Tag: 2018

Netflix Launches “Afflicted,” a Docuseries about Chronic Illnesses

On Friday, August 10, Netflix is launching a docuseries called “Afflicted.” The series chronicles the stories of seven chronically ill people who are searching for answers to their baffling symptoms, and for relief.

“Afflicted” features ME patient Jamison Hill, a former bodybuilder and personal trainer, who became sick at the age of 22. His disease progressed to its most severe form, leaving him unable to speak, eat solid food, or leave his bed. His moving personal essays have been published in Men’s Journal, The Washington Post, VICE, and the New York Times. He was featured in “Forgotten Plague,” a full-length documentary about myalgic encephalomyelitis. Jamison maintains a popular blog on ME.

Visit him at jamisonwrites.com.

You can watch the trailer HERE.

You can read an interview with Jamison HERE.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis?

Abstract:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease characterized by debilitating fatigue, lasting for at least 6 months, with severe impairment of daily functioning and associated symptoms. A significant percentage of ME/CFS patients remains undiagnosed, mainly due to the complexity of the disease and the lack of reliable objective biomarkers. ME/CFS patients display decreased metabolism and the severity of symptoms appears to be directly correlated to the degree of metabolic reduction that may be unique to each individual patient. However, the precise pathogenesis is still unknown preventing the development of effective treatments. The ME/CFS phenotype has been associated with abnormalities in energy metabolism, mostly with mitochondrial dysfunction, resulting in reduced oxidative metabolism. Mitochondrial dysfunction may be further contributing to the ME/CSF symptomatology by extracellular secretion of mitochondrial DNA, which could create an “innate” inflammatory state in the hypothalamus, thus disrupting normal homeostasis. We propose that stimulation of hypothalamic mast cells activates microglia leading to focal inflammation in the brain and disturbed homeostasis.

Source: Hatziagelaki E, Adamaki M, Tsilioni I, Dimitriadis G, Theoharides TC. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis? J Pharmacol Exp Ther. 2018 Aug 3. pii: jpet.118.250845. doi: 10.1124/jpet.118.250845. [Epub ahead of print]   http://jpet.aspetjournals.org/content/early/2018/08/03/jpet.118.250845.long (Full article)

Association between cytokines and psychiatric symptoms in chronic fatigue syndrome and healthy controls

Abstract:

PURPOSE: The reports regarding the status of the immune system in patients with chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) have been inconclusive. We approached this question by comparing a strictly defined group of CFS/ME outpatients to healthy control individuals, and thereafter studied cytokines in subgroups with various psychiatric symptoms.

MATERIALS AND METHODS: Twenty patients diagnosed with CFS/ME according to the Fukuda criteria and 20 age- and sex-matched healthy controls were enrolled in the study. Plasma was analysed by ELISA for levels of the cytokines TNF-α, IL-4, IL-6 and IL-10. Participants also answered questionnaires regarding health in general, and psychiatric symptoms in detail.

RESULTS: Increased plasma levels of TNF-α in CFS/ME patients almost reached significance compared to healthy controls (p = .056). When studying the CFS/ME and control groups separately, there was a significant correlation between TNF-α and The Hospital Anxiety and Depression Scale (HADS) depressive symptoms in controls only, not in the CFS/ME group. A correlation between IL-10 and psychoticism was found in both groups, whereas the correlation for somatisation was seen only in the CFS/ME group. When looking at the total population, there was a significant correlation between TNF-α and both the HADS depressive symptoms and the SCL-90-R cluster somatisation. Also, there was a significant association between IL-10 and the SCL-90-R cluster somatisation when analyzing the cohort (patients and controls together).

CONCLUSIONS: These findings indicate that immune activity in CFS/ME patients deviates from that of healthy controls, which implies potential pathogenic mechanisms and possible therapeutic approaches to CFS/ME. More comprehensive studies should be carried out on defined CFS/ME subgroups.

Source: Groven N, Fors EA, Iversen VC, White LR, Reitan SK. Association between cytokines and psychiatric symptoms in chronic fatigue syndrome and healthy controls. Nord J Psychiatry. 2018 Jul 31:1-5. doi: 10.1080/08039488.2018.1493747. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30063870

The putative glymphatic signature of chronic fatigue syndrome: A new view on the disease pathogenesis and therapy

Abstract:

The underlying pathophysiology of chronic fatigue syndrome remains incompletely understood and there are no curative treatments for this disorder at present. However, increasing neuroimaging evidence indicates that functional and structural abnormalities exist in the brains of chronic fatigue syndrome patients, suggesting that the central nervous system is involved in this disorder and that at least some chronic fatigue syndrome patients may have an underlying neurological basis for their illness.

In the present paper, we speculate that glymphatic dysfunction, causing toxic build up within the central nervous system, may be responsible for at least some cases of chronic fatigue syndrome. We further postulate that cerebrospinal fluid diversion such as lumboperitoneal shunting may be beneficial to this subgroup of patients by restoring glymphatic transport and waste removal from the brain.

Although recent evidence indicates that at least some chronic fatigue syndrome patients may benefit from cerebrospinal fluid drainage, further studies are needed to confirm this finding and to determine whether this can be attributed to enhancement of glymphatic fluid flow and interstitial fluid clearance. If confirmed, this could offer promising avenues for the future treatment of chronic fatigue syndrome. Clearly, given the relative invasive nature of cerebrospinal fluid diversion, such procedures should be reserved for chronic fatigue syndrome patients who are severely debilitated, or for those with severe headaches. Anyhow, it seems worthwhile to make every effort to identify new therapies for patients who suffer from this devastating disease, especially given that there are currently no effective treatments for this condition.

Source: Wostyn P, De Deyn PP. The putative glymphatic signature of chronic fatigue syndrome: A new view on the disease pathogenesis and therapy. Med Hypotheses. 2018 Sep;118:142-145. doi: 10.1016/j.mehy.2018.07.007. Epub 2018 Jul 6. https://www.ncbi.nlm.nih.gov/pubmed/30037603

Identification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-associated DNA methylation patterns

Abstract:

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition involving multiple organ systems and characterized by persistent/relapsing debilitating fatigue, immune dysfunction, neurological problems, and other symptoms not curable for at least 6 months. Disruption of DNA methylation patterns has been tied to various immune and neurological diseases; however, its status in ME/CFS remains uncertain. Our study aimed at identifying changes in the DNA methylation patterns that associate with ME/CFS.

METHODS: We extracted genomic DNA from peripheral blood mononuclear cells from 13 ME/CFS study subjects and 12 healthy controls and measured global DNA methylation by ELISA-like method and site-specific methylation status using Illumina MethylationEPIC microarrays. Pyrosequencing validation included 33 ME/CFS cases and 31 controls from two geographically distant cohorts.

RESULTS: Global DNA methylation levels of ME/CFS cases were similar to those of controls. However, microarray-based approach allowed detection of 17,296 differentially methylated CpG sites in 6,368 genes across regulatory elements and within coding regions of genes. Analysis of DNA methylation in promoter regions revealed 307 differentially methylated promoters. Ingenuity pathway analysis indicated that genes associated with differentially methylated promoters participated in at least 15 different pathways mostly related to cell signaling with a strong immune component.

CONCLUSIONS: This is the first study that has explored genome-wide epigenetic changes associated with ME/CFS using the advanced Illumina MethylationEPIC microarrays covering about 850,000 CpG sites in two geographically distant cohorts of ME/CFS cases and matched controls. Our results are aligned with previous studies that indicate a dysregulation of the immune system in ME/CFS. They also suggest a potential role of epigenetic de-regulation in the pathobiology of ME/CFS. We propose screening of larger cohorts of ME/CFS cases to determine the external validity of these epigenetic changes in order to implement them as possible diagnostic markers in clinical setting.

Source: Trivedi MS, Oltra E, Sarria L, Rose N, Beljanski V, Fletcher MA, Klimas NG, Nathanson L. Identification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-associated DNA methylation patterns. PLoS One. 2018 Jul 23;13(7):e0201066. doi: 10.1371/journal.pone.0201066. eCollection 2018.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051500/ (Full study)

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

Abstract:

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 ± 11.8 yrs) and 26 normal controls (NCs, 43.4 ± 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.

Source: Shan ZY, Finegan K, Bhuta S, Ireland T, Staines DR, Marshall-Gradisnik SM, Barnden LR. Brain function characteristics of chronic fatigue syndrome: A task fMRI study. Neuroimage Clin. 2018 Apr 25;19:279-286. doi: 10.1016/j.nicl.2018.04.025. eCollection 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051500/ (Full study)

High-fidelity discrete modeling of the HPA axis: a study of regulatory plasticity in biology

Abstract:

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis is a central regulator of stress response and its dysfunction has been associated with a broad range of complex illnesses including Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS). Though classical mathematical approaches have been used to model HPA function in isolation, its broad regulatory interactions with immune and central nervous function are such that the biological fidelity of simulations is undermined by the limited availability of reliable parameter estimates.

METHOD: Here we introduce and apply a generalized discrete formalism to recover multiple stable regulatory programs of the HPA axis using little more than connectivity between physiological components. This simple discrete model captures cyclic attractors such as the circadian rhythm by applying generic constraints to a minimal parameter set; this is distinct from Ordinary Differential Equation (ODE) models, which require broad and precise parameter sets. Parameter tuning is accomplished by decomposition of the overall regulatory network into isolated sub-networks that support cyclic attractors. Network behavior is simulated using a novel asynchronous updating scheme that enforces priority with memory within and between physiological compartments.

RESULTS: Consistent with much more complex conventional models of the HPA axis, this parsimonious framework supports two cyclic attractors, governed by higher and lower levels of cortisol respectively. Importantly, results suggest that stress may remodel the stability landscape of this system, favoring migration from one stable circadian cycle to the other. Access to each regime is dependent on HPA axis tone, captured here by the tunable parameters of the multi-valued logic. Likewise, an idealized glucocorticoid receptor blocker alters the regulatory topology such that maintenance of persistently low cortisol levels is rendered unstable, favoring a return to normal circadian oscillation in both cortisol and glucocorticoid receptor expression.

CONCLUSION: These results emphasize the significance of regulatory connectivity alone and how regulatory plasticity may be explored using simple discrete logic and minimal data compared to conventional methods.

Source: Sedghamiz H, Morris M, Craddock TJA, Whitley D, Broderick G. High-fidelity discrete modeling of the HPA axis: a study of regulatory plasticity in biology. BMC Syst Biol. 2018 Jul 17;12(1):76. doi: 10.1186/s12918-018-0599-1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050677/ (Full article)

Personalised relaxation practice to improve sleep and functioning in patients with chronic fatigue syndrome and depression: study protocol for a randomised controlled trial

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) and major depressive disorder (MDD) are both debilitating but heterogeneous conditions sharing core features of fatigue, unrefreshing sleep, and impaired functioning. The aetiology of these conditions is not fully understood, and ‘best-practice’ treatments are only moderately effective in relieving symptoms. Unrecognised individual differences in the response to such treatments are likely to underlie poor treatment outcomes.

METHODS/DESIGN: We are undertaking a two-group, parallel, randomised controlled trial (RCT) comparing the effects of a personalised relaxation intervention on sleep quality, daytime symptoms, and functioning in patients with CFS (n = 64) and MDD (n = 64). Following identification of the method that best enhances autonomic responding (such as heart rate variability), participants randomised to the active intervention will practise their recommended method nightly for 4 weeks. All participants will keep a sleep diary and monitor symptoms during the trial period, and they will complete two face-to-face assessments, one at baseline and one at 4 weeks, and a further online assessment to evaluate lasting effects of the intervention at 2 months. Assessments include self-report measures of sleep, wellbeing, and function and monitoring of autonomic responses at rest, in response to the relaxation method and during nocturnal sleep. Treatment outcomes will be analysed using linear mixed modelling.

DISCUSSION: This is the first RCT examining the effects of a personalised relaxation intervention, pre-tested to maximise the autonomic relaxation response, in patients with unrefreshing sleep and fatigue attributed to CFS or MDD. Detailed monitoring of sleep quality and symptoms will enable sensitive detection of improvements in the core symptoms of these debilitating conditions. In addition, repeated monitoring of autonomic functioning can elucidate mechanisms underlying potential benefits. The findings have translational potential, informing novel, personalised symptom management techniques for these conditions, with the potential for better clinical outcomes.

TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ANZCTR), ACTRN12616001671459 . Registered on 5 December 2016.

Source: Macnamara CL, Cvejic E, Parker GB, Lloyd AR, Lee G, Beilharz JE, Vollmer-Conna U. Personalised relaxation practice to improve sleep and functioning in patients with chronic fatigue syndrome and depression: study protocol for a randomised controlled trial. Trials. 2018 Jul 11;19(1):371. doi: 10.1186/s13063-018-2763-8.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042263/ (Full article)