Peng; Zhu, Tong; Fung, Hau-Yee; Wong, Tin-Long; Wen, Xin; Ma, Dik-Lung; Leung, Chung-Hang; Han, Quan-Bin

2017-01-18

Dendrobium officinale extract shows potent anti-fatigue effects; however, the active substance responsible for these effects remains undetermined. A glucomannan with a huge molecular size of 730 kDa, called DOP, was identified as the unique authentication marker of this expensive herb. DOP exhibited immunomodulating effects on macrophages and lymphocytes in our previous study. Clinical reports also showed that people with fatigue syndrome have a disturbed immune system. Because DOP is the unique and dominant component of D. officinale , we hypothesize that DOP may also have anti-fatigue activity. The present study aims to evaluate the anti-fatigue activity of DOP on BALB/c mice, with Rhodiola rosea extract as a positive control. DOP and Rhodiola rosea extract were orally administered at doses of 50 mg/kg and 100 mg/kg, respectively, for four weeks, and the anti-fatigue activity of DOP on BALB/c mice was evaluated using the weight-loaded swimming test. The contents of lactic dehydrogenase (LDH), creatine phosphokinase (CK), triglyceride (TG), blood urea nitrogen (BUN), superoxide dismutase (SOD), malondialdehyde (MDA), lactic acid (LD), and glutathione peroxidase (GSH-Px) in serum, glycogen of liver and gastrocnemius muscle were also determined. Their effects on variability of T cells and B cells were determined by using tetrazolium compound (MTS) method. The weight-loaded swimming exercise caused fatigue syndrome, mainly including the decreases of serum SOD/GSH-Px and gastrocnemius glycogen, as well as the increases of LDH, BUN, MDA, CK, TG, and LD in serum. All of these indicators of fatigue were inhibited to a certain extent by both DOP and Rhodiola rosea extract; however, the effects of DOP were much stronger than those of Rhodiola rosea extract. Compared to the positive control, mice dosed with DOP showed increases in endurance, body weight, and food intake. Furthermore, DOP-feeding mice significantly increased the cell variability of T lymphocytes and B lymphocytes, compared with that of mice in control group. This study indicates that the unique and dominant polysaccharide DOP of D. officinale has stronger anti-fatigue activity than Rhodiola rosea extract. As such, DOP has promising potential for pharmaceutical development into health products to reduce fatigue.

HIV-1, Reactive Oxygen Species and Vascular Complications

PubMed Central

Porter, Kristi M.; Sutliff, Roy L.

2012-01-01

Over 1 million people in the United States and 33 million individuals worldwide suffer from HIV/AIDS. Since its discovery, HIV/AIDS has been associated with an increased susceptibility to opportunistic infection due to immune dysfunction. Highly active antiretroviral therapies (HAART) restore immune function and, as a result, people infected with HIV-1 are living longer. This improved survival of HIV-1 patients has revealed a previously unrecognized risk of developing vascular complications, such as atherosclerosis and pulmonary hypertension. The mechanisms underlying these HIV-associated vascular disorders are poorly understood. However, HIV-induced elevations in reactive oxygen species, including superoxide and hydrogen peroxide, may contribute to vascular disease development and progression by altering cell function and redox-sensitive signaling pathways. In this review, we summarize the clinical and experimental evidence demonstrating HIV- and HIV antiretroviral therapy-induced alterations in reactive oxygen species (ROS) and how these effects likely contribute to vascular dysfunction and disease. PMID:22564529

Autism Spectrum Disorders: Is Mesenchymal Stem Cell Personalized Therapy the Future?

PubMed Central

Siniscalco, Dario; Sapone, Anna; Cirillo, Alessandra; Giordano, Catia; Maione, Sabatino; Antonucci, Nicola

2012-01-01

Autism and autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders. They are enigmatic conditions that have their origins in the interaction of genes and environmental factors. ASDs are characterized by dysfunctions in social interaction and communication skills, in addition to repetitive and stereotypic verbal and nonverbal behaviours. Immune dysfunction has been confirmed with autistic children. There are no defined mechanisms of pathogenesis or curative therapy presently available. Indeed, ASDs are still untreatable. Available treatments for autism can be divided into behavioural, nutritional, and medical approaches, although no defined standard approach exists. Nowadays, stem cell therapy represents the great promise for the future of molecular medicine. Among the stem cell population, mesenchymal stem cells (MSCs) show probably best potential good results in medical research. Due to the particular immune and neural dysregulation observed in ASDs, mesenchymal stem cell transplantation could offer a unique tool to provide better resolution for this disease. PMID:22496609

Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy

PubMed Central

Hotchkiss, Richard S.; Monneret, Guillaume; Payen, Didier

2014-01-01

Sepsis — severe life-threatening infection with organ dysfunction — initiates a complex interplay of host pro- and anti-inflammatory processes. In a real sense, sepsis can be considered a race to the death between the pathogens and the host immune system. It is the proper balance between the often competing pro- and anti-inflammatory pathways that determines the fate of the individual. Although the field of sepsis research has witnessed the failure of many highly-touted clinical trials, a better understanding of the pathophysiological basis of the disorder and the mechanisms responsible for the associated pro- and anti-inflammatory responses is leading to a novel approach to treat this highly lethal condition. Biomarker-guided immunotherapy administered to patients at the proper immune phase of sepsis represents a potential major advance in the treatment of sepsis and more broadly in the field of infectious disease. PMID:24232462

Modified Mediterranean Diet for Enrichment of Short Chain Fatty Acids: Potential Adjunctive Therapeutic to Target Immune and Metabolic Dysfunction in Schizophrenia?

PubMed Central

Joseph, Jamie; Depp, Colin; Shih, Pei-an B.; Cadenhead, Kristen S.; Schmid-Schönbein, Geert

2017-01-01

Growing interest in gut and digestive processes and their potential link to brain and peripheral based inflammation or biobehavioral phenotypes has led to an increasing number of basic and translational scientific reports focused on the role of gut microbiota within the context of neuropsychiatric disorders. However, the effect of dietary modification on specific gut metabolites, in association with immune, metabolic, and psychopathological functioning in schizophrenia spectrum disorders has not been well characterized. The short chain fatty acids (SCFA) acetate, butyrate, and propionate, major metabolites derived from fermentation of dietary fibers by gut microbes, interact with multiple immune and metabolic pathways. The specific pathways that SCFA are thought to target, are dysregulated in cardiovascular disease, type II diabetes, and systemic inflammation. Most notably, these disorders are consistently linked to an attenuated lifespan in schizophrenia. Although, unhealthy dietary intake patterns and increased prevalence of immune and metabolic dysfunction has been observed in people with schizophrenia; dietary interventions have not been well utilized to target immune or metabolic illness. Prior schizophrenia patient trials primarily focused on the effects of gluten free diets. Findings from these studies indicate that a diet avoiding gluten benefits a limited subset of patients, individuals with celiac disease or non-celiac gluten sensitivity. Therefore, alternative dietary and nutritional modifications such as high-fiber, Mediterranean style, diets that enrich the production of SCFA, while being associated with a minimal likelihood of adverse events, may improve immune and cardiovascular outcomes linked to premature mortality in schizophrenia. With a growing literature demonstrating that SCFA can cross the blood brain barrier and target key inflammatory and metabolic pathways, this article highlights enriching dietary intake for SCFA as a potential adjunctive therapy for people with schizophrenia. PMID:28396623

Pathogenic Correlates of Simian Immunodeficiency Virus-Associated B Cell Dysfunction.

PubMed

Brocca-Cofano, Egidio; Kuhrt, David; Siewe, Basile; Xu, Cuiling; Haret-Richter, George S; Craigo, Jodi; Labranche, Celia; Montefiori, David C; Landay, Alan; Apetrei, Cristian; Pandrea, Ivona

2017-12-01

We compared and contrasted pathogenic (in pig-tailed macaques [PTMs]) and nonpathogenic (in African green monkeys [AGMs]) SIVsab infections to assess the significance of the B cell dysfunction observed in simian (SIV) and human immunodeficiency virus (HIV) infections. We report that the loss of B cells is specifically associated with the pathogenic SIV infection, while in the natural hosts, in which SIV is nonpathogenic, B cells rapidly increase in both lymph nodes (LNs) and intestine. SIV-associated B cell dysfunction associated with the pathogenic SIV infection is characterized by loss of naive B cells, loss of resting memory B cells due to their redistribution to the gut, increases of the activated B cells and circulating tissue-like memory B cells, and expansion of the B regulatory cells (Bregs). While circulating B cells are virtually restored to preinfection levels during the chronic pathogenic SIV infection, restoration is mainly due to an expansion of the "exhausted," virus-specific B cells, i.e., activated memory cells and tissue-like memory B cells. Despite of the B cell dysfunction, SIV-specific antibody (Ab) production was higher in the PTMs than in AGMs, with the caveat that rapid disease progression in PTMs was strongly associated with lack of anti-SIV Ab. Neutralization titers and the avidity and maturation of immune responses did not differ between pathogenic and nonpathogenic infections, with the exception of the conformational epitope recognition, which evolved from low to high conformations in the natural host. The patterns of humoral immune responses in the natural host are therefore more similar to those observed in HIV-infected subjects, suggesting that natural hosts may be more appropriate for modeling the immunization strategies aimed at preventing HIV disease progression. The numerous differences between the pathogenic and nonpathogenic infections with regard to dynamics of the memory B cell subsets point to their role in the pathogenesis of HIV/SIV infections and suggest that monitoring B cells may be a reliable approach for assessing disease progression. IMPORTANCE We report here that the HIV/SIV-associated B cell dysfunction (defined by loss of total and memory B cells, increased B regulatory cell [Breg] counts, and B cell activation and apoptosis) is specifically associated with pathogenic SIV infection and absent during the course of nonpathogenic SIV infection in natural nonhuman primate hosts. Alterations of the B cell population are not correlated with production of neutralizing antibodies, the levels of which are similar in the two species. Rapid progressive infections are associated with a severe impairment in SIV-specific antibody production. While we did not find major differences in avidity and maturation between the pathogenic and nonpathogenic SIV infections, we identified a major difference in conformational epitope recognition, with the nonpathogenic infection being characterized by an evolution from low to high conformations. B cell dysfunction should be considered in designing immunization strategies aimed at preventing HIV disease progression. Copyright © 2017 American Society for Microbiology.

Studies of Cell-Mediated Immunity Against Immune Disorders Using Synthetic Peptides and Rotating Bioreactor System

NASA Technical Reports Server (NTRS)

Sastry, Jagannadha K.

1998-01-01

We conducted a series of experiments using mouse immune-precursor cells, and observed that bioreactor culturing results in the loss of antigen-specific cytotoxic T lymphocyte (CTL) function. The reason for the abrogation of CTL function is microgravity conditions in the bioreactor, but not the antigen per se or its MHC restriction. Similarly, we observed that allostimulation of human PBMC in the bioreactor, but not in the T flask, resulted in the blunting of both allo-CTL function and the NK activity, indicating that the microgravity-associated functional defects are not unique to the mouse system. These results provide further confirmation to the microgravity-associated immune dysfunction, and constitute ground-based confirmatory data for those related to space-travel.

A discrete element model for damage and fracture of geomaterials under fatigue loading

NASA Astrophysics Data System (ADS)

Gao, Xiaofeng; Koval, Georg; Chazallon, Cyrille

2017-06-01

Failure processes in geomaterials (concrete, asphalt concrete, masonry, etc.) under fatigue loading (repeated moving loads, cycles of temperature, etc.) are responsible for most of the dysfunctions in pavements, brick structures, etc. In the beginning of the lifetime of a structure, the material presents only inner defects (micro cracks, voids, etc.). Due to the effect of the cyclic loading, these small defects tend to grow in size and quantity which damage the material, reducing its stiffness. With a relatively high number of cycles, these growing micro cracks become large cracks, which characterizes the fracture behavior. From a theoretical point of view, both mechanisms are treated differently. Fracture is usually described locally, with the propagation of cracks defined by the energy release rate at the crack tip; damage is usually associated to non-local approaches. In the present work, damage and fracture mechanics are combined in a local discrete element approach.

A meta-analysis to determine the effect of pharmacological and non-pharmacological treatments on fibromyalgia symptoms comprising OMERACT-10 response criteria.

PubMed

Papadopoulou, Despoina; Fassoulaki, Argyro; Tsoulas, Christos; Siafaka, Ioanna; Vadalouca, Athina

2016-03-01

Fibromyalgia is characterized by widespread pain, sleep problems, fatigue, functional impairment, psychological distress, and cognitive dysfunction. The objective of this meta-analysis is to synthesize the available data on the effectiveness of pharmacological and non-pharmacological interventions across all domains included in the Outcome Measures in Rheumatology Clinical Trials (OMERACT-10) fibromyalgia response definitions, and to examine response based on these definitions. We searched Cochrane, PubMed, Scopus, and the reference lists of articles for randomized controlled trials of any drug formulation or non-pharmacological intervention used for fibromyalgia treatment. We extracted efficacy data regarding pain, sleep, physical function, fatigue, anxiety, depression, and cognition. The available data were insufficient to draw definite conclusions regarding response. Indirect evidence indicates that it may be expected with the use of serotonin noradrenaline reuptake inhibitors (SNRIs), noradrenaline reuptake inhibitors (NRIs), and multidisciplinary treatment.

IFN-α and CD46 stimulation are associated with active lupus and skew natural T regulatory cell differentiation to type 1 regulatory T (Tr1) cells

PubMed Central

Le Buanec, Hélène; Gougeon, Marie-Lise; Mathian, Alexis; Lebon, Pierre; Dupont, Jean-Michel; Peltre, Gabriel; Hemon, Patrice; Schmid, Michel; Bizzini, Bernard; Künding, Thomas; Burny, Arsène; Bensussan, Armand; Amoura, Zahir; Gallo, Robert C.; Zagury, Daniel

2011-01-01

Immune suppressive activities exerted by regulatory T-cell subsets have several specific functions, including self-tolerance and regulation of adaptive immune reactions, and their dysfunction can lead to autoimmune diseases and contribute to AIDS and cancer. Two functionally distinct regulatory T-cell subsets are currently identified in peripheral tissues: thymus-developed natural T regulatory cells (nTregs) controlling self-tolerance and antiinflammatory IL-10–secreting type 1 regulatory T cells (Tr1) derived from Ag-stimulated T cells, which regulate inflammation-dependent adaptive immunity and minimize immunopathology. We establish herein that cell contact-mediated nTreg regulatory function is inhibited by inflammation, especially in the presence of the complement C3b receptor (CD46). Instead, as with other T-cell subsets, the latter inflammatory conditions of stimulation skew nTreg differentiation to Tr1 cells secreting IL-10, an effect potentiated by IFN-α. The clinical relevance of these findings was verified in a study of 152 lupus patients, in which we showed that lupus nTreg dysfunction is not due to intrinsic defects but is rather induced by C3b stimulation of CD46 and IFN-α and that these immune components of inflammation are directly associated with active lupus. These results provide a rationale for using anti–IFN-α Ab immunotherapy in lupus patients. PMID:22065791

Crosstalk between cancer and the neuro-immune system.

PubMed

Kuol, Nyanbol; Stojanovska, Lily; Apostolopoulos, Vasso; Nurgali, Kulmira

2018-02-15

In the last decade, understanding of cancer initiation and progression has been given much attention with studies mainly focusing on genetic abnormalities. Importantly, cancer cells can influence their microenvironment and bi-directionally communicate with other systems such as the immune system. The nervous system plays a fundamental role in regulating immune responses to a range of disease states including cancer. Its dysfunction influences the progression of cancer. The role of the immune system in tumor progression is of relevance to the nervous system since they can bi-directionally communicate via neurotransmitters and neuropeptides, common receptors, and, cytokines. However, cross-talk between these cells is highly complex in nature, and numerous variations are possible according to the type of cancer involved. The neuro-immune interaction is essential in influencing cancer development and progression. Copyright © 2017 Elsevier B.V. All rights reserved.

Innate Immunity in the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome and Its Implications for Therapy

PubMed Central

Horiguchi, Hiroyuki; Loftus, Tyler J.; Hawkins, Russell B.; Raymond, Steven L.; Stortz, Julie A.; Hollen, McKenzie K.; Weiss, Brett P.; Miller, Elizabeth S.; Bihorac, Azra; Larson, Shawn D.; Mohr, Alicia M.; Brakenridge, Scott C.; Tsujimoto, Hironori; Ueno, Hideki; Moore, Frederick A.; Moldawer, Lyle L.; Efron, Philip A.

2018-01-01

Clinical and technological advances promoting early hemorrhage control and physiologic resuscitation as well as early diagnosis and optimal treatment of sepsis have significantly decreased in-hospital mortality for many critically ill patient populations. However, a substantial proportion of severe trauma and sepsis survivors will develop protracted organ dysfunction termed chronic critical illness (CCI), defined as ≥14 days requiring intensive care unit (ICU) resources with ongoing organ dysfunction. A subset of CCI patients will develop the persistent inflammation, immunosuppression, and catabolism syndrome (PICS), and these individuals are predisposed to a poor quality of life and indolent death. We propose that CCI and PICS after trauma or sepsis are the result of an inappropriate bone marrow response characterized by the generation of dysfunctional myeloid populations at the expense of lympho- and erythropoiesis. This review describes similarities among CCI/PICS phenotypes in sepsis, cancer, and aging and reviews the role of aberrant myelopoiesis in the pathophysiology of CCI and PICS. In addition, we characterize pathogen recognition, the interface between innate and adaptive immune systems, and therapeutic approaches including immune modulators, gut microbiota support, and nutritional and exercise therapy. Finally, we discuss the future of diagnostic and prognostic approaches guided by machine and deep-learning models trained and validated on big data to identify patients for whom these approaches will yield the greatest benefits. A deeper understanding of the pathophysiology of CCI and PICS and continued investigation into novel therapies harbor the potential to improve the current dismal long-term outcomes for critically ill post-injury and post-infection patients. PMID:29670613

Effects of geldanamycin and thalidomide on the Th1/Th2 cytokine balance in mice subjected to operative trauma.

PubMed

Nakano, Takumi; Araki, Keijiro; Nakatani, Hajime; Kobayashi, Michiya; Sugimoto, Takeki; Furuya, Yasuo; Matsuoka, Takanori; Jin, Toufeng; Hanazaki, Kazuhiro

2007-04-01

Persistence of postoperative immune dysfunction is a critical problem because it increases the risk of serious infectious complications. The mechanisms of the immune dysfunction that occur initially after non-thermal operative injury remain to be fully elucidated. Two mouse models of operative trauma (simple laparotomy to represent minor operative injury and ileocecal resection to represent major operative injury) were used to define the characteristics of initial cytokine synthesis. Geldanamycin and thalidomide were independently added intraperitoneally before and after operative injury to examine the effect on postoperative immune dysfunction. Mice were sacrificed at scheduled times (3, 6, 12, and 24 h after operative injury) and TNF-alpha, IL-2, IL-4, and IL-10 were analyzed. Spleen was used for intracellular cytokines and RT-PCR. Sera were used for ELISA. Major operative injury caused an initial upregulation of IL-10 synthesis with delayed synthesis of TNF-alpha and IL-2. Minor operative injury caused an early induction of IL-2 synthesis preceded by an initial induction of IL-4 synthesis. GA caused a specific early upregulation of TNF-alpha mRNA expression and intracellular TNF-alpha synthesis. The GA and THD groups showed early serum IL-2 production with reduction of IL-10 mRNA expression and intracellular IL-10 synthesis in the early post-operative phase. Major and minor operative injury showed different Th1/Th2 cytokine patterns in the initial post-operative period. Geldanamycin and thalidomide improved the Th1/Th2 imbalance independently after major operative injury.

The roles and potential therapeutic implications of CXCL4 and its variant CXCL4L1 in the pathogenesis of chronic liver allograft dysfunction.

PubMed

Li, Jing; Liu, Bin; Yan, Lu-nan; Lau, Wan-yee

2015-02-01

Chronic liver allograft dysfunction is the leading cause of patient morbidity and late allograft loss after liver transplantation. The pathogenesis of chronic liver allograft dysfunction remains unknown. Recent studies have demonstrated that CXCL4 and its variant CXCL4L1 are involved in organ damage induced through inflammatory and immune responses throughout all stages of liver transplantation. CXCL4 and CXCL4L1 are low-molecular-weight proteins that have been implicated in hematopoiesis, angiostasis, organ fibrogenesis, mitogenesis, tumor growth and metastasis. The purpose of this review is to discuss the current status and future developments of research into the roles of CXCL4 and CXCL4L1 in the pathogenesis of chronic liver allograft dysfunction. The potential utilization of CXCL4 and CXCL4L1 as therapeutic targets for chronic liver allograft dysfunction will also be discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

Disrupted Skeletal Muscle Mitochondrial Dynamics, Mitophagy, and Biogenesis during Cancer Cachexia: A Role for Inflammation

PubMed Central

VanderVeen, Brandon N.; Fix, Dennis K.

2017-01-01

Chronic inflammation is a hallmark of cancer cachexia in both patients and preclinical models. Cachexia is prevalent in roughly 80% of cancer patients and accounts for up to 20% of all cancer-related deaths. Proinflammatory cytokines IL-6, TNF-α, and TGF-β have been widely examined for their regulation of cancer cachexia. An established characteristic of cachectic skeletal muscle is a disrupted capacity for oxidative metabolism, which is thought to contribute to cancer patient fatigue, diminished metabolic function, and muscle mass loss. This review's primary objective is to highlight emerging evidence linking cancer-induced inflammation to the dysfunctional regulation of mitochondrial dynamics, mitophagy, and biogenesis in cachectic muscle. The potential for either muscle inactivity or exercise to alter mitochondrial dysfunction during cancer cachexia will also be discussed. PMID:28785374

Modafinil treatment for fatigue in HIV/AIDS: a randomized placebo-controlled study.

PubMed

Rabkin, Judith G; McElhiney, Martin C; Rabkin, Richard; McGrath, Patrick J

2010-06-01

To evaluate the efficacy and safety of modafinil in the treatment of fatigue in patients with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) and to assess effect on depressive symptoms. Patients who were HIV+ and had clinically significant fatigue (according to the Fatigue Severity Scale [FSS]) were included in a 4-week randomized, placebo-controlled, double-blind trial. This was followed by an additional 8 weeks of open-label treatment for modafinil responders and 12 weeks for placebo nonresponders. The primary outcome measure for fatigue and depression was the Clinical Global Impressions-Improvement scale, supplemented by the FSS, Hamilton Depression Rating Scale, and Beck Depression Inventory. Safety was assessed with assays of CD4 cell count and HIV ribonucleic acid (RNA) viral load. Visits were weekly for 4 weeks, then biweekly, with a follow-up visit at 6 months. Maximum trial dose of modafinil was 200 mg/d. Data for this study were collected between December 2004 and December 2008. 115 patients were randomly assigned. In intention-to-treat analyses, fatigue response rate to modafinil was 73% and to placebo, 28%. Attrition was 9%. Modafinil did not have an effect on mood alone in the absence of improved energy. At week 4, CD4 cell counts did not change significantly; HIV RNA viral load showed a trend decline for patients taking modafinil but not for those taking placebo. At 6 months, those still taking modafinil had more energy and fewer depressive symptoms than patients who were not taking modafinil, and only those still taking modafinil showed a significant decline from baseline in their HIV RNA viral load. Modafinil appears to be effective and well tolerated in treating fatigue in HIV+ patients. Consideration of its use is warranted considering the high prevalence of fatigue in the HIV community, its minimal side effects, and overall patient acceptance. clinicaltrials.gov Identifier: NCT00118378. 2010 Physicians Postgraduate Press, Inc.

An Unusual Presentation of Addison's Disease-A Case Report.

PubMed

Choudhary, Sandeep; Alam, Anwer; Dewan, Vivek; Yadav, Dinesh; Dubey, N K

2011-07-01

Addison's disease is most commonly due to autoimmune adrenalitis and tuberculosis and refers to primary hypoadrenalism caused by a total or near total destruction or dysfunction of both adrenal cortices. Usual manifestations involve chronic fatigue, muscle weakness, loss of appetite, nausea, vomiting, diarrhea, hypotension and hyperpigmentation of skin. We herein report a case of primary adrenal insufficiency presenting with fever and seizures in an 11-yr-old boy. His symptoms resolved after starting specific therapy. This kind of presentation of Addison's disease is rather unusual.

Hypothesis: the chaos and complexity theory may help our understanding of fibromyalgia and similar maladies.

PubMed

Martinez-Lavin, Manuel; Infante, Oscar; Lerma, Claudia

2008-02-01

Modern clinicians are often frustrated by their inability to understand fibromyalgia and similar maladies since these illnesses cannot be explained by the prevailing linear-reductionist medical paradigm. This article proposes that new concepts derived from the Complexity Theory may help understand the pathogenesis of fibromyalgia, chronic fatigue syndrome, and Gulf War syndrome. This hypothesis is based on the recent recognition of chaos fractals and complex systems in human physiology. These nonlinear dynamics concepts offer a different perspective to the notion of homeostasis and disease. They propose that the essence of disease is dysfunction and not structural damage. Studies using novel nonlinear instruments have shown that fibromyalgia and similar maladies may be caused by the degraded performance of our main complex adaptive system. This dysfunction explains the multifaceted manifestations of these entities. To understand and alleviate the suffering associated with these complex illnesses, a paradigm shift from reductionism to holism based on the Complexity Theory is suggested. This shift perceives health as resilient adaptation and some chronic illnesses as rigid dysfunction.

Oxidative Stress and COPD: The Impact of Oral Antioxidants on Skeletal Muscle Fatigue

PubMed Central

Rossman, Matthew J.; Groot, H. Jonathan; Van Reese; Zhao, Jia; Amann, Markus; Richardson, Russell S.

2014-01-01

PURPOSE Oxidative stress may contribute to exercise intolerance in patients with chronic obstructive pulmonary disease (COPD). This study sought to determine the effect of an acute oral antioxidant cocktail (AOC: vitamins C, E, and alpha-lipoic acid) on skeletal muscle function during dynamic quadriceps exercise in COPD. METHODS Ten patients with COPD performed knee extensor exercise to exhaustion and isotime trials following either the AOC or placebo (PL). Pre- to post-exercise changes in quadriceps maximal voluntary contractions (MVCs) and potentiated twitch forces (Qtw,pot) quantified quadriceps fatigue. RESULTS Under PL conditions, the plasma electron paramagnetic resonance (EPR) spectroscopy signal was inversely correlated with the forced expiratory volume in one second to forced vital capacity ratio (FEV1/FVC), an index of lung dysfunction (r=−0.61, p=0.02), and MVC force (r=−0.56, p=0.04). AOC consumption increased plasma ascorbate levels (10.1±2.2 to 24.1±3.8 ug/ml, p<0.05) and attenuated the area under the curve of the EPR spectroscopy free radical signal (11.6±3.7 to 4.8±2.2 AU, p<0.05), but did not alter endurance time or quadriceps fatigue. The ability of the AOC to decrease the EPR spectroscopy signal, however, was prominent in those with high basal free radicals (n=5, PL: 19.7±5.8 to AOC: 5.8±4.5 AU, p<0.05) with minimal effects in those with low levels (n=5, PL: 1.6±0.5 to AOC: 3.4±1.1 AU). DISCUSSION These data document a relationship between directly measured free radicals and lung dysfunction, and the ability of the AOC to decrease oxidative stress in COPD. Acute amelioration of free radicals, however, does not appear to impact dynamic quadriceps exercise performance. PMID:23299763

Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

PubMed Central

Díez-Noguera, Antoni

2018-01-01

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients frequently show autonomic symptoms which may be associated with a hypothalamic dysfunction. This study aimed to explore circadian rhythm patterns in rest and activity and distal skin temperature (DST) and their association with self-reported outcome measures, in CFS/ME patients and healthy controls at two different times of year. Ten women who met both the 1994 CDC/Fukuda definition and 2003 Canadian criteria for CFS/ME were included in the study, along with ten healthy controls matched for age, sex and body mass index. Self-reported measures were used to assess fatigue, sleep quality, anxiety and depression, autonomic function and health-related quality of life. The ActTrust actigraph was used to record activity, DST and light intensity, with data intervals of one minute over seven consecutive days. Sleep variables were obtained through actigraphic analysis and from subjective sleep diary. The circadian variables and the spectral analysis of the rhythms were calculated. Linear regression analysis was used to evaluate the relationship between the rhythmic variables and clinical features. Recordings were taken in the same subjects in winter and summer. Results showed no differences in rhythm stability, sleep latency or number of awakenings between groups as measured with the actigraph. However, daily activity, the relative amplitude and the stability of the activity rhythm were lower in CFS/ME patients than in controls. DST was sensitive to environmental temperature and showed lower nocturnal values in CFS/ME patients than controls only in winter. A spectral analysis showed no differences in phase or amplitude of the 24h rhythm, but the power of the second harmonic (12h), revealed differences between groups (controls showed a post-lunch dip in activity and peak in DST, while CFS/ME patients did not) and correlated with clinical features. These findings suggest that circadian regulation and skin vasodilator responses may play a role in CFS/ME. PMID:29874259

Comparison of the Efficacy and Safety of Aripiprazole Versus Bupropion Augmentation in Patients With Major Depressive Disorder Unresponsive to Selective Serotonin Reuptake Inhibitors: A Randomized, Prospective, Open-Label Study.

PubMed

Cheon, Eun-Jin; Lee, Kwang-Hun; Park, Young-Woo; Lee, Jong-Hun; Koo, Bon-Hoon; Lee, Seung-Jae; Sung, Hyung-Mo

2017-04-01

The purpose of this study was to compare the efficacy and safety of aripiprazole versus bupropion augmentation in patients with major depressive disorder (MDD) unresponsive to selective serotonin reuptake inhibitors (SSRIs). This is the first randomized, prospective, open-label, direct comparison study between aripiprazole and bupropion augmentation. Participants had at least moderately severe depressive symptoms after 4 weeks or more of SSRI treatment. A total of 103 patients were randomized to either aripiprazole (n = 56) or bupropion (n = 47) augmentation for 6 weeks. Concomitant use of psychotropic agents was prohibited. Montgomery Asberg Depression Rating Scale, 17-item Hamilton Depression Rating scale, Iowa Fatigue Scale, Drug-Induced Extrapyramidal Symptoms Scale, Psychotropic-Related Sexual Dysfunction Questionnaire scores were obtained at baseline and after 1, 2, 4, and 6 weeks of treatment. Overall, both treatments significantly improved depressive symptoms without causing serious adverse events. There were no significant differences in the Montgomery Asberg Depression Rating Scale, 17-item Hamilton Depression Rating scale, and Iowa Fatigue Scale scores, and response rates. However, significant differences in remission rates between the 2 groups were evident at week 6 (55.4% vs 34.0%, respectively; P = 0.031), favoring aripiprazole over bupropion. There were no significant differences in adverse sexual events, extrapyramidal symptoms, or akathisia between the 2 groups. The present study suggests that aripiprazole augmentation is at least comparable to bupropion augmentation in combination with SSRI in terms of efficacy and tolerability in patients with MDD. Both aripiprazole and bupropion could help reduce sexual dysfunction and fatigue in patients with MDD. Aripiprazole and bupropion may offer effective and safe augmentation strategies in patients with MDD who are unresponsive to SSRIs. Double-blinded trials are warranted to confirm the present findings.

miR-29b and miR-198 overexpression in CD8+ T cells of renal cell carcinoma patients down-modulates JAK3 and MCL-1 leading to immune dysfunction.

PubMed

Gigante, Margherita; Pontrelli, Paola; Herr, Wolfgang; Gigante, Maddalena; D'Avenia, Morena; Zaza, Gianluigi; Cavalcanti, Elisabetta; Accetturo, Matteo; Lucarelli, Giuseppe; Carrieri, Giuseppe; Battaglia, Michele; Storkus, Walter J; Gesualdo, Loreto; Ranieri, Elena

2016-04-11

Mammalian microRNAs (miR) regulate the expression of genes relevant for the development of adaptive and innate immunity against cancer. Since T cell dysfunction has previously been reported in patients with renal cell carcinoma (RCC; clear cell type), we aimed to analyze these immune cells for genetic and protein differences when compared to normal donor T cells freshly after isolation and 35 days after in vitro stimulation (IVS) with HLA-matched RCC tumor cells. We investigated gene expression profiles of tumor-reactive CD8(+) T cells obtained from RCC patient and compared with their HLA-matched healthy sibling donors using a microarray approach. In addition, miRNAs analysis was performed in a validation cohort of peripheral blood CD8(+) T cells from 25 RCC patients compared to 15 healthy volunteers. We observed that CD8(+) T cells from RCC patients expressed reduced levels of anti-apoptotic and proliferation-associated gene products when compared with normal donor T cells both pre- and post-IVS. In particular, JAK3 and MCL-1 were down-regulated in patient CD8(+) T cells versus their normal counterparts, likely due to defective suppressor activity of miR-29b and miR-198 in RCC CD8(+) T cells. Indeed, specific inhibition of miR-29b or miR-198 in peripheral blood mononuclear cells (PBMCs) isolated from RCC patients, resulted in the up-regulation of JAK3 and MCL-1 proteins and significant improvement of cell survival in vitro. Our results suggest that miR-29b and miR-198 dysregulation in RCC patient CD8(+) T cells is associated with dysfunctional immunity and foreshadow the development of miR-targeted therapeutics to correct such T cell defects in vivo.

CD8+T cells expressing both PD-1 and TIGIT but not CD226 are dysfunctional in acute myeloid leukemia (AML) patients.

PubMed

Wang, Mengjie; Bu, Jin; Zhou, Maohua; Sido, Jessica; Lin, Yu; Liu, Guanfang; Lin, Qiwen; Xu, Xiuzhang; Leavenworth, Jianmei W; Shen, Erxia

2018-05-01

Acute myeloid leukemia (AML) is one of the most common types of leukemia among adults with an overall poor prognosis and very limited treatment management. Immune checkpoint blockade of PD-1 alone or combined with other immune checkpoint blockade has gained impressive results in murine AML models by improving anti-leukemia CD8 + T cell function, which has greatly promoted the strategy to utilize combined immune checkpoint inhibitors to treat AML patients. However, the expression profiles of these immune checkpoint receptors, such as co-inhibitory receptors PD-1 and TIGIT and co-stimulatory receptor CD226, in T cells from AML patients have not been clearly defined. Here we have defined subsets of CD8 + and CD4 + T cells in the peripheral blood (PB) from newly diagnosed AML patients and healthy controls (HCs). We have observed increased frequencies of PD-1- and TIGIT- expressing CD8 + T cells but decreased occurrence of CD226-expressing CD8 + T cells in AML patients. Further analysis of these CD8 + T cells revealed a unique CD8 + T cell subset that expressed PD-1 and TIGIT but displayed lower levels of CD226 was associated with failure to achieve remission after induction chemotherapy and FLT3-ITD mutations which predict poor clinical prognosis in AML patients. Importantly, these PD-1 + TIGIT + CD226 - CD8 + T cells are dysfunctional with lower expression of intracellular IFN-γ and TNF-α than their counterparts in HCs. Therefore, our studies revealed that an increased frequency of a unique CD8 + T cell subset, PD-1 + TIGIT + CD226 - CD8 + T cells, is associated with CD8 + T cell dysfunction and poor clinical prognosis of AML patients, which may reveal critical diagnostic or prognostic biomarkers and direct more efficient therapeutic strategies. Copyright © 2017. Published by Elsevier Inc.

Endocrine dysfunction in sepsis: a beneficial or deleterious host response?

PubMed Central

Gheorghiţă, Valeriu; Barbu, Alina Elena; Gheorghiu, Monica Livia; Căruntu, Florin Alexandru

2015-01-01

Sepsis is a systemic, deleterious inflammatory host response triggered by an infective agent leading to severe sepsis, septic shock and multi-organ failure. The host response to infection involves a complex, organized and coherent interaction between immune, autonomic, neuroendocrine and behavioral systems. Recent data have confirmed that disturbances of the autonomic nervous and neuroendocrine systems could contribute to sepsis-induced organ dysfunction. Through this review, we aimed to summarize the current knowledge about the endocrine dysfunction as response to sepsis, specifically addressed to vasopressin, copeptin, cortisol, insulin and leptin. We searched the following readily accessible, clinically relevant databases: PubMed, UpToDate, BioMed Central. The immune system could be regarded as a “diffuse sensory organ” that signals the presence of pathogens to the brain through different pathways, such as the vagus nerve, endothelial activation/dysfunction, cytokines and neurotoxic mediators and the circumventricular organs, especially the neurohypophysis. The hormonal profile changes substantially as a consequence of inflammatory mediators and microorganism products leading to inappropriately low levels of vasopressin, sick euthyroid syndrome, reduced adrenal responsiveness to ACTH, insulin resistance, hyperglycemia as well as hyperleptinemia. In conclusion, clinical diagnosis of this “pan-endocrine illness” is frequently challenging due to the many limiting factors. The most important benefits of endocrine markers in the management of sepsis may be reflected by their potential to be used as biomarkers in different scoring systems to estimate the severity of the disease and the risk of death. PMID:25763364

Subgrouping Chronic Fatigue Syndrome Patients by Genetic and Immune Profiling

DTIC Science & Technology

2014-10-01

system play as well as the differences between CFS cases and Controls. All team members are aware of the goals for this DOD Grant and we look forward...process of being completed. All PCR were done as in Dough Levinson (i.e. A, B, C, DPA, DPB, DRB with old conditions and DQA, DQB with modified dNTPs and

Checkpoint inhibitors and radiation treatment in Hodgkin's lymphoma : New study concepts of the German Hodgkin Study Group.

PubMed

Baues, C; Semrau, R; Gaipl, U S; Bröckelmann, P J; Rosenbrock, J; Engert, A; Marnitz, S

2017-02-01

Patients with classical Hodgkin's lymphoma (cHL) have a good prognosis even in advanced stages. However, combined chemo- and radiotherapy, as the standard of care, is also associated with treatment-related toxicities such as organ damage, secondary neoplasias, infertility, or fatigue and long-term fatigue. Many patients suffer from this burden although their cHL was cured. Therefore, the efficacy of immune checkpoint inhibitors like anti-PD1/PD-L1 antibodies in the treatment of solid cancers and also in HL offers new options. A remarkable and durable response rate with a favorable toxicity profile was observed in heavily pretreated cHL patients. Planning to perform prospective randomized clinical trials in the content of radio-immune treatment in patients with Hodgkin's lymphoma (HL), we transferred the results of preliminary clinical studies and basic research in clinical relevant study concepts. Based on these promising early phase trial data, the German Hodgkin Study Group (GHSG) will investigate innovative treatment regimens in upcoming phase II trials. The therapeutic efficacy and potential synergies of anti-PD1 antibodies in combination with chemo- or radiotherapy will be investigated in various settings of HL.

Gastric motor dysfunctions in Parkinson's disease: Current pre-clinical evidence.

PubMed

Pellegrini, Carolina; Antonioli, Luca; Colucci, Rocchina; Ballabeni, Vigilio; Barocelli, Elisabetta; Bernardini, Nunzia; Blandizzi, Corrado; Fornai, Matteo

2015-12-01

Parkinson's disease (PD) is associated with several non-motor symptoms, such as behavioral changes, urinary dysfunction, sleep disorders, fatigue and, above all, gastrointestinal (GI) dysfunction, including gastric dysmotility, constipation and anorectal dysfunction. Delayed gastric emptying, progressing to gastroparesis, is reported in up to 100% of patients with PD, and it occurs at all stages of the disease with severe consequences to the patient's quality of life. The presence of α-synuclein (α-syn) aggregates in myenteric neurons throughout the digestive tract, as well as morpho-functional alterations of the enteric nervous system (ENS), have been documented in PD. In particular, gastric dysmotility in PD has been associated with an impairment of the brain-gut axis, involving the efferent fibers of the vagal pathway projecting directly to the gastric myenteric plexus. The present review intends to provide an integrated overview of available knowledge on the possible role played by the ENS, considered as a semi-autonomous nervous network, in the pathophysiology of gastric dysmotility in PD. Particular attention has been paid review how translational evidence in humans and studies in pre-clinical models are allowing a better understanding of the functional, neurochemical and molecular alterations likely underlying gastric motor abnormalities occurring in PD. Copyright © 2015 Elsevier Ltd. All rights reserved.

Unravelling thyroid dysfunction in rheumatoid arthritis: History matters.

PubMed

Anoop, Joseph; Geetha, Francis; Jyothi, Idiculla; Rekha, Pradeep; Shobha, Vineeta

2018-03-01

Autoimmune thyroid disease (AITD) frequently coexists with other systemic autoimmune conditions such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Due to the overlapping and nonspecific nature of symptoms, it is difficult to clinically uncover thyroidal illnesses in RA patients. This study was conducted to estimate the prevalence of thyroid dysfunction including the presence of anti-thyroid peroxidase (antiTPO) autoantibodies in patients with RA and to analyze symptomatology of thyroid dysfunction in patients diagnosed with RA. This cross-sectional, prospective study was conducted on 100 patients with RA, attending the Rheumatology Outpatient Department at St John's Medical College and Hospital, Bangalore, India. Twenty-two patients had biochemical evidence of thyroid dysfunction, hypothyroidism being the commonest (15/22 patients). Although fatigue and hair loss were the most common symptoms, only weight gain and cold intolerance were found to be statistically significant (P < 0.05) predictors of hypothyroidism and 32 patients were antiTPO positive. It was observed that equal numbers of patients developed hypothyroidism after diagnosis of RA and vice versa. History taking at the bedside to elicit symptoms, especially weight gain and cold intolerance, is quintessential to ensure timely diagnosis of hypothyroidism. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Dysregulation of metabolic-associated pathways in muscle of breast cancer patients: preclinical evaluation of interleukin-15 targeting fatigue.

PubMed

Bohlen, Joseph; McLaughlin, Sarah L; Hazard-Jenkins, Hannah; Infante, Aniello M; Montgomery, Cortney; Davis, Mary; Pistilli, Emidio E

2018-03-26

Breast cancer patients report a perception of increased muscle fatigue, which can persist following surgery and standardized therapies. In a clinical experiment, we tested the hypothesis that pathways regulating skeletal muscle fatigue are down-regulated in skeletal muscle of breast cancer patients and that different muscle gene expression patterns exist between breast tumour subtypes. In a preclinical study, we tested the hypothesis that mammary tumour growth in mice induces skeletal muscle fatigue and that overexpression of the cytokine interleukin-15 (IL-15) can attenuate mammary tumour-induced muscle fatigue. Early stage non-metastatic female breast cancer patients (n = 14) and female non-cancer patients (n = 6) provided a muscle biopsy of the pectoralis major muscle during mastectomy, lumpectomy, or breast reconstruction surgeries. The breast cancer patients were diagnosed with either luminal (ER + /PR + , n = 6), triple positive (ER + /PR + /Her2/neu + , n = 5), or triple negative (ER - /PR - /Her2/neu - , n = 3) breast tumours and were being treated with curative intent either with neoadjuvant chemotherapy followed by surgery or surgery followed by standard post-operative therapy. Biopsies were used for RNA-sequencing to compare the skeletal muscle gene expression patterns between breast cancer patients and non-cancer patients. The C57BL/6 mouse syngeneic mammary tumour cell line, E0771, was used to induce mammary tumours in immunocompetent mice, and isometric muscle contractile properties and fatigue properties were analysed following 4 weeks of tumour growth. RNA-sequencing and subsequent bioinformatics analyses revealed a dysregulation of canonical pathways involved in oxidative phosphorylation, mitochondrial dysfunction, peroxisome proliferator-activated receptor signalling and activation, and IL-15 signalling and production. In a preclinical mouse model of breast cancer, the rate of muscle fatigue was greater in mice exposed to mammary tumour growth for 4 weeks, and this greater muscle fatigue was attenuated in transgenic mice that overexpressed the cytokine IL-15. Our data identify novel genes and pathways dysregulated in the muscles of breast cancer patients with early stage non-metastatic disease, with particularly aberrant expression among genes that would predispose these patients to greater muscle fatigue. Furthermore, we demonstrate that IL-15 overexpression can attenuate muscle fatigue associated with mammary tumour growth in a preclinical mouse model of breast cancer. Therefore, we propose that skeletal muscle fatigue is an inherent consequence of breast tumour growth, and this greater fatigue can be targeted therapeutically. © 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Staphylococcal toxic shock syndrome: superantigen-mediated enhancement of endotoxin shock and adaptive immune suppression.

PubMed

Kulhankova, Katarina; King, Jessica; Salgado-Pabón, Wilmara

2014-08-01

Infectious diseases caused by Staphylococcus aureus present a significant clinical and public health problem. S. aureus causes some of the most severe hospital-associated and community-acquired illnesses. Specifically, it is the leading cause of infective endocarditis and osteomyelitis, and the second leading cause of sepsis in the USA. While pathogenesis of S. aureus infections is at the center of current research, many questions remain about the mechanisms underlying staphylococcal toxic shock syndrome (TSS) and associated adaptive immune suppression. Both conditions are mediated by staphylococcal superantigens (SAgs)-secreted staphylococcal toxins that are major S. aureus virulence factors. Toxic shock syndrome toxin-1 (TSST-1) is the SAg responsible for almost all menstrual TSS cases in the USA. TSST-1, staphylococcal enterotoxin B and C are also responsible for most cases of non-menstrual TSS. While SAgs mediate all of the hallmark features of TSS, such as fever, rash, hypotension, and multi-organ dysfunction, they are also capable of enhancing the toxic effects of endogenous endotoxin. This interaction appears to be critical in mediating the severity of TSS and related mortality. In addition, interaction between SAgs and the host immune system has been recognized to result in a unique form of adaptive immune suppression, contributing to poor outcomes of S. aureus infections. Utilizing rabbit models of S. aureus infective endocarditis, pneumonia and sepsis, and molecular genetics techniques, we aim to elucidate the mechanisms of SAg and endotoxin synergism in the pathogenesis of TSS, and examine the cellular and molecular mechanisms underlying SAg-mediated immune dysfunction.

Intradermal reactions to purified protein derivative in patients with diabetes mellitus.

PubMed

Nwabudike, L C; Ionescu-Tîrgovişte, C

2005-01-01

Diabetes mellitus is known to adversely affect the immune system. Immune dysfunction is also associated with the etiology of diabetes mellitus. Immune dysfunction is associated with diminished chemotactic, phagocytic and monocyte activity. There is also increased T-cell activity. All these are associated with acute hyperglycemia. We investigated the cellular arm of the immune system of patients with diabetes mellitus using intradermal reactions (IDR) to purified protein derivative (PPD). Both groups high blood glucose [HBG] vs. low blood glucose [LBG]) were homogeneous in terms of size and sex and average age (24. vs. 22.; 21 F vs 25 M; 56.5yrs. vs. 54.5 yrs.). The LBG had a greater average duration of diabetes (13.6 yrs vs. 9.3 yrs), which suggests an increased tendency to complications of diabetes mellitus. The results showed an average blood glucose and IDR (HBG vs. LBG) of 235.8 +/- 46.5 mg/dl vs. 144.3 +/- 26.7 mg/dl and 18.5 +/- 8.5 mm vs. 12.2 +/- 7.0 mm respectively. These results showed that IDR is significantly affected by hyperglycemia. This increased IDR may be a consequence of the synergy between interferon-gamma and tumor necrosis factor alpha which is a significant factor in diabetes. Also, there is an accentuation of this synergy following injection of PPD. It appears to be clear that IDR to PPD may be influenced by the diabetic state, especially acute hyperglycemia. However, it also appears that IDR to PPD may not be an adequate method for assessing cutaneous cell-mediated immunity.

Copolymer-1 enhances cognitive performance in young adult rats

PubMed Central

Meneses, Alfredo; Cruz-Martínez, Yolanda; Anaya-Jiménez, Rosa María; Liy-Salmerón, Gustavo; Carvajal, Horacio Guillermo; Ponce-López, Maria Teresa

2018-01-01

Cognitive impairment is a dysfunction observed as a sequel of various neurodegenerative diseases, as well as a concomitant element in the elderly stages of life. In clinical settings, this malfunction is identified as mild cognitive impairment. Previous studies have suggested that cognitive impairment could be the result of a reduction in the expression of brain-derived neurotrophic factor (BDNF) and/or immune dysfunction. Copolymer-1 (Cop-1) is an FDA-approved synthetic peptide capable of inducing the activation of Th2/3 cells, which are able to release BDNF, as well as to migrate and accumulate in the brain. In this study, we evaluated the effect of Cop-1 immunization on improvement of cognition in adult rats. For this purpose, we performed four experiments. We evaluated the effect of Cop-1 immunization on learning/memory using the Morris water maze for spatial memory and autoshaping for associative memory in 3- or 6-month-old rats. BDNF concentrations at the hippocampus were determined by ELISA. Cop-1 immunization induced a significant improvement of spatial memory and associative memory in 6-month-old rats. Likewise, Cop-1 improved spatial memory and associative memory when animals were immunized at 3 months and evaluated at 6 months old. Additionally, Cop-1 induced a significant increase in BDNF levels at the hippocampus. To our knowledge, the present investigation reports the first instance of Cop-1 treatment enhancing cognitive function in normal young adult rats, suggesting that Cop-1 may be a practical therapeutic strategy potentially useful for age- or disease-related cognitive impairment. PMID:29494605

Recent advances in the field of nutritional immunology.

PubMed

Monk, Jennifer M; Hou, Tim Y; Chapkin, Robert S

2011-11-01

Every 4 years, researchers in the cross-disciplinary field of nutritional immunology convene for a FASEB-sponsored meeting entitled, "Nutritional Immunology: Role in Health and Disease", which was held this summer in Carefree, AZ, USA. The scope of the conference encompassed a diverse list of research topics, including, but not restricted to, obesity and immune dysfunction, nutrient-gene interactions, mucosal immunity and a discussion of future directions for the field. Here, we summarize some of the findings shared at the conference, specifically focusing on obesity, immunological function of dietary components (n-3 polyunsaturated fatty acids and flavanoids), gut immunity and the microbiota, and relevant emerging technologies and databases.

[Channels: a new way to revisit pathology].

PubMed

Fournier, Emmanuel

2014-02-01

Many "essential" diseases that manifest themselves in the form of crises or fits (epilepsies, episodic ataxia, periodic paralyses, myotonia, heart rhythm disorders, etc.) are due to ionic channel dysfunction and are thus referred to as "channelopathies". Some of these disorders are congenital, due to mutations of genes encoding channel subunits, while others result from toxic, immune or hormonal disturbances affecting channelfunction. Channelopathies take on a wide variety of clinical forms, depending on the type of channel (sodium, potassium, calcium, chloride...) and the type of dysfunction (loss or gain of function). Some apparently unrelated diseases affecting distinct organs are due to a similar dysfunction of the same channel, revealing unsuspected relationships between organs and between medical specialties. In addition, a given syndrome can be caused by distinct channel dysfunctions. This provides new opportunities for diferential diagnosis and specific correction of the causal defects, although some treatments find applications across multiple medical specialties.

Impacts of obesity and stress on neuromuscular fatigue development and associated heart rate variability.

PubMed

Mehta, R K

2015-02-01

Obesity and stress are independently associated with decrements in neuromuscular functions. The present study examined the interplay of obesity and stress on neuromuscular fatigue and associated heart rate variability (HRV). Forty-eight non-obese (18.5

Bedtime mobile phone use and sleep in adults.

PubMed

Exelmans, Liese; Van den Bulck, Jan

2016-01-01

The few studies that have investigated the relationship between mobile phone use and sleep have mainly been conducted among children and adolescents. In adults, very little is known about mobile phone usage in bed our after lights out. This cross-sectional study set out to examine the association between bedtime mobile phone use and sleep among adults. A sample of 844 Flemish adults (18-94 years old) participated in a survey about electronic media use and sleep habits. Self-reported sleep quality, daytime fatigue and insomnia were measured using the Pittsburgh Sleep Quality Index (PSQI), the Fatigue Assessment Scale (FAS) and the Bergen Insomnia Scale (BIS), respectively. Data were analyzed using hierarchical and multinomial regression analyses. Half of the respondents owned a smartphone, and six out of ten took their mobile phone with them to the bedroom. Sending/receiving text messages and/or phone calls after lights out significantly predicted respondents' scores on the PSQI, particularly longer sleep latency, worse sleep efficiency, more sleep disturbance and more daytime dysfunction. Bedtime mobile phone use predicted respondents' later self-reported rise time, higher insomnia score and increased fatigue. Age significantly moderated the relationship between bedtime mobile phone use and fatigue, rise time, and sleep duration. An increase in bedtime mobile phone use was associated with more fatigue and later rise times among younger respondents (≤ 41.5 years old and ≤ 40.8 years old respectively); but it was related to an earlier rise time and shorter sleep duration among older respondents (≥ 60.15 years old and ≥ 66.4 years old respectively). Findings suggest that bedtime mobile phone use is negatively related to sleep outcomes in adults, too. It warrants continued scholarly attention as the functionalities of mobile phones evolve rapidly and exponentially. Copyright © 2015 Elsevier Ltd. All rights reserved.

Clinical characteristics of a novel subgroup of chronic fatigue syndrome patients with postural orthostatic tachycardia syndrome.

PubMed

Lewis, I; Pairman, J; Spickett, G; Newton, J L

2013-05-01

A significant proportion of patients with chronic fatigue syndrome (CFS) also have postural orthostatic tachycardia syndrome (POTS). We aimed to characterize these patients and differentiate them from CFS patients without POTS in terms of clinical and autonomic features. A total of 179 patients with CFS (1994 Centers for Disease Control and Prevention criteria) attending one of the largest Department of Health-funded CFS clinical services were included in this study. Outcome measures were as follows: (i) symptom assessment tools including the fatigue impact scale, Chalder fatigue scale, Epworth sleepiness scale (ESS), orthostatic grading scale (OGS) and hospital anxiety and depression scale (HADS-A and -D, respectively), (ii) autonomic function analysis including heart rate variability and (iii) haemodynamic responses including left ventricular ejection time and systolic blood pressure drop upon standing. CFS patients with POTS (13%, n = 24) were younger (29 ± 12 vs. 42 ± 13 years, P < 0.0001), less fatigued (Chalder fatigue scale, 8 ± 4 vs. 10 ± 2, P = 0.002), less depressed (HADS-D, 6 ± 4 vs. 9 ± 4, P = 0.01) and had reduced daytime hypersomnolence (ESS, 7 ± 6 vs. 10 ± 5, P = 0.02), compared with patients without POTS. In addition, they exhibited greater orthostatic intolerance (OGS, 11 ± 5; P < 0.0001) and autonomic dysfunction. A combined clinical assessment tool of ESS ≤9 and OGS ≥9 identifies accurately CFS patients with POTS with 100% positive and negative predictive values. The presence of POTS marks a distinct clinical group of CFS patents, with phenotypic features differentiating them from those without POTS. A combination of validated clinical assessment tools can determine which CFS patients have POTS with a high degree of accuracy, and thus potentially identify those who require further investigation and consideration for therapy to control heart rate. © 2013 The Association for the Publication of the Journal of Internal Medicine.

Inflammatory response and extracorporeal circulation.

PubMed

Kraft, Florian; Schmidt, Christoph; Van Aken, Hugo; Zarbock, Alexander

2015-06-01

Patients undergoing cardiac surgery with extracorporeal circulation (EC) frequently develop a systemic inflammatory response syndrome. Surgical trauma, ischaemia-reperfusion injury, endotoxaemia and blood contact to nonendothelial circuit compounds promote the activation of coagulation pathways, complement factors and a cellular immune response. This review discusses the multiple pathways leading to endothelial cell activation, neutrophil recruitment and production of reactive oxygen species and nitric oxide. All these factors may induce cellular damage and subsequent organ injury. Multiple organ dysfunction after cardiac surgery with EC is associated with an increased morbidity and mortality. In addition to the pathogenesis of organ dysfunction after EC, this review deals with different therapeutic interventions aiming to alleviate the inflammatory response and consequently multiple organ dysfunction after cardiac surgery. Copyright © 2015 Elsevier Ltd. All rights reserved.

Sympathetic Nerve Hyperactivity in the Spleen: Causal for Nonpathogenic-Driven Chronic Immune-Mediated Inflammatory Diseases (IMIDs)?

PubMed

Bellinger, Denise L; Lorton, Dianne

2018-04-13

Immune-Mediated Inflammatory Diseases (IMIDs) is a descriptive term coined for an eclectic group of diseases or conditions that share common inflammatory pathways, and for which there is no definitive etiology. IMIDs affect the elderly most severely, with many older individuals having two or more IMIDs. These diseases include, but are not limited to, type-1 diabetes, obesity, hypertension, chronic pulmonary disease, coronary heart disease, inflammatory bowel disease, and autoimmunity, such as rheumatoid arthritis (RA), Sjőgren's syndrome, systemic lupus erythematosus, psoriasis, psoriatic arthritis, and multiple sclerosis. These diseases are ostensibly unrelated mechanistically, but increase in frequency with age and share chronic systemic inflammation, implicating major roles for the spleen. Chronic systemic and regional inflammation underlies the disease manifestations of IMIDs. Regional inflammation and immune dysfunction promotes targeted end organ tissue damage, whereas systemic inflammation increases morbidity and mortality by affecting multiple organ systems. Chronic inflammation and skewed dysregulated cell-mediated immune responses drive many of these age-related medical disorders. IMIDs are commonly autoimmune-mediated or suspected to be autoimmune diseases. Another shared feature is dysregulation of the autonomic nervous system and hypothalamic pituitary adrenal (HPA) axis. Here, we focus on dysautonomia. In many IMIDs, dysautonomia manifests as an imbalance in activity/reactivity of the sympathetic and parasympathetic divisions of the autonomic nervous system (ANS). These major autonomic pathways are essential for allostasis of the immune system, and regulating inflammatory processes and innate and adaptive immunity. Pathology in ANS is a hallmark and causal feature of all IMIDs. Chronic systemic inflammation comorbid with stress pathway dysregulation implicate neural-immune cross-talk in the etiology and pathophysiology of IMIDs. Using a rodent model of inflammatory arthritis as an IMID model, we report disease-specific maladaptive changes in β₂-adrenergic receptor (AR) signaling from protein kinase A (PKA) to mitogen activated protein kinase (MAPK) pathways in the spleen. Beta₂-AR signal "shutdown" in the spleen and switching from PKA to G-coupled protein receptor kinase (GRK) pathways in lymph node cells drives inflammation and disease advancement. Based on these findings and the existing literature in other IMIDs, we present and discuss relevant literature that support the hypothesis that unresolvable immune stimulation from chronic inflammation leads to a maladaptive disease-inducing and perpetuating sympathetic response in an attempt to maintain allostasis. Since the role of sympathetic dysfunction in IMIDs is best studied in RA and rodent models of RA, this IMID is the primary one used to evaluate data relevant to our hypothesis. Here, we review the relevant literature and discuss sympathetic dysfunction as a significant contributor to the pathophysiology of IMIDs, and then discuss a novel target for treatment. Based on our findings in inflammatory arthritis and our understanding of common inflammatory process that are used by the immune system across all IMIDs, novel strategies to restore SNS homeostasis are expected to provide safe, cost-effective approaches to treat IMIDs, lower comorbidities, and increase longevity.

Fatigue During and After Breast Cancer Therapy-A Prospective Study.

PubMed

Reinertsen, Kristin V; Engebraaten, Olav; Loge, Jon H; Cvancarova, Milada; Naume, Bjørn; Wist, Erik; Edvardsen, Hege; Wille, Elisabeth; Bjøro, Trine; Kiserud, Cecilie E

2017-03-01

Chronic fatigue (CF) in breast cancer (BC) survivors is multifactorial and may be caused by immune activation triggered by BC or its treatment. In the Neoadjuvant Avastin in Breast Cancer study, BC patients received neoadjuvant chemotherapy (FEC100→taxane) ± bevacizumab, a monoclonal antibody with fatigue as a potential side effect. To examine fatigue levels and prevalence of CF before and during chemotherapy and at follow-up, and their associations with C-reactive protein (CRP) and clinical variables. Eighty-four HER2-negative patients with cT2-4N0-3M0 BC responded to questionnaires and had CRP measured before treatment (T0), after FEC100 (T1), after taxanes before surgery (T2), and at two-year follow-up (T3). The prevalence of CF increased from 8% at T0 to 36% at T3, P < 0.0001. Fatigue levels peaked during chemotherapy from 12.0 at T0 to 20.0 at T2, and declined to 16.7 at T3, P < 0.001. Women with CF at T3 had higher fatigue levels at T0, T2, and T3 than those without CF (P ≤ 0.01). Psychological distress (P = 0.03) and pain (P = 0.04) at T3 were associated with CF at T3. Only psychological distress remained a significant predictor in multivariate analysis. CRP increased from T0 to T1 (P < 0.01) and declined to baseline values at T3, but changes were not associated with bevacizumab treatment. No association was found between bevacizumab or CRP, and fatigue levels or CF. Neither bevacizumab treatment nor low-grade systemic inflammation as measured by CRP was associated with the increased fatigue levels and raised prevalence of CF, observed during and after BC therapy. Increased fatigue levels at baseline and psychological distress at T3 were associated with CF at T3. Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Correlates of cognitive dysfunction in multiple sclerosis.

PubMed

Heesen, C; Schulz, K H; Fiehler, J; Von der Mark, U; Otte, C; Jung, R; Poettgen, J; Krieger, T; Gold, S M

2010-10-01

Cognitive impairment is one of the most frequent symptoms in patients with multiple sclerosis (MS) but its underlying mechanisms are poorly understood. A number of pathogenetic correlates have previously been proposed including psychosocial factors (such as depression and fatigue), inflammation, neurodegeneration, and neuroendocrine dysregulation. However, these different systems have never been studied in parallel and their differential contributions to cognitive impairment in MS are unknown. We studied a well-characterized cohort of cognitively impaired (CI, n=25) and cognitively preserved (CP, n=25) MS patients based on a comprehensive neuropsychological testing battery, a test of hypothalamo-pituitary-adrenal axis functioning (dexamethasone-corticotropin-releasing hormone suppression test, Dex-CRH test) as well as peripheral blood and MRI markers of inflammatory activity. CI patients had significantly higher disability. In addition, CI patients showed higher levels of fatigue and depression. Fatigue was more closely associated with measures of attention while depression showed strongest correlations with memory tests. Furthermore, percentage of IFNγ-positive CD4+ and CD8+ T cells showed modest correlations with processing speed and working memory. MRI markers of inflammation or global atrophy were not associated with neuropsychological function. Compared to previous studies, the number of patients exhibiting HPA axis hyperactivity was very low and no correlations were found with neuropsychological function. We conclude that fatigue and depression are the main correlates of cognitive impairment, which show domain-specific associations with measures of attention and memory. Copyright © 2010 Elsevier Inc. All rights reserved.

Multidimensional Fatigue Inventory: Spanish adaptation and psychometric properties for fibromyalgia patients. The Al-Andalus study.

PubMed

Munguía-Izquierdo, Diego; Segura-Jiménez, Victor; Camiletti-Moirón, Daniel; Pulido-Martos, Manuel; Alvarez-Gallardo, Inmaculada C; Romero, Alejandro; Aparicio, Virginia A; Carbonell-Baeza, Ana; Delgado-Fernández, Manuel

2012-01-01

The aim of this study was to assess the psychometric properties and transcultural adaptation into Spanish of the Multidimensional Fatigue Inventory in fibromyalgia patients. The Spanish version of the Multidimensional Fatigue Inventory (MFI-S) was translated and cognitively pretested following cross-cultural adaptation guidelines. Test-retest reliability, convergent validity, and operational qualities were evaluated in a total of 116 fibromyalgia patients. Convergent validity was assessed comparing MFI-S with a visual analogue scale for global fatigue. The intra-class correlation coefficients varied from moderate to excellent (from 0.64 to 0.91) and the standard errors of the mean ranged from 0.5 to 1.1 points for the five MFI-S domains. The coefficient of repeatability was less than 2 standard deviations and the limits of agreement ranged from 2 to 4 points for the MFI-S domains. A weak to fair significant relationship was found between each MFI-S domain and the visual analogue scale (from 0.21 to 0.32). The mean time required to complete the MFI-S was 3.2±2.0 minutes. None of the patients needed external help to complete the MFI-S, and there were very few missing values. The MFI-S developed in this study presents a good reliability and reasonable construct validity for Spanish fibromyalgia patients unaffected by cognitive dysfunction and severe depression. This questionnaire is quick, easy to administer and interpret.

Pilot study to assess toxicity and pharmacokinetics of docetaxel in patients with metastatic breast cancer and impaired liver function secondary to hepatic metastases.

PubMed

Eckmann, Karen; Michaud, Laura B; Rivera, Edgardo; Madden, Timothy L; Esparza-Guerra, Laura; Kawedia, Jitesh; Booser, Daniel J; Green, Marjorie C; Hortobagyi, Gabriel N; Valero, Vicente

2014-04-01

Limited clinical data are available regarding the safety of docetaxel in metastatic breast cancer patients with liver dysfunction. Eligible patients had breast cancer with impaired liver function secondary to hepatic metastases and were candidates for docetaxel therapy. They were assigned to one of five groups on the basis of total bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels. All other causes of liver dysfunction were excluded, and bile duct obstruction was corrected, if possible, prior to study entry. Patients received docetaxel every three weeks. The chemotherapy dose was chosen on the basis of the patient's level of hepatic dysfunction and escalated as tolerated. The primary outcome of this study was safety. The secondary outcomes were pharmacokinetic data and efficacy in terms of time to disease progression. Twenty-three patients were enrolled. No unexpected toxicities occurred. Grade 3/4 fatigue (65%), neutropenia (30%), myalgias (26%), neutropenic fever (26%), vomiting (9%), and rash (9%) were the most common serious adverse events. The median time to progression was three months (range 1-18 months). Pharmacokinetic results indicated that patients with more severe hepatic dysfunction may have been underdosed based on our conservative dosing strategy. Docetaxel can be administered to patients with metastatic breast cancer and liver dysfunction after dose attenuation. However, because of a narrow therapeutic index in this clinical setting, therapy should be closely monitored with subsequent dose escalation when possible.

Novel insights of microRNAs in the development of systemic lupus erythematosus.

PubMed

Le, Xiong; Yu, Xiang; Shen, Nan

2017-09-01

To provide a brief overview of recent progress in microRNA biogenesis and homeostasis, its function in immune system and systemic lupus erythematosus (SLE), as well as successful microRNA-based therapy in vivo. Stepwise microRNA biogenesis is elaborately regulated at multiple levels, ranging from transcription to ultimate function. Mature microRNAs have inhibitory effects on various biological molecules, which are crucial for stabilizing and normalizing differentiation and function of immune cells. Abnormality in microRNA expression contributes to dysfunction of lupus immune cells and resident cells in local tissues. Manipulation of dysregulated microRNAs in vivo through microRNA delivery or targeting microRNA might be promising for SLE treatment. Recent advances highlight that microRNAs are important in immunity, lupus autoimmunity and as potential therapy target for SLE.

Countermeasure for space flight effects on immune system: nutritional nucleotides

NASA Technical Reports Server (NTRS)

Kulkarni, A. D.; Yamauchi, K.; Sundaresan, A.; Ramesh, G. T.; Pellis, N. R.

2005-01-01

Microgravity and its environment have adverse effects on the immune system. Abnormal immune responses observed in microgravity may pose serious consequences, especially for the recent directions of NASA for long-term space missions to Moon, Mars and deep Space exploration. The study of space flight immunology is limited due to relative inaccessibility, difficulty of performing experiments in space, and inadequate provisions in this area in the United States and Russian space programs (Taylor 1993). Microgravity and stress experienced during space flights results in immune system aberration (Taylor 1993). In ground-based mouse models for some of the microgravity effects on the human body, hindlimb unloading (HU) has been reported to cause abnormal cell proliferation and cytokine production (Armstrong et al., 1993, Chapes et al. 1993). In this report, we document that a nutritional nucleotide supplementation as studied in ground-based microgravity analogs, has potential to serve as a countermeasure for the immune dysfunction observed in space travel.

Reduced Expression of SARM in Mouse Spleen during Polymicrobial Sepsis.

PubMed

Gong, Yu; Zou, Lin; Cen, Dongzhi; Chao, Wei; Chen, Dunjin

2016-12-01

Objective Immune dysfunction, including prominent apoptosis of immune cells and decreased functioning of the remaining immune cells, plays a central role in the pathogenesis of sepsis. Sterile α and HEAT/armadillo motif-containing protein (SARM) is implicated in the regulation of immune cell apoptosis. This study aimed to elucidate SARM contributes to sepsis-induced immune cell death and immunosuppression. Methods A mouse model of polymicrobial sepsis was generated by cecum ligation and puncture (CLP). SARM gene and protein expression, caspase 3 cleavage and intracellular ATP production were measured in the mouse spleens. Results CLP-induced polymicrobial sepsis specifically attenuated both the gene and protein expression of SARM in the spleens. Moreover, the attenuation of SARM expression synchronized with splenocyte apoptosis, as evidenced by increased caspase 3 cleavage and ATP depletion. Conclusions These findings suggest that SARM is a potential regulator of sepsis-induced splenocyte apoptosis.

Autonomic components of Complex Regional Pain Syndrome (CRPS) are favourably affected by Electrical Twitch-Obtaining Intramuscular Stimulation (ETOIMS): effects on blood pressure and heart rate.

PubMed

Chu, Jennifer; Bruyninckx, Frans; Neuhauser, Duncan V

2017-07-01

Favourable pain relief results on evoking autonomous twitches at myofascial trigger points with Electrical Twitch Obtaining Intramuscular Stimulation (ETOIMS). To document autonomic nervous system (ANS) dysfunction in Complex Regional Pain Syndrome (CRPS) from blood pressure (BP) and pulse/heart rate changes with ETOIMS. A patient with persistent pain regularly received serial ETOIMS sessions of 60, 90, 120 or ≥150 min over 24 months. Outcome measures include BP: systolic, diastolic, pulse pressure and pulse/heart rate, pre-session/immediate-post-session summed differences (SDPPP index), and pain reduction. His results were compared with that of two other patients and one normal control. Each individual represented the following maximal elicitable twitch forces (TWF) graded 1-5: maximum TWF2: control subject; maximum TWF3: CRPS patient with suspected ANS dysfunction; and maximum TWF4 and TWF5: two patients with respective slow-fatigue and fast-fatigue twitches who during ETOIMS had autonomous twitching at local and remote myotomes simultaneously from denervation supersensitivity. ETOIMS results between TWFs were compared using one-way analysis of variance test. The patients showed immediate significant pain reduction, BP and pulse/heart rate changes/reduction(s) except for diastolic BP in the TWF5 patient. TWF2 control subject had diastolic BP reduction with ETOIMS but not with rest. Linear regression showed TWF grade to be the most significant variable in pain reduction, more so than the number of treatments, session duration and treatment interval. TWF grade was the most important variable in significantly reducing outcome measures, especially pulse/heart rate. Unlike others, the TWF3 patient had distinctive reductions in SDPPP index. Measuring BP and pulse/heart rate is clinically practical for alerting ANS dysfunction maintained CRPS. SDPPP index (≥26) and pulse/heart rate (≥8) reductions with almost every ETOIMS treatment, plus inability to evoke autonomous twitches due to pain-induced muscle hypertonicity, are pathognomonic of this problem.

Fatigue as Presenting Symptom and a High Burden of Premature Ventricular Contractions Are Independently Associated With Increased Ventricular Wall Stress in Patients With Normal Left Ventricular Function.

PubMed

van Huls van Taxis, Carine F B; Piers, Sebastiaan R D; de Riva Silva, Marta; Dekkers, Olaf M; Pijnappels, Daniël A; Schalij, Martin J; Wijnmaalen, Adrianus P; Zeppenfeld, Katja

2015-12-01

High idiopathic premature ventricular contractions (PVC) burden has been associated with PVC-induced cardiomyopathy. Patients may be symptomatic before left ventricular (LV) dysfunction develops. N-terminal pro-B-type natriuretic peptide (NT-proBNP) and circumferential end-systolic wall stress (cESS) on echocardiography are markers for increased ventricular wall stress. This study aimed to evaluate the relation between presenting symptoms, PVC burden, and increased ventricular wall stress in patients with frequent PVCs and preserved LV function. Eighty-three patients (41 men; 49±15 years) with idiopathic PVCs and normal LV function referred for PVC ablation were included. Type of symptoms (palpitations, fatigue, and [near-]syncope), PVC burden on 24-hour Holter, NT-proBNP levels, and cESS on echocardiography were assessed before and 3 months after ablation. Sustained successful ablation was defined as ≥80% PVC burden reduction during follow-up. Patients were symptomatic for 24 months (Q1-Q3, 16-60); 73% reported palpitations, 47% fatigue, and 30% (near-)syncope. Baseline PVC burden was 23±13%, median NT-proBNP 92 pg/mL (Q1-Q3 50-156), and cESS 143±35 kdyne/cm(2). Fatigue was associated with higher baseline NT-proBNP and cESS (P<0.001, P=0.011, respectively). After sustained successful ablation, achieved in 81%, NT-proBNP and cESS decreased significantly (P<0.001 and P=0.036, respectively). Fatigue was independently associated with a significantly larger reduction in NT-proBNP. In patients with nonsuccessful ablation, NT-proBNP and cESS remained unchanged. In patients with frequent PVCs and preserved LV function, fatigue was associated with higher baseline NT-proBNP and cESS, and with a significantly larger reduction in NT-proBNP after sustained successful ablation. These findings support a link between fatigue and PVC-induced increased ventricular wall stress, despite preserved LV function. © 2015 American Heart Association, Inc.

A finite element model on effects of impact load and cavitation on fatigue crack propagation in mechanical bileaflet aortic heart valve.

PubMed

Mohammadi, H; Klassen, R J; Wan, W-K

2008-10-01

Pyrolytic carbon mechanical heart valves (MHVs) are widely used to replace dysfunctional and failed heart valves. As the human heart beats around 40 million times per year, fatigue is the prime mechanism of mechanical failure. In this study, a finite element approach is implemented to develop a model for fatigue analysis of MHVs due to the impact force between the leaflet and the stent and cavitation in the aortic position. A two-step method to predict crack propagation in the leaflets of MHVs has been developed. Stress intensity factors (SIFs) are computed at a small initiated crack located on the leaflet edge (the worst case) using the boundary element method (BEM). Static analysis of the crack is performed to analyse the stress distribution around the front crack zone when the crack is opened; this is followed by a dynamic crack analysis to consider crack propagation using the finite element approach. Two factors are taken into account in the calculation of the SIFs: first, the effect of microjet formation due to cavitation in the vicinity of leaflets, resulting in water hammer pressure; second, the effect of the impact force between the leaflet and the stent of the MHVs, both in the closing phase. The critical initial crack length, the SIFs, the water hammer pressure, and the maximum jet velocity due to cavitation have been calculated. With an initial crack length of 35 microm, the fatigue life of the heart valve is greater than 60 years (i.e. about 2.2 x 10(9) cycles) and, with an initial crack length of 170 microm, the fatigue life of the heart valve would be around 2.5 years (i.e. about 9.1 x 10(7) cycles). For an initial crack length greater than 170 microm, there is catastrophic failure and fatigue cracking no longer occurs. A finite element model of fatigue analysis using Patran command language (PCL custom code) in MSC software can be used to evaluate the useful lifespan of MHVs. Similar methodologies can be extended to other medical devices under cyclic loads.

Potentially Modifiable Factors Associated With Physical Activity in Individuals With Multiple Sclerosis.

PubMed

Reider, Nadia; Salter, Amber R; Cutter, Gary R; Tyry, Tuula; Marrie, Ruth Ann

2017-04-01

Physical activity levels among persons with multiple sclerosis (MS) are worryingly low. We aimed to identify the factors associated with physical activity for people with MS, with an emphasis on factors that have not been studied previously (bladder and hand dysfunction) and are potentially modifiable. This study was a secondary analysis of data collected in the spring of 2012 during the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry. NARCOMS participants were surveyed regarding smoking using questions from the Behavioral Risk Factor Surveillance Survey; disability using the Patient Determined Disease Steps; fatigue, cognition, spasticity, sensory, bladder, vision and hand function using self-reported Performance Scales; health literacy using the Medical Term Recognition Test; and physical activity using questions from the Health Information National Trends Survey. We used a forward binary logistic regression to develop a predictive model in which physical activity was the outcome variable. Of 8,755 respondents, 1,707 (19.5%) were classified as active and 7,068 (80.5%) as inactive. In logistic regression, being a current smoker, moderate or severe level of disability, depression, fatigue, hand, or bladder dysfunction and minimal to mild spasticity were associated with lower odds of meeting physical activity guidelines. MS type was not linked to activity level. Several modifiable clinical and lifestyle factors influenced physical activity in MS. Prospective studies are needed to evaluate whether modification of these factors can increase physical activity participation in persons with MS. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Dynamics of mononuclear phagocyte system Fc receptor function in systemic lupus erythematosus. Relation to disease activity and circulating immune complexes.

PubMed Central

Kimberly, R P; Parris, T M; Inman, R D; McDougal, J S

1983-01-01

Seventeen pairs of longitudinal studies of mononuclear phagocyte system (MPS) Fc receptor function in 15 patients with systemic lupus were performed to explore the dynamic range of Fc receptor dysfunction in lupus and to establish the relationships between MPS function, clinical disease activity and circulating immune complexes (CIC). Fc receptor function was measured by the clearance of IgG sensitized autologous erythrocytes. At the time of first study the degree of MPS dysfunction was correlated with both clinical activity (P less than 0.05) and CIC (P less than 0.05). At follow-up patients with a change in clinical status show significantly larger changes in clearance function compared to clinically stable patients (206 min vs 7 min; P less than 0.001). MPS function changed concordantly with a change in clinical status in all cases (P = 0.002). Longitudinal assessments did not demonstrate concordance of changes in MPS function and CIC, measured by three different assays. The MPS Fc receptor defect in systemic lupus is dynamic and closely associated with disease activity. The lack of concordance of the defect with changes in CIC suggests that either CIC does not adequately reflect receptor site saturation or that other factors may also contribute to the magnitude of MPS dysfunction. PMID:6839542

Defining immunological dysfunction in sepsis: A requisite tool for precision medicine.

PubMed

Bermejo-Martin, Jesús F; Andaluz-Ojeda, David; Almansa, Raquel; Gandía, Francisco; Gómez-Herreras, Jose Ignacio; Gomez-Sanchez, Esther; Heredia-Rodríguez, María; Eiros, Jose Maria; Kelvin, David J; Tamayo, Eduardo

2016-05-01

Immunological dysregulation is now recognised as a major pathogenic event in sepsis. Stimulation of immune response and immuno-modulation are emerging approaches for the treatment of this disease. Defining the underlying immunological alterations in sepsis is important for the design of future therapies with immuno-modulatory drugs. Clinical studies evaluating the immunological response in adult patients with Sepsis and published in PubMed were reviewed to identify features of immunological dysfunction. For this study we used key words related with innate and adaptive immunity. Ten major features of immunological dysfunction (FID) were identified involving quantitative and qualitative alterations of [antigen presentation](FID1), [T and B lymphocytes] (FID2), [natural killer cells] (FID3), [relative increase in T regulatory cells] (FID4), [increased expression of PD-1 and PD-ligand1](FID5), [low levels of immunoglobulins](FID6), [low circulating counts of neutrophils and/or increased immature forms in non survivors](FID7), [hyper-cytokinemia] (FID8), [complement consumption] (FID9), [defective bacterial killing by neutrophil extracellular traps](FID10). This review article identified ten major features associated with immunosuppression and immunological dysregulation in sepsis. Assessment of these features could help in utilizing precision medicine for the treatment of sepsis with immuno-modulatory drugs. Copyright © 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

DETECTION,QUANTIFICATION AND CHARACTERIZATION OF MYCOBACTERIUM AVIUM COMPLEX (MAC) ORGANISMS IN DRINKING WATER.

EPA Science Inventory

Bacteria belonging to the Mycobacterium avium complex (MAC), including Mycobacterium avium and M. intracellulare, are clinically relevant and cause a myriad of opportunistic infections. Children, the elderly, and persons with previous lung conditions or immune system dysfunction...

Innate Immunity and Saliva in Candida albicans–mediated Oral Diseases

PubMed Central

Salvatori, O.; Puri, S.; Tati, S.; Edgerton, M.

2016-01-01

The oral cavity is a unique niche where Candida albicans infections occur in immunocompetent as well as immunosuppressed individuals. Here we critically review the significance of human innate immune response in preventing oral candidiasis. One important line of defense against oropharyngeal candidiasis is the oral microbiota that prevents infection by competing for space and nutrients as well as by secreting antagonistic molecules and triggering local inflammatory responses. C. albicans is able to induce mucosal defenses through activation of immune cells and production of cytokines. Also, saliva contains various proteins that affect C. albicans growth positively by promoting mucosal adherence and negatively through immune exclusion and direct fungicidal activity. We further discuss the role of saliva in unifying host innate immune defenses against C. albicans as a communicating medium and how C. albicans overgrowth in the oral cavity may be a result of aberrations ranging from microbial dysbiosis and salivary dysfunction to epithelial damage. Last we underscore select oral diseases in which C. albicans is a contributory microorganism in immune-competent individuals. PMID:26747422

Exosomes carrying immunoinhibitory proteins and their role in cancer.

PubMed

Whiteside, T L

2017-09-01

Recent emergence of exosomes as information carriers between cells has introduced us to a new previously unknown biological communication system. Multi-directional cross-talk mediated by exosomes carrying proteins, lipids and nucleic acids between normal cells, cells harbouring a pathogen or cancer and immune cells has been instrumental in determining outcomes of physiological as well as pathological conditions. Exosomes play a key role in the broad spectrum of human diseases. In cancer, tumour-derived exosomes carry multiple immunoinhibitory signals, disable anti-tumour immune effector cells and promote tumour escape from immune control. Exosomes delivering negative signals to immune cells in cancer, viral infections, autoimmune or other diseases may interfere with therapy and influence outcome. Exosomes can activate tissue cells to produce inhibitory factors and thus can suppress the host immune responses indirectly. Exosomes also promise to be non-invasive disease biomarkers with a dual capability to provide insights into immune dysfunction as well as disease progression and outcome. © 2017 British Society for Immunology.

Adipose tissue immunity and cancer

PubMed Central

Catalán, Victoria; Gómez-Ambrosi, Javier; Rodríguez, Amaia; Frühbeck, Gema

2013-01-01

Inflammation and altered immune response are important components of obesity and contribute greatly to the promotion of obesity-related metabolic complications, especially cancer development. Adipose tissue expansion is associated with increased infiltration of various types of immune cells from both the innate and adaptive immune systems. Thus, adipocytes and infiltrating immune cells secrete pro-inflammatory adipokines and cytokines providing a microenvironment favorable for tumor growth. Accumulation of B and T cells in adipose tissue precedes macrophage infiltration causing a chronic low-grade inflammation. Phenotypic switching toward M1 macrophages and Th1 T cells constitutes an important mechanism described in the obese state correlating with increased tumor growth risk. Other possible synergic mechanisms causing a dysfunctional adipose tissue include fatty acid-induced inflammation, oxidative stress, endoplasmic reticulum stress, and hypoxia. Recent investigations have started to unravel the intricacy of the cross-talk between tumor cell/immune cell/adipocyte. In this sense, future therapies should take into account the combination of anti-inflammatory approaches that target the tumor microenvironment with more sophisticated and selective anti-tumoral drugs. PMID:24106481

Skeletal Muscle and Lymphocyte Mitochondrial Dysfunctions in Septic Shock Trigger ICU-Acquired Weakness and Sepsis-Induced Immunoparalysis.

PubMed

Maestraggi, Quentin; Lebas, Benjamin; Clere-Jehl, Raphaël; Ludes, Pierre-Olivier; Chamaraux-Tran, Thiên-Nga; Schneider, Francis; Diemunsch, Pierre; Geny, Bernard; Pottecher, Julien

2017-01-01

Fundamental events driving the pathological processes of septic shock-induced multiorgan failure (MOF) at the cellular and subcellular levels remain debated. Emerging data implicate mitochondrial dysfunction as a critical factor in the pathogenesis of sepsis-associated MOF. If macrocirculatory and microcirculatory dysfunctions undoubtedly participate in organ dysfunction at the early stage of septic shock, an intrinsic bioenergetic failure, sometimes called "cytopathic hypoxia," perpetuates cellular dysfunction. Short-term failure of vital organs immediately threatens patient survival but long-term recovery is also severely hindered by persistent dysfunction of organs traditionally described as nonvital, such as skeletal muscle and peripheral blood mononuclear cells (PBMCs). In this review, we will stress how and why a persistent mitochondrial dysfunction in skeletal muscles and PBMC could impair survival in patients who overcome the first acute phase of their septic episode. First, muscle wasting protracts weaning from mechanical ventilation, increases the risk of mechanical ventilator-associated pneumonia, and creates a state of ICU-acquired muscle weakness, compelling the patient to bed. Second, failure of the immune system ("immunoparalysis") translates into its inability to clear infectious foci and predisposes the patient to recurrent nosocomial infections. We will finally emphasize how mitochondrial-targeted therapies could represent a realistic strategy to promote long-term recovery after sepsis.

The polyomavirus puzzle: is host immune response beneficial in controlling BK virus after adult hematopoietic cell transplantion?

PubMed Central

Satyanarayana, G.; Marty, F.M.; Tan, C.S.

2014-01-01

BK virus (BKV), an ubiquitous human polyomavirus, usually does not cause disease in healthy individuals. BKV reactivation and disease can occur in immunosuppressed individuals, such as those who have undergone renal transplantation or hematopoietic cell transplantation (HCT). Clinical manifestations of BKV disease include graft dysfunction and failure in renal transplant recipients; HCT recipients frequently experience hematuria, cystitis, hemorrhagic cystitis (HC), and renal dysfunction. Studies of HCT patients have identified several risk factors for the development of BKV disease including myeloablative conditioning, acute graft-versus-host disease, and undergoing an umbilical cord blood (uCB) HCT. Although these risk factors indicate that alterations in the immune system are necessary for BKV pathogenesis in HCT patients, few studies have examined the interactions between host immune responses and viral reactivation in BKV disease. Specifically, having BKV immunoglobulin-G before HCT does not protect against BKV infection and disease after HCT. A limited number of studies have demonstrated BKV- specific cytotoxic T-cells in healthy adults as well as in post-HCT patients who had experienced HC. New areas of research are required for a better understanding of this emerging infectious disease post HCT, including prospective studies examining BK viruria, viremia, and their relationship to clinical disease, a detailed analysis of urothelial histopathology, and laboratory evaluation of systemic and local cellular and humoral immune responses to BKV in patients receiving HCT from different sources, including uCB and haploidentical donors. PMID:24834968

A Protective Vaccine against Chlamydia Genital Infection Using Vault Nanoparticles without an Added Adjuvant.

PubMed

Jiang, Janina; Liu, Guangchao; Kickhoefer, Valerie A; Rome, Leonard H; Li, Lin-Xi; McSorley, Stephen J; Kelly, Kathleen A

2017-01-19

Chlamydia trachomatis genital infection is the most common sexually transmitted bacterial disease, causing a significant burden to females due to reproductive dysfunction. Intensive screening and antibiotic treatment are unable to completely prevent female reproductive dysfunction, thus, efforts have become focused on developing a vaccine. A major impediment is identifying a safe and effective adjuvant which induces cluster of differentiation 4 (CD4) cells with attributes capable of halting genital infection and inflammation. Previously, we described a natural nanocapsule called the vault which was engineered to contain major outer membrane protein (MOMP) and was an effective vaccine which significantly reduced early infection and favored development of a cellular immune response in a mouse model. In the current study, we used another chlamydial antigen, a polymorphic membrane protein G-1 (PmpG) peptide, to track antigen-specific cells and evaluate, in depth, the vault vaccine for its protective capacity in the absence of an added adjuvant. We found PmpG-vault immunized mice significantly reduced the genital bacterial burden and histopathologic parameters of inflammation following a C. muridarum challenge. Immunization boosted antigen-specific CD4 cells with a multiple cytokine secretion pattern and reduced the number of inflammatory cells in the genital tract making the vault vaccine platform safe and effective for chlamydial genital infection. We conclude that vaccination with a Chlamydia -vault vaccine boosts antigen-specific immunities that are effective at eradicating infection and preventing reproductive tract inflammation.

Impaired immune function in children and adults with Fanconi anemia.

PubMed

Myers, Kasiani C; Sauter, Sharon; Zhang, Xue; Bleesing, Jacob J; Davies, Stella M; Wells, Susanne I; Mehta, Parinda A; Kumar, Ashish; Marmer, Daniel; Marsh, Rebecca; Brown, Darron; Butsch Kovacic, Melinda

2017-11-01

Fanconi anemia (FA) is a rare genetic disorder characterized by genome instability, bone marrow failure, and cancer predisposition. Previously, small studies have reported heterogeneous immune dysfunction in FA. We performed a detailed immunologic assessment in a large FA cohort who have not undergone bone marrow transplantation or developed malignancies. Comprehensive quantitative and functional immunologic assessment of 29 FA individuals was compared to healthy age-matched controls. Compared to non-FA persons of similar ages, FA individuals showed lower absolute total B cells (P < 0.001), lower memory B cells (P < 0.001), and decreased IgM (P < 0.001) but normal IgG. NK cells (P < 0.001) and NK cytotoxicity (P < 0.001) were decreased. CD4 + T cells were decreased (P = 0.022), while CD8 + T cell and absolute T-cell numbers were comparable. Cytotoxic T cells (P < 0.003), and antigen proliferation response to tetanus (P = 0.019) and candida (P = 0.019), were diminished in FA. Phytohemagglutinin responses and plasma cytokines were normal. Within FA subjects, adults and older children (≥10 years) exhibited higher CD8 + T cells than younger children (P = 0.004). Documented atypical infections were infrequent, although oral human papilloma virus (HPV) prevalence was higher (31% positive) in FA. Overall, these results demonstrate a high rate of significant humoral and cellular immune dysfunction. Continued longitudinal study of immune function is critical to understand evolution with age, bone marrow failure, and cancer development. © 2017 Wiley Periodicals, Inc.

Protracted immune disorders at one year after ICU discharge in patients with septic shock.

PubMed

Riché, Florence; Chousterman, Benjamin G; Valleur, Patrice; Mebazaa, Alexandre; Launay, Jean-Marie; Gayat, Etienne

2018-02-21

Sepsis is a leading cause of mortality and critical illness worldwide and is associated with an increased mortality rate in the months following hospital discharge. The occurrence of persistent or new organ dysfunction(s) after septic shock raises questions about the mechanisms involved in the post-sepsis status. The present study aimed to explore the immune profiles of patients one year after being discharged from the intensive care unit (ICU) following treatment for abdominal septic shock. We conducted a prospective, single-center, observational study in the surgical ICU of a university hospital. Eighty-six consecutive patients admitted for septic shock of abdominal origin were included in this study. Fifteen different plasma biomarkers were measured at ICU admission, at ICU discharge and at one year after ICU discharge. Three different clusters of biomarkers were distinguished according to their functions, namely: (1) inflammatory response, (2) cell damage and apoptosis, (3) immunosuppression and resolution of inflammation. The primary objective was to characterize variations in the immune status of septic shock patients admitted to ICU up to one year after ICU discharge. The secondary objective was to evaluate the relationship between these biomarker variations and patient outcomes. At the onset of septic shock, we observed a cohesive pro-inflammatory profile and low levels of inflammation resolution markers. At ICU discharge, the immune status demonstrated decreased but persistent inflammation and increased immunosuppression, with elevated programmed cell death protein-1 (PD-1) levels, and a counterbalanced resolution process, with elevated levels of interleukin-10 (IL-10), resolvin D5 (RvD5), and IL-7. One year after hospital discharge, homeostasis was not completely restored with several markers of inflammation remaining elevated. Remarkably, IL-7 was persistently elevated, with levels comparable to those observed after ICU discharge, and PD-1, while lower, remained in the elevated abnormal range. In this study, protracted immune disturbances were observed one year after ICU discharge. The study results suggested the presence of long-lasting immune illness disorders following a long-term septic insult, indicating the need for long-term patient follow up after ICU discharge and questioning the use of immune intervention to restore immune homeostasis after abdominal septic shock.

Immune system gene dysregulation in autism and schizophrenia.

PubMed

Michel, Maximilian; Schmidt, Martin J; Mirnics, Karoly

2012-10-01

Gene*environment interactions play critical roles in the emergence of autism and schizophrenia pathophysiology. In both disorders, recent genetic association studies have provided evidence for disease-linked variation in immune system genes and postmortem gene expression studies have shown extensive chronic immune abnormalities in brains of diseased subjects. Furthermore, peripheral biomarker studies revealed that both innate and adaptive immune systems are dysregulated. In both disorders symptoms of the disease correlate with the immune system dysfunction; yet, in autism this process appears to be chronic and sustained, while in schizophrenia it is exacerbated during acute episodes. Furthermore, since immune abnormalities endure into adulthood and anti-inflammatory agents appear to be beneficial, it is likely that these immune changes actively contribute to disease symptoms. Modeling these changes in animals provided further evidence that prenatal maternal immune activation alters neurodevelopment and leads to behavioral changes that are relevant for autism and schizophrenia. The converging evidence strongly argues that neurodevelopmental immune insults and genetic background critically interact and result in increased risk for either autism or schizophrenia. Further research in these areas may improve prenatal health screening in genetically at-risk families and may also lead to new preventive and/or therapeutic strategies. Copyright © 2012 Wiley Periodicals, Inc.

Epitopes of Microbial and Human Heat Shock Protein 60 and Their Recognition in Myalgic Encephalomyelitis

PubMed Central

Elfaitouri, Amal; Herrmann, Björn; Bölin-Wiener, Agnes; Wang, Yilin; Gottfries, Carl-Gerhard; Zachrisson, Olof; Pipkorn, Rϋdiger; Rönnblom, Lars; Blomberg, Jonas

2013-01-01

Myalgic encephalomyelitis (ME, also called Chronic Fatigue Syndrome), a common disease with chronic fatigability, cognitive dysfunction and myalgia of unknown etiology, often starts with an infection. The chaperonin human heat shock protein 60 (HSP60) occurs in mitochondria and in bacteria, is highly conserved, antigenic and a major autoantigen. The anti-HSP60 humoral (IgG and IgM) immune response was studied in 69 ME patients and 76 blood donors (BD) (the Training set) with recombinant human and E coli HSP60, and 136 30-mer overlapping and targeted peptides from HSP60 of humans, Chlamydia, Mycoplasma and 26 other species in a multiplex suspension array. Peptides from HSP60 helix I had a chaperonin-like activity, but these and other HSP60 peptides also bound IgG and IgM with an ME preference, theoretically indicating a competition between HSP60 function and antibody binding. A HSP60-based panel of 25 antigens was selected. When evaluated with 61 other ME and 399 non-ME samples (331 BD, 20 Multiple Sclerosis and 48 Systemic Lupus Erythematosus patients), a peptide from Chlamydia pneumoniae HSP60 detected IgM in 15 of 61 (24%) of ME, and in 1 of 399 non-ME at a high cutoff (p<0.0001). IgM to specific cross-reactive epitopes of human and microbial HSP60 occurs in a subset of ME, compatible with infection-induced autoimmunity. PMID:24312270

Effects of OXPHOS complex deficiencies and ESA dysfunction in working intact skeletal muscle: implications for mitochondrial myopathies.

PubMed

Korzeniewski, Bernard

2015-10-01

The effects of inborn oxidative phosphorylation (OXPHOS) complex deficiencies or possible each-step activation (ESA) dysfunction on the bioenergetic system in working intact skeletal muscle are studied using a computer model of OXPHOS published previously. The curves representing the dependencies of V˙O2 and metabolite concentrations on single complex activity, entire OXPHOS activity or ESA intensity exhibit a characteristic threshold at some OXPHOS complex activity/ESA intensity. This threshold for V˙O2 of single complex activities is significantly lower in intact muscle during moderate and heavy work, than in isolated mitochondria in state 3. Metabolite concentrations and pH in working muscle start to change significantly at much higher OXPHOS complex activities/ESA intensities than V˙O2. The effect of entire OXPHOS deficiency or ESA dysfunction is potentially much stronger than the effect of a single complex deficiency. Implications of these findings for the genesis of mitochondrial myopathies are discussed. It is concluded that V˙O2 in state 3 and its dependence on complex activity in isolated mitochondria is not a universal quantitative determinant of the effect of mitochondrial dysfunctions in vivo. Moderate and severe mitochondria dysfunctions are defined: the former affect significantly only metabolite concentrations and pH, while the latter also decrease significantly V˙O2 in intact skeletal muscle during work. The dysfunction-caused decrease in V˙O2/oxidative ATP synthesis flux, disturbance of metabolite homeostasis, elevated ROS production and anaerobic glycolysis recruitment can account for such mitochondrial myopathy symptoms as muscle weakness, exercise intolerance (exertional fatigue) and lactic acidosis. Copyright © 2015 Elsevier B.V. All rights reserved.

Stimulation of dendritic cells enhances immune response after photodynamic therapy

NASA Astrophysics Data System (ADS)

Mroz, Pawel; Castano, Ana P.; Hamblin, Michael R.

2009-02-01

Photodynamic therapy (PDT) involves the administration of photosensitizers followed by illumination of the primary tumor with red light producing reactive oxygen species that cause vascular shutdown and tumor cell necrosis and apoptosis. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, priming of the immune system to recognize tumor-associated antigens (TAA). The induction of specific CD8+ Tlymphocyte cells that recognize major histocompatibility complex class I (MHC-I) restricted epitopes of TAAs is a highly desirable goal in cancer therapy. The PDT killed tumor cells may be phagocytosed by dendritic cells (DC) that then migrate to draining lymph nodes and prime naÃve T-cells that recognize TAA epitopes. This process is however, often sub-optimal, in part due to tumor-induced DC dysfunction. Instead of DC that can become mature and activated and have a potent antigen-presenting and immune stimulating phenotype, immature dendritic cells (iDC) are often found in tumors and are part of an immunosuppressive milieu including regulatory T-cells and immunosuppressive cytokines such as TGF-beta and IL10. We here report on the use of a potent DC activating agent, an oligonucleotide (ODN) that contains a non-methylated CpG motif and acts as an agonist of toll like receptor (TLR) 9. TLR activation is a danger signal to notify the immune system of the presence of invading pathogens. CpG-ODN (but not scrambled non-CpG ODN) increased bone-marrow DC activation after exposure to PDT-killed tumor cells, and significantly increased tumor response to PDT and mouse survival after peri-tumoral administration. CpG may be a valuable immunoadjuvant to PDT especially for tumors that produce DC dysfunction.

Higher frequencies of GARP(+)CTLA-4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality.

PubMed

Kalathil, Suresh; Lugade, Amit A; Miller, Austin; Iyer, Renuka; Thanavala, Yasmin

2013-04-15

The extent to which T-cell-mediated immune surveillance is impaired in human cancer remains a question of major importance, given its potential impact on the development of generalized treatments of advanced disease where the highest degree of heterogeneity exists. Here, we report the first global analysis of immune dysfunction in patients with advanced hepatocellular carcinoma (HCC). Using multi-parameter fluorescence-activated cell sorting analysis, we quantified the cumulative frequency of regulatory T cells (Treg), exhausted CD4(+) helper T cells, and myeloid-derived suppressor cells (MDSC) to gain concurrent views on the overall level of immune dysfunction in these inoperable patients. We documented augmented numbers of Tregs, MDSC, PD-1(+)-exhausted T cells, and increased levels of immunosuppressive cytokines in patients with HCC, compared with normal controls, revealing a network of potential mechanisms of immune dysregulation in patients with HCC. In dampening T-cell-mediated antitumor immunity, we hypothesized that these processes may facilitate HCC progression and thwart the efficacy of immunotherapeutic interventions. In testing this hypothesis, we showed that combined regimens to deplete Tregs, MDSC, and PD-1(+) T cells in patients with advanced HCC restored production of granzyme B by CD8(+) T cells, reaching levels observed in normal controls and also modestly increased the number of IFN-γ producing CD4(+) T cells. These clinical findings encourage efforts to restore T-cell function in patients with advanced stage disease by highlighting combined approaches to deplete endogenous suppressor cell populations that can also expand effector T-cell populations. ©2013 AACR.

T cell deficiency leads to cognitive dysfunction: Implications for therapeutic vaccination for schizophrenia and other psychiatric conditions

PubMed Central

Kipnis, Jonathan; Cohen, Hagit; Cardon, Michal; Ziv, Yaniv; Schwartz, Michal

2004-01-01

The effects of the adaptive immune system on the cognitive performance and abnormal behaviors seen in mental disorders such as schizophrenia have never been documented. Here, we show that mice deprived of mature T cells manifested cognitive deficits and behavioral abnormalities, which were remediable by T cell restoration. T cell-based vaccination, using glatiramer acetate (copolymer-1, a weak agonist of numerous self-reactive T cells), can overcome the behavioral and cognitive abnormalities that accompany neurotransmitter imbalance induced by (+)dizocilpine maleate (MK-801) or amphetamine. The results, by suggesting that peripheral T cell deficit can lead to cognitive and behavioral impairment, highlight the importance of properly functioning adaptive immunity in the maintenance of mental activity and in coping with conditions leading to cognitive deficits. These findings point to critical factors likely to contribute to age- and AIDS-related dementias and might herald the development of a therapeutic vaccination for fighting off cognitive dysfunction and psychiatric conditions. PMID:15141078

Pathophysiology of the Effects of Alcohol Abuse on the Endocrine System.

PubMed

Rachdaoui, Nadia; Sarkar, Dipak K

2017-01-01

Alcohol can permeate virtually every organ and tissue in the body, resulting in tissue injury and organ dysfunction. Considerable evidence indicates that alcohol abuse results in clinical abnormalities of one of the body's most important systems, the endocrine system. This system ensures proper communication between various organs, also interfacing with the immune and nervous systems, and is essential for maintaining a constant internal environment. The endocrine system includes the hypothalamic-pituitary-adrenal axis, the hypothalamic-pituitary-gonadal axis, the hypothalamic-pituitary-thyroid axis, the hypothalamic-pituitary-growth hormone/insulin-like growth factor-1 axis, and the hypothalamic-posterior pituitary axis, as well as other sources of hormones, such as the endocrine pancreas and endocrine adipose tissue. Alcohol abuse disrupts all of these systems and causes hormonal disturbances that may result in various disorders, such as stress intolerance, reproductive dysfunction, thyroid problems, immune abnormalities, and psychological and behavioral disorders. Studies in both humans and animal models have helped shed light on alcohol's effects on various components of the endocrine system and their consequences.

Role of Microglia Disturbances and Immune-Related Marker Abnormalities in Cortical Circuitry Dysfunction in Schizophrenia

PubMed Central

Volk, David W.

2017-01-01

Studies of genetics, serum cytokines, and autoimmune illnesses suggest that immune-related abnormalities are involved in the disease process of schizophrenia. Furthermore, direct evidence of cortical immune activation, including markedly elevated levels of many immune-related markers, have been reported in the prefrontal cortex in multiple cohorts of schizophrenia subjects. Within the prefrontal cortex in schizophrenia, deficits in the basilar dendritic spines of layer 3 pyramidal neurons and disturbances in inhibitory inputs to pyramidal neurons have also been commonly reported. Interestingly, microglia, the resident immune-related cells of the brain, also regulate excitatory and inhibitory input to pyramidal neurons. Consequently, in this review, we describe the cytological and molecular evidence of immune activation that has been reported in the brains of individuals with schizophrenia and the potential links between these immune-related disturbances with previously reported disturbances in pyramidal and inhibitory neurons in the disorder. Finally, we discuss the role that activated microglia may play in connecting these observations and as potential therapeutic treatment targets in schizophrenia. PMID:28007586

Regulation of metabolic health and adipose tissue function by group 2 innate lymphoid cells.

PubMed

Cautivo, Kelly M; Molofsky, Ari B

2016-06-01

Adipose tissue (AT) is home to an abundance of immune cells. With chronic obesity, inflammatory immune cells accumulate and promote insulin resistance and the progression to type 2 diabetes mellitus. In contrast, recent studies have highlighted the regulation and function of immune cells in lean, healthy AT, including those associated with type 2 or "allergic" immunity. Although traditionally activated by infection with multicellular helminthes, AT type 2 immunity is active independently of infection, and promotes tissue homeostasis, AT "browning," and systemic insulin sensitivity, protecting against obesity-induced metabolic dysfunction and type 2 diabetes mellitus. In particular, group 2 innate lymphoid cells (ILC2s) are integral regulators of AT type 2 immunity, producing the cytokines interleukin-5 and IL-13, promoting eosinophils and alternatively activated macrophages, and cooperating with and promoting AT regulatory T (Treg) cells. In this review, we focus on the recent developments in our understanding of group 2 innate lymphoid cell cells and type 2 immunity in AT metabolism and homeostasis. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Regulation of metabolic health and adipose tissue function by group 2 innate lymphoid cells

PubMed Central

Cautivo, Kelly M.; Molofsky, Ari B.

2016-01-01

Adipose tissue (AT) is home to an abundance of immune cells. With chronic obesity, inflammatory immune cells accumulate and promote insulin resistance and the progression to type 2 diabetes mellitus (T2DM). In contrast, recent studies have highlighted the regulation and function of immune cells in lean, healthy adipose tissue, including those associated with type 2 or “allergic” immunity. Although traditionally activated by infection with multicellular helminthes, AT type 2 immunity is active independently of infection, and promotes tissue homeostasis, adipose tissue “browning”, and systemic insulin sensitivity, protecting against obesity-induced metabolic dysfunction and T2DM. In particular, group 2 innate lymphoid cells (ILC2s) are integral regulators of AT type 2 immunity, producing the cytokines IL-5 and IL-13, promoting eosinophils and alternatively activated macrophages, and cooperating with and promoting AT regulatory T (Treg) cells. In this review, we focus on the recent developments in our understanding of ILC2 cells and type 2 immunity in adipose tissue metabolism and homeostasis. PMID:27120716

Advances in our understanding of immunization and vaccines for patients with systemic lupus erythematosus.

PubMed

Bragazzi, Nicola Luigi; Watad, Abdulla; Sharif, Kassem; Adawi, Mohammad; Aljadeff, Gali; Amital, Howard; Shoenfeld, Yehuda

2017-10-01

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease. In SLE, immune system dysfunction is postulated to result by virtue of the disease itself as well as by the impact of treatment modalities employed. A myriad of immune dysregulations occur including complement system dysfunction among others. Infectious agents are known to complicate the disease course in close to 25-45% of SLE patients. Areas covered: In this review a discussion of the immunogenicity and safety of viral and bacterial vaccinations in SLE was performed. The search included ISI Web of Science (WoS), Scopus, MEDLINE/PubMed, Google-Scholar, DOAJ, EbscoHOST, Scirus, Science Direct, Cochrane Library and ProQuest. Proper string made up of a key-words including 'SLE', 'vaccination', 'safety' and 'efficacy' was used. Expert commentary: Vaccination of SLE patients is proven to be immunogenic. Concerns regarding vaccine safety are postulated, yet no direct relationship between vaccination and disease exacerbation were established. While live virus vaccines are generally contraindicated in immunosuppressive states, generally live attenuated vaccinations are recommended in SLE patients on a case-to-case basis. In SLE patients, clinical parameters such as vaccination during disease exacerbations have not been intensively studied and therefore while apparently safe, vaccination is generally recommended while disease is quiescent.

[Immune dysfunction and cognitive deficit in stress and physiological aging. Part II: New approaches to cognitive disorder prevention and treatment ].

PubMed

Pukhal'skiĭ, A L; Shmarina, G V; Aleshkin, V A

2014-01-01

Long-term stress as well as physiological aging result in similar immunological and hormonal disturbances including hypothalamic-pituitary-adrenal) axis depletion, aberrant immune response (regulatory T-cells, Tregs, and T(h17)-lymphocyte accumulation) and decreased dehydroepian-drosterone synthesis both in the brain and in the adrenal glands. Since the main mechanisms of inflammation control, "prompt" (stress hormones) and "delayed" (Tregs), are broken, serum cytokine levels increase and become sufficient for blood-brain-barrier disruption. As a result peripheral cytokines penetrate into the brain where they begin to perform new functions. Structural and functional alterations of blood-brain-barrier as well as stress- (or age-) induced neuroinflammation promote influx of bone marrow derived dendritic cells and lymphocyte effectors into the brain parenchyma. Thereafter, mass intrusion ofpro-inflammatory mediators and immune cells having a lot of specific targets alters the brain work that we can observe both in humans and in animal experiments. The concept of stressful cognitive dysfunction, which is under consideration in this review, allows picking out several therapeutic targets: 1) reduction of excessive Treg accumulation; 2) supporting hypothalamic-pituitary-adrenal axis and inflammatory reaction attenuation; 3) recovery of dehydroepiandrosterone level; 4) improvement of blood-brain-barrier function.

Protective Effect of Chitosan Oligosaccharides Against Cyclophosphamide-Induced Immunosuppression and Irradiation Injury in Mice.

PubMed

Zhai, Xingchen; Yang, Xin; Zou, Pan; Shao, Yong; Yuan, Shoujun; Abd El-Aty, A M; Wang, Jing

2018-02-01

Chitosan oligosaccharides (COS), hydrolyzed products of chitosan, was found to display various biological activities. Herein, we assessed the immunostimulatory activity of COS both in in vitro and in vivo studies. In vitro cytotoxicity studies to murine macrophage RAW264.7 revealed that COS is safe even at the maximum tested concentration of 1000 μg/mL. It also stimulates the production of nitric oxide (NO) and tumor necrosis factor (TNF-α) and enhances the phagocytosis in COS-stimulated RAW264.7. We have shown that the COS could significantly (P < 0.05) restore the reduced immune organs indices, phagocytic index, lymphocyte proliferation, natural killer cell activity, and antioxidant enzyme activities in a cyclophosphamide-induced immunosuppressed mice model. COS can also improve the survival rate in irradiation injury mice and significantly (P < 0.05) increased the spleen indices and up-regulates the CD4+/CD8+ ratio in splenocytes. In sum, the aforementioned results suggest that COS might has the potential to be used as an immunostimulatory agent in patients with immune dysfunctions or be a model for functional food development. COS might has the potential to be used as an immunostimulatory agent in patients with immune dysfunctions or be a model for functional food development. © 2018 Institute of Food Technologists®.

Addison's Disease: A Diagnostic Dilemma.

PubMed

Afroz, S; Bain, S

2017-07-01

Adrenal insufficiency is a rare disease, but is life threatening when overlooked. Addison's disease may be an acquired form of adrenal insufficiency due to the destruction or dysfunction of the adrenal cortex. It affects both glucocorticoid and mineralocorticoid function. Main presenting symptoms of Addison's disease such as fatigue, anorexia, vomiting and convulsion often mimics central nervous system (CNS) infections. We describe a case of Addison's disease who was initially misdiagnosed as a case of meningo-encephalitis subsequently renal tubular acidosis and finally Addison's disease. Addison's disease can remain unrecognized until acute crisis and sometimes it may be misdiagnosed.

Medical management of brain tumors and the sequelae of treatment

PubMed Central

Schiff, David; Lee, Eudocia Q.; Nayak, Lakshmi; Norden, Andrew D.; Reardon, David A.; Wen, Patrick Y.

2015-01-01

Patients with malignant brain tumors are prone to complications that negatively impact their quality of life and sometimes their overall survival as well. Tumors may directly provoke seizures, hypercoagulable states with resultant venous thromboembolism, and mood and cognitive disorders. Antitumor treatments and supportive therapies also produce side effects. In this review, we discuss major aspects of supportive care for patients with malignant brain tumors, with particular attention to management of seizures, venous thromboembolism, corticosteroids and their complications, chemotherapy including bevacizumab, and fatigue, mood, and cognitive dysfunction. PMID:25358508

Increased Ventricular Cerebrospinal Fluid Lactate in Depressed Adolescents

PubMed Central

Bradley, Kailyn A. L.; Mao, Xiangling; Case, Julia A. C.; Kang, Guoxin; Shungu, Dikoma C.; Gabbay, Vilma

2016-01-01

Background Mitochondrial dysfunction has been increasingly examined as a potential pathogenic event in psychiatric disorders, although its role early in the course of major depressive disorder (MDD) is unclear. Therefore, the purpose of this study was to investigate mitochondrial dysfunction in medication-free adolescents with MDD through in vivo measurements of neurometabolites using high-spatial resolution multislice/multivoxel proton magnetic resonance spectroscopy. Methods Twenty-three adolescents with MDD and 29 healthy controls, ages 12–20, were scanned at 3T and concentrations of ventricular cerebrospinal fluid lactate, as well as N-acetyl-aspartate (NAA), total creatine (tCr), and total choline (tCho) in the bilateral caudate, putamen, and thalamus were reported. Results Adolescents with MDD exhibited increased ventricular lactate compared to healthy controls [F(1, 41) = 6.98, p = .01]. However, there were no group differences in the other neurometabolites. Dimensional analyses in the depressed group showed no relation between any of the neurometabolites and symptomatology, including anhedonia and fatigue. Conclusions Increased ventricular lactate in depressed adolescents suggests mitochondrial dysfunction may be present early in the course of MDD; however it is still not known whether the presence of mitochondrial dysfunction is a trait vulnerability of individuals predisposed to psychopathology or a state feature of the disorder. Therefore, there is a need for larger multimodal studies to clarify these chemical findings in the context of network function. PMID:26802978

Thermoregulatory and Immune Responses During Cold Exposure: Effects of Repeated Cold Exposure and Acute Exercise

DTIC Science & Technology

2000-03-01

shivering thermogenesis and vasoconstriction) during cold exposure is unknown. Thus, a series of experiments were executed to determine if serial cold ...to cold exposure? The results of these studies suggest that 1) serial cold water blunts shivering leadmg™ower core temperatures, 2) thermoregulatory...fatigues (i.e., causes blunted shivering thermogenesis and vasoconstriction) during cold exposure is unknown. Thus, a series of experiments were

Subgrouping Chronic Fatigue Syndrome Patients By Genetic and Immune Profiling

DTIC Science & Technology

2015-12-01

participant inclusion was also verified against our master demographic file. This process revealed that only a small percentage of participants (...the ! ! − !!! , ∈ ℤ!| ≤ 7 , is a cubic -spline basis on three knots, ! is value of outcome for batch control, and is residual ...tests. Specifically, -value adjustments will employ an 8 adaptive two- stage linear step-up procedure to control the FDR at 5% (Benjamani et al. 2006

PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response?

PubMed Central

Xu-Monette, Zijun Y.; Zhang, Mingzhi; Li, Jianyong; Young, Ken H.

2017-01-01

PD-1–PD-L1 interaction is known to drive T cell dysfunction, which can be blocked by anti-PD-1/PD-L1 antibodies. However, studies have also shown that the function of the PD-1–PD-L1 axis is affected by the complex immunologic regulation network, and some CD8+ T cells can enter an irreversible dysfunctional state that cannot be rescued by PD-1/PD-L1 blockade. In most advanced cancers, except Hodgkin lymphoma (which has high PD-L1/L2 expression) and melanoma (which has high tumor mutational burden), the objective response rate with anti-PD-1/PD-L1 monotherapy is only ~20%, and immune-related toxicities and hyperprogression can occur in a small subset of patients during PD-1/PD-L1 blockade therapy. The lack of efficacy in up to 80% of patients was not necessarily associated with negative PD-1 and PD-L1 expression, suggesting that the roles of PD-1/PD-L1 in immune suppression and the mechanisms of action of antibodies remain to be better defined. In addition, important immune regulatory mechanisms within or outside of the PD-1/PD-L1 network need to be discovered and targeted to increase the response rate and to reduce the toxicities of immune checkpoint blockade therapies. This paper reviews the major functional and clinical studies of PD-1/PD-L1, including those with discrepancies in the pathologic and biomarker role of PD-1 and PD-L1 and the effectiveness of PD-1/PD-L1 blockade. The goal is to improve understanding of the efficacy of PD-1/PD-L1 blockade immunotherapy, as well as enhance the development of therapeutic strategies to overcome the resistance mechanisms and unleash the antitumor immune response to combat cancer. PMID:29255458

PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response?

PubMed

Xu-Monette, Zijun Y; Zhang, Mingzhi; Li, Jianyong; Young, Ken H

2017-01-01

PD-1-PD-L1 interaction is known to drive T cell dysfunction, which can be blocked by anti-PD-1/PD-L1 antibodies. However, studies have also shown that the function of the PD-1-PD-L1 axis is affected by the complex immunologic regulation network, and some CD8 + T cells can enter an irreversible dysfunctional state that cannot be rescued by PD-1/PD-L1 blockade. In most advanced cancers, except Hodgkin lymphoma (which has high PD-L1/L2 expression) and melanoma (which has high tumor mutational burden), the objective response rate with anti-PD-1/PD-L1 monotherapy is only ~20%, and immune-related toxicities and hyperprogression can occur in a small subset of patients during PD-1/PD-L1 blockade therapy. The lack of efficacy in up to 80% of patients was not necessarily associated with negative PD-1 and PD-L1 expression, suggesting that the roles of PD-1/PD-L1 in immune suppression and the mechanisms of action of antibodies remain to be better defined. In addition, important immune regulatory mechanisms within or outside of the PD-1/PD-L1 network need to be discovered and targeted to increase the response rate and to reduce the toxicities of immune checkpoint blockade therapies. This paper reviews the major functional and clinical studies of PD-1/PD-L1, including those with discrepancies in the pathologic and biomarker role of PD-1 and PD-L1 and the effectiveness of PD-1/PD-L1 blockade. The goal is to improve understanding of the efficacy of PD-1/PD-L1 blockade immunotherapy, as well as enhance the development of therapeutic strategies to overcome the resistance mechanisms and unleash the antitumor immune response to combat cancer.

Dire deadlines: coping with dysfunctional family dynamics in an end-of-life care setting.

PubMed

Holst, Lone; Lundgren, Maren; Olsen, Lutte; Ishøy, Torben

2009-01-01

Working in a hospice and being able to focus on individualized, specialized end-of-life care is a privilege for the hospice staff member. However, it also presents the hospice staff with unique challenges. This descriptive study is based upon two cases from an end-of-life care setting in Denmark, where dysfunctional family dynamics presented added challenges to the staff members in their efforts to provide optimal palliative care. The hospice triad--the patient, the staff member and the family member--forms the basis for communication and intervention in a hospice. Higher expectations and demands of younger, more well-informed patients and family members challenge hospice staff in terms of information and communication when planning for care. The inherent risk factors of working with patients in the terminal phase of life become a focal point in the prevention of the development of compassion fatigue among staff members. A series of coping strategies to more optimally manage dysfunctional families in a setting where time is of the essence are then presented in an effort to empower the hospice team, to prevent splitting among staff members, and to improve quality of care.

"A" motor neuron disease.

PubMed

Vishnu, Venugopalan Y; Modi, Manish; Prabhakar, Sudesh; Bhansali, Anil; Goyal, Manoj Kumar

2014-01-15

Allgrove syndrome is a rare autosomal recessive disorder characterised by achalasia, alacrima, adrenal insufficiency, autonomic dysfunction and amyotrophy. The syndrome has been described in childhood and adult presentation, as in our case, is very rare. There is a considerable delay in diagnosis due to lack of awareness about the syndrome. We report a single case of a 36 year old man who was initially diagnosed and treated for achalasia cardia in our institute 14 years before. After 8 years he presented again with weakness and wasting predominantly distally. He had tongue fasciculations, brisk reflexes and extensor plantar. After supportive electrophysiological studies he was diagnosed as Amyotrophic lateral sclerosis. After 5 years he presented with generalised fatigue without any significant worsening of his neurological status. On reevaluation he had alacrimia, autonomic dysfunction and mild ACTH resistance. Allgrove syndrome may be an underdiagnosed cause of multisystem neurological disease due to the heterogeneous clinical presentation as well as for ignorance of clinician about the syndrome. Based on our case, we also believe that there does exist a subgroup of patients who follow a less severe and chronic course. Recognition of syndrome allows for treatment of autonomic dysfunction, adrenal insufficiency and dysphagia. © 2013.

Aging and Immune Function: Molecular Mechanisms to Interventions

PubMed Central

Ponnappan, Subramaniam

2011-01-01

Abstract The immune system of an organism is an essential component of the defense mechanism aimed at combating pathogenic stress. Age-associated immune dysfunction, also dubbed “immune senescence,” manifests as increased susceptibility to infections, increased onset and progression of autoimmune diseases, and onset of neoplasia. Over the years, extensive research has generated consensus in terms of the phenotypic and functional defects within the immune system in various organisms, including humans. Indeed, age-associated alterations such as thymic involution, T cell repertoire skewing, decreased ability to activate naïve T cells and to generate robust memory responses, have been shown to have a causative role in immune decline. Further, understanding the molecular mechanisms underlying the generation of proteotoxic stress, DNA damage response, modulation of ubiquitin proteasome pathway, and regulation of transcription factor NFκB activation, in immune decline, have paved the way to delineating signaling pathways that cross-talk and impact immune senescence. Given the role of the immune system in combating infections, its effectiveness with age may well be a marker of health and a predictor of longevity. It is therefore believed that a better understanding of the mechanisms underlying immune senescence will lead to an effective interventional strategy aimed at improving the health span of individuals. Antioxid. Redox Signal. 14, 1551–1585. PMID:20812785

Characterisation of cell functions and receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME).

PubMed

Hardcastle, Sharni Lee; Brenu, Ekua Weba; Johnston, Samantha; Nguyen, Thao; Huth, Teilah; Wong, Naomi; Ramos, Sandra; Staines, Donald; Marshall-Gradisnik, Sonya

2015-06-02

Abnormal immune function is often an underlying component of illness pathophysiology and symptom presentation. Functional and phenotypic immune-related alterations may play a role in the obscure pathomechanism of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). The objective of this study was to investigate the functional ability of innate and adaptive immune cells in moderate and severe CFS/ME patients. The 1994 Fukuda criteria for CFS/ME were used to define CFS/ME patients. CFS/ME participants were grouped based on illness severity with 15 moderately affected (moderate) and 12 severely affected (severe) CFS/ME patients who were age and sex matched with 18 healthy controls. Flow cytometric protocols were used for immunological analysis of dendritic cells, monocytes and neutrophil function as well as measures of lytic proteins and T, natural killer (NK) and B cell receptors. CFS/ME patients exhibited alterations in NK receptors and adhesion markers and receptors on CD4(+)T and CD8(+)T cells. Moderate CFS/ME patients had increased CD8(+) CD45RA effector memory T cells, SLAM expression on NK cells, KIR2DL5(+) on CD4(+)T cells and BTLA4(+) on CD4(+)T central memory cells. Moderate CFS/ME patients also had reduced CD8(+)T central memory LFA-1, total CD8(+)T KLRG1, naïve CD4(+)T KLRG1 and CD56(dim)CD16(-) NK cell CD2(+) and CD18(+)CD2(+). Severe CFS/ME patients had increased CD18(+)CD11c(-) in the CD56(dim)CD16(-) NK cell phenotype and reduced NKp46 in CD56(bright)CD16(dim) NK cells. This research accentuated the presence of immunological abnormalities in CFS/ME and highlighted the importance of assessing functional parameters of both innate and adaptive immune systems in the illness.

Idiopathic Hypersomnia.

PubMed

Trotti, Lynn Marie

2017-09-01

Idiopathic hypersomnia (IH) is a chronic neurologic disorder of daytime sleepiness, accompanied by long sleep times, unrefreshing sleep, difficulty in awakening, cognitive dysfunction, and autonomic symptoms. The cause is unknown; a genetic predisposition is suggested. Autonomic, inflammatory, or immune dysfunction has been proposed. Diagnosis involves a clinical history and objective testing. There are no approved treatments for IH, but modafinil is typically considered first-line. A substantial fraction of patients with IH are refractory or intolerant to standard treatments, and different treatment strategies using novel therapeutics are necessary. Even with current treatment options, quality of life and safety may remain impaired. Copyright © 2017 Elsevier Inc. All rights reserved.

Pharmacotherapy for Irritable Bowel Syndrome

PubMed Central

Camilleri, Michael

2017-01-01

Irritable bowel syndrome (IBS) is a disorder of the brain-gut axis; the pathophysiological mechanisms include altered colonic motility, bile acid metabolism, neurohormonal regulation, immune dysfunction, alterations in the epithelial barrier and secretory properties of the gut. This article reviews the mechanisms, efficacy, and safety of current pharmacotherapy, and medications that are in phase III trials for the treatment of IBS. There remains a significant unmet need for effective treatments—particularly for the pain component of IBS—although the introduction of drugs directed at secretion, motility and a non-absorbable antibiotic provide options for the bowel dysfunction in IBS. PMID:29077050

Immunological findings in autism.

PubMed

Cohly, Hari Har Parshad; Panja, Asit

2005-01-01

The immunopathogenesis of autism is presented schematically in Fig. 1. Two main immune dysfunctions in autism are immune regulation involving pro-inflammatory cytokines and autoimmunity. Mercury and an infectious agent like the measles virus are currently two main candidate environmental triggers for immune dysfunction in autism. Genetically immune dysfunction in autism involves the MHC region, as this is an immunologic gene cluster whose gene products are Class I, II, and III molecules. Class I and II molecules are associated with antigen presentation. The antigen in virus infection initiated by the virus particle itself while the cytokine production and inflammatory mediators are due to the response to the putative antigen in question. The cell-mediated immunity is impaired as evidenced by low numbers of CD4 cells and a concomitant T-cell polarity with an imbalance of Th1/Th2 subsets toward Th2. Impaired humoral immunity on the other hand is evidenced by decreased IgA causing poor gut protection. Studies showing elevated brain specific antibodies in autism support an autoimmune mechanism. Viruses may initiate the process but the subsequent activation of cytokines is the damaging factor associated with autism. Virus specific antibodies associated with measles virus have been demonstrated in autistic subjects. Environmental exposure to mercury is believed to harm human health possibly through modulation of immune homeostasis. A mercury link with the immune system has been postulated due to the involvement of postnatal exposure to thimerosal, a preservative added in the MMR vaccines. The occupational hazard exposure to mercury causes edema in astrocytes and, at the molecular level, the CD95/Fas apoptotic signaling pathway is disrupted by Hg2+. Inflammatory mediators in autism usually involve activation of astrocytes and microglial cells. Proinflammatory chemokines (MCP-1 and TARC), and an anti-inflammatory and modulatory cytokine, TGF-beta1, are consistently elevated in autistic brains. In measles virus infection, it has been postulated that there is immune suppression by inhibiting T-cell proliferation and maturation and downregulation MHC class II expression. Cytokine alteration of TNF-alpha is increased in autistic populations. Toll-like-receptors are also involved in autistic development. High NO levels are associated with autism. Maternal antibodies may trigger autism as a mechanism of autoimmunity. MMR vaccination may increase risk for autism via an autoimmune mechanism in autism. MMR antibodies are significantly higher in autistic children as compared to normal children, supporting a role of MMR in autism. Autoantibodies (IgG isotype) to neuron-axon filament protein (NAFP) and glial fibrillary acidic protein (GFAP) are significantly increased in autistic patients (Singh et al., 1997). Increase in Th2 may explain the increased autoimmunity, such as the findings of antibodies to MBP and neuronal axonal filaments in the brain. There is further evidence that there are other participants in the autoimmune phenomenon. (Kozlovskaia et al., 2000). The possibility of its involvement in autism cannot be ruled out. Further investigations at immunological, cellular, molecular, and genetic levels will allow researchers to continue to unravel the immunopathogenic mechanisms' associated with autistic processes in the developing brain. This may open up new avenues for prevention and/or cure of this devastating neurodevelopmental disorder.

Interrelation between Neuroendocrine Disturbances and Medical Complications Encountered during Rehabilitation after TBI

PubMed Central

Renner, Caroline I. E.

2015-01-01

Traumatic brain injury is not a discrete event but an unfolding sequence of damage to the central nervous system. Not only the acute phase but also the subacute and chronic period after injury, i.e., during inpatient rehabilitation, is characterized by multiple neurotransmitter alterations, cellular dysfunction, and medical complications causing additional secondary injury. Neuroendocrine disturbances also influence neurological outcome and are easily overlooked as they often present with diffuse symptoms such as fatigue, depression, poor concentration, or a decline in overall cognitive function; these are also typical sequelae of traumatic brain injury. Furthermore, neurological complications such as hydrocephalus, epilepsy, fatigue, disorders of consciousness, paroxysmal sympathetic hyperactivity, or psychiatric-behavioural symptoms may mask and/or complicate the diagnosis of neuroendocrine disturbances, delay appropriate treatment and impede neurorehabilitation. The present review seeks to examine the interrelation between neuroendocrine disturbances with neurological complications frequently encountered after moderate to severe TBI during rehabilitation. Common neuroendocrine disturbances and medical complications and their clinical implications are discussed. PMID:26402710

[Social crisis and occupational fatigue among health professionals: warnings and resources].

PubMed

Wolfberg, Elsa

Due to the crisis of the welfare state, the smashing of the state budget and the labour flexibility, the "helping professions" (health service, education, etc.) are the main assistance for the poor, the elderly people and the victims of violence. This result in the emergence of occupational pathologies, mainly in the health workers, such as burnout, secondary traumatic stress or empaty caused fatigue, mobbing or moral harassment -all of them affecting not only the quality of life of professionals but also the body health. The corporal disorders may begin with mild malfunctions, considered as "natural" facts of life, then becoming severe illness. The professional may attempt to meliorate the situation with the use of alcohol, tobacco, ansiolitics, etc. thus worsening the whole health. At the moment there are not legal regulations for this emergent pathologies. We have to pay attention to the signals in order to be able to overcome the dysfunctional defense mechanisms and to activate the preventive and protective resources, such as reflexion groups at workplaces.

REACTIVE OXYGEN SPECIES: IMPACT ON SKELETAL MUSCLE

PubMed Central

Powers, Scott K.; Ji, Li Li; Kavazis, Andreas N.; Jackson, Malcolm J.

2014-01-01

It is well established that contracting muscles produce both reactive oxygen and nitrogen species. Although the sources of oxidant production during exercise continue to be debated, growing evidence suggests that mitochondria are not the dominant source. Regardless of the sources of oxidants in contracting muscles, intense and prolonged exercise can result in oxidative damage to both proteins and lipids in the contracting myocytes. Further, oxidants regulate numerous cell signaling pathways and modulate the expression of many genes. This oxidant-mediated change in gene expression involves changes at transcriptional, mRNA stability, and signal transduction levels. Furthermore, numerous products associated with oxidant-modulated genes have been identified and include antioxidant enzymes, stress proteins, and mitochondrial electron transport proteins. Interestingly, low and physiological levels of reactive oxygen species are required for normal force production in skeletal muscle, but high levels of reactive oxygen species result in contractile dysfunction and fatigue. Ongoing research continues to explore the redox-sensitive targets in muscle that are responsible for both redox-regulation of muscle adaptation and oxidant-mediated muscle fatigue. PMID:23737208

Symptomatology associated with accommodative and binocular vision anomalies.

PubMed

García-Muñoz, Ángel; Carbonell-Bonete, Stela; Cacho-Martínez, Pilar

2014-01-01

To determine the symptoms associated with accommodative and non-strabismic binocular dysfunctions and to assess the methods used to obtain the subjects' symptoms. We conducted a scoping review of articles published between 1988 and 2012 that analysed any aspect of the symptomatology associated with accommodative and non-strabismic binocular dysfunctions. The literature search was performed in Medline (PubMed), CINAHL, PsycINFO and FRANCIS. A total of 657 articles were identified, and 56 met the inclusion criteria. We found 267 different ways of naming the symptoms related to these anomalies, which we grouped into 34 symptom categories. Of the 56 studies, 35 employed questionnaires and 21 obtained the symptoms from clinical histories. We found 11 questionnaires, of which only 3 had been validated: the convergence insufficiency symptom survey (CISS V-15) and CIRS parent version, both specific for convergence insufficiency, and the Conlon survey, developed for visual anomalies in general. The most widely used questionnaire (21 studies) was the CISS V-15. Of the 34 categories of symptoms, the most frequently mentioned were: headache, blurred vision, diplopia, visual fatigue, and movement or flicker of words at near vision, which were fundamentally related to near vision and binocular anomalies. There is a wide disparity of symptoms related to accommodative and binocular dysfunctions in the scientific literature, most of which are associated with near vision and binocular dysfunctions. The only psychometrically validated questionnaires that we found (n=3) were related to convergence insufficiency and to visual dysfunctions in general and there no specific questionnaires for other anomalies. Copyright © 2014. Published by Elsevier Espana.

Thyroid Dysfunction from Antineoplastic Agents

PubMed Central

Larsen, P. Reed; Marqusee, Ellen

2011-01-01

Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated with thyroid dysfunction. These include tyrosine kinase inhibitors, bexarotene, radioiodine-based cancer therapies, denileukin diftitox, alemtuzumab, interferon-α, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide. Primary hypothyroidism is the most common side effect, although thyrotoxicosis and effects on thyroid-stimulating hormone secretion and thyroid hormone metabolism have also been described. Most agents cause thyroid dysfunction in 20%–50% of patients, although some have even higher rates. Despite this, physicians may overlook drug-induced thyroid dysfunction because of the complexity of the clinical picture in the cancer patient. Symptoms of hypothyroidism, such as fatigue, weakness, depression, memory loss, cold intolerance, and cardiovascular effects, may be incorrectly attributed to the primary disease or to the antineoplastic agent. Underdiagnosis of thyroid dysfunction can have important consequences for cancer patient management. At a minimum, the symptoms will adversely affect the patient’s quality of life. Alternatively, such symptoms can lead to dose reductions of potentially life-saving therapies. Hypothyroidism can also alter the kinetics and clearance of medications, which may lead to undesirable side effects. Thyrotoxicosis can be mistaken for sepsis or a nonendocrinologic drug side effect. In some patients, thyroid disease may indicate a higher likelihood of tumor response to the agent. Both hypothyroidism and thyrotoxicosis are easily diagnosed with inexpensive and specific tests. In many patients, particularly those with hypothyroidism, the treatment is straightforward. We therefore recommend routine testing for thyroid abnormalities in patients receiving these antineoplastic agents. PMID:22010182

Blood pressure normalization post-jugular venous balloon angioplasty.

PubMed

Sternberg, Zohara; Grewal, Prabhjot; Cen, Steven; DeBarge-Igoe, Frances; Yu, Jinhee; Arata, Michael

2015-05-01

This study is the first in a series investigating the relationship between autonomic nervous system dysfunction and chronic cerebrospinal venous insufficiency in multiple sclerosis patients. We screened patients for the combined presence of the narrowing of the internal jugular veins and symptoms of autonomic nervous system dysfunction (fatigue, cognitive dysfunction, sleeping disorders, headache, thermal intolerance, bowel/bladder dysfunction) and determined systolic and diastolic blood pressure responses to balloon angioplasty. The criteria for eligibility for balloon angioplasty intervention included ≥ 50% narrowing in one or both internal jugular veins, as determined by the magnetic resonance venography, and ≥ 3 clinical symptoms of autonomic nervous system dysfunction. Blood pressure was measured at baseline and post-balloon angioplasty. Among patients who were screened, 91% were identified as having internal jugular veins narrowing (with obstructing lesions) combined with the presence of three or more symptoms of autonomic nervous system dysfunction. Balloon angioplasty reduced the average systolic and diastolic blood pressure. However, blood pressure categorization showed a biphasic response to balloon angioplasty. The procedure increased blood pressure in multiple sclerosis patients who presented with baseline blood pressure within lower limits of normal ranges (systolic ≤ 105 mmHg, diastolic ≤ 70 mmHg) but decreased blood pressure in patients with baseline blood pressure above normal ranges (systolic ≥ 130 mmHg, diastolic ≥ 80 mmHg). In addition, gender differences in baseline blood pressure subcategories were observed. The coexistence of internal jugular veins narrowing and symptoms of autonomic nervous system dysfunction suggests that the two phenomena may be related. Balloon angioplasty corrects blood pressure deviation in multiple sclerosis patients undergoing internal jugular vein dilation. Further studies should investigate the association between blood pressure deviation and internal jugular veins narrowing, and whether blood pressure normalization affects Patient's clinical outcomes. © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Brain 18F-FDG PET Metabolic Abnormalities in Patients with Long-Lasting Macrophagic Myofascitis.

PubMed

Van Der Gucht, Axel; Aoun Sebaiti, Mehdi; Guedj, Eric; Aouizerate, Jessie; Yara, Sabrina; Gherardi, Romain K; Evangelista, Eva; Chalaye, Julia; Cottereau, Anne-Ségolène; Verger, Antoine; Bachoud-Levi, Anne-Catherine; Abulizi, Mukedaisi; Itti, Emmanuel; Authier, François-Jérôme

2017-03-01

The aim of this study was to characterize brain metabolic abnormalities in patients with macrophagic myofascitis (MMF) and the relationship with cognitive dysfunction through the use of PET with 18 F-FDG. Methods: 18 F-FDG PET brain imaging and a comprehensive battery of neuropsychological tests were performed in 100 consecutive MMF patients (age [mean ± SD], 45.9 ± 12 y; 74% women). Images were analyzed with statistical parametric mapping (SPM12). Through the use of analysis of covariance, all 18 F-FDG PET brain images of MMF patients were compared with those of a reference population of 44 healthy subjects similar in age (45.4 ± 16 y; P = 0.87) and sex (73% women; P = 0.88). The neuropsychological assessment identified 4 categories of patients: those with no significant cognitive impairment ( n = 42), those with frontal subcortical (FSC) dysfunction ( n = 29), those with Papez circuit dysfunction ( n = 22), and those with callosal disconnection ( n = 7). Results: In comparison with healthy subjects, the whole population of patients with MMF exhibited a spatial pattern of cerebral glucose hypometabolism ( P < 0.001) involving the occipital lobes, temporal lobes, limbic system, cerebellum, and frontoparietal cortices, as shown by analysis of covariance. The subgroup of patients with FSC dysfunction exhibited a larger extent of involved areas (35,223 voxels vs. 13,680 voxels in the subgroup with Papez circuit dysfunction and 5,453 voxels in patients without cognitive impairment). Nonsignificant results were obtained for the last subgroup because of its small population size. Conclusion: Our study identified a peculiar spatial pattern of cerebral glucose hypometabolism that was most marked in MMF patients with FSC dysfunction. Further studies are needed to determine whether this pattern could represent a diagnostic biomarker of MMF in patients with chronic fatigue syndrome and cognitive dysfunction. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Sepsis-induced myocardial dysfunction and myocardial protection from ischemia/reperfusion injury.

PubMed

McDonough, Kathleen H; Virag, Jitka Ismail

2006-01-01

Sepsis, bacteremia and inflammation cause myocardial depression. The mechanism of the dysfunction is not clearly established partly because dysfunction can be elicited by many different mechanisms which can all manifest in disruption of myocardial mechanical function. In addition the models of sepsis and bacteremia and inflammation may vary drastically in the sequence of the coordinated immune response to the inflammatory or septic stimulus. Patterns of cytokine expression can vary as can other responses of the immune system. Patterns of neurohumoral activation in response to the stress of sepsis or bacteremia or inflammation can also vary in both magnitude of response and temporal sequence of response. Stress induced activation of the sympathetic nervous system and humoral responses to stress have a wide range of intensity that can be elicited. The fairly uniform response of the myocardium indicating cardiac dysfunction is surprisingly constant. Systolic performance, as measured by stroke volume or cardiac output and pressure work as estimated by ventricular pressure, are impaired when myocardial contraction is compromised. At times, diastolic function, assessed by ventricular relaxation and filling, is impaired. In addition to the dysfunction that occurs, there is a longer term response of the myocardium to sepsis, and this response is similar to that which is elicited in the heart by multiple brief ischemia/reperfusion episodes and by numerous pharmacological agents as well as heat stress and modified forms of lipopolysaccharide. The myocardium develops protection after an initial stress such that during a second stress, the myocardium does not exhibit as much damage as does a non-protected heart. Many agents can induce this protection which has been termed preconditioning. Both early preconditioning (protection that is measurable min to hours after the initial stimulus) and late preconditioning (protection that is measurable hours to days after the initial trigger or stimulus) are effective in protecting the heart from prolonged ischemia and reperfusion injury. Understanding the mechanisms of sepsis/bacteremia induced dysfunction and protection and if the dysfunction and protection are the products of the same intracellular pathways is important in protecting the heart from failing to perform adequately during severe sepsis and/or septic shock and for understanding the multitude of mechanism by which the myocardium maintains reserve capacity.

Autoimmunity in the pathogenesis and treatment of keratoconjunctivitis sicca.

PubMed

Liu, Katy C; Huynh, Kyle; Grubbs, Joseph; Davis, Richard M

2014-01-01

Dry eye is a chronic corneal disease that impacts the quality of life of many older adults. Keratoconjunctivitis sicca (KCS), a form of aqueous-deficient dry eye, is frequently associated with Sjögren's syndrome and mechanisms of autoimmunity. For KCS and other forms of dry eye, current treatments are limited, with many medications providing only symptomatic relief rather than targeting the pathophysiology of disease. Here, we review proposed mechanisms in the pathogenesis of autoimmune-based KCS: genetic susceptibility and disruptions in antigen recognition, immune response, and immune regulation. By understanding the mechanisms of immune dysfunction through basic science and translational research, potential drug targets can be identified. Finally, we discuss current dry eye therapies as well as promising new treatment options and drug therapy targets.

Parasitic nematode-induced modulation of body weight and associated metabolic dysfunction in mouse models of obesity

USDA-ARS?s Scientific Manuscript database

Obesity is associated with a chronic low grade inflammation characterized by high level of pro-inflammatory cytokines and mediators implicated in disrupted metabolic homeostasis. Parasitic nematode infection induces a polarized Th2 cytokine response and has been shown to modulate immune-based pathol...

Life Events, Social Support, and Immune Response in Elderly Individuals.

ERIC Educational Resources Information Center

McIntosh, William Alex; And Others

1993-01-01

Investigated effects of recent life events, psychological adjustment, and social support on lymphocyte count among 192 older adults. For males, recent sexual dysfunction lowered lymphocyte count, whereas psychological adjustment and percentage kin in intimate network elevated it. For females, family or legal problems elevated count as did frequent…

Brief Report: Alternative Approaches to the Development of Effective Treatments for Autism.

ERIC Educational Resources Information Center

Rimland, Bernard; Baker, Sidney M.

1996-01-01

The most widely used "alternative" biomedical treatments for autism are reviewed, including: nutritional supplements, especially megadose vitamin B6 and magnesium; treatment of food allergies and intolerances; treatment of microbial infections; and treatment of immune system dysfunction. The Defeat Autism Now! project is briefly…

Effect of borax on immune cell proliferation and sister chromatid exchange in human chromosomes

PubMed Central

Pongsavee, Malinee

2009-01-01

Background Borax is used as a food additive. It becomes toxic when accumulated in the body. It causes vomiting, fatigue and renal failure. Methods The heparinized blood samples from 40 healthy men were studied for the impact of borax toxicity on immune cell proliferation (lymphocyte proliferation) and sister chromatid exchange in human chromosomes. The MTT assay and Sister Chromatid Exchange (SCE) technic were used in this experiment with the borax concentrations of 0.1, 0.15, 0.2, 0.3 and 0.6 mg/ml. Results It showed that the immune cell proliferation (lymphocyte proliferation) was decreased when the concentrations of borax increased. The borax concentration of 0.6 mg/ml had the most effectiveness to the lymphocyte proliferation and had the highest cytotoxicity index (CI). The borax concentrations of 0.15, 0.2, 0.3 and 0.6 mg/ml significantly induced sister chromatid exchange in human chromosomes (P < 0.05). Conclusion Borax had effects on immune cell proliferation (lymphocyte proliferation) and induced sister chromatid exchange in human chromosomes. Toxicity of borax may lead to cellular toxicity and genetic defect in human. PMID:19878537

YAP is essential for Treg mediated suppression of anti-tumor immunity.

PubMed

Ni, Xuhao; Tao, Jinhui; Barbi, Joseph; Chen, Qian; Park, Benjamin V; Li, Zhiguang; Zhang, Nailing; Lebid, Andriana; Ramaswamy, Anjali; Wei, Ping; Zheng, Ying; Zhang, Xuehong; Wu, Xingmei; Vignali, Paolo D A; Yang, Cuiping; Li, Huabin; Pardoll, Drew; Lu, Ling; Pan, Duojia; Pan, Fan

2018-06-15

Regulatory T cells (Tregs) are critical for maintaining self-tolerance and immune homeostasis, but their suppressive function can impede effective anti-tumor immune responses. Foxp3 is a transcription factor expressed in Tregs that is required for their function. However, the pathways and microenvironmental cues governing Foxp3 expression and Treg function are not completely understood. Herein, we report that Yes-associated protein (YAP), a co-activator of the Hippo pathway, is highly expressed in Tregs and bolsters Foxp3 expression and Treg function in vitro and in vivo. This potentiation stemmed from YAP-dependent upregulation of Activin signaling which amplifies TGFβ/SMAD activation in Tregs. YAP-deficiency resulted in dysfunctional Tregs unable to suppress anti-tumor immunity or promote tumor growth in mice. Chemical YAP antagonism and knockout or blockade of the YAP-regulated Activin Receptor similarly improved anti-tumor immunity. Thus we identify YAP as an unexpected amplifier of a Treg-reinforcing pathway with significant potential as an anti-cancer immunotherapeutic target. Copyright ©2018, American Association for Cancer Research.

Immune Cells Link Obesity-associated Type 2 Diabetes and Periodontitis

PubMed Central

Zhu, M.; Nikolajczyk, B.S.

2014-01-01

The clinical association between obesity-associated type 2 diabetes (T2D) and periodontitis, coupled with the increasing prevalence of these diseases, justifies studies to identify mechanisms responsible for the vicious feed-forward loop between systemic and oral disease. Changes in the immune system are critical for both obesity-associated T2D and periodontitis and therefore may link these diseases. Recent studies at the intersection of immunology and metabolism have greatly advanced our understanding of the role the immune system plays in the transition between obesity and obesity-associated T2D and have shown that immune cells exhibit similar functional changes in obesity/T2D and periodontitis. Furthermore, myeloid and lymphoid cells likely synergize to promote obesity/T2D-associated periodontitis despite complexities introduced by disease interaction. Thus the groundwork is being laid for researchers to exploit existing models to understand immune cell dysfunction and break the devastating relationship between obesity-associated T2D and oral disease. PMID:24393706

N-Acetyl-Seryl-Aspartyl-Lysyl-Proline: mechanisms of renal protection in mouse model of systemic lupus erythematosus

PubMed Central

Liao, Tang-Dong; Nakagawa, Pablo; Janic, Branislava; D'Ambrosio, Martin; Worou, Morel E.; Peterson, Edward L.; Rhaleb, Nour-Eddine; Yang, Xiao-Ping

2015-01-01

Systemic lupus erythematosus is an autoimmune disease characterized by the development of auto antibodies against a variety of self-antigens and deposition of immune complexes that lead to inflammation, fibrosis, and end-organ damage. Up to 60% of lupus patients develop nephritis and renal dysfunction leading to kidney failure. N-acetyl-seryl-aspartyl-lysyl-proline, i.e., Ac-SDKP, is a natural tetrapeptide that in hypertension prevents inflammation and fibrosis in heart, kidney, and vasculature. In experimental autoimmune myocarditis, Ac-SDKP prevents cardiac dysfunction by decreasing innate and adaptive immunity. It has also been reported that Ac-SDKP ameliorates lupus nephritis in mice. We hypothesize that Ac-SDKP prevents lupus nephritis in mice by decreasing complement C5-9, proinflammatory cytokines, and immune cell infiltration. Lupus mice treated with Ac-SDKP for 20 wk had significantly lower renal levels of macrophage and T cell infiltration and proinflammatory chemokine/cytokines. In addition, our data demonstrate for the first time that in lupus mouse Ac-SDKP prevented the increase in complement C5-9, RANTES, MCP-5, and ICAM-1 kidney expression and it prevented the decline of glomerular filtration rate. Ac-SDKP-treated lupus mice had a significant improvement in renal function and lower levels of glomerular damage. Ac-SDKP had no effect on the production of autoantibodies. The protective Ac-SDKP effect is most likely achieved by targeting the expression of proinflammatory chemokines/cytokines, ICAM-1, and immune cell infiltration in the kidney, either directly or via C5-9 proinflammatory arm of complement system. PMID:25740596

Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eµ-TCL1 CLL mouse model.

PubMed

McClanahan, Fabienne; Riches, John C; Miller, Shaun; Day, William P; Kotsiou, Eleni; Neuberg, Donna; Croce, Carlo M; Capasso, Melania; Gribben, John G

2015-07-09

T-cell defects, immune suppression, and poor antitumor immune responses are hallmarks of chronic lymphocytic leukemia (CLL), and PD-1/PD-L1 inhibitory signaling has emerged as a major immunosuppressive mechanism. However, the effect of different microenvironments and the confounding influence of aging are poorly understood. The current study uses the Eμ-TCL1 mouse model, which replicates human T-cell defects, as a preclinical platform to longitudinally examine patterns of T-cell dysfunction alongside developing CLL and in different microenvironments, with a focus on PD-1/PD-L1 interactions. The development of CLL was significantly associated with changes in T-cell phenotype across all organs and function. Although partly mirrored in aging wild-type mice, CLL-specific T-cell changes were identified. Murine CLL cells highly expressed PD-L1 and PD-L2 in all organs, with high PD-L1 expression in the spleen. CD3(+)CD8(+) T cells from leukemic and aging healthy mice highly expressed PD-1, identifying aging as a confounder, but adoptive transfer experiments demonstrated CLL-specific PD-1 induction. Direct comparisons of PD-1 expression and function between aging CLL mice and controls identified PD-1(+) T cells in CLL as a heterogeneous population with variable effector function. This is highly relevant for therapeutic targeting of CD8(+) T cells, showing the potential of reprogramming and selective subset expansion to restore antitumor immunity. © 2015 by The American Society of Hematology.

Cytotoxic immune responses in the lungs correlate to disease severity in patients with hantavirus infection.

PubMed

Rasmuson, J; Pourazar, J; Mohamed, N; Lejon, K; Evander, M; Blomberg, A; Ahlm, C

2016-04-01

Hantavirus infections may cause severe and sometime life-threatening lung failure. The pathogenesis is not fully known and there is an urgent need for effective treatment. We aimed to investigate the association between pulmonary viral load and immune responses, and their relation to disease severity. Bronchoscopy with sampling of bronchoalveolar lavage (BAL) fluid was performed in 17 patients with acute Puumala hantavirus infection and 16 healthy volunteers acting as controls. Lymphocyte subsets, granzyme concentrations, and viral load were determined by flow cytometry, enzyme-linked immunosorbent assay (ELISA), and quantitative reverse transcription polymerase chain reaction (RT-PCR), respectively. Analyses of BAL fluid revealed significantly higher numbers of activated CD8(+) T cells and natural killer (NK) cells, as well as higher concentrations of the cytotoxins granzymes A and B in hantavirus-infected patients, compared to controls. In patients, Puumala hantavirus RNA was detected in 88 % of BAL cell samples and correlated inversely to the T cell response. The magnitude of the pulmonary cytotoxic lymphocyte response correlated to the severity of disease and systemic organ dysfunction, in terms of need for supplemental oxygen treatment, hypotension, and laboratory data indicating renal failure, cardiac dysfunction, vascular leakage, and cell damage. Regulatory T cell numbers were significantly lower in patients compared to controls, and may reflect inadequate immune regulation during hantavirus infection. Hantavirus infection elicits a pronounced cytotoxic lymphocyte response in the lungs. The magnitude of the immune response was associated with disease severity. These results give insights into the pathogenesis and possibilities for new treatments.

Immunomodulatory intervention with Gamma interferon in mice with sepsis.

PubMed

Wang, Yu; Kong, Bing-Bing; Yang, Wen-Ping; Zhao, Xin; Zhang, Rong

2017-09-15

Sepsis-triggered immune paralysis including T-cell dysfunction increase susceptibility to infection. Gamma interferon (IFNg) exert beneficial effects in patients with sepsis. Herein, we speculated that IFNg may attenuate T-cell dysfunction induced by sepsis, although the mechanisms remain elusive. To test this hypothesis, we used a model based on cecal ligation and puncture (CLP) to induce sepsis in mice. Male C57BL/6 mice were pretreated with recombinant human IFNg (0.01μg/g of body weight) before CLP. The immunophenotyping of cell surface receptor expression, and regulatory T cells (CD4+CD25+Foxp3+) were quantified by flow cytometry. Immunohistochemical staining was performed to evaluate the loss of immune effector cells. Formation of IFNg and interleukin 4 (IL-4) in the spleen and plasma levels of TNF-α, IL-6, high-mobility group box 1 (HMGB1) were determined using enzyme-linked immunosorbent assay. IFNg markedly inhibited the reduction in cytokine secretion from lipopolysaccharide (LPS)-stimulated splenocytes. IFNg-treated mices had significantly decreased percentages of programmed cell death 1 (PD-1) receptors, increased the percentages of positive costimulatory receptor CD28 on CD4 T cells expressing. IFNg markedly reduced T-cell apoptosis through upregulating the expression of Bcl-2. CLP-induced formation of regulatory T cells in the spleen was abolished in IFNg -treated mices. Moreover, IFNg treatment reduced plasma levels of TNF-α, IL-6, HMGB1. IFNg can be a powerful regulator of immune function under sepsis conditions. Therefore, targeted immune-enhancement with IFNg may be a valid therapeutic approach in sepsis. Copyright © 2017 Elsevier Inc. All rights reserved.

The polyomavirus puzzle: is host immune response beneficial in controlling BK virus after adult hematopoietic cell transplantion?

PubMed

Satyanarayana, G; Marty, F M; Tan, C S

2014-08-01

BK virus (BKV), a ubiquitous human polyomavirus, usually does not cause disease in healthy individuals. BKV reactivation and disease can occur in immunosuppressed individuals, such as those who have undergone renal transplantation or hematopoietic cell transplantation (HCT). Clinical manifestations of BKV disease include graft dysfunction and failure in renal transplant recipients; HCT recipients frequently experience hematuria, cystitis, hemorrhagic cystitis (HC), and renal dysfunction. Studies of HCT patients have identified several risk factors for the development of BKV disease including myeloablative conditioning, acute graft-versus-host disease, and undergoing an umbilical cord blood (uCB) HCT. Although these risk factors indicate that alterations in the immune system are necessary for BKV pathogenesis in HCT patients, few studies have examined the interactions between host immune responses and viral reactivation in BKV disease. Specifically, having BKV immunoglobulin-G before HCT does not protect against BKV infection and disease after HCT. A limited number of studies have demonstrated BKV-specific cytotoxic T cells in healthy adults as well as in post-HCT patients who had experienced HC. New areas of research are required for a better understanding of this emerging infectious disease post HCT, including prospective studies examining BK viruria, viremia, and their relationship with clinical disease, a detailed analysis of urothelial histopathology, and laboratory evaluation of systemic and local cellular and humoral immune responses to BKV in patients receiving HCT from different sources, including uCB and haploidentical donors. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Mechanisms of PD-L1/PD-1–mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eµ-TCL1 CLL mouse model

PubMed Central

McClanahan, Fabienne; Riches, John C.; Miller, Shaun; Day, William P.; Kotsiou, Eleni; Neuberg, Donna; Croce, Carlo M.; Capasso, Melania

2015-01-01

T-cell defects, immune suppression, and poor antitumor immune responses are hallmarks of chronic lymphocytic leukemia (CLL), and PD-1/PD-L1 inhibitory signaling has emerged as a major immunosuppressive mechanism. However, the effect of different microenvironments and the confounding influence of aging are poorly understood. The current study uses the Eμ-TCL1 mouse model, which replicates human T-cell defects, as a preclinical platform to longitudinally examine patterns of T-cell dysfunction alongside developing CLL and in different microenvironments, with a focus on PD-1/PD-L1 interactions. The development of CLL was significantly associated with changes in T-cell phenotype across all organs and function. Although partly mirrored in aging wild-type mice, CLL-specific T-cell changes were identified. Murine CLL cells highly expressed PD-L1 and PD-L2 in all organs, with high PD-L1 expression in the spleen. CD3+CD8+ T cells from leukemic and aging healthy mice highly expressed PD-1, identifying aging as a confounder, but adoptive transfer experiments demonstrated CLL-specific PD-1 induction. Direct comparisons of PD-1 expression and function between aging CLL mice and controls identified PD-1+ T cells in CLL as a heterogeneous population with variable effector function. This is highly relevant for therapeutic targeting of CD8+ T cells, showing the potential of reprogramming and selective subset expansion to restore antitumor immunity. PMID:25979947

Effect of Mesenchymal Stromal Cells on T Cells in a Septic Context: Immunosuppression or Immunostimulation?

PubMed

Le Burel, Sébastien; Thepenier, Cédric; Boutin, Laetitia; Lataillade, Jean-Jacques; Peltzer, Juliette

2017-10-15

Sepsis is a complex process, including a first wave of damage partially due to the body's response to pathogens, followed by a phase of immune cell dysfunction. The efficacy of a pharmacological approach facing a rapidly evolving system implies a perfect timing of administration-this difficulty could explain the recent failure of clinical trials. Mesenchymal stromal cells (MSCs) are usually defined as immunosuppressive and their beneficial effects in preclinical models of acute sepsis have been shown to rely partly on such ability. If nonregulated, this phenotype could be harmful in the immunosuppressed context arising hours after sepsis onset. However, MSCs being environment sensitive, we hypothesized that they could reverse their immunosuppressive properties when confronted with suffering immune cells. Our objective was to evaluate the effect of human MSCs on activated human lymphocytes in an in vitro endotoxemia model. Peripheral blood mononuclear cells (PBMCs) underwent a 24-h lipopolysaccharide (LPS) intoxication and were stimulated with phytohemagglutinin (PHA) in contact with MSCs. MSCs induced a differential effect on lymphocytes depending on PBMC intoxication with LPS. Unintoxicated lymphocytes were highly proliferative with PHA and were inhibited by MSCs, whereas LPS-intoxicated lymphocytes showed a low proliferation rate, but were supported by MSCs, even when monocytes were depleted. These data, highlighting MSC plasticity in their immunomodulatory activity, pave the way for further studies investigating the mechanisms of mutual interactions between MSCs and immune cells in sepsis. Thus, MSCs might be able to fight against both early sepsis-induced hyperinflammatory response and later time points of immune dysfunction.

Surface-Micromachined Microfiltration Membranes for Efficient Isolation and Functional Immunophenotyping of Subpopulations of Immune Cells

PubMed Central

Oh, Boram; Lam, Raymond H. W.; Fan, Rong; Cornell, Timothy T.; Shanley, Thomas P.; Kurabayashi, Katsuo; Fu, Jianping

2015-01-01

An accurate measurement of the immune status in patients with immune system disorders is critical in evaluating the stage of diseases and tailoring drug treatments. The functional cellular immunity test is a promising method to establish the diagnosis of immune dysfunctions. The conventional functional cellular immunity test involves measurements of the capacity of peripheral blood mononuclear cells to produce pro-inflammatory cytokines when stimulated ex vivo. However, this “bulk” assay measures the overall reactivity of a population of lymphocytes and monocytes, making it difficult to pinpoint the phenotype or real identity of the reactive immune cells involved. In this research, we develop a large surface micromachined polydimethylsiloxane (PDMS) microfiltration membrane (PMM) with high porosity, which is integrated in a microfluidic microfiltration platform. Using the PMM with functionalized microbeads conjugated with antibodies against specific cell surface proteins, we demonstrated rapid, efficient and high-throughput on-chip isolation, enrichment, and stimulation of subpopulations of immune cells from blood specimens. Furthermore, the PMM-integrated microfiltration platform, coupled with a no-wash homogeneous chemiluminescence assay (“AlphaLISA”), enables us to demonstrate rapid and sensitive on-chip immunophenotyping assays for subpopulations of immune cells isolated directly from minute quantities of blood samples. PMID:23335389

Modulation of Multiple Sclerosis and Its Animal Model Experimental Autoimmune Encephalomyelitis by Food and Gut Microbiota

PubMed Central

van den Hoogen, Ward J.; Laman, Jon D.; ’t Hart, Bert A.

2017-01-01

Multiple sclerosis (MS) is an autoimmune neurological disease characterized by chronic inflammation of the central nervous system (CNS), leading to demyelination, axonal damage, and symptoms such as fatigue and disability. Although the cause of MS is not known, the infiltration of peripherally activated immune cells into the CNS has a key pathogenic role. Accumulating evidence supports an important role of diet and gut microbiota in immune-mediated diseases. Preclinical as well as clinical studies suggest a role for gut microbiota and dietary components in MS. Here, we review these recent studies on gut microbiota and dietary interventions in MS and its animal model experimental autoimmune encephalomyelitis. We also propose directions for future research. PMID:28928747

Influence of diabetes mellitus on immunity to human tuberculosis.

PubMed

Kumar Nathella, Pavan; Babu, Subash

2017-09-01

Type 2 diabetes mellitus(DM) is a major risk factor for the development of active pulmonary tuberculosis (TB), with development of DM pandemic in countries where TB is also endemic. Understanding the impact of DM on TB and the determinants of co-morbidity is essential in responding to this growing public health problem with improved therapeutic approaches. Despite the clinical and public health significance posed by the dual burden of TB and DM, little is known about the immunological and biochemical mechanisms of susceptibility. One possible mechanism is that an impaired immune response in patients with DM facilitates either primary infection with Mycobacterium tuberculosis or reactivation of latent TB. Diabetes is associated with immune dysfunction and alterations in the components of the immune system, including altered levels of specific cytokines and chemokines. Some effects of DM on adaptive immunity that are potentially relevant to TB defence have been identified in humans. In this review, we summarize current findings regarding the alterations in the innate and adaptive immune responses and immunological mechanisms of susceptibility of patients with DM to M. tuberculosis infection and disease. © 2017 John Wiley & Sons Ltd.

Mechanistic Modelling of Drug-Induced Liver Injury: Investigating the Role of Innate Immune Responses.

PubMed

Shoda, Lisl Km; Battista, Christina; Siler, Scott Q; Pisetsky, David S; Watkins, Paul B; Howell, Brett A

2017-01-01

Drug-induced liver injury (DILI) remains an adverse event of significant concern for drug development and marketed drugs, and the field would benefit from better tools to identify liver liabilities early in development and/or to mitigate potential DILI risk in otherwise promising drugs. DILIsym software takes a quantitative systems toxicology approach to represent DILI in pre-clinical species and in humans for the mechanistic investigation of liver toxicity. In addition to multiple intrinsic mechanisms of hepatocyte toxicity (ie, oxidative stress, bile acid accumulation, mitochondrial dysfunction), DILIsym includes the interaction between hepatocytes and cells of the innate immune response in the amplification of liver injury and in liver regeneration. The representation of innate immune responses, detailed here, consolidates much of the available data on the innate immune response in DILI within a single framework and affords the opportunity to systematically investigate the contribution of the innate response to DILI.

Nucleic acid sensing and innate immunity: signaling pathways controlling viral pathogenesis and autoimmunity.

PubMed

Ahlers, Laura R H; Goodman, Alan G

2016-09-01

Innate immunity refers to the body's initial response to curb infection upon exposure to invading organisms. While the detection of pathogen-associated molecules is an ancient form of host defense, if dysfunctional, autoimmune disease may result. The innate immune response during pathogenic infection is initiated through the activation of receptors recognizing conserved molecular patterns, such as nucleic acids from a virus' genome or replicative cycle. Additionally, the host's own nucleic acids are capable of activating an immune response. Therefore, it follows that the nucleic acid-sensing pathways must be tightly controlled to avoid an autoimmune response from recognition of self, yet still be unimpeded to respond to viral infections. In this review, we will describe the nucleic acid sensing pathways and how they respond to virus infection. Moreover, we will discuss autoimmune diseases that develop when these pathways fail to signal properly and identify knowledge gaps that are prime for interrogation.

HLA Immune Function Genes in Autism

PubMed Central

Torres, Anthony R.; Westover, Jonna B.; Rosenspire, Allen J.

2012-01-01

The human leukocyte antigen (HLA) genes on chromosome 6 are instrumental in many innate and adaptive immune responses. The HLA genes/haplotypes can also be involved in immune dysfunction and autoimmune diseases. It is now becoming apparent that many of the non-antigen-presenting HLA genes make significant contributions to autoimmune diseases. Interestingly, it has been reported that autism subjects often have associations with HLA genes/haplotypes, suggesting an underlying dysregulation of the immune system mediated by HLA genes. Genetic studies have only succeeded in identifying autism-causing genes in a small number of subjects suggesting that the genome has not been adequately interrogated. Close examination of the HLA region in autism has been relatively ignored, largely due to extraordinary genetic complexity. It is our proposition that genetic polymorphisms in the HLA region, especially in the non-antigen-presenting regions, may be important in the etiology of autism in certain subjects. PMID:22928105

Polymorphism in liver-stage malaria vaccine candidate proteins: immune evasion and implications for vaccine design.

PubMed

Flanagan, Katie L; Wilson, Kirsty L; Plebanski, Magdalena

2016-01-01

The pre-erythrocytic stage of infection by malaria parasites represents a key target for vaccines that aim to eradicate malaria. Two important broad immune evasion strategies that can interfere with vaccine efficacy include the induction of dendritic cell (DC) dysfunction and regulatory T cells (Tregs) by blood-stage malaria parasites, leading to inefficient priming of T cells targeting liver-stage infections. The parasite also uses 'surgical strike' strategies, whereby polymorphism in pre-erythrocytic antigens can interfere with host immunity. Specifically, we review how even single amino acid changes in T cell epitopes can lead to loss of binding to major histocompatibility complex (MHC), lack of cross-reactivity, or antagonism and immune interference, where simultaneous or sequential stimulation with related variants of the same T cell epitope can cause T cell anergy or the conversion of effector to immunosuppressive T cell phenotypes.

Influence of chemotherapy for lymphoma in canine parvovirus DNA distribution and specific humoral immunity.

PubMed

Elias, M A; Duarte, A; Nunes, T; Lourenço, A M; Braz, B S; Vicente, G; Henriques, J; Tavares, L

2014-12-01

In man, the combination of cancer and its treatment increases patients' susceptibility to opportunistic infections, due to immune system impairment. In veterinary medicine little information is available concerning this issue. In order to evaluate if a similar dysfunction is induced in small animals undergoing chemotherapy, we assessed the complete blood count, leukocytic, plasma and fecal canine parvovirus (CPV) viral load, and anti-CPV protective antibody titers, in dogs with lymphoma treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) protocol, before and during chemotherapy. There was no evidence of decreased immune response, either at admission or after two chemotherapy cycles, indicating that the previously established immunity against CPV was not significantly impaired, supporting the idea that immunosuppression as a result of hematopoietic neoplasms and their treatment in dogs requires further investigation and conclusions cannot be extrapolated from human literature. Copyright © 2014 Elsevier Ltd. All rights reserved.

Endocrine toxicity of immune checkpoint inhibitors: essential crosstalk between endocrinologists and oncologists.

PubMed

Illouz, Frédéric; Briet, Claire; Cloix, Lucie; Le Corre, Yannick; Baize, Nathalie; Urban, Thierry; Martin, Ludovic; Rodien, Patrice

2017-08-01

Two types of immune checkpoint inhibitors, both antibodies that target cytotoxic T-lymphocyte antigen-4 and those that target programmed cell death-protein 1, have been approved for use in melanoma, non-small-cell lung cancer, and renal cell carcinoma as first-line or second-line therapy. Their adverse events are primarily regarded as immune-related adverse events. We felt it was important to pinpoint and discuss certain preconceptions or misconceptions regarding thyroid dysfunction, hypophysitis, and diabetes induced by immune checkpoint inhibitors. We have identified areas of uncertainty and unmet requirements, including essential interaction between endocrinologists and oncologists. Five issues have been identified for discussion: (1) diagnosis of endocrine toxicity, (2) assessment of toxicity severity, (3) treatment of toxicity, (4) withdrawal or continuation of immunotherapy, (5) preventive action. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Blood Pressure, Sleep Quality and Fatigue in Shift Working Police Officers: Effects of a Twelve Hour Roster System on Cardiovascular and Sleep Health.

PubMed

Elliott, Jaymen L; Lal, Sara

2016-01-29

Police officers have been reported to exhibit a high incidence of pathologies, which present prematurely in an otherwise healthy population. Shift work has also been associated with an increased risk of cardiovascular and sleep disorders, attributable to its propensity for circadian rhythm dysfunction. However, contention exists as to whether shift work has a direct effect upon blood pressure (BP) regulation. This cross-sectional study sought to determine changes in BP and associations with the overall sleep quality and fatigue in 206 general duties police officers (n = 140 males) of the New South Wales Police Force in Australia. The subjects' BP was assessed before and after their twelve hour shift, during which time they also completed the Lifestyle Appraisal Questionnaire, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale and Fatigue Severity Scale (FSS). Poor sleep quality (PSQI) and fatigue severity (FSS) were found to predominate in the sample (69% and 51% respectively). Although there was no change in BP for male participants, female officers' systolic blood pressure (SBP) was found to increase significantly across the shift (p < 0.001), but with no change found in females' diastolic blood pressure (DBP). Finally, higher pre and post-shift SBP (r = -0.26, p = 0.001; r = -0.25, p = 0.001, respectively) and DBP (r = -0.26, p = 0.001; r = -0.26, p = 0.001, respectively) were significantly correlated with lower FSS scores after accounting for age, waist-hip ratio and lifestyle risk factors. Based on these preliminary findings, there was a significant increase in SBP of female police officers after shift work, while BP and fatigue levels in all police officers were strongly related. Moreover, the predominating poor sleep quality and impact of fatigue in this sample remain a concern. Further research is required to ensure the physiological welfare of police officers, while strategies must be implemented to manage the detrimental effects shift work may be having upon their cardiovascular and sleep health.