Tag: Newton

Reduction of Glucocorticoid Receptor Function in Chronic Fatigue Syndrome

Abstract:

Glucocorticoid receptor (GR) function may have aetiopathogenic significance in chronic fatigue syndrome (CFS), via its essential role in mediating inflammatory responses as well as in hypothalamic-pituitary-adrenal axis regulation. GR function can be estimated ex vivo by measuring dexamethasone (dex) modulation of cytokine response to lipopolysaccharide (LPS), and in vivo using the impact of dex on cortisol levels. This study aimed to compare the GR function between CFS (n = 48), primary Sjögren’s syndrome (a disease group control) (n = 27), and sedentary healthy controls (HCs) (n = 20), and to investigate its relationship with clinical measures.

In the GR ex vivo response assay, whole blood was diluted and incubated with LPS (to stimulate cytokine production), with or without 10 or 100 nanomolar concentrations of dex. Cytometric bead array (CBA) and flow cytometry enabled quantification of cytokine levels (TNFα, interleukin- (IL-) 6, and IL-10) in the supernatants. In the in vivo response assay, five plasma samples were taken for determination of total cortisol concentration using ELISA at half-hourly intervals on two consecutive mornings separated by ingestion of 0.5 mg of dex at 11 pm. The association of the data from the in vivo and ex vivo analyses with reported childhood adversity was also examined.

CFS patients had reduced LPS-induced IL-6 and TNFα production compared to both control groups and reduced suppression of TNFα by the higher dose of dex compared to HCs. Cortisol levels, before or after dex, did not differ between CFS and HCs. Cortisol levels were more variable in CFS than HCs. In the combined group (CFS plus HC), cortisol concentrations positively and ex vivo GR function (determined by dex-mediated suppression of IL-10) negatively correlated with childhood adversity score.

The results do not support the hypothesis that GR dysregulation is aetiopathogenic in CFS and suggest that current and future endocrine cross-sectional studies in CFS may be vulnerable to the confounding influence of childhood trauma which is likely increased by comorbid depression.

Source: Lynn M, Maclachlan L, Finkelmeyer A, Clark J, Locke J, Todryk S, Ng WF, Newton JL, Watson S. Reduction of Glucocorticoid Receptor Function in Chronic Fatigue Syndrome. Mediators Inflamm. 2018 Jun 10;2018:3972104. doi: 10.1155/2018/3972104. eCollection 2018. https://www.ncbi.nlm.nih.gov/pubmed/29983634

Intracranial compliance is associated with symptoms of orthostatic intolerance in chronic fatigue syndrome

Abstract:

Symptoms of orthostatic intolerance (OI) are common in Chronic Fatigue Syndrome (CFS) and similar disorders. These symptoms may relate to individual differences in intracranial compliance and cerebral blood perfusion.

The present study used phase-contrast, quantitative flow magnetic resonance imaging (MRI) to determine intracranial compliance based on arterial inflow, venous outflow and cerebrospinal fluid flow along the spinal canal into and out of the cranial cavity. Flow-sensitive Alternating Inversion Recovery (FAIR) Arterial Spin Labelling was used to measure cerebral blood perfusion at rest.

Forty patients with CFS and 10 age and gender matched controls were scanned. Severity of symptoms of OI was determined from self-report using the Autonomic Symptom Profile. CFS patients reported significantly higher levels of OI (p < .001). Within the patient group, higher severity of OI symptoms were associated with lower intracranial compliance (r = -.346, p = .033) and higher resting perfusion (r = .337, p = .038). In both groups intracranial compliance was negatively correlated with cerebral perfusion. There were no significant differences between the groups in intracranial compliance or perfusion.

In patients with CFS, low intracranial compliance and high resting cerebral perfusion appear to be associated with an increased severity of symptoms of OI. This may signify alterations in the ability of the cerebral vasculature to cope with changes to systemic blood pressure due to orthostatic stress, but this may not be specific to CFS.

Source: Andreas Finkelmeyer, Jiabao He, Laura Maclachlan, Andrew M. Blamire, Julia L. Newton. Intracranial compliance is associated with symptoms of orthostatic intolerance in chronic fatigue syndrome. PLoS ONE. Published: July 3, 2018 https://doi.org/10.1371/journal.pone.0200068 (Full article)

Liver volume is lower and associates with resting and dynamic blood pressure variability in chronic fatigue syndrome

Abstract:

Background: Chronic fatigue syndrome (CFS) in many cases is characterised by abnormal autonomic function and lower blood pressure (BP). In animals the liver is a capacitance vessel for BP homeostasis. We developed a novel liver magnetic resonance (MR) imaging technique to compare liver volume in CFS to controls, and to explore its role in cardiovascular physiology.

Methods: Liver MR (single breath-hold, enhanced T1-weighted, high-resolution isotropic volume excitation 3-Tesla Achieva, NL) determined liver volume. Red cell and plasma volume were also measured. A 10 min resting cardiac autonomic assessment using beat-to-beat measurement (Taskforce; CNSystems) was followed by assessment of hemodynamic response to standing to determine blood pressure drop and return to baseline.

Results: Forty-four CFS patients (age = 45.5, 34f/10 m, Fukuda criteria) and 10 age, activity and sex matched controls (age = 49.4, 7f/3 m) participated. Adjusted for body size, CFS patients had significantly reduced liver volumes (775 (101) ml/m2 v 846 (96) ml/m2; p = 0.02). At rest, liver volume was unrelated to symptom severity, heart rate, BP or heart rate variability. Both increased systolic and diastolic low frequency (LF) BP variability (predominantly sympathetic) were associated with lower liver volumes. On standing, liver volume was unrelated to BP drop but was associated with successful BP return-to-baseline. Red cell and plasma volume were associated positively with liver volume. Multivariate analysis confirmed return-to-baseline BP on standing which was independently associated with liver volume.

Conclusion: Liver volumes were smaller in CFS compared to controls. The relationship between return-to-baseline BP after standing and liver volume suggests, as in animals, that the liver is involved in maintenance of BP.

Abbreviations: ACI: Accelerated cardiac index; BPV: Blood pressure variability; BRS: Baroreflex sensitivity; CFS: chronic fatigue syndrome; Chr: Chromium; CI: cardiac index; FIS: Fatigue impact scale; HF: High frequency; HRV: Heart rate variability; LF: Low frequency; MR: magnetic resonance; NU: normalised units; SD: Standardised deviation; PSD: power spectral density; SI: Stroke index; TPRI: Total peripheral resistance index

Source: Pawel Zalewski, Andreas Finkelmeyer, James Frith, Laura Maclachlan, Andrew Blamire & Julia L. Newton (2018) Liver volume is lower and associates with resting and dynamic blood pressure variability in chronic fatigue syndrome, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2018.1488525

Cardiac sympathetic innervation associates with autonomic dysfunction in chronic fatigue syndrome – a pilot study

Despite hemodynamic abnormalities being well documented in chronic fatigue syndrome (CFS), it remains unclear the nature of the underlying autonomic nervous system problems that underpin these findings. Studies performed in subgroups of those with CFS suggest cardiac sympathetic denervation.

Meta-iodo-benzylguanidine (MIBG) imaging provides a quantitative measure of cardiac sympathetic innervation. Clinically, cardiac MIBG scanning is used to estimate local myocardial sympathetic nerve damage in heart disease and dysautonomia, particularly abnormalities arising due to sympathetic innervation [1,2]. In this study, we explored potential mechanisms that underpin the autonomic abnormalities seen in CFS using I125 MIBG participants that fulfilled Fukuda diagnostic criteria for CFS [3]. Participants were excluded if screened positive for a major depressive episode (Structured Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders). Fatigue was measured using the Fatigue Impact Scale (FIS).

Read the rest of this article HERE.

Source: Petrides G, Zalewski P, McCulloch D, Maclachlan L, Finkelmeyer A, Hodgson T, Blamire A, Newton JL. Cardiac sympathetic innervation associates with autonomic dysfunction in chronic fatigue syndrome – a pilot study. Fatigue. 2017 May 4;5(3):184-186. doi: 10.1080/21641846.2017.1322235. eCollection 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942146/ (Full article)

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

Abstract:

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.

Source: Cara Tomas; Julia Newton. Metabolic abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a mini-review. Biochemical Society Transactions Apr 17, 2018; DOI: https://doi.org/10.1042/BST20170503. http://www.biochemsoctrans.org/content/early/2018/04/16/BST20170503

Pharmacological activation of AMPK and glucose uptake in cultured human skeletal muscle cells from patients with ME/CFS

Abstract:

Background: Skeletal muscle fatigue and post-exertional malaise are key symptoms of Myalgic Encephalomyelitis (ME/CFS). We have previously shown that AMPK activation and glucose uptake are impaired in primary human skeletal muscle cell cultures derived from patients with ME/CFS in response to electrical pulse stimulation, a method which induces contraction of muscle cells in vitro. The aim of this study was to assess if AMPK could be activated pharmacologically in ME/CFS.

Methods: Primary skeletal muscle cell cultures from patients with ME/CFS and healthy controls were treated with either metformin or 991. AMPK activation was assessed by Western blot and glucose uptake measured.

Results: Both metformin and 991 treatment significantly increased AMPK activation and glucose uptake in muscle cell cultures from both controls and ME/CFS. Cellular ATP content was unaffected by treatment although ATP content was significantly decreased in ME/CFS compared to controls.

Conclusions: Pharmacological activation of AMPK can improve glucose uptake in muscle cell cultures from patients with ME/CFS. This suggests that the failure of electrical pulse stimulation to activate AMPK in these muscle cultures is due to a defect proximal to AMPK. Further work is required to delineate the defect and determine whether pharmacological activation of AMPK improves muscle function in patients with ME/CFS.

Source: Brown AE, Dibnah B, Fisher E, Newton JL, Walker M. Pharmacological activation of AMPK and glucose uptake in cultured human skeletal muscle cells from patients with ME/CFS. Biosci Rep. 2018 Apr 13. pii: BSR20180242. doi: 10.1042/BSR20180242. [Epub ahead of print]  https://www.ncbi.nlm.nih.gov/pubmed/29654166/

 

Comment by ME Research UK: Reduced cardiac volumes in chronic fatigue syndrome associate with plasma volume but not length of disease: a cohort study

Reprinted with the kind permission of ME Research UK.

Authors

Newton JL, Finkelmeyer A, Petrides G, Frith J, Hodgson T, Maclachlan L, MacGowan G and Blamire AM

Institution

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne Hospitals NHS; Newcastle Magnetic Resonance Centre, Newcastle upon Tyne, UK

Published abstract

Objectives

To explore potential mechanisms that underpin the cardiac abnormalities seen in chronic fatigue syndrome (CFS) using non-invasive cardiac impedance, red cell mass and plasma volume measurements.

Methods

Cardiac MR (MR) examinations were performed using 3 T Philips Intera Achieva scanner (Best, NL) in participants with CFS (Fukuda; n=47) and matched case-by-case controls. Total volume (TV), red cell volume (RCV) and plasma volume (PV) measurements were performed (41 CFS and 10 controls) using the indicator dilution technique using simultaneous 51-chromium labelling of red blood cells and 125-iodine labelling of serum albumin.

Results

The CFS group length of history (mean±SD) was 14±10 years. Patients with CFS had significantly reduced end-systolic and end-diastolic volumes together with reduced end-diastolic wall masses (all p<0.0001). Mean±SD RCV was 1565±443 mL with 26/41 (63%) having values below 95% of expected. PV was 2659±529 mL with 13/41 (32%) <95% expected. There were strong positive correlations between TV, RCV and PV and cardiac end-diastolic wall mass (all p<0.0001; r2=0.5). Increasing fatigue severity correlated negatively with lower PV (p=0.04; r2=0.2). There were no relationships between any MR or volume measurements and length of history, suggesting that deconditioning was unlikely to be the cause of these abnormalities.

Conclusions

This study confirms an association between reduced cardiac volumes and blood volume in CFS. Lack of relationship between length of disease, cardiac and plasma volumes suggests findings are not secondary to deconditioning. The relationship between plasma volume and severity of fatigue symptoms suggests a potential therapeutic target in CFS.

Publication

Newton et al, Open Heart, 2016 Jun 24; 3(1):e000381

Funding

Medical Research Council, ME Research UK

 

Comment by ME Research UK

Over the years, a number of reports in the scientific literature have pointed to the presence of abnormalities of heart (cardiac) function in ME/CFS. For example, a study in 2006 found that ME/CFS patients had relatively short QT intervals (measures of the heart’s electrical cycle) compared with healthy people (read more). Also, in 2009, Japanese researchers reported cardiac dysfunction with low cardiac output in some oriental patients (read more), and another investigation found that cardiac function was diminished (read more).

Alongside these reports, ME Research UK-funded investigations by Prof Julia Newton, Dr Kieren Hollingsworth and colleagues at Newcastle University have also throw up some intriguing findings concerning the function of the heart in ME/CFS. For example, they have shown that ‘bioenergetic abnormalities’ could be found both in heart muscle and in the muscles of the skeleton, with a correlation between the two suggesting the existence of linked underlying mechanisms (read more). In the same investigation, they found that the hearts of the ME/CFS patients had to work harder during prolonged standing than in healthy people. The research group has also looked at the function of the heart using cardiac MRI tagging to identify defects that are not yet clinically apparent. One of their main findings has been a dramatic increase in ‘residual torsion’ in patients compared with controls. This is a measure of the efficiency of the release of torsion and strain during the relaxation phase of the heartbeat, and ME/CFS patients had 200% more residual torsion than healthy people, indicating that their heart muscle was taking longer to relax. Also, the left ventricular mass (the thickness of the heart wall at the ventricle) was reduced compared with controls; and cardiac output (the output of blood by the heart per minute) was lower (read more).

The Newcastle researchers have been continuing their investigations, and their latest report has just been published in the journal Open Heart (read more). It describes work to confirm these previous findings in a larger group of new patients and controls, and extend them to include cardiac output and blood volume. In the experiments, cardiac magnetic resonance examinations were performed in 47 patients with ME/CFS who had been ill for 14 years on average and 47 case-matched controls, and blood volume measurements in 41 CFS and 10 controls. Patients with a diagnosis of depression were specifically excluded from the study so that depression could be ruled out as a potential, if unlikely, cause of the abnormalities.

The results were fascinating. Compared with healthy controls, stroke volume(the amount of blood pumped by the left ventricle in one contraction) was 23% lower in the ME/CFS patients; end-diastolic volumes were 25% lower; end-systolic volumes were 29% lower; and end-diastolic wall masses were 26% lower (all p<0.0001). In essence, these findings confirm, in a larger and different group of patients, the reductions in cardiac volume observed previously in ME/CFS patients in Newcastle.

The total volume of blood (plasma and red cells) was 4% lower in the ME/CFS group compared with controls, though this difference was not statistically significant. In 63% of the patients, however, the volume of red blood cells was below 95% of the expected levels for healthy people. Also, there were strong positive correlations between blood volume measurements and cardiac end-diastolic wall mass, and a weak relationship between plasma volume and fatigue severity. Importantly, the length of illness was not related to any cardiac magnetic resonance or volume measurements, suggesting that deconditioning (which would be greater the longer a person was ill) was unlikely to be the cause of these abnormalities.

The finding that red cell volume was low is intriguing, and it may be that blood volume plays at least a part in the symptoms experienced by ME/CFS patients. One intriguing possibility alluded to by the researchers is that the abnormalities detected in this study, particularly the reduction in end-diastolic blood volume,  may be due to problems with venous compliance (see diagram above), as nearly two-thirds of the blood in the systemic circulation is stored in the venous system and compliance is controlled by the autonomic nervous system which is also affected in ME/CFS. In fact, low total blood volume has been proposed as part of the disease process in subgroups of ME/CFS patients before. One investigation in 2002 found a 9% lower blood volume in ME/CFS patients than in controls (read more). A further study in 2009 showed that the reductions in cardiac output and end-diastolic volume in ME/CFS could be entirely accounted for by a reduction in the total blood volume (read more), and an accompanying editorial pointed out that the results did not imply heart disease, but rather pointed to “circulatory impairment” (read more).

Overall, these findings using state-of-the art MRI confirm the presence of cardiac abnormalities in people with ME/CFS. It remains unknown, however, whether these are caused by ME/CFS and its consequences per se or whether, for instance, a (pre-existing) reduced cardiac volume may make people more vulnerable to the development of the illness. As regards low blood volume, there is anecdotal evidence that the symptoms of ME/CFS improve in some patients after treatment with intravenous fluid (although the procedure is not without drawbacks and risks), and the team in Newcastle intend to explore interventions to restore fluid volume in ME/CFS patients in further studies.

_________________

ME Research UK commissions and funds high-quality scientific (biomedical) investigation into ME/CFS. 

 

Rethinking childhood adversity in chronic fatigue syndrome

Abstract:

Background: Previous studies have consistently shown increased rates of childhood adversity in chronic fatigue syndrome (CFS). However, such aetiopathogenic studies of CFS are potentially confounded by co-morbidity and misdiagnosis particularly with depression.

Purpose: We examined the relationship between rates of childhood adversity using two complimentary approaches (1) a sample of CFS patients who had no lifetime history of depression and (2) a modelling approach.

Methods: Childhood trauma questionnaire (CTQ) administered to a sample of 52 participants with chronic fatigue syndrome and 19 controls who did not meet criteria for a psychiatric disorder (confirmed using the Structured Clinical Interview for DSM-IV). Subsequently, Mediation Analysis (Baye’s Rules) was used to establish the risk childhood adversity poses for CFS with and without depression.

Results: In a cohort of CFS patients with depression comprehensively excluded, CTQ scores were markedly lower than in all previous studies and, in contrast to these previous studies, not increased compared with healthy controls. Post-hoc analysis showed that CTQ scores correlated with the number of depressive symptoms during the lifetime worst period of low mood. The probability of developing CFS given a history of childhood trauma is 4%, a two-fold increased risk compared to the general population. However, much of this risk is mediated by the concomitant development of major depression.

Conclusions: The data suggests that previous studies showing a relationship between childhood adversity and CFS may be attributable to the confounding effects of co-morbid or misdiagnosed depressive disorder.

Abbreviations: CFS: Chronic fatigue syndrome; CTQ: Childhood trauma questionnaire; MDD: Major depressive disorder; CA: Childhood adversity; P: Probability.

Source: Clark JE, Davidson SL, Maclachlan L, Newton JL, Watson S. Rethinking childhood adversity in chronic fatigue syndrome. Fatigue. 2017 Oct 10;6(1):20-29. doi: 10.1080/21641846.2018.1384095. eCollection 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774185/ (Full article)

Elevated brain natriuretic peptide levels in chronic fatigue syndrome associate with cardiac dysfunction: a case control study

Abstract:

Objectives: To explore levels of the brain natriuretic peptide (BNP) and how these associate with the cardiac abnormalities recently identified in chronic fatigue syndrome (CFS).

Methods: Cardiac magnetic resonance examinations were performed using 3T Philips Intera Achieva scanner (Best, Netherlands) in CFS (Fukuda) participants and sedentary controls matched group wise for age and sex. BNP was also measured by using an enzyme immunoassay in plasma from 42 patients with CFS and 10 controls.

Results: BNP levels were significantly higher in the CFS cohort compared with the matched controls (P=0.013). When we compared cardiac volumes (end-diastolic and end-systolic) between those with high BNP levels (BNP>400 pg/mL) and low BNP (<400 pg/mL), there were significantly lower cardiac volumes in those with the higher BNP levels in both end-systolic and end-diastolic volumes (P=0.05). There were no relationships between fatigue severity, length of disease and BNP levels (P=0.2) suggesting that our findings are unlikely to be related to deconditioning.

Conclusion: This study confirms an association between reduced cardiac volumes and BNP in CFS. Lack of relationship between length of disease suggests that findings are not secondary to deconditioning. Further studies are needed to explore the utility of BNP to act as a stratification paradigm in CFS that directs targeted treatments.

Source: Cara Tomas, Andreas Finkelmeyer, Tim Hodgson, Laura MacLachlan, Guy A MacGowan, Andrew M Blamire, Julia L Newton. Elevated brain natriuretic peptide levels in chronic fatigue syndrome associate with cardiac dysfunction: a case control study. Open Heart 2017;4:e000697. doi:10.1136/ openhrt-2017-000697 http://openheart.bmj.com/content/openhrt/4/2/e000697.full.pdf (Full article)

Energy envelope maintenance among patients with myalgic encephalomyelitis and chronic fatigue syndrome: Implications of limited energy reserves

Abstract:

Objective: The Energy Envelope Theory of myalgic encephalomyelitis and chronic fatigue syndrome postulates that individuals with myalgic encephalomyelitis and chronic fatigue syndrome may experience some increase in functioning if their level of exertion consistently remains within the limits of their available energy. Findings of several studies support this theory; however, the current study is the first to explore how an individual’s initial level of available energy may influence the relation between energy envelope maintenance and level of functioning.

Method:The functioning, activity, and symptomatology of six groups of individuals with myalgic encephalomyelitis and chronic fatigue syndrome were compared. Groups were created based upon level of available energy (higher or lower) and energy envelope adherence (underextended, within, overextended).

Results: Results indicate that, as expected, individuals with myalgic encephalomyelitis and chronic fatigue syndrome who had higher available energy also had better functioning than individuals with lower available energy; however, this relation was less pronounced for individuals who were overexerting themselves.

Discussion: These results are consistent with the Energy Envelope Theory, and they suggest that overexertion was particularly impactful for individuals with higher levels of available energy.

Source: O’connor K, Sunnquist M, Nicholson L, Jason LA, Newton JL, Strand EB. Energy envelope maintenance among patients with myalgic encephalomyelitis and chronic fatigue syndrome: Implications of limited energy reserves. Chronic Illn. 2017 Jan 1:1742395317746470. doi: 10.1177/1742395317746470. [Epub ahead of print]