BMJ 2018; 361 doi: https://doi.org/10.1136/bmj.k1261 (Published 12 April 2018) Cite this as: BMJ 2018;361:k1261
- Maria Cruickshank, senior research fellow1, Norma O’Flynn, chief operating officer1,
- Saul N Faust, professor of paediatric immunology and infectious diseases, director of NIHR Clinical Research Facility2
- on behalf of the Guideline Committee
- Lyme disease can occur anywhere in the UK
- Erythema migrans is diagnostic of Lyme disease. Use a combination of clinical presentation and laboratory testing to guide diagnosis and treatment in people without erythema migrans
- Serological testing is a two tier approach: a sensitive initial test is performed first (ELISA), followed by a more specific confirmatory test (immunoblot) in case of a positive or equivocal initial result
- Symptoms of Lyme disease may take months or years to resolve even after treatment for several reasons, including alternative diagnoses, reinfection, treatment failure, immune reaction, and organ damage caused by Lyme disease
- Consider a second course of antibiotics for people with ongoing symptoms as treatment may have failed
The guideline focuses on diagnosis and management of Lyme disease according to clinical presentation and symptoms rather than using the differing classifications of Lyme disease, which are poorly defined and contested. There is a lack of good quality evidence on the epidemiology, prevalence, diagnosis, and management of Lyme disease.
This article summarises the most recent recommendations from the National Institute for Health and Care Excellence (NICE).1
Emotional awareness and expression therapy, cognitive behavioral therapy, and education for fibromyalgia: a cluster-randomized controlled trial
Lumley, Mark A.a,*; Schubiner, Howardb; Lockhart, Nancy A.a; Kidwell, Kelley M.c; Harte, Steven E.d,e; Clauw, Daniel J.d,e,f; Williams, David A.d,e,f,g
PAIN: December 2017 - Volume 158 - Issue 12 - p 2354–2363
© 2017 International Association for the Study of Pain
Chronic exposure to insufficient sleep alters processes of pain habituation and sensitizationSimpson, Norah, S.a; Scott-Sutherland, Jenniferb; Gautam, Shivac; Sethna, Navild; Haack, Monikab,*
PAIN: January 2018 - Volume 159 - Issue 1 - p 33–40
Chronic pain conditions are highly comorbid with insufficient sleep. While the mechanistic relationships between the 2 are not understood, chronic insufficient sleep may be 1 pathway through which central pain-modulatory circuits deteriorate, thereby contributing to chronic pain vulnerability over time. To test this hypothesis, an in-laboratory model of 3 weeks of restricted sleep with limited recovery (5 nights of 4-hour sleep per night followed by 2 nights of 8-hour sleep per night) was compared with 3 weeks of 8-hour sleep per night (control protocol). Seventeen healthy adults participated, with 14 completing both 3-week protocols. Measures of spontaneous pain, heat-pain thresholds, cold-pain tolerance (measuring habituation to cold over several weeks), and temporal summation of pain (examining the slope of pain ratings during cold water immersion) were assessed at multiple points during each protocol. Compared with the control protocol, participants in the sleep-restriction protocol experienced mild increases in spontaneous pain (P < 0.05). Heat-pain thresholds decreased after the first week of sleep restriction (P < 0.05) but normalized with longer exposure to sleep restriction. By contrast, chronic exposure to restricted sleep was associated with decreased habituation to, and increased temporal summation in response to cold pain (both P < 0.05), although only in the past 2 weeks of the sleep-restriction protocol. These changes may reflect abnormalities in central pain-modulatory processes. Limited recovery sleep did not completely resolve these alterations in pain-modulatory processes, indicating that more extensive recovery sleep is required. Results suggest that exposure to chronic insufficient sleep may increase vulnerability to chronic pain by altering processes of pain habituation and sensitization.
Pain-modulatory processes deteriorate with more chronic forms of sleep insufficiency and a couple of nights with limited recovery sleep do not resolve alterations.
Corresponding author. Address: 330 Brookline Ave, Dana 779, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Tel.: 617-667-5234. E-mail address: firstname.lastname@example.org
Received March 28, 2017 Received in revised form July 28, 2017 Accepted August 03, 2017
© 2018 International Association for the Study of Pain
Tai Chi Beats Aerobic Exercise for Fibromyalgia
March 22, 2018
Compared with aerobic exercise, the traditional martial art of tai chi is as good as, or better than, aerobic exercise, for improving the overall severity of fibromyalgia symptoms, new research shows.
Results of a 52-week single-blind trial showed that in addition to fibromyalgia symptom relief, tai chi was associated greater improvements in depression, anxiety, self-efficacy, and the mental component of the Short-Form Health Survey (SF-36) quality-of-life measure.
"Compared with aerobic exercise, the most commonly prescribed non-drug treatment, tai chi appears as effective as or better for managing fibromyalgia," the investigators, led by Chenchen Wang, MD, Tufts University School of Medicine in Boston, Massachusetts, write. "This mind-body approach may be considered a therapeutic option in the multidisciplinary management of fibromyalgia."
The study was published online March 21 in the BMJ.
Clin Exp Immunol. 2017 Feb; 187(2): 284–293.
Published online 2016 Nov 23. doi: 10.1111/cei.12882
Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels
T. Nguyen, 1 , 2 S. Johnston, 1 , 2 L. Clarke, 1 , 2 P. Smith, 1 D. Staines, 1 , 2 and S. Marshall‐Gradisnik 1 , 2
AbstractTransient receptor potential melastatin subfamily 3 (TRPM3) ion channels play a role in calcium (Ca2+ ) cell signalling. Reduced TRPM3 protein expression has been identified in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) patients. However, the significance of TRPM3 and association with intracellular Ca2+ mobilization has yet to be determined. Fifteen CFS/ME patients (mean age 48·82 ± 9·83 years) and 25 healthy controls (mean age 39·2 ± 12·12 years) were examined. Isolated natural killer (NK) cells were labelled with fluorescent antibodies to determine TRPM3, CD107a and CD69 receptors on CD56dim CD16+ NK cells and CD56bright CD16dim/- NK cells. Ca2+ flux and NK cytotoxicity activity was measured under various stimulants, including pregnenolone sulphate (PregS), thapsigargin (TG), 2-aminoethoxydiphenyl borate (2APB) and ionomycin. Unstimulated CD56bright CD16dim/- NK cells showed significantly reduced TRPM3 receptors in CFS/ME compared with healthy controls (HC). Ca2+ flux showed no significant difference between groups. Moreover, PregS-stimulated CD56bright CD16dim/- NK cells showed a significant increase in Ca2+ flux in CFS/ME patients compared with HC. By comparison, unstimulated CD56dim CD16+ NK cells showed no significant difference in both Ca2+ flux and TRPM3 expression. PregS-stimulated CD56dimCD16+ NK cells increased TRPM3 expression significantly in CFS/ME, but this was not associated with a significant increase in Ca2+ flux. Furthermore, TG-stimulated CD56dim CD16+ NK cells increased K562 cell lysis prior to PregS stimulation in CFS/ME patients compared with HC. Differential expression of TRPM3 and Ca2+ flux between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity activity in CFS/ME.
Transient receptor potential melastatin subfamily 3 (TRPM3) ion channels play a role in calcium (Ca2+) cell signalling. Reduced TRPM3 protein expression has been identified in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) patients. However, the significance of TRPM3 and association with intracellular Ca2+ mobilization has yet to be determined. Fifteen CFS/ME patients (mean age 48·82 ± 9·83 years) and 25 healthy controls (mean age 39·2 ± 12·12 years) were examined. Isolated natural killer (NK) cells were labelled with fluorescent antibodies to determine TRPM3, CD107a and CD69 receptors on CD56dimCD16+NK cells and CD56brightCD16dim/– NK cells. Ca2+ flux and NK cytotoxicity activity was measured under various stimulants, including pregnenolone sulphate (PregS), thapsigargin (TG), 2‐aminoethoxydiphenyl borate (2APB) and ionomycin. Unstimulated CD56brightCD16dim/– NK cells showed significantly reduced TRPM3 receptors in CFS/ME compared with healthy controls (HC). Ca2+ flux showed no significant difference between groups. Moreover, PregS‐stimulated CD56brightCD16dim/–NK cells showed a significant increase in Ca2+ flux in CFS/ME patients compared with HC. By comparison, unstimulated CD56dimCD16+ NK cells showed no significant difference in both Ca2+ flux and TRPM3 expression. PregS‐stimulated CD56dimCD16+ NK cells increased TRPM3 expression significantly in CFS/ME, but this was not associated with a significant increase in Ca2+flux. Furthermore, TG‐stimulated CD56dimCD16+ NK cells increased K562 cell lysis prior to PregS stimulation in CFS/ME patients compared with HC. Differential expression of TRPM3 and Ca2+ flux between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity activity in CFS/ME.
J Pain 2018 Apr;19(4):410-417. doi: 10.1016/j.jpain.2017.11.013. Epub 2017 Dec 14.
Daily Fluctuations of Progesterone and Testosterone Are Associated With Fibromyalgia Pain Severity.
Schertzinger M1, Wesson-Sides K1, Parkitny L1, Younger J2.
The purpose of this longitudinal blood sampling study was to examine relationships between sex hormones and fibromyalgia pain. Eight women meeting case definition criteria for fibromyalgia provided venous blood samples and reported their fibromyalgia pain severity over 25 consecutive days. All women exhibited normal menstrual cycles and were not taking oral contraceptives. Cortisol, and the sex hormones estradiol, progesterone, and testosterone, were assayed from serum. A linear mixed model was used to determine if fluctuations of sex hormones were associated with changes in pain severity. In the entire sample, day to day changes in progesterone (P = .002) as well as testosterone (P = .015) were significantly and inversely correlated with pain severity. There was no relationship between estradiol and pain (P = .551) or cortisol and pain (P = .633). These results suggest that progesterone and testosterone play a protective role in fibromyalgia pain severity. Sex and other hormones may serve to increase as well as decrease fibromyalgia pain severity.
Sex hormones fluctuate normally in women with fibromyalgia, but may still contribute to pain severity.
Be Wary of Liver Injury From Herbals or Dietary SupplementsDavid A. Johnson, MD
May 07, 2018
Dietary supplements are regarded by the US Food and Drug Administration (FDA) as a food but not as a drug. The use of herbal and dietary supplements is common in the United States, with surveys suggesting that up to 50% of adults use them, and sales of these products (most typically vitamins and minerals) were estimated to be nearly $40 billion in 2014. The allure of these agents is far-reaching and includes claims for bodybuilding, weight loss, reduction of stress/anxiety, and enhanced immunity or sexual performance.
Associated with their use, however, is an increasing awareness of resultant drug-induced liver injury (DILI). Recent data suggest that herbal and dietary supplements account for approximately 20% of drug-induced hepatotoxicity in the United States. In other countries, they may account for a high rate of DILI-notably ≥ 70% in Singapore and South Korea.
The focus of this viewpoint is to highlight key messages from a 2-day research symposium, sponsored by the American Association for the Study of Liver Diseases and the National Institutes of Health, on the challenges associated with DILI, as presented in a recent article by Navarro and colleagues. The Drug-Induced Liver Injury Network, a program funded by the National Institute of Diabetes and Digestive and Kidney Diseases, also provides insight into this problem.
Anabolic steroids are a major implicated agent in DILI. Many bodybuilding supplements include anabolic steroids, which can induce prolonged cholestatic but self-limited liver injury. The bilirubin level may be in the range of 40-50 mg/dL, but chronic liver injury or death is unusual. For the most part, these agents involve synthetic derivatives of testosterone, added illicitly without a prescription.
Weight-loss agents have also been associated with DILI, but with more of a hepatocellular pattern of injury and most notably related to a specific product, OxyELITE Pro®. Aegeline, an alkaloid from the fruit of the bael tree that has been used for centuries as a digestive aid, was added to the product in March 2013. This product was recalled from the market in November 2013, after an FDA warning in October 2013 that certain OxyElite Pro products and another supplement, Versa-1, were considered adulterated because they contained aegeline (a new dietary ingredient), for which evidence of safety was not provided. This addition of aegeline was suspected to be a factor in cases of fatal liver failure and urgent liver transplantation.
Green tea extract, derived from the plant Camellia sinensis, is another notable supplement identified in DILI. Its weight-reduction claims are attributed to purported enhancement of fat metabolism. This additive has been increasingly linked to acute hepatocellular injury, which is idiosyncratic, typically within 3 months of initiation of use. Approximately 10% of these cases have been fatal.Some countries (eg, Spain, France) have removed weight-loss products containing green tea extract from the market; however, green tea extract remains available in the United States.
According to Navarro and colleagues, other herbal supplements that have been implicated in DILI include black cohosh, kratom, valerian, wormwood, cat's claw, artist's conk, fo-ti, and red yeast rice.[1
There is increasing evidence of significant hepatotoxicity associated with the use of herbal and dietary supplements. Given that many, if not most, patients do not report the use of these agents when asked about medications, it is critical for healthcare providers to ask patients to disclose this use and also to accurately define their use. Having patients bring in the supplement package for review by their providers would be helpful, although it is often very difficult to determine the specific agents or amounts involved, because many are included in multi-ingredient nutritional supplements. Heightened suspicion should be the standard for any patient presenting with acute liver injury. DILI presents many challenges in diagnosis and management, but the first step is a heightened awareness of the harm associated with these purportedly "health-promoting" herbal and dietary supplements.
Navarro VJ, Barnhart H, Bonkovsky HL, et al. Liver injury from herbals and dietary supplements in the US Drug Induced Liver Injury Network. Hepatology. 2014;60:1399-1408.
Task Related Cerebral Blood Flow Changes Of Patients With Chronic Fatigue Syndrome: An Arterial Spin Labeling Study.
PURPOSE: One hallmark of chronic fatigue syndrome (ME/CFS) is task related worsening of fatigue. Global brain hypoperfusion, abnormal regional activation, and altered functional connectivity of brain areas associated with cognition and memory have been reported but remain controversial.
METHODS: We enrolled 17 female participants fulfilling the CDC Criteria for ME/CFS and 16 matched healthy controls (HC). Using a 3T-Phillips Achieva MRI-scanner, pseudo-continuous arterial spin-labeling (pCASL), was used to study the dynamics of regional cerebral blood flow (rCBF) and their relationship to mental fatigue in ME/CFS patients and HC during a demanding cognitive task, i.e. modified Paced-Auditory-Serial-Addition-Testing (PASAT).
RESULTS: ME/CFS subjects reported more fatigue than HC at baseline (p < .01). Global brain perfusion of ME/CFS and HC subjects was similar at rest. The PASAT resulted in significantly increased fatigue in ME/CFS participants and HC. Although not different between groups, overall CBF significantly increased over the first 3 min of the PASAT and then decreased thereafter. Regional CBF (rCBF) changes were significantly different between groups during the post-task recovery period. Whereas improvement of fatigue of ME/CFS subjects was associated with decreased rCBF in both superior temporal gyri (STG), precuneus, and fusiform gyrus, it was associated with increased rCBF in the same areas in HC.
CONCLUSIONS: Our results suggest that ME/CFS is associated with normal global CBF at rest and during a strenuous task (PASAT); however rCBF of several brain regions associated with memory, goal-oriented attention, and visual function was differentially associated with recovery from fatigue in ME/CFS patients and HC.
Source: Staud R, Boissoneault J, Craggs JG, Lai S, Robinson ME. Task Related Cerebral Blood Flow Changes of Patients with Chronic Fatigue Syndrome: An Arterial Spin Labeling Study. Fatigue. 2018;6(2):63-79. doi: 10.1080/21641846.2018.1453919. Epub 2018 Mar 20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914525/ (Full study)
Posted in Neurology 2018,
Weighting Of Orthostatic Intolerance Time Measurements With Standing Difficulty Score Stratifies ME/CFS Symptom Severity And Analyte Detection
BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is clinically defined and characterised by persistent disabling tiredness and exertional malaise, leading to functional impairment.
METHODS: This study introduces the weighted standing time (WST) as a proxy for ME/CFS severity, and investigates its behaviour in an Australian cohort. WST was calculated from standing time and subjective standing difficulty data, collected via orthostatic intolerance assessments. The distribution of WST for healthy controls and ME/CFS patients was correlated with the clinical criteria, as well as pathology and cytokine markers. Included in the WST cytokine analyses were activins A and B, cytokines causally linked to inflammation, and previously demonstrated to separate ME/CFS from healthy controls. Forty-five ME/CFS patients were recruited from the CFS Discovery Clinic (Victoria) between 2011 and 2013. Seventeen healthy controls were recruited concurrently and identically assessed.
RESULTS: WST distribution was significantly different between ME/CFS participants and controls, with six diagnostic criteria, five analytes and one cytokine also significantly different when comparing severity via WST. On direct comparison of ME/CFS to study controls, only serum activin B was significantly elevated, with no significant variation observed for a broad range of serum and urine markers, or other serum cytokines.
CONCLUSIONS: The enhanced understanding of standing test behaviour to reflect orthostatic intolerance as a ME/CFS symptom, and the subsequent calculation of WST, will encourage the greater implementation of this simple test as a measure of ME/CFS diagnosis, and symptom severity, to the benefit of improved diagnosis and guidance for potential treatments.
Source: Richardson AM, Lewis DP, Kita B, Ludlow H, Groome NP, Hedger MP, de Kretser DM, Lidbury BA. Weighting of orthostatic intolerance time measurements with standing difficulty score stratifies ME/CFS symptom severity and analyte detection. J Transl Med. 2018 Apr 12;16(1):97. doi: 10.1186/s12967-018-1473-z. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1473-z
Integration Of DNA Methylation & Health Scores Identifies Subtypes In Myalgic Encephalomyelitis/Chronic Fatigue SyndromeAbstract:
AIM: To identify subtypes in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) based on DNA methylation profiles and health scores.
METHODS: DNA methylome profiles in immune cells were integrated with symptomatology from 70 women with ME/CFS using similarity network fusion to identify subtypes.
RESULTS: We discovered four ME/CFS subtypes associated with DNA methylation modifications in 1939 CpG sites, three RAND-36 categories and five DePaul Symptom Questionnaire measures. Methylation patterns of immune response genes and differences in physical functioning and postexertional malaise differentiated the subtypes.
CONCLUSION: ME/CFS subtypes are associated with specific DNA methylation differences and health symptomatology and provide additional evidence of the potential relevance of metabolic and immune differences in ME/CFS with respect to specific symptoms.
Source: de Vega WC, Erdman L, Vernon SD, Goldenberg A, McGowan PO. Integration of DNA methylation & health scores identifies subtypes in myalgic encephalomyelitis/chronic fatigue syndrome. Epigenomics. 2018 Apr 25. doi: 10.2217/epi-2017-0150. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29692205
Posted in Genetics
Good outlook for patients with confirmed Lyme neuroborreliosisBMJ 2018; 361 doi: https://doi.org/10.1136/bmj.k2284 (Published 30 May 2018) Cite this as: BMJ 2018;361:k2284
- Saul N Faust, professor of paediatric immunology and infectious diseases and director1,
- Stephen Barton, retired marketer and Lyme disease patient2,
- Caroline Rayment, general practitioner3,
- Norma O’Flynn, chief operating officer and general practitioner4
- Correspondence to: S Faust email@example.com
In the linked paper (doi:10.1136/bmj.k1998), Obel and colleagues report on one of the largest, and highest quality longitudinal follow-up studies to date of people with neurological forms of Lyme disease.1 The study included more than 2000 people with neuroborreliosis and 20 000 controls and the data are reassuring. If you are a patient with a confirmed microbiological diagnosis and neurological symptoms of Lyme disease, this will have no effect on your survival, wellbeing (health status), or social parameters (such as school results and marriage and divorce rates) 10 years after your diagnosis compared with a control population.
This means that you will be able to recover fully and lead a normal working life, although if you are an adult you may have marginally less income and activity in the labour market than you did before the infection (rather than in comparison with the control population). Development, health, and educational achievement were not different in children diagnosed as having neuroborreliosis compared with controls.
Neurosci. 2018 Apr 26;12:78. doi: 10.3389/fnbeh.2018.00078. eCollection 2018.
The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure. Lacourt TE1, Vichaya EG1, Chiu GS1, Dantzer R1, Heijnen CJ1.
Inflammation, the brain and energy metabolism – it’s like the trifecta in chronic fatigue syndrome (ME/CFS) research. It seems like virtually everyone in the ME/CFS field believes that all three are involved but that belief only carries so much weight in a small field. What this field really needs is buy-in from outside researchers who can help move it forward.
That appears to have happened recently when a major research group lead by Robert Dantzer penned a review paper proposing that low-grade inflammation is causing energy production problems in chronic fatigue syndrome (ME/CFS) and probably many other diseases. The authors didn’t shy away from the chronic fatigue syndrome (ME/CFS) connection. In fact, they lead their review paper off with it, placing the fatigue in ME/CFS in the same context as the fatigue in cancer, MS, rheumatoid arthritis and others.
The study was published in the Frontiers in Neuroscience journal series which is touted as the 1st most cited series in the Neurosciences journal field.
The Dantzer group’s involvement in the intersection between inflammation and energy production is welcome but not entirely surprising; it’s a logical outcome of their past work. Dantzer spearheaded the now accepted idea that the immune system produces the symptoms of “sickness behavior” (fatigue, headache, muscle aches, sore throat, etc.) that occur during an infection which serve to reduce our energy usage and to keep us isolated from others (they posit to prevent pathogen spread).
What’s new is his group’s focus on the energy production process itself – a focus, interestingly, made possible largely by the work of ME/CFS researchers. The piece, with lead author Tamara LaCourt, shows how low-grade inflammation can cause the same energy problems we’re seeing in ME/CFS: a metabolic switch from energy-efficient, oxygen-based energy production process to a fast-acting, inefficient glycolysis-based approach.
Immune cells aren’t like other cells; jumping into action causes them to rev their motors up tremendously, placing enormous stress on their energy production systems. As they do this, they switch from a focus on aerobic energy metabolism to what the authors call “aerobic glycolysis” in order to churn out energy more quickly. That process results in less mitochondrial energy production and the increased production of toxic by-products like lactate. Plus, over time this process results in reduced nutrient availability and less energy for the rest of the body.
Several studies from the Solve ME/CFS Initiative are examining whether the energy production of immune cells in ME/CFS is up to the task.
Prolonged inflammation also tends to result in two other energy production problems: increased insulin resistance and reduced glucose tolerance. Reduced glucose tolerance smacks glucose uptake by immune cells at the very time that they’re clamoring for it, causing the body to break down fats and proteins, thus removing resources it would ordinarily use elsewhere. In yet another whack at the energy production, inflammation increases reactive oxygen species production which can hammer mitochondrial energy production.
The authors believe that neurons – which rely on glycolytic processes in astrocytes to get their energy – may be hit hardest by chronic inflammation. This is because insulin resistance – a common outcome of chronic inflammation – destroys the glycolytic process in astrocytes, causing neurons to get their energy from fats – a slower and less efficient process.
Miller’s work on ME/CFS suggests that problems with the basal ganglia – the dopamine-producing center of the brain – may be causing problems with movement, reward and fatigue in ME/CFS. That’s a particularly interesting finding given that dopaminergic neurons in the brain are particularly vulnerable to inflammation. Shungu’s studies, which have consistently found high lactate and low gluthathione levels in the ventricles of ME/CFS patients brains, suggest that high levels of oxidative stress could be causing inflammation in the brain itself.
Plus, even low-level inflammation can disrupt a key element in ME/CFS and FM – sleep – which, in turn, increases fatigue. Simply altering one’s circadian rhythm (i.e. one’s sleep times) can have significant metabolic effects, leading to increased glucose levels and decreased insulin sensitivity. The effects don’t end with sleep; sleep deprivation results in the need for increased energy expenditures the next day.
Then add in the extra ten percent in extra energy needs that chronic low-level inflammation imposes on the body – and the potential for a dramatic drop in energy production rises. (We’ll find out more about total energy production in ME/CFS during the metabolic chamber tests in the NIH’s intramural study).
The authors believe that impaired energy production represents a “final common pathway” in persistent fatigue.
Frontiers in Immunology2018; 9: 1028.
Published online 2018 May 9. doi: 10.3389/fimmu.2018.01028
Association of T and NK Cell Phenotype With the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Jose Luis Rivas,1,* Teresa Palencia,1 Guerau Fernández,2 and Milagros García1,3
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a pathological condition characterized by incapacitating fatigue and a combination of neurologic, immunologic, and endocrine symptoms. At present its diagnosis is based exclusively on clinical criteria. Several studies have described altered immunologic profiles; therefore, we proposed to further examine the more significant differences, particularly T and NK cell subpopulations that could be conditioned by viral infections, to discern their utility in improving the diagnosis and characterization of the patients. The study included 76 patients that fulfilled the revised Canadian Consensus Criteria (CCC 2010) for ME/CFS and 73 healthy controls, matched for age and gender. Immunophenotyping of different T cell and natural killer cell subpopulations in peripheral blood was determined by flow cytometry. ME/CFS patients showed significantly lower values of T regulatory cells (CD4+CD25++(high)FOXP3+) and higher NKT-like cells (CD3+CD16+/−CD56+) than the healthy individuals. Regarding NK phenotypes, NKG2C was significantly lower and NKCD69 and NKCD56 bright were significantly higher in the patients group. A classification model was generated using the more relevant cell phenotype differences (NKG2C and T regulatory cells) that was able to classify the individuals as ME/CFS patients or healthy in a 70% of cases. The observed differences in some of the subpopulations of T and NK cells between patients and healthy controls could define a distinct immunological profile that can help in the diagnostic process of ME/CFS patients, contribute to the recognition of the disease and to the search of more specific treatments. However, more studies are needed to corroborate these findings and to contribute to establish a consensus in diagnosis.
Keywords: chronic fatigue syndrome, natural killer cells, T regulatory cells, NKp46, NKG2C, diagnosis, biomarker
Large NK Cell Study Points to Autoimmunity and Inflammation in Chronic Fatigue Syndrome (ME/CFS)June 14, 2018
Problems with natural killer (NK) cell functioning have been like an anchor in the storm for immunologists interested in chronic fatigue syndrome (ME/CFS). While other immune results like cytokines have flipped and flopped all over the place, the NK cytotoxic results have been solid. Almost every study has found that when given the chance to kill infected cells, the NK cells in ME/CFS patients poop out. (The studies which have not found differences in NK cell functioning have tended not to use whole blood or used older samples – suggesting that something in the blood could be impairing NK cell functioning in ME/CFS.)
Dr. Daniel Peterson, Sierra Internal Medicine and Simmaron Scientific Advisor
The most extensive study – a year-long 2012 study involving Dr. Peterson and Griffith University in Australia – found reduced natural killer cell functioning at all time points. (Peterson has a long history of interest in natural killer cells; he was a co-author of the first study, over thirty years ago, to find deficient NK cell functioning in chronic fatigue syndrome (ME/CFS).)
NK cells are important because they maintain the lines of our initial immune defense, holding the fort, so to speak, until the big guns – the T and B cells- wipe out the infection. – They also regulate the immune response.
Normally our cells signal that they are infected by displaying peptide fragments from the pathogen (using MHC Class 1 molecules) on their surface. NK cells then hunt out and destroy these infected cells. However, some pathogens have learned how to prevent the cells they’ve infected from displaying these peptide fragments.
If NK cells and other parts of the innate immune response can’t hold back the invaders, the pathogens may invade more deeply into the body, potentially causing more problems before the adaptive immune response (T and B-cells) can kick in.
A deficient early response to pathogens would then very likely translate into more symptoms. We don’t know when the problems with NK cell killing got started in ME/CFS, but if they were in place prior to the illness or occurred early in the illness they could have played a role in the inception of ME/CFS as people who have more trouble fighting off a pathogen; i.e. people with more severe symptoms, are more likely to come down with ME/CFS.
Once ME/CFS has begun, the inhibited NIK killing response could mean more trouble removing tumor and infected cells – particularly herpes virus infected cells- as people deficient in NK cells have trouble fighting off herpes viruses.
NK cells, then, are vitally important, but attempts to identify issues other than cytotoxic killing abilities have been less successful. NK cells come in different types (cytotoxic and regulatory) and the balance of these subpopulations is important. Some studies have found differences in these subpopulations in ME/CFS and some have not.
Many of those studies, however, have been small and used less than stringent criteria for defining ME/CFS. A Spanish group decided to rectify those problems with a more definitive study which examined NK cell populations in a larger study (n=149) with patients who met the Canadian Consensus Criteria for ME/CFS. In order to ensure they captured all factors in the blood that might be whacking NK cells, they used whole blood and analyzed it within 6 hours of collection.
Then they tried to reverse engineer their results to see if a diagnostic test could be developed which simply charted which kinds of NK cells a person had. That was pretty good, but then they went further and asked if people who were worse off had different subpopulations of NK cells or more evidence of herpes virus reactivations (EBV, HMCV).
Fever of Unknown Origin in an Adult? Consider Periodic Fever SyndromesPaul G. Auwaerter, MD - Medscape - Jul 02, 2018.
Johns Hopkins University School of Medicine.
Fevers of unknown origin (FUO) are a not infrequent cause for ID consultation. Fellows, residents, or students often go straight to the usual definition of FUO, but I ask them to pause and consider whether the patient truly fits the FUO pattern that has been used since the early 1960s: unexplained fever lasting 3 or more weeks versus a longer-term pattern, such as episodic FUO which often have a benign diagnosis. Some fevers occur periodically and are not limited to a day or two. People might have fevers lasting 5-7 days at a time, and when you closely question them, it seems that they have fevers once or twice a month, or every 4-8 weeks. These fevers seem to have a periodicity.
We don't typically encounter periodic FUO in adult infectious diseases, but they can certainly occur and are worth considering, especially in the outpatient clinic. We've seen a number of these patients over the years and it's always gratifying if you can get to a diagnosis.
A recent patient—a 23-year-old, accompanied by his mother—had a history of problems as a youth with recurrent and severe sore throats that didn't seem to be due to Group A streptococcal infections. He had a tonsillectomy which seemed to solve this problem through his elementary and high school years; however, in college, he started to have very frequent sore throats. These were not Group A strep-related, and he had swollen glands and rather high fevers (up to 102-103˚ F), chills, sores in his mouth, and occasionally other complaints of feeling run down. This might last 5-7 days and then abate.
This patient was referred to us as having a FUO, but upon interviewing him, we learned that these fevers were occurring about once every 2 months, and then becoming even more frequent, occurring every 2-4 weeks. He has taken copious quantities of antibiotics which seemed to yield some benefit, but it was unclear whether this was just a time issue. When lab tests were done during these flare-ups, there were marked elevations in C-reactive protein levels and erythrocyte sedimentation rate.
Unlike children (for whom we have a long list of possible genetic bases for periodic fever), adults have their own menu of periodic fevers to consider. These include familial Mediterranean fever, the TNF receptor–associated periodic syndrome (known as TRAPS), or cryopyrin-associated periodic syndromes. Many of these patients have other signs and symptoms, such as rash or abdominal complaints, and a positive family history with fairly high frequency. These fevers can be diagnosed using genetic means; however, there is one entity that deserves consideration for which this patient fit fairly well—periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome).
PFAPA was first described in children, but in 2008 it was described for the first time in adults. We've diagnosed several of these patients and have referred some to the National Institutes of Health for further study. Of interest, these patients often have a history of frequent sore throats as a child, with improvement after tonsillectomy. As adults, they present once again with similar symptoms. They generally lack belly symptoms and often have an exclusive response to prednisone in the course of a few hours. The basis for this condition is not well understood. These patients may have disorders of innate immunity or IL-1-like responses. The genetic basis isn't fully known, although it's generally helpful to exclude other genetic explanations. A number of companies are providing increasingly lower-cost genetic panels to assess for some of the other genetic syndromes. You can find out more about the availability of these genetic tests here, although insurers might not pay for them, even though the costs are dropping. A number of my patients have been willing to pursue this route.
The PFAPA syndrome is a diagnosis of exclusion if it fits. Some patients will not have all of the components, although our 23-year-old patient did. Patients are often gratified just to have the syndromic name, and some are willing to soldier on through, perhaps using nonsteroidal drugs. Sometimes, when they are feeling especially ill, a brief course of prednisone seems helpful. Others have suggested that cimetidine is helpful, although I haven't tried that.
In conclusion, there is certainly a rationale for taking some time to decide what kind of fever you might be evaluating, particularly in the outpatient setting. If there is a concern for periodic fever, take a step back and think about some of the periodic fever syndromes that might occur in adults. You might have to pursue genetic testing. If you can get a diagnosis, it's often gratifying to the patients, who are highly frustrated and might have been diagnosed with other conditions, such as fibromyalgia, chronic fatigue syndrome, or other somatic disorders. So, it is worth considering.
Thanks very much for listening.
Medscape Infectious Diseases © 2018 WebMD, LLC
Reduced Selective Learning in Patients With Fibromyalgia vs Healthy Controls
Ann Meulders; Yannick Boddez; Fernando Blanco; Maaike Van Den Houte; Johan W.S. Vlaeyen
Impaired selective fear learning has been advanced as a core mechanism involved in excessive spreading of protective responses such as pain-related fear and avoidance leading to disability in chronic pain conditions. Using the litmus test for selective learning effects, the blocking procedure, we tested the hypothesis that patients with fibromyalgia (FM) show less selective threat learning than healthy controls (HCs). We introduce a novel selective learning task based around a clinical diary scenario. On a trial-by-trial basis, participants rated whether they expected certain situations (A, B, Z, and X) in the diary of a fictive FM patient would trigger pain in that patient. The procedure did not involve any experimental pain induction because the verbal outcomes "pain" or "no pain" were used. During the elemental acquisition phase, one situation was followed by "pain" (A+, eg, "Kim slept badly, and reports pain"), whereas another situation was followed by "no pain" (Z-, eg, "Kim was stressed, and reports no pain"). During the compound acquisition phase, another situation (X), referred to as the blocked stimulus, was presented in compound with a previously pain-eliciting situation and also paired with "pain" (AX+, eg, Kim slept badly" and "Kim has vacuumed," and reports pain). Simultaneously, a novel situation was introduced and also followed by "pain" (B+). Within-group comparisons showed blocking (ie, significant difference between B and X) in the HCs, but not in the patients with FM. This study is the first in directly assessing differences in selective learning between patients with FM and HCs using a blocking procedure.
Distribution of mast cell subtypes in interstitial cystitis: implications for novel diagnostic and therapeutic strategies?
- Shabana T Malik1, Brian R Birch2, David Voegeli1, Vipul Foria3, Alan J Cooper4, Andrew F Walls2, Bashir A Lwaleed1
AbstractAims To identify the presence and geographical distribution of mast cell (MC) subtypes: MCT (tryptase positive–chymase negative) and MCTC (tryptase positive–chymase positive) in bladder tissue.
Methods Bladder tissue was obtained from patients with painful bladder syndrome/interstitial cystitis (n=14) and normal histology from University Hospital Southampton tissue bank. Sequential tissue slices were immunohistochemically stained for MC subtypes using anti-MC tryptase (for MCT and MCTC) and anti-MC chymase (for MCTC). Stained sections were photographed, and positively stained MCs were quantified using ImageJ. Data were analysed using descriptive statistics and individual paired t-tests.
Results There was a significant difference in the density of MCs between each layer of the disease bladder, with the greatest accumulation within the detrusor (p<0.001). There was a significant increase in MCTC subtype in the lamina (p=0.009) in painful bladder syndrome/interstitial cystitis.
Conclusions Our results suggest that mastocytosis is present within all layers of disease bladder, especially the muscle layer. The varying increase in MC subtypes in the lamina and mucosa may explain the variability in painful bladder syndrome/interstitial cystitis symptoms. A high influx of MCTC in the mucosa of individuals who also had ulceration noted within their diagnostic notes may be of the Hunner’s ulcer subclassification. These findings suggest a relationship between the pathogenesis of MC subtypes and the clinical presentation of painful bladder syndrome/interstitial cystitis. A cohort study would further elucidate the diagnostic and/or therapeutic potential of MCs in patients with painful bladder syndrome/interstitial cystitis.
Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in chronic fatigue syndromeAuthor links open overlay panelLeighton R.BarndenaZack Y.ShanaDonald R.StainesaSonyaMarshall-GradisnikaKevinFineganbTimothyIrelandbSandeepBhutab
NeuroImage: ClinicalVolume 20, 2018, Pages 102-109
AbstractWe 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 MRIsignal 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 increasedsignal-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 matteror 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.
Visual Aspects of Reading Performance in Myalgic Encephalomyelitis (ME)Rachel L. Wilson, Kevin B. Paterson, Victoria McGowan and Claire V. Hutchinson*
- Department of Neuroscience, Psychology and Behaviour, College of Life Sciences, University of Leicester, Leicester, United Kingdom
Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model
Jonas Blomberg 1, Carl-Gerhard Gottfries 2, Amal Elfaitouri 3, Muhammad Rizwan 1 and Anders Rosén 4
Department of Medical Sciences, Uppsala University, Clinical Microbiology, Academic Hospital, Uppsala, Sweden
Front. Immunol., 15 February 2018 | https://doi.org/10.3389/fimmu.2018.00229
Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging.
In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease. A pattern emerged, giving rise to an explanatory model.
ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism.
According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance.
Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension.
A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain.
In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones.
Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.
Medical Cannabis for the Treatment of FibromyalgiaGeorge Habib, MD, MPH; Suheil Artul, MD
J Clin Rheumatol. 2018;24(5):255-258.
Background: Fibromyalgia is a chronic pain syndrome, characterized by chronic musculoskeletal pain, fatigue, and mood disturbances. There are nearly no data on the effect of medical cannabis (MC) treatment on patients with fibromyalgia.
Methods: Data were obtained from the registries of 2 hospitals in Israel (Laniado Hospital and Nazareth Hospital) on patients with a diagnosis of fibromyalgia who were treated with MC. After obtaining patient consent, demographic, clinical, and laboratory parameters were documented. All the patients also completed the Revised Fibromyalgia Impact Questionnaire regarding the period before and after MC treatment.
Results: Thirty patients were identified, and 26 patients were included in the study. There were 19 female patients (73%), and the mean age of the study group was 37.8 ± 7.6 years. The mean dosage of MC was 26 ± 8.3 g per month, and the mean duration of MC use was 10.4 ± 11.3 months. After commencing MC treatment, all the patients reported a significant improvement in every parameter on the questionnaire, and 13 patients (50%) stopped taking any other medications for fibromyalgia. Eight patients (30%) experienced very mild adverse effects.
Conclusions: Medical cannabis treatment had a significant favorable effect on patients with fibromyalgia, with few adverse effects.
Brain, Behavior, and Immunity Available online 14 September 2018
Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation
DanielAlbrechta1AntonForsbergb1AngelicaSandströmcdCourtneyBerganaDianaKadetoffcdeEkaterinaProtsenkoaJonLampafYvonneC.LeeghCarolineOlgartHöglundiCiprianCatanaaSimonCervenkabOluwaseunAkejujMatsLekandercdkGeorgeCohenlChristerHalldinbNormanTaylorjMinhaeKimlJacob M.Hookerl…Marco L.Loggiaa2
Fibromyalgia patients exhibit elevated cortical levels of [11C]PBR28 signal.
[11C]PBR28 signal was correlated with subjective fatigue in patients.
Results from [11C]PBR28 SUVR and VT analyses show strong regional overlap.
No differences in [11C]-L-deprenyl-D2 signal implicate microglia, not astrocytes.
Our data support glial modulation as a potential therapeutic strategy for FM.
Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [11C]-L-deprenyl-D2 PET, thought to primarily reflect astrocytic (but not microglial) signal.
Thirty-one FM patients and 27 healthy controls (HC) were examined using [11C]PBR28 PET. 11 FM patients and 11 HC were scanned using [11C]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (VT) were computed from the [11C]PBR28 data. [11C]-L-deprenyl-D2 was quantified using λ k3. PET imaging metrics were compared across groups, and when differing across groups, against clinical variables.
Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [11C]PBR28 VT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [11C]-L-deprenyl-D2 signal, including those demonstrating elevated [11C]PBR28 signal in patients (p’s ≥ 0.53, uncorrected). The elevations in [11C]PBR28 VT and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [11C]PBR28 SUVR in the anterior and posterior middle cingulate cortices (p’s < 0.03). SUVR was not significantly associated with any other clinical variable.
Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [11C]PBR28 signal were not also accompanied by increased [11C]-L-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [11C]-L-deprenyl-D2 signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.
Chinese Medical journal META ANALYSIS
Year : 2018 | Volume : 131 | Issue : 7 | Page : 829-838
Mindfulness Meditation for Primary Headache Pain: A Meta-Analysis
Qiang Gu1, Jin-Chao Hou2, Xiang-Ming Fang1
1 School of Medicine, Zhejiang University, Hangzhou, Zhejiang 210029, China
2 Department of Anesthesiology, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang 210029, China
Date of Submission
Date of Web Publication
Background: Several studies have reported that mindfulness meditation has a potential effect in controlling headaches, such as migraine and tension-type headache; however, its role remains controversial. This review assessed the evidence regarding the effects of mindfulness meditation for primary headache pain.
Methods: Only English databases (PubMed, Cochrane Central Register of Controlled Trials [the Cochrane Library], PsycINFO, Psychology and behavioral science collection, PsyArticles, Web of Science, and Scopus) were searched from their inception to November 2016 with the keywords (“meditation” or “mindfulness” or “vipassana” or “dzogchen” or “zen” or “integrative body-mind training” or “IBMT” or “mindfulness-based stress reduction” or “MBSR” or “mindfulness-based cognitive therapy” or “MBCT” and “Headache” or “Head pain” or “Cephalodynia” or “Cephalalgia” or “Hemicrania” or “Migraine”). Titles, abstracts, and full-text articles were screened against study inclusion criteria: controlled trials of structured meditation programs for adult patients with primary headache pain. The quality of studies included in the meta-analysis was assessed with the Yates Quality Rating Scale. The meta-analysis was conducted with Revman 5.3.
Results: Ten randomized controlled trials and one controlled clinical trial with a combined study population of 315 patients were included in the study. When compared to control group data, mindfulness meditation induced significant improvement in pain intensity (standardized mean difference, −0.89; 95% confidence interval, −1.63 to −0.15; P = 0.02) and headache frequency (−0.67; −1.24 to −0.10; P = 0.02). In a subgroup analysis of different meditation forms, mindfulness-based stress reduction displayed a significant positive influence on pain intensity (P < 0.000). Moreover, 8-week intervention had a significant positive effect (P < 0.000).
Conclusions: Mindfulness meditation may reduce pain intensity and is a promising treatment option for patients. Clinicians may consider mindfulness meditation as a viable complementary and alternative medical option for primary headache.
Association of Coffee Drinking With Mortality by Genetic Variation in Caffeine MetabolismFindings From the UK Biobank
Erikka Loftfield, PhD1; Marilyn C. Cornelis, PhD2; Neil Caporaso, MD3; et al Kai Yu, PhD4; Rashmi Sinha, PhD1; Neal Freedman, PhD1
JAMA Intern Med. 2018;178(8):1086-1097. doi:10.1001/jamainternmed.2018.2425
Question Moderate coffee consumption has been inversely associated with mortality; however, does heavy intake, particularly among those with common genetic polymorphisms that impair caffeine metabolism, increase risk of mortality?
Findings This large prospective cohort study of a half million people found inverse associations for coffee drinking with mortality, including among participants drinking 1 up to 8 or more cups per day. No differences were observed in analyses that were stratified by genetic polymorphisms affecting caffeine metabolism.
Meaning This study provides further evidence that coffee drinking can be part of a healthy diet and offers reassurance to coffee drinkers.
Importance Prospective cohorts in North America, Europe, and Asia show consistent inverse associations between coffee drinking and mortality, including deaths from cardiovascular disease and some cancers. However, concerns about coffee, particularly among people with common genetic polymorphisms affecting caffeine metabolism and among those drinking more than 5 cups per day, remain.
Objective To evaluate associations of coffee drinking with mortality by genetic caffeine metabolism score.
Design, Setting, and Participants The UK Biobank is a population-based study that invited approximately 9.2 million individuals from across the United Kingdom to participate. We used baseline demographic, lifestyle, and genetic data form the UK Biobank cohort, with follow-up beginning in 2006 and ending in 2016, to estimate hazard ratios (HRs) for coffee intake and mortality, using multivariable-adjusted Cox proportional hazards models. We investigated potential effect modification by caffeine metabolism, defined by a genetic score of previously identified polymorphisms in AHR, CYP1A2, CYP2A6, and POR that have an effect on caffeine metabolism. Of the 502 641 participants who consented with baseline data, we included those who were not pregnant and had complete data on coffee intake and smoking status (n = 498 134).
Exposures Total, ground, instant, and decaffeinated coffee intake.
Main Outcomes and Measures All-cause and cause-specific mortality.
Results The mean age of the participants was 57 years (range, 38-73 years); 271 019 (54%) were female, and 387 494 (78%) were coffee drinkers. Over 10 years of follow-up, 14 225 deaths occurred. Coffee drinking was inversely associated with all-cause mortality. Using non–coffee drinkers as the reference group, HRs for drinking less than 1, 1, 2 to 3, 4 to 5, 6 to 7, and 8 or more cups per day were 0.94 (95% CI, 0.88-1.01), 0.92 (95% CI, 0.87-0.97), 0.88 (95% CI, 0.84-0.93), 0.88 (95% CI, 0.83-0.93), 0.84 (95% CI, 0.77-0.92), and 0.86 (95% CI, 0.77-0.95), respectively. Similar associations were observed for instant, ground, and decaffeinated coffee, across common causes of death, and regardless of genetic caffeine metabolism score. For example, the HRs for 6 or more cups per day ranged from 0.70 (95% CI, 0.53-0.94) to 0.92 (95% CI, 0.78-1.10), with no evidence of effect modification across strata of caffeine metabolism score (P = .17 for heterogeneity).
Conclusions and Relevance Coffee drinking was inversely associated with mortality, including among those drinking 8 or more cups per day and those with genetic polymorphisms indicating slower or faster caffeine metabolism. These findings suggest the importance of noncaffeine constituents in the coffee-mortality association and provide further reassurance that coffee drinking can be a part of a healthy diet.
Impact of Empathy in the Patient-Doctor Relationship on Chronic Pain Relief and Quality of Life: A Prospective Study in Spanish Pain Clinics
Luz Cánovas, PhD
Pain Clinic, Complejo Hospitalario Universitario de Ourense (CHUO), Ourense, Spain
Correspondence to: Luz Cánovas, PhD, Pain Clinic, Complejo Hospitalario Universitario de Ourense (CHUO), Ramon Puga Noguerol 54, 32005 Ourense, Spain. Tel: +34-98-838-5500; Fax: 98-838-5551; E-mail: firstname.lastname@example.org.
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Luz Cánovas, PhD Antonio-José Carrascosa, PhD, Modesto García, PhD, Mariano Fernández, PhD, , Almudena Calvo, PhD, Vicente Monsalve, PhD, José-Francisco Soriano, PhD
Empathy Study Group
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Department of Anesthesiology, Hospital Civil (Complejo Hosp. Regional Carlos Haya), Málaga, Spain
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Medical Department, Mundipharma, S.L., Madrid, Spain
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Pain Clinic, Consorci Hospital General Universitari de València, Valencia, Spain
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Department of Psychology, University of Valencia, Valencia, Spain
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Pain Medicine, Volume 19, Issue 7, 1 July 2018, Pages 1304–1314, https://doi.org/10.1093/pm/pnx160
Published:13 July 2017
To assess the impact of the empathy of physicians, perceived by patients with chronic pain, regarding pain relief and health-related quality of life (HR-QoL).
A prospective non-interventional study was conducted in 2,898 patients with moderate to severe chronic pain who were referred to pain clinics. The same physician visited each patient at baseline and after one and three months. Study questionnaires included the Jefferson Scale of Patient Perceptions of Physician Empathy (JSPPPE), the Life Orientation Test–Revised (LOT-R), the Pain Coping Questionnaire (CAD-R), the Brief Pain Inventory Short Form (BPI-SF), and the EuroQol-5D (EQ-5D). Regression analyses were used to evaluate the independent contribution of the changes in perceived empathy over pain intensity and improvement of HR-QoL.
BPI-SF scores for pain intensity, rated as worst, least, average, and current pain, decreased significantly (P < 0.001) from baseline to month 3, with reductions of 33.7%, 42.5%, 40.0%, and 46.9%, respectively. Pain intensity decreased from 6.3 ± 1.5 at baseline to 4.7 ± 1.8 at one month and 3.8 ± 1.9 at three months (P < 0.050). Significant (P < 0.001) improvements in the EQ-5D tariff (+37.1%) and EQ-5D VAS (+26.7%) were also recorded. In the linear regression analysis, JSPPPE and LOT-R, but not CAD-R, were significantly associated with pain relief and HR-QoL.
Physicians’ empathy and patients’ dispositional optimism have a role in determining positive outcomes in patients with chronic pain. Physicians’ empathy may therefore be a suitable, yet relatively unexplored, target for intervention.
A new hypothesis for the pathophysiology of complex regional pain syndromeMarcRussoaPeterGeorgiusbDanielle MSantarellia
https://doi.org/10.1016/j.mehy.2018.07.026Get rights and content
Medical Hypotheses Volume 119, October 2018, Pages 41-53
Complex Regional Pain Syndrome (CRPS) has defied a clear unified pathological explanation to date. Not surprisingly, treatments for the condition are limited in number, efficacy and their ability to enact a cure. Whilst many observations have been made of physiological abnormalities, how these explain the condition and who does and doesn’t develop CRPS remains unclear. We propose a new overarching hypothesis to explain the condition that invokes four dynamically changing and interacting components of tissue trauma, pathological pain processing, autonomic dysfunction (both peripheral and central) and immune dysfunction, primarily involving excessive and pathological activation of dendritic cells following trauma or atrophy. We outline pathophysiological changes that may initiate a cascade of events involving dendritic cells and the cholinergic anti-inflammatory pathway resulting in the condition, and the changes that maintain the condition into its chronic phase. This hypothesis should provide fertile ground for further investigations and development of new treatments that holistically address the nature of the disorder along its developmental continuum.
Graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective and unsafe. Re-analysis of a Cochrane review
Mark Vink, Alexandra Vink-Niese,First Published October 8, 2018 Review Article
The analysis of the 2017 Cochrane review reveals flaws, which means that contrary to its findings, there is no evidence that graded exercise therapy is effective. Because of the failure to report harms adequately in the trials covered by the review, it cannot be said that graded exercise therapy is safe. The analysis of the objective outcomes in the trials provides sufficient evidence to conclude that graded exercise therapy is an ineffective treatment for myalgic encephalomyelitis/chronic fatigue syndrome.
Keywords chronic fatigue syndrome, Cochrane review, graded exercise therapy, myalgic encephalomyelitis
CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Fane F. K. Mensah1, Christopher W. Armstrong2, Venkat Reddy1, Amolak S. Bansal3, Saul Berkovitz4, Maria J. Leandro1 and Geraldine Cambridge1*
- 1Division of Medicine, Centre of Rheumatology Research, University College London, London, United Kingdom
- 2Bio 21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC, Australia
- 3Department of Immunology, Epsom and St. Helier University Hospitals NHS Trust, Carshalton, United Kingdom
- 4Chronic Fatigue Service, Royal London Hospital of Integrated Medicine, University College Hospitals NHS Trust, London, United Kingdom
CD24 expression on pro-B cells plays a role in B cell selection and development in the bone marrow. We previously detected higher CD24 expression and frequency within IgD+ naïve and memory B cells in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) compared with age-matched healthy controls (HC). Here, we investigated the relationship between CD24 expression and B cell maturation. In vitro stimulation of isolated B cells in response to conventional agonists were used to follow the dynamics of CD24 positivity during proliferation and differentiation (or maturation). The relationship between CD24 expression to cycles of proliferation and metabolism in purified B cells from HC was also investigated using phospho-flow (phosphorylation of AMPK-pAMPK), 1proton nuclear magnetic resonance and Mitotracker Far-red (Mitochondrial mass-MM). In vitro, in the absence of stimulation, there was an increased percentage of CD24+ viable B cells in ME/CFS patients compared to HC (p < 0.05) following 5 days culture. Following stimulation with B cell agonists, percentage of CD24+B cells in both naïve and memory B cell populations decreased. P < 0.01). There was a negative relationship between percentage of CD24+B cells with MM (R2 = 0.76; p < 0.01), which was subsequently lost over sequential cycles of proliferation. There was a significant correlation between CD24 expression on B cells and the usage of glucose and secretion of lactate in vitro. Short term ligation of the B cell receptor with anti-IgM antibody significantly reduced the viability of CD24+ memory B cells compared to those cross-linked by anti-IgD or anti-IgG antibody. A clear difference was found between naïve and memory B cells with respect to CD24 expression and pAMPK, most notably a strong positive association in IgD+IgM+ memory B cells. In vitro findings confirmed dysregulation of CD24-expressing B cells from ME/CFS patients previously suggested by immunophenotype studies of B cells from peripheral blood. CD24-negative B cells underwent productive proliferation whereas CD24+ B cells were either unresponsive or susceptible to cell death upon BCR-engagement alone. We suggest that CD24 expression may reflect variations in energy metabolism on different B cell subsets.
The Probiotics Trend: Should We Be All In or Call Time Out? - Medscape - Nov 09, 2018. David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School,Norfolk, Virginia.
The ingestion of dietary live bacteria supplementation, or probiotics, has become widespread in recent years. In the United States, it is estimated that approximately 4 million adults consume probiotics on a daily basis.Furthermore, nearly 60% of care providers recommend probiotic supplements on a routine basis.
This trend warrants further scrutiny, and three recently published studies give us more information about whether we should be all in on probiotics or call time out on their increasing use.
Is Their Effect Consistent and Durable?
The first study, which comes to us from the Weizmann Institute in Rehovot, Israel, looked at the durability of the effect of these probiotics.
Researchers began by giving probiotics to germ-free mice, in which they were actually able to induce the desired microbial changes. When they gave the probiotics to mice that were already colonized with their own innate bacteria, however, there were evident resistance patterns. They were not able to induce the colonization that they thought they would when they gave the probiotic. The same effect was evident when they tested it in humans. There seems to be certain bacterial resistant patterns in hosts that either facilitate or block the colonization intended by this probiotic effect.
Probiotics are recommended for a variety of clinical reasons, including fortifying the immune system, protecting against cardiovascular or metabolic diseases, enhancing post-infectious health, and improving bowel function. But this study indicates that probiotics may not actually have these intended effects.
This raises a couple of concerns. First, when probiotics are given, it may not stick. Second, and quite interestingly, when it does stick, the effect might be quite variable in the colon. This was shown when researchers found that stool and biopsy microbiome analyses were not equivalent. In other words, there were variations across the microbiome and geographic variance within the colon where the biome would resist or enhance the colonization based on that probiotic effect.
Do They Help Post-antibiotic Recovery?
The second study, which also comes from the brilliant researchers at the Weizmann Institute, looked at post-antibiotic microbiome changes in mice and humans who were given either multistrain probiotics or autologous fecal microbiome transplantation (ie, transferring the pre-antibiotic microbiome back to subjects via their earlier stool).
Researchers found that there was a rapid reconstitution of the normal biome when they gave the patients their pre-antibiotic stool back. Comparatively, the use of probiotics was associated with a marked delay in patients being able to return to what their normal microbiome was before antibiotics.
This study shows that we may want to reconsider the use of probiotics in the post-antibiotic setting, as they may actually delay the return to the normal biome. Instead, there may be existing or as-yet-undeveloped strategies that allow for reconstitution of the microbiome by targeting the individual host microbiome.
Have They Been Proven Safe?
The third study deals with the safety of various strategies for modifying the microbiota. This comprehensive meta-analysis, published in the Annals of Internal Medicine, looked at approximately 340 studies, of which 245 specifically evaluated probiotics.It was remarkable how few of these studies actually reported adverse events of harm. Nearly a third or more of all trials included reported no adverse event monitoring or harm, whereas 98% provided no adequate documentation, validation, or standardization in reporting adverse events or serious adverse events. Given the high variability in the quality of existing data, the authors concluded that it may be too premature to make any broad conclusions about the safety of these interventions.
Certainly, just like any other medication, potential harm needs to be assessed in probiotics. This is especially true given that probiotics contain a variety of additives. For example, a couple of years ago, a group of researchers from Columbia University in New York City found that of the 22 market-leading probiotics they studied, 12 contained gluten. Of these 12 products, eight claimed to be "gluten free" on their labeling.
The over-the-counter industry is fairly loosely regulated, particularly as it applies to probiotics. Their additives may cause symptoms in and of themselves, and we have to remember our first rule in medicine is to do no harm. Probiotics may have some benefit in select patients, but in others there may be some harm. Particular caution should be exercised for immunosuppressed and immunocompromised patients, as well as those in the hospital with indwelling lines, in whom there have been reports of mortality and disseminated fungemias.[7,8]
When it comes to a verdict, I'd lean more toward "time out" than going "all in." Probiotics have a lot to potentially offer, but we may be better off delivering and tailoring to the individual host rather than adopting a one-size-fits-all approach.
Front. Pediatr., 15 November 2018 | https://doi.org/10.3389/fped.2018.00352
Blood Volume Status in ME/CFS Correlates With the Presence or Absence of Orthostatic Symptoms: Preliminary Results
C. (Linda) M. C. van Campen1*, Peter C. Rowe2 and Frans C. Visser1
- 1Stichting Cardiozorg, Hoofddorp, Netherlands
- 2Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Methods and results: Twenty consecutive adults with ME/CFS participated in the study. All underwent dual isotope blood volume measurement and were evaluated for a clinical suspicion of orthostatic intolerance (OI). The mean age was 34 (10) years, and median duration of disease was 7.5 (6–10) years. The mean (SD) absolute blood volume was 59 (8) ml/kg, a value −11 (7) ml/kg below the reference blood volume. Of the 12 patients, 4 had no OI and 8 had a clinical suspicion of OI. In 8 patients with OI, absolute blood volumes were significantly lower than for the 4 without OI (56  vs. 66 ; p < 0.05) as were the differences between the measured and the reference blood volume (−14 ; vs. −4 ; p < 0.02).
Conclusions: Adults with ME/CFS had a significantly lower blood volume if they had a clinical suspicion of OI compared to those without a clinical suspicion of OI, as well as a significantly lower blood volume compared to the expected value. The data suggest that accounting for symptoms of OI could enhance the detection of the subset with reduced blood volume.
Front. Pediatr., 16 November 2018 | https://doi.org/10.3389/fped.2018.00349
Low Sensitivity of Abbreviated Tilt Table Testing for Diagnosing Postural Tachycardia Syndrome in Adults With ME/CFS
C. (Linda) M. C. van Campen1, Peter C. Rowe2* and Frans C. Visser1
- 1Stichting CardioZorg, Hoofddorp, Netherlands
- 2Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Introduction: Orthostatic intolerance is common among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In some ME/CFS case definitions, orthostatic intolerance is considered a core feature of the disorder. Some studies have employed tilt table tests lasting 2–5 min to diagnose one common form of orthostatic intolerance, postural tachycardia syndrome (POTS). We examined the diagnostic yield of abbreviated durations of tilt testing in adults meeting criteria for
ME/CFS, and identified the proportion with POTS misdiagnosed using testing of <10 min.
Methods: Eligible participants were consecutive individuals satisfying study criteria for ME/CFS and POTS evaluated at the Stichting CardioZorg (SCZ, Hoofddorp, NL) between November 2012 and August 2018. Individuals being treated with medications commonly used to manage orthostatic intolerance were excluded. Head-up tilt table testing involved 15 min of supine posture then 20 min at 70 degrees upright. Only the data from the first 10-min upright were used. POTS was defined as an increase in HR during a maximum of 10 min of upright tilt of at least 30 beats per minute (bpm), in the absence of either classical or delayed orthostatic hypotension. We measured the time until HR criteria for POTS were reached using survival curves, and compared survival curves between subgroups divided by age, sex, disease duration, and degree of hypocapnia during the test.
Results: Of 627 individuals with ME/CFS evaluated during the study period, 155 met criteria for POTS. The median time to reaching HR criteria for POTS was 3 min. A two-minute tilt table test would miss 55% (95% CI, 48–63%) of those meeting POTS criteria over the course of 10 min upright. The median time to reaching HR criteria for POTS did not differ by sex, age, duration of ME/CFS, or hypocapnia during tilt.
Conclusions: Abbreviated tilt table testing misses a substantial proportion of those ultimately diagnosed with POTS during a 10-min tilt table test, and should be abandoned for the clinical diagnosis and in epidemiologic studies designed to estimate the prevalence of POTS among those with ME/CFS.