Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease (COVID-19) triggers the development of numerous pathologies and infection-linked complications and exacerbates existing pathologies in nearly all body systems. Aside from the primarily targeted respiratory organs, adverse SARS-CoV-2 effects were observed in nervous, cardiovascular, gastrointestinal/metabolic, immune, and other systems in COVID-19 survivors. Long-term effects of this viral infection have been recently observed and represent distressing sequelae recognised by the World Health Organisation (WHO) as a distinct clinical entity defined as post-COVID-19 condition. Considering the pandemic is still ongoing, more time is required to confirm post COVID-19 condition diagnosis in the COVID-19 infected cohorts, although many reported post COVID-19 symptoms overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). AIMS OF REVIEW: In this study, COVID-19 clinical presentation and associated post-infection sequelae (post-COVID-19 condition) were reviewed and compared with ME/CFS symptomatology. KEY SCIENTIFIC CONCEPTS OF REVIEW: The onset, progression, and symptom profile of post COVID-19 condition patients have considerable overlap with ME/CFS. Considering the large scope and range of pro-inflammatory effects of this virus, it is reasonable to expect development of post COVID-19 clinical complications in a proportion of the affected population. There are reports of a later debilitating syndrome onset three months post COVID-19 infection (often described as long-COVID-19), marked by the presence of fatigue, headache, cognitive dysfunction, post-exertional malaise, orthostatic intolerance, and dyspnoea. Acute inflammation, oxidative stress, and increased levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), have been reported in SARS-CoV-2 infected patients. Longitudinal monitoring of post COVID-19 patients is warranted to understand the long-term effects of SARS-CoV-2 infection and the pathomechanism of post COVID-19 condition.

Network Analysis of Symptoms Co-Occurrence in Chronic Fatigue Syndrome.

Chronic fatigue syndrome (CFS) is a heterogenous disorder of multiple disabling symptoms with complex manifestations. Network analysis is a statistical and interrogative methodology to investigate the prevalence of symptoms (nodes) and their inter-dependent (inter-nodal) relationships. In the present study, we explored the co-occurrence of symptoms in a cohort of Polish CFS patients using network analysis. A total of 110 patients with CFS were examined (75 females). The mean age of the total sample was 37.93 (8.5) years old while the mean duration of symptoms in years was 4.4 (4). Post-exertional malaise (PEM) was present in 75.45% of patients, unrefreshing sleep was noted in 89.09% and impaired memory or concentration was observed in 87.27% of patients. The least prevalent symptom was tender cervical or axillary lymph nodes, noted in 34.55% of the total sample. Three of the most densely connected nodes were the total number of symptoms, sore throat and PEM. PEM was positively related with impairment in memory or concentration. Both PEM and impairment in memory or concentration presence are related to more severe fatigue measured by CFQ and FIS. PEM presence was positively related with the presence of multi-joint pain and negatively with tender lymph nodes and muscle pain. Sore throat was related with objective and subjective autonomic nervous system impairment. This study helps define symptom presentation of CFS with the pathophysiology of specific systems and links with multidisciplinary contemporary molecular pathology, including comparative MRI.

Intra brainstem connectivity is impaired in chronic fatigue syndrome.

In myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), abnormal MRI correlations with symptom severity and autonomic measures have suggested impaired nerve signal conduction within the brainstem. Here we analyse fMRI correlations to directly test connectivity within and from the brainstem. Resting and task functional MRI (fMRI) were acquired for 45 ME/CFS (Fukuda criteria) and 27 healthy controls (HC). We selected limited brainstem reticular activation system (RAS) regions-of-interest (ROIs) based on previous structural MRI findings in a different ME/CFS cohort (bilateral rostral medulla and midbrain cuneiform nucleus), the dorsal Raphe nucleus, and two subcortical ROIs (hippocampus subiculum and thalamus intralaminar nucleus) reported to have rich brainstem connections. When HC and ME/CFS were analysed separately, significant correlations were detected for both groups during both rest and task, with stronger correlations during task than rest. In ME/CFS, connections were absent between medulla and midbrain nuclei, although hippocampal connections with these nuclei were enhanced. When corresponding correlations from HC and ME/CFS were compared, ME/CFS connectivity deficits were detected within the brainstem between the medulla and cuneiform nucleus and between the brainstem and hippocampus and intralaminar thalamus, but only during task. In CFS/ME, weaker connectivity between some RAS nuclei was associated with increased symptom severity. RAS neuron oscillatory signals facilitate coherence in thalamo-cortical oscillations. Brainstem RAS connectivity deficits can explain autonomic changes and diminish cortical oscillatory coherence which can impair attention, memory, cognitive function, sleep quality and muscle tone, all symptoms of ME/CFS.

Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in chronic fatigue syndrome.

We recruited 43 Chronic Fatigue Syndrome (CFS) subjects who met Fukuda criteria and 27 healthy controls and performed 3T MRI T1 and T2 weighted spin-echo (T1wSE and T2wSE) scans. T1wSE signal follows T1 relaxation rate (1/T1 relaxation time) and responds to myelin and iron (ferritin) concentrations. We performed MRI signal level group comparisons with SPM12. Spatial normalization after segmentation was performed using T2wSE scans and applied to the coregistered T1wSE scans. After global signal-level normalization of individual scans, the T1wSE group comparison detected decreased signal-levels in CFS in a brainstem region (cluster-based inference controlled for family wise error rate, PFWE= 0.002), and increased signal-levels in large bilateral clusters in sensorimotor cortex white matter (cluster PFWE < 0.0001). Moreover, the brainstem T1wSE values were negatively correlated with the sensorimotor values for both CFS (R2 = 0.31, P = 0.00007) and healthy controls (R2 = 0.34, P = 0.0009), and the regressions were co-linear. This relationship, previously unreported in either healthy controls or CFS, in view of known thalamic projection-fibre plasticity, suggests brainstem conduction deficits in CFS may stimulate the upregulation of myelin in the sensorimotor cortex to maintain brainstem - sensorimotor connectivity. VBM did not find group differences in regional grey matter or white matter volumes. We argued that increased T1wSE observed in sensorimotor WM in CFS indicates increased myelination which is a regulatory response to deficits in the brainstem although the causality cannot be tested in this study. Altered brainstem myelin may have broad consequences for cerebral function and should be a focus of future research.

Brain function characteristics of chronic fatigue syndrome: A task fMRI study.

The mechanism underlying neurological dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is yet to be established. This study investigated the temporal complexity of blood oxygenation level dependent (BOLD) changes in response to the Stroop task in CFS patients. 43 CFS patients (47.4 ±â€¯11.8 yrs) and 26 normal controls (NCs, 43.4 ±â€¯13.9 yrs) were included in this study. Their mental component summary (MCS) and physical component summary (PCS) from the 36-item Short Form Health Survey (SF-36) questionnaire were recorded. Their Stroop colour-word task performance was measured by accuracy and response time (RT). The BOLD changes associated with the Stroop task were evaluated using a 2-level general linear model approach. The temporal complexity of the BOLD responses, a measure of information capacity and thus adaptability to a challenging environment, in each activated region was measured by sample entropy (SampEn). The CFS patients showed significantly longer RTs than the NCs (P < 0.05) but no significant difference in accuracy. One sample t-tests for the two groups (Family wise error adjusted PFWE < 0.05) showed more BOLD activation regions in the CFS, although a two sample group comparison did not show significant difference. BOLD SampEns in ten regions were significantly lower (FDR-q < 0.05) in CFS patients. BOLD SampEns in 15 regions were significantly associated with PCS (FDR-q < 0.05) and in 9 regions were associated with MCS (FDR-q < 0.05) across all subjects. SampEn of the BOLD signal in the medioventral occipital cortex could explain 40% and 31% of the variance in the SF-36 PCS and MCS scores, and those in the precentral gyrus could explain an additional 16% and 7% across all subjects. This is the first study to investigate BOLD signal SampEn in response to tasks in CFS. The results suggest the brain responds differently to a cognitive challenge in patients with CFS, with recruitment of wider regions to compensate for lower information capacity.

Decreased Connectivity and Increased Blood Oxygenation Level Dependent Complexity in the Default Mode Network in Individuals with Chronic Fatigue Syndrome.

The chronic fatigue syndrome (CFS)/myalgic encephalomyelitis is a debilitating disease with unknown pathophysiology and no diagnostic test. This study investigated the default mode network (DMN) to understand the pathophysiology of CFS and to identify potential biomarkers. Using functional MRI (fMRI) collected from 72 subjects (45 CFS and 27 controls) with a temporal resolution of 0.798 sec, we evaluated the DMN using static functional connectivity (FC), dynamic functional connectivity (DFC) and DFC complexity, blood oxygenation level dependent (BOLD) activation maps, and complexity of activity. General linear model univariate analysis was used for intergroup comparison to account for age and gender differences. Hierarchical regression analysis was used to test whether fMRI measures could be used to explain variances of health scores. BOLD signals in the posterior cingulate cortex (PCC), the driving hub in the DMN, were more complex in CFS in both resting state and task (p < 0.05). The FCs between medial prefrontal cortex (mPFC) and both inferior parietal lobules (IPLs) were weaker (p < 0.05) during resting state, whereas during task mPFC-left IPL and mPFC-PCC were weaker (p < 0.05). The DFCs between the DMN hubs were more complex in CFS (p < 0.05) during task. Each of these differences accounted for 7-11% variability of health scores. This study showed that DMN activity is more complex and less coordinated in CFS, suggesting brain network analysis could be potentially used as a diagnostic biomarker for CFS.

Medial prefrontal cortex deficits correlate with unrefreshing sleep in patients with chronic fatigue syndrome.

Unrefreshing sleep is a hallmark of chronic fatigue syndrome/myalgic encephalomyelitis (CFS). This study examined brain structure variations associated with sleep quality in patients with CFS. 38 patients with CFS (34.8 ± 10.1 years old) and 14 normal controls (NCs) (34.7 ± 8.4 years old) were recruited. All subjects completed the Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index (PSQI), and Chalder Fatigue Scale (CFQ) questionnaires. Brain MRI measures included global and regional grey and white matter volumes, magnetization transfer T1 weighted (MT-T1w) intensities, and T1 weighted (T1w) and T2 weighted spin echo signal intensities. We performed voxel based group comparisons of these regional brain MRI measures and regressions of these measures with the PSQI and CFQ scales adjusted for age, anxiety and depression, and the appropriate global measure. In CFS patients, negative correlations were observed in the medial prefrontal cortex (mPFC) between PSQI and MT-T1w intensities (family-wise error corrected cluster, PFWE  < 0.05) and between PSQI and T1w intensities (PFWE  < 0.05). In the same mPFC location, both MT and T1w intensities were lower in CFS patients compared with NCs (uncorrected voxel P < 0.001). This study is the first to report that brain structural differences are associated with unrefreshing sleep in CFS. This result refutes the suggestion that unrefreshing sleep is a misperception in CFS patients and further investigation of this symptom is warranted.

Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients.

BACKGROUND: The etiology and pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) are unknown. However, natural killer (NK) cell dysfunction, in particular reduced NK cytotoxic activity, is a consistent finding in CFS/ME patients. Previous research has reported significant changes in intracellular mitogen-activated protein kinase pathways from isolated NK cells. The purpose of this present investigation was to examine whether protein kinase genes have a role in abnormal NK cell intracellular signaling in CFS/ME. METHOD: Messenger RNA (mRNA) expression of 528 protein kinase genes in isolated NK cells was analyzed (nCounter GX Human Kinase Kit v2 (XT); NanoString Technologies) from moderate (n = 11; age, 54.9 ± 10.3 years) and severe (n = 12; age, 47.5 ± 8.0 years) CFS/ME patients (classified by the 2011 International Consensus Criteria) and nonfatigued controls (n = 11; age, 50.0 ± 12.3 years). RESULTS: The expression of 92 protein kinase genes was significantly different in the severe CFS/ME group compared with nonfatigued controls. Among these, 37 genes were significantly upregulated and 55 genes were significantly downregulated in severe CFS/ME patients compared with nonfatigued controls. CONCLUSIONS: In severe CFS/ME patients, dysfunction in protein kinase genes may contribute to impairments in NK cell intracellular signaling and effector function. Similar changes in protein kinase genes may be present in other cells, potentially contributing to the pathomechanism of this illness.

Epidemiological characteristics of chronic fatigue syndrome/myalgic encephalomyelitis in Australian patients.

BACKGROUND: No epidemiological investigations have previously been conducted in Australia according to the current clinical definitions of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). The aim of this study was to describe sociodemographic and illness characteristics of Australian patients with CFS/ME. METHODS: A cross-sectional survey on the medical history of patients enrolled in an Australian CFS/ME research database between April 2013 and April 2015. Participants were classified according to Fukuda criteria and International Consensus Criteria. RESULTS: A total of 535 patients diagnosed with CFS/ME by a primary care physician were identified. The mean age of all patients was 46.4 years (standard deviation 12.0); the majority were female (78.61%), Caucasian, and highly educated. Of these, 30.28% met Fukuda criteria. A further 31.96% met both Fukuda criteria and International Consensus Criteria. There were 14.58% reporting chronic fatigue but did not meet criteria for CFS/ME and 23.18% were considered noncases due to exclusionary conditions. Within those meeting CFS/ME criteria, the most common events prior to illness included cold or flu, gastrointestinal illness, and periods of undue stress. Of the 60 symptoms surveyed, fatigue, cognitive, and short-term memory symptoms, headaches, muscle and joint pain, unrefreshed sleep, sensory disturbances, muscle weakness, and intolerance to extremes of temperature were the most commonly occurring symptoms (reported by more than two-thirds of patients). Significant differences in symptom occurrence between Fukuda- and International Consensus Criteria-defined cases were also identified. CONCLUSION: This is the first study to summarize sociodemographic and illness characteristics of a cohort of Australian CFS/ME patients. This is vital for identifying potential risk factors and predictors associated with CFS/ME and for guiding decisions regarding health care provision, diagnosis, and management.

A Systematic Review of Drug Therapies for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

PURPOSE: The pathogenesis of chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is complex and remains poorly understood. Evidence regarding the use of drug therapies in CFS/ME is currently limited and conflicting. The aim of this systematic review was to examine the existing evidence on the efficacy of drug therapies and determine whether any can be recommended for patients with CFS/ME. METHODS: MEDLINE, EMBASE, and PubMed databases were searched from the start of their records to March 2016 to identify relevant studies. Randomized controlled trials focusing solely on drug therapy to alleviate and/or eliminate chronic fatigue symptoms were included in the review. Any trials that considered graded exercise therapy, cognitive behavior therapy, adaptive pacing, or any other nonpharmaceutical treatment plans were excluded. The inclusion criteria were examined to ensure that study participants met specific CFS/ME diagnostic criteria. Study size, intervention, and end point outcome domains were summarized. FINDINGS: A total of 1039 studies were identified with the search terms; 26 studies met all the criteria and were considered suitable for review. Three different diagnostic criteria were identified: the Holmes criteria, International Consensus Criteria, and the Fukuda criteria. Primary outcomes were identified as fatigue, pain, mood, neurocognitive dysfunction and sleep quality, symptom severity, functional status, and well-being or overall health status. Twenty pharmaceutical classes were trialed. Ten medications were shown to be slightly to moderately effective in their respective study groups (P < 0.05). IMPLICATIONS: These findings indicate that no universal pharmaceutical treatment can be recommended. The unknown etiology of CFS/ME, and complications arising from its heterogeneous nature, contributes to the lack of clear evidence for pharmaceutical interventions. However, patients report using a large number and variety of medications. This finding highlights the need for trials with clearly defined CFS/ME cohorts. Trials based on more specific criteria such as the International Consensus Criteria are recommended to identify specific subgroups of patients in whom treatments may be beneficial.

Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study.

PURPOSE: To examine progressive brain changes associated with chronic fatigue syndrome (CFS). MATERIALS AND METHODS: We investigated progressive brain changes with longitudinal MRI in 15 CFS and 10 normal controls (NCs) scanned twice 6 years apart on the same 1.5 Tesla (T) scanner. MR images yielded gray matter (GM) volumes, white matter (WM) volumes, and T1- and T2-weighted signal intensities (T1w and T2w). Each participant was characterized with Bell disability scores, and somatic and neurological symptom scores. We tested for differences in longitudinal changes between CFS and NC groups, inter group differences between pooled CFS and pooled NC populations, and correlations between MRI and symptom scores using voxel based morphometry. The analysis methodologies were first optimized using simulated atrophy. RESULTS: We found a significant decrease in WM volumes in the left inferior fronto-occipital fasciculus (IFOF) in CFS while in NCs it was unchanged (family wise error adjusted cluster level P value, PFWE < 0.05). This longitudinal finding was consolidated by the group comparisons which detected significantly decreased regional WM volumes in adjacent regions (PFWE < 0.05) and decreased GM and blood volumes in contralateral regions (PFWE < 0.05). Moreover, the regional GM and WM volumes and T2w in those areas showed significant correlations with CFS symptom scores (PFWE < 0.05). CONCLUSION: The results suggested that CFS is associated with IFOF WM deficits which continue to deteriorate at an abnormal rate. J. Magn. Reson. Imaging 2016;44:1301-1311.

High-throughput sequencing of plasma microRNA in chronic fatigue syndrome/myalgic encephalomyelitis.

BACKGROUND: MicroRNAs (miRNAs) are known to regulate many biological processes and their dysregulation has been associated with a variety of diseases including Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). The recent discovery of stable and reproducible miRNA in plasma has raised the possibility that circulating miRNAs may serve as novel diagnostic markers. The objective of this study was to determine the role of plasma miRNA in CFS/ME. RESULTS: Using Illumina high-throughput sequencing we identified 19 miRNAs that were differentially expressed in the plasma of CFS/ME patients in comparison to non-fatigued controls. Following RT-qPCR analysis, we were able to confirm the significant up-regulation of three miRNAs (hsa-miR-127-3p, hsa-miR-142-5p and hsa-miR-143-3p) in the CFS/ME patients. CONCLUSION: Our study is the first to identify circulating miRNAs from CFS/ME patients and also to confirm three differentially expressed circulating miRNAs in CFS/ME patients, providing a basis for further study to find useful CFS/ME biomarkers.

A comparison of health status in patients meeting alternative definitions for chronic fatigue syndrome/myalgic encephalomyelitis.

BACKGROUND: Several diagnostic definitions are available for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) that varies significantly in their symptom criteria. This pilot study was conducted to determine whether simple biological and clinical measures differed between CFS/ME patients meeting the 1994 Centres for Disease Control and Prevention (CDC) criteria, the International Consensus Criteria (ICC), as well as healthy controls. METHODS: A total of 45 CFS/ME patients and 30 healthy controls from the South East Queensland region of Australia provided a blood sample, reported on their current symptoms, as well as aspects of their physical and social health using the Short-Form Health Survey (SF-36), and the World Health Organisation Disability Adjustment Schedule 2.0 (WHO DAS 2.0). Differences were examined using independent sample t-testing. RESULTS: Patients fulfilling the ICC definition reported significantly lower scores (p < 0.05) for physical functioning, physical role, bodily pain, and social functioning than those that only fulfilled the 1994 CDC definition. ICC patients reported significantly greater (p < 0.05) disability across all domains of the WHO DAS 2.0. CONCLUSIONS: These preliminary findings suggest that the ICC identifies a distinct subgroup found within patients complying with the 1994 CDC definition, with more severe impairment to their physical and social functioning.

The adoption of chronic fatigue syndrome/myalgic encephalomyelitis case definitions to assess prevalence: a systematic review.

PURPOSE: Prevalence estimates have been based on several case definitions of chronic fatigue syndrome (CFS). The purpose of this work is to provide a rigorous overview of their application in prevalence research. METHODS: A systematic review of primary studies reporting the prevalence of CFS since 1990 was conducted. Studies were summarized according to study design, prevalence estimates, and case definition used to ascertain cases. RESULTS: Thirty-one studies were retrieved, and eight different case definitions were found. Early estimates of CFS prevalence were based on the 1988 Centers for Disease Control and Prevention, Australian, and Oxford. The 1994 Centers for Disease Control and Prevention, however, has been adopted internationally, as a general standard. Only one study has reported prevalence according to the more recent, Canadian Consensus Criteria. Additional estimates were also found according to definitions by Ho-Yen, the 2005 Centers for Disease Control and Prevention empirical definition, and an epidemiological case definition. CONCLUSIONS: Advances in clinical case definitions during the past 10 years such as the Canadian Consensus Criteria have received little attention in prevalence research. Future assessments of prevalence should consider adopting more recent developments, such as the newly available International Consensus Criteria. This move could improve the surveillance of more specific cases found within CFS.

Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis.

BACKGROUND: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is an etiologically unexplained disorder characterised by irregularities in various aspects of the immunological function. Presently, it is unknown whether these immunological changes remain consistent over time. This study investigates Natural Killer (NK) cell cytotoxic activity, NK cell subsets (CD56brightCD16- and CD56dimCD16+) and cytokines, over the course of a12 month period in patients with CFS/ME. METHODS: The participants in the study comprised 65 (47.2 ± 11.5 years) CFS/ME participants and 21 (45.2 ± 9.3 years) non-fatigued controls. Flow cytometry protocols were used to assess NK subsets and NK cytotoxic activity at various time points that included baseline (T1), 6 (T2) and 12 months (T3). Cytokine secretions were measured following mitogenic stimulation of peripheral blood mononuclear cells. RESULTS: NK cytotoxic activity was significantly decreased in the CFS/ME patients at T1, T2 and T3 compared to the non-fatigued group. Additionally, in comparison to the non-fatigued controls, the CFS/ME group had significantly lower numbers of CD56brightCD16- NK cells at both T1 and T2. Interestingly, following mitogenic stimulation, cytokine secretion revealed significant increases in IL-10, IFN-γ and TNF-α at T1 in the CFS/ME group. A significant decrease was observed at T2 in the CFS/ME group for IL-10 and IL-17A while at T3, IL-2 was increased in the CFS/ME group in comparison to the non-fatigued controls. Overall cytotoxic activity was significantly decreased at T3 compared to T1 and T2. CD56brightCD16- NK cells were much lower at T2 compared to T1 and T3. IL-10 and IL-17A secretion was elevated at T2 in comparison to T1 and T3. CONCLUSION: These results confirm decreases in immune function in CFS/ME patients, suggesting an increased susceptibility to viral and other infections. Furthermore, NK cytotoxic activity may be a suitable biomarker for diagnosing CFS/ME as it was consistently decreased during the course of the 12 months study.

Cytotoxic lymphocyte microRNAs as prospective biomarkers for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

BACKGROUND: Immune dysfunction associated with a disease often has a molecular basis. A novel group of molecules known as microRNAs (miRNAs) have been associated with suppression of translational processes involved in cellular development and proliferation, protein secretion, apoptosis, immune function and inflammatory processes. MicroRNAs may be implicated in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), where immune function is impaired. The objective of this study was to determine the association between miRNAs in cytotoxic cells and CFS/ME. METHODS: Natural Killer (NK) and CD8(+)T cells were preferentially isolated from peripheral blood mononuclear cells from all participants (CFS/ME, n=28; mean age=41.8±9.6 years and controls, n=28; mean age=45.3±11.7 years), via negative cell enrichment. Following total RNA extraction and subsequent synthesis of cDNA, reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) was used to determine the expression levels of nineteen miRNAs. RESULTS: There was a significant reduction in the expression levels of miR-21, in both the NK and CD8(+)T cells in the CFS/ME sufferers. Additionally, the expression of miR-17-5p, miR-10a, miR-103, miR-152, miR-146a, miR-106, miR-223 and miR-191 was significantly decreased in NK cells of CFS/ME patients in comparison to the non-fatigued controls. LIMITATIONS: The results from these investigations are not yet transferable into the clinical setting, further validatory studies are now required. CONCLUSIONS: Collectively these miRNAs have been associated with apoptosis, cell cycle, development and immune function. Changes in miRNAs in cytotoxic cells may reduce the functional capacity of these cells and disrupt effective cytotoxic activity along with other immune functions in CFS/ME patients.

Immune and hemorheological changes in chronic fatigue syndrome.

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a multifactorial disorder that affects various physiological systems including immune and neurological systems. The immune system has been substantially examined in CFS with equivocal results, however, little is known about the role of neutrophils and natural killer (NK) phenotypes in the pathomechanism of this disorder. Additionally the role of erythrocyte rheological characteristics in CFS has not been fully expounded. The objective of this present study was to determine deficiencies in lymphocyte function and erythrocyte rheology in CFS patients. METHODS: Flow cytometric measurements were performed for neutrophil function, lymphocyte numbers, NK phenotypes (CD56(dim)CD16(+) and CD56(bright)CD16(-)) and NK cytotoxic activity. Erythrocyte aggregation, deformability and fibrinogen levels were also assessed. RESULTS: CFS patients (n = 10) had significant decreases in neutrophil respiratory burst, NK cytotoxic activity and CD56(bright)CD16(-) NK phenotypes in comparison to healthy controls (n = 10). However, hemorheological characteristic, aggregation, deformability, fibrinogen, lymphocyte numbers and CD56(dim)CD16(+) NK cells were similar between the two groups. CONCLUSION: These results indicate immune dysfunction as potential contributors to the mechanism of CFS, as indicated by decreases in neutrophil respiratory burst, NK cell activity and NK phenotypes. Thus, immune cell function and phenotypes may be important diagnostic markers for CFS. The absence of rheological changes may indicate no abnormalities in erythrocytes of CFS patients.

Vasoactive neuropeptides in clinical ophthalmology: An association with autoimmune retinopathy?

The mammalian eye is protected against pathogens and inflammation in a relatively immune-privileged environment. Stringent mechanisms are activated that regulate external injury, infection, and autoimmunity. The eye contains a variety of cells expressing vasoactive neuropeptides (VNs), and their receptors, located in the sclera, cornea, iris, ciliary body, ciliary process, and the retina. VNs are important activators of adenylate cyclase, deriving cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). Impairment of VN function would arguably impede cAMP production and impede utilization of ATP. Thus VN autoimmunity may be an etiological factor in retinopathy involving perturbations of purinergic signaling. A sound blood supply is necessary for the existence and functional properties of the retina. This paper postulates that impairments in the endothelial barriers and the blood-retinal barrier, as well as certain inflammatory responses, may arise from disruption to VN function. Phosphodiesterase inhibitors and purinergic modulators may have a role in the treatment of postulated VN autoimmune retinopathy.

Postulated vasoactive neuropeptide immunopathology affecting the blood-brain/blood-spinal barrier in certain neuropsychiatric fatigue-related conditions: A role for phosphodiesterase inhibitors in treatment?

Neuropsychiatric symptoms occur in a number of neurological fatigue-related conditions including multiple sclerosis (MS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and chronic fatigue syndrome (CFS). These conditions have been attributed variably to neuroinflammatory and neurodegenerative processes. While autoimmune pathology, at least in part, has long been suspected in these conditions proof has been elusive. Autoimmune pathomechanisms affecting the blood-brain barrier (BBB) or blood-spinal barrier (BSB) may predispose the BBB/BSB to 'leakiness' and be a precursor to additional autoimmune events resulting in neuroinflammatory or neurodegenerative processes. The aim of the paper is to postulate immunopathology of the cerebrospinal perivascular compartment involving certain vasoactive neuropeptides, specifically pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP), in the etiology of certain neuropsychiatric fatigue-related conditions such as MS, ALS, PD, and CFS. Vasoactive neuropeptides (VNs) such as PACAP and VIP have critical roles as neurotransmitters, vasodilators including perfusion and hypoxia regulators, and immune and nociception modulators. PACAP and VIP are widely distributed in the central nervous system (CNS) and have key roles in CNS blood vessels including maintaining functional integrity of the BBB and BSB. Autoimmunity affecting these VNs would likely have a detrimental effect on BBB and BSB functioning arguably predisposing to further pathological processes. Virchow-Robin spaces (VRS) are perivascular compartments surrounding small vessels within the CNS which contribute to the BBB and BSB integrity and contain PACAP and VIP receptors. Autoimmunity of these receptors would likely affect BBB and VRS function and therefore may contribute to the etiology of these conditions by affecting CNS and immunological homeostasis, including promoting neuropsychological symptomatology. PACAP and VIP, as potent activators of adenylate cyclase (AC), have a key role in cyclic adenosine monophosphate (cAMP) production affecting regulatory T cell (Treg) and other immune functions. Phosphodiesterase enzymes (PDEs) catalyze cAMP and PDE inhibitors (PDEIs) maintain cAMP levels and have proven and well known therapeutic benefit in animal models such as experimental allergic encephalomyelitis (EAE). Therefore PDEIs may have a role in therapy for certain neuropsychiatric fatigue-related conditions.

Does autoimmunity of endogenous vasoactive neuropeptides cause retinopathy in humans?

Immune privilege is a physiologic mechanism within the eye which protects it against pathogens, while also protecting it from inflammation. Immunological mechanisms in the eye must be tightly regulated to ensure externally mediated injury and infection or internally mediated autoimmunity do not exceed self-defence tolerance. Vasoactive neuropeptides (VNs) including vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase polypeptide (PACAP) and their receptors exist in the mammalian eye including the sclera, cornea, iris, ciliary body, ciliary process and the retina and may have a role in protecting these normally immune privileged sites. VN receptors are class II G protein-coupled receptors (GPCRs) which couple primarily to the adenylate cyclase (AC)-cyclic AMP pathway. A sound blood supply is essential for retinal survival hence vascular compromise will have serious consequences. Retinal vasculitis is a potentially blinding condition with a strong association with systemic inflammatory diseases. Compromise of the endothelial barriers and the blood retina barrier (BRB) may instigate inflammatory responses setting up a chain of events involving VNs in a manner which provokes autoimmunity to them. Protection from BRB breakdown may be linked to nitric oxide (NO) effects and actions of phosphodiesterase inhibitors and cAMP production. Induced NO expressed under influences of inflammatory mediators evokes neurodegeneration and cell apoptosis and may lead to serious ocular disease including retinal injury. Other inflammatory mediators also play a role in retinal pathology. PACAP and glutamate are co-stored in the retinohypothalamic tract and PACAP attenuates glutamate induced neurotoxicity in cultured retinal neurons suggesting that compromise of this VN would have significant detrimental impact on retinal viability though glutamate toxicity. Additional effects of VN compromise would possibly occur through unopposed vasoconstriction and inflammation. Proof of this hypothesis has important implications for treatment and prevention of autoimmune retinopathy and blindness as a number of therapeutic pathways may be opened. Importantly for therapeutic contexts cAMP effects are maintained by phosphodiesterase (PDE) inhibitors which could be used in VN autoimmune disorders. A compelling case may exist to undertake a therapeutic trial of VN replacement, PDE inhibitors and other agents in autoimmune retinopathies resulting from possible VN autoimmunity.