Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with high symptom burden, of unknown etiology, with no established treatment. We observed patients with long-standing ME/CFS who got cancer, and who reported improvement of ME/CFS symptoms after chemotherapy including cyclophosphamide, forming the basis for this prospective trial. Materials and methods: This open-label phase II trial included 40 patients with ME/CFS diagnosed by Canadian criteria. Treatment consisted of six intravenous infusions of cyclophosphamide, 600-700 mg/m2, given at four-week intervals with follow-up for 18 months, extended to 4 years. Response was defined by self-reported improvements in symptoms by Fatigue score, supported by Short Form 36 (SF-36) scores, physical activity measures and other instruments. Repeated measures of outcome variables were assessed by General linear models. Responses were correlated with specific Human Leukocyte Antigen (HLA) alleles. Results: The overall response rate by Fatigue score was 55.0% (22 of 40 patients). Fatigue score and other outcome variables showed significant improvements compared to baseline. The SF-36 Physical Function score increased from mean 33.0 at baseline to 51.5 at 18 months (all patients), and from mean 35.0 to 69.5 among responders. Mean steps per 24 h increased from mean 3,199 at baseline to 4,347 at 18 months (all patients), and from 3,622 to 5,589 among responders. At extended follow-up to 4 years 68% (15 of 22 responders) were still in remission. Patients positive for HLA-DQB1*03:03 and/or HLA-C*07:04 (n = 12) had significantly higher response rate compared to patients negative for these alleles (n = 28), 83 vs. 43%, respectively. Nausea and constipation were common grade 1-2 adverse events. There were one suspected unexpected serious adverse reaction (aggravated POTS) and 11 serious adverse events in eight patients. Conclusion: Intravenous cyclophosphamide treatment was feasible for ME/CFS patients and associated with an acceptable toxicity profile. More than half of the patients responded and with prolonged follow-up, a considerable proportion of patients reported ongoing remission. Without a placebo group, clinical response data must be interpreted with caution. We nevertheless believe a future randomized trial is warranted. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02444091.

OBJECTIVE: This pilot pre-and post-intervention study investigated the effects of a short-term aquatic exercise programme on physiological outcomes, symptoms and exercise capacity in women with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).
METHODS: Eleven women (54.8 ± 12.4 year) volunteered for the 5-week program; an initial 20-min aquatic exercise session then two self-paced 20-min sessions per week for 4 weeks. Pre- and post-intervention outcomes were physiological measures, 6 min Walk Test (6MWT), perceived exertion (RPE), hand grip strength, Sit-to-Stand, Sit-Reach test, Apley\'s shoulder test, FACIT questionnaire, and 24-h post-test tiredness and pain scores (0-10 visual analogue scale). Heart rates, RPE, 24- and 48-h post-session tiredness/pain scores were recorded each session.
RESULTS: 6MWT distance increased by 60.8 m (p = 0.006), left hand grip strength by 6 kg (p = 0.038), Sit-Reach test by 4.0 cm (p = 0.017), right shoulder flexibility by 2.9 cm (p = 0.026), FACIT scores by 8.2 (p = 0.041); 24-h post-test tiredness and pain decreased by 1.5 and 1.6, respectively (p = 0.002). There were significant post-intervention increases in exercising heart rates (6MWT 4- and 6-min time points), oxygen saturation at 2-min, and reduced RPE at 4-min. Weekly resting and exercising heart rates increased significantly during the study but RPE decreased; immediately post- and 24-h post-session tiredness decreased significantly. There were no reports of symptom exacerbation.
CONCLUSIONS: Five weeks of low-moderate intensity aquatic exercise significantly improved exercise capacity, RPE and fatigue. This exercise mode exercise may potentially be a manageable and safe physical activity for CFS/ME patients.

NHS specialist chronic fatigue syndrome (CFS/ME) services in England treat approximately 8000 adult patients each year. Variation in therapy programmes and treatment outcomes across services has not been described.
We described treatments provided by 11 CFS/ME specialist services and we measured changes in patient-reported fatigue (Chalder, Checklist Individual Strength), function (SF-36 physical subscale, Work & Social Adjustment Scale), anxiety and depression (Hospital Anxiety & Depression Scale), pain (visual analogue rating), sleep (Epworth, Jenkins), and overall health (Clinical Global Impression) 1 year after the start of treatment, plus questions about impact of CFS/ME on employment, education/training and domestic tasks/unpaid work. A subset of these outcome measures was collected from former patients 2-5 years after assessment at 7 of the 11 specialist services.
Baseline data at clinical assessment were available for 952 patients, of whom 440 (46.2%) provided 1-year follow-up data. Treatment data were available for 435/440 (98.9%) of these patients, of whom 175 (40.2%) had been discharged at time of follow-up. Therapy programmes varied substantially in mode of delivery (individual or group) and number of sessions. Overall change in health 1 year after first attending specialist services was \'very much\' or \'much better\' for 27.5% (115/418) of patients, \'a little better\' for 36.6% (153/418), \'no change\' for 15.8% (66/418), \'a little worse\' for 12.2% (51/418), and \'worse\' or \'very much worse\' for 7.9% (33/418). Among former patients who provided 2- to 5-year follow-up (30.4% (385/1265)), these proportions were 30.4% (117/385), 27.5% (106/385), 11.4% (44/385), 13.5% (52/385), and 17.1% (66/385), respectively. 85.4% (327/383) of former patients responded \"Yes\" to \"Do you think that you are still suffering from CFS/ME?\" 8.9% (34/383) were \"Uncertain\", and 5.7% (22/383) responded \"No\".
This multi-centre NHS study has shown that, although one third of patients reported substantial overall improvement in their health, CFS/ME is a long term condition that persists for the majority of adult patients even after receiving specialist treatment.

Paediatric chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a relatively common and disabling condition, yet there is a limited evidence base for treatment. There is good evidence that graded exercise therapy is moderately effective in adults with CFS/ME, but there is little evidence for the effectiveness, cost-effectiveness, acceptability or best method of delivery for paediatric CFS/ME. This study aims to investigate the acceptability and feasibility of carrying out a multicentre randomised controlled trial investigating the effectiveness of graded exercise therapy compared with activity management for children/teenagers who are mildly or moderately affected with CFS/ME.
100 paediatric patients (8-17 years) with CFS/ME will be recruited from 3 specialist UK National Health Service (NHS) CFS/ME services (Bath, Cambridge and Newcastle). Patients will be randomised (1:1) to receive either graded exercise therapy or activity management. Feasibility analysis will include the number of young people eligible, approached and consented to the trial; attrition rate and treatment adherence; questionnaire and accelerometer completion rates. Integrated qualitative methods will ascertain perceptions of feasibility and acceptability of recruitment, randomisation and the interventions. All adverse events will be monitored to assess the safety of the trial.
The trial has received ethical approval from the National Research Ethics Service (South West-Frenchay 15/SW/0124).
ISRCTN23962803; Pre-results.

While the neuronal basis of spatial memory consolidation has been thoroughly studied, the substrates mediating the process of extinction remain largely unknown. This study aimed to evaluate the functional contribution of selected brain regions during the extinction of a previously acquired spatial memory task in the Morris water maze. For that purpose, we used adult male Wistar rats trained in a spatial reference memory task. Learning-related changes in c-Fos inmunoreactive cells after training were evaluated in cortical and subcortical regions. Results show that removal of the hidden platform in the water maze induced extinction of the previously reinforced escape behavior after 16 trials, without spontaneous recovery 24h later. Extinction was related with significantly higher numbers of c-Fos positive nuclei in amygdala nuclei and prefrontal cortex. On the other hand, the lateral mammillary bodies showed higher number of c-Fos positive cells than the control group. Therefore, in contrast with the results obtained in studies of classical conditioning, we show the involvement of diencephalic structures mediating this kind of learning. In summary, our findings suggest that medial prefrontal cortex, the amygdala complex and diencephalic structures like the lateral mammillary nuclei are relevant for the extinction of spatial memory.

The incomplete inhibition of platelet function by acetylsalicylic acid (ASA), despite the patients are receiving therapeutic doses of the drug (\'aspirin-resistance\'), is caused by numbers of risk factors. In this study we verified the idea that plasma homocysteine (Hcy) contributes to \'aspirin-resistance\' in patients with coronary artery disease (CAD) and with or without type 2 diabetes mellitus (T2DM). A cross-designed randomized controlled intervention study has been performed (126 CAD pts incl. 26 with T2DM) to determine whether increasing ASA dose from 75mg to 150mg daily may result in the increased antiplatelet effect, in the course of four-week treatment. Platelet response to collagen (coll) or arachidonic acid (AA) was monitored with whole blood aggregometry, plasma thromboxane (Tx), and Hcy levels were determined immunochemically. The ASA-mediated reductions in platelet response to coll (by 12±3%) or AA (by 10±3%) and in plasma Tx (by 20±9%; p<0.02 or less) were significantly greater for higher ASA dose and significantly correlated with plasma Hcy, which was significantly lower in \"good\" ASA responders compared to \"poor\" responders (p<0.001). Higher plasma Hcy appeared a significant risk factor for blood platelet refractoriness to low ASA dose (OR=1.11; ±95%CI: 1.02-1.20, p<0.02, adjusted to age, sex and CAD risk factors). Hcy diminished in vitro antiplatelet effect of low ASA concentration and augmented platelet aggregation (by up to 62% (p<0.005) for coll and up to 15% (p<0.005) for AA), whereas its acetyl derivative acted oppositely. Otherwise, Hcy intensified antiplatelet action of high ASA. Hyperhomocysteinaemia may be a novel risk factor for the suppressed blood platelet response to ASA, and homocysteine may act as a specific sensitizer of blood platelets to some agonists. While homocysteine per se acts as a proaggregatory agent to blood platelets, its acetylated form is able to reverse this effect. Thus, these findings reveal a possibly new challenging potential of the acetylating properties of ASA therapy.

Young people with chronic fatigue syndrome or myalagic encephalopathy (CFS/ME) (CFS/ME) experience higher levels of psychological distress than healthy controls and young people with other chronic illnesses, and it was recently demonstrated that 38% of this population scored above the clinical cut-off on the Spence Child Anxiety Scale. Subscales of social and separation anxiety were consistently high across gender and age groups. In this study, we used qualitative methods to help us understand more about these two types of anxiety in young people with CFS/ME. Eleven young people (age 12-18) were interviewed. Interviews were self-directed by the participants and were wide ranging. The transcripts were analysed using interpretative phenomenological analysis. Five superordinate themes were identified: social loss and adjustment; introduction of uncertainty and unpredictability; the vulnerable self; individual differences; and contributions towards recovery. Many themes were identical to those described in young people coping with other chronic illnesses in adolescence. In addition, young people with CFS/ME describe experiences associated with the perceived illegitimacy of this condition, namely: feeling unable to explain their illness; bullying from peers; disbelief; and distrust from adults around them. This becomes an additional challenge for these young people. Clinicians need to be aware of these problems, and offer appropriate support.