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    • Mega-responders?
       I put this over on the other thread, but thought I'd back it up with a pic, showing how seven patients - 25% of patient - seem to have done spectacularly well at the end of the trial (my compilation of three figures, and highlighting). This seems way too good to be mere placebo response and is the main reason I'm so taken with the results of this study.
       
       
           3ways.png   
       note that although this is an open access paper, all the figures are copyright the authors. You can see the originals here, specific details of which figures I used are below.
       
          
       
  • 3ways.png
Jul 23, 15

"PEM in the IOM report (2)

The IOM team clearly carried out an exhaustive literature search (hard work since there isn't that much focusing on PEM, and many of the findings come from studies with other primary aims). For example:

PEM exacerbates a patient’s baseline symptoms and, in addition to fatigue and functional impairment ), may result in

flu-like symptoms (e.g., sore throat, tender lymph nodes, feverishness) (VanNess et al., 2010);
pain (e.g., headaches, generalized muscle/joint aches) (Meeus et al., 2014; Van Oosterwijck et al., 2010);
cognitive dysfunction (e.g., difficulty with comprehension, impaired short-term memory, prolonged processing time) (LaManca et al., 1998; Ocon et al., 2012; VanNess et al., 2010);
nausea/ gastrointestinal discomfort; weakness/instability; light-headedness/vertigo; sensory changes (e.g., tingling skin, increased sensitivity to noise) (VanNess et al., 2010);
depression/anxiety;
sleep disturbances (e.g., trouble falling or staying asleep, hypersomnia, unrefreshing sleep) (Davenport et al., 2011a);
and difficulty recovering capacity after physical exertion (Davenport et al., 2011a,b).

While it's a big symptom list, I like the Canadian Criteria approach of focusing on how it's each patient's characteristic symptom cluster that flares with PEM
Canadian Criteria said:

Post-Exertional Malaise and/or Fatigue: There is an inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, post exertio1nal malaise and/or fatigue and/or pain and a tendency for other associated symptoms within the patient's cluster of symptoms to worsen.

This Van Ness study Postexertional malaise in women with chronic fatigue syndrome (n=25) has good tracking of symptoms flaring after a maximal exercise test vs healthy controls, as does this one by Jo Nijs/Van Oostewjick (n=22) after submaximal exercise. (Would be nice to have bigger studies and I hope that will happen in future.)

But I particularly like the Lights' work looking at gene expression after moderate exercise where they also tracked PEM/fatigue, especially as they used an MS comparison group: the differences with MS are marked. I based the graph below on the original data, but simplified for readability (and because I think copyright restrictions may prevent me reproducing the original).

The lower of each pair of lines is for mental fatigue, upper is physical fatigue; pain (not shown) followed a similar pattern but at a lower than mental fatigue. Scores are 0-100, self-rated.

Differences in metabolite-detecting, adrenergic, and immune gene expression following moderate exercise in chronic fatigue syndrome, multiple sclerosis and healthy controls (White 2012)

white-2012-PEM-graph.gif

(view original graph)
Maybe IOM weren't allowed to reproduce the graph either but they cited the study numerous times re PEM.

PEM after cognitive exertion
The best evidence for PEM comes after physical exertion, maximal or moderate. The situation after cognitive exertion is mixed, according to research covered by the IOM. A Cockshell & Mathias study foudn that after a 2-hour neurocognitive battery of tests controls recovered fully after 7 hours on average compared with 57 hours for CFS patients. Not everyone finds such affects, though this might be because people have different PEM thresholds. While a maximal exercise test is likely to push all to PEM, and even a 'moderate' one (70% max heart rate) is likely to affect most, there isn't such an obvious cognitive challenge. At the CMRC conference last autumn, Andrew Lloyd said his group were going to use a driving simulator as a more intensive cognitive challenge - will be interesting to see how this pans out.

PEM in other illnesses
Depending on how it's defined, up to19% of healthy controls recorded PEM, though this falls to 2-7% if stricter criteria are used. By contrast it's very high for CFS patients, even for those defined by Fukuda. One study found 19-20% of depressed patients recorded PEM, another found 64% for depressed patients, but as the report said it's not clear how it was measured. A Komaroff study from 1996 found PEM in 52% of MS patients, which is why I like the White graph above carefully tracking patients after an exercise challenge.

Objective measures of PEM
There's a great summary of this from Julie Rehmeyer in her New York Times Op-Ed that's a lot easier to read than the IOM report:

Unfortunately, no one test can reliably distinguish patients who have chronic fatigue syndrome from those who don’t. The closest thing to a reliable, objective test is a two-day exercise-to-exhaustion challenge on a stationary bike. Sick patients of all varieties may poop out quickly on Day 1 but whatever they do, they can generally repeat it the next day. Not C.F.S. patients; their performance tanks. Physiological measures ensure that the results can’t be faked, and so far, researchers haven’t seen similar results in any other illness. But large studies haven’t been done. The test also has a big problem. It can leave patients much sicker for months.

Oh, did I mention that's my blog Julie kindly links to?
(New Exercise Study Brings Both Illumination and Questions)
I'm pretty sure this section of the IOM report was written by Betsy Keller, who I interviewed for the blog, so same info in a slightly more digestible form.

The IOM concludes re CPET:
IOM said:

By contrast, a single CPET may be insufficient to document the abnormal response of ME/CFS patients to exercise (Keller et al., 2014; Snell et al., 2013). Although some ME/CFS subjects show very low VO2max results on a single CPET, others may show results similar to or only slightly lower than those of healthy sedentary controls (Cook et al., 2012; De Becker et al., 2000; Farquhar et al., 2002; Inbar et al., 2001; Sargent et al., 2002; VanNess et al., 2007). Thus, the functional capacity of a patient may be erroneously overestimated and decreased values attributed only to deconditioning. Repeating the CPET will guard against such misperceptions given that deconditioned but healthy persons are able to replicate their results, even if low, on the second CPET."

  • PEM in the IOM report (p78- )
     
     my take on the full IOM report section, apologies if I have repeated points made before as I don't have time to re-read the full thread.
     
     First, some highlights of the reports findings on PEM, which is the primary symptom of the SEID case definition - then a closer look at the evidence they cite:
     
        
       
    As I think @Bob first pointed out, the report also emphasises that PEM varies between patients, that patients adapt their life to minimise PEM and that careful questioning is needed to identify if PEM is present:
        
       

     Closer look follows.
  • white-2012-PEM-graph.gif

  • By examining different socio-economic and demographic indicators, he has argued that material rather than cultural resources are the key determinants of socio-economic or ethnic differentials in health

  • he 3 pilot patients all had response to treatment and one thing we observed in these 3 patients is that we have a pattern of responses and relapses after the rituximab treatment with a lag time of several months from initial and rapid B-cell depletion until they start getting clinical responses. Such patients are also seen in established autoimmune diseases after rituximab treatment
  • So, our hypothesis is that the immune system somehow disturbs the fine-tune regulation of blood flow and tissues including in the brain.
  • But these two studies are not designed to give a definite answer to whether rituximab works in ME
Jun 10, 15

"A Vast Graveyard of Undead Theories"

  • Publication bias remains a controversial issue in psychological science. The tendency of psychological science to avoid publishing  null results produces a situation that limits the replicability assumption of science, as replication cannot be meaningful  without the potential acknowledgment of failed replications. We argue that the field often constructs arguments to block the  publication and interpretation of null results and that null results may be further extinguished through questionable researcher  practices. Given that science is dependent on the process of falsification, we argue that these problems reduce psychological  science’s capability to have a proper mechanism for theory falsification, thus resulting in the promulgation of numerous “undead”  theories that are ideologically popular but have little basis in fact.
  • Psychological science will benefit greatly from  increased efforts to improve rigor in meta-analyses and by ending the culture in which null results are aversely treated.  Otherwise psychology risks never rising above being little more than opinions with numbers

  • Abstract

    Background

    In 2010–2011, two large waterborne outbreaks caused by Cryptosporidium hominis affected two cities in Sweden, Östersund and Skellefteå. We investigated potential post-infection health consequences in people who had reported symptoms compatible with cryptosporidiosis during the outbreaks using questionnaires.

    Methods

    We compared cases linked to these outbreaks with non-cases in terms of symptoms present up to eleven months after the initial infection. We examined if cases were more likely to report a list of symptoms at follow-up than non-cases, calculating odds ratios (OR) and 95 % confidence intervals (CI) obtained through logistic regression.

    Results

    A total of 872 (310 cases) and 743 (149 cases) individuals responded to the follow-up questionnaires in Östersund and Skellefteå respectively. Outbreak cases were more likely to report diarrhea (Östersund OR: 3.3, CI: 2.0-5.3. Skellefteå OR: 3.6, CI: 2.0-6.6), watery diarrhea (Östersund OR: 3.4, CI: 1.9-6.3. Skellefteå OR: 2.8, CI: 1.5-5.1) abdominal pain (Östersund OR: 2.1, CI: 1.4-3.3, Skellefteå OR: 2.7, CI: 1.5-4.6) and joint pain (Östersund OR: 2.0, CI: 1.2-3.3, Skellefteå OR: 2.0, CI: 1.1-3.6) at follow-up compared to non-cases.

    Conclusions

    Our findings suggest that gastrointestinal- and joint symptoms can persist several months after the initial infection with Cryptosporidium and should be regarded as a potential cause of unexplained symptoms in people who have suffered from the infection.

  • Microglial Activation in Immunologically Induced Fatigue
  • Abstract:   The clinical symptoms of chronic fatigue syndrome (CFS) have been shown to include disorders in the neuroendocrine, autonomic, and immune systems. On the other hand, it has been demonstrated that cytokines produced in the brain play significant roles in neural-immune interactions through their various central actions, such as activation of the hypothalamo-pituitary axis. We have recently developed an animal for fatigue induced by intraperitoneal (i.p.) injection of synthetic double-stranded RNAs, polyriboinosinic: polyribocytidylic acid (poly I:C, 3 mg/kg), in rats, and shown a decrease in the daily amounts of spontaneous running wheel activity to about 60% of preinjection level for more than 1 week. Simultaneously, mRNA for Interleukin-1β (IL-1β) increased for 1 day following poly I:C injection in the same hypothalamic nuclei. It is thus possible that brain cytokines may play some roles in the central mechanisms of fatigue. In this review article, we showed a role of microglia, one of the major cytokine-producing cells in the central nervous system, in the onset of fatigue using immunologically induced fatigue model rats. Microglia were morphologically activated in the medial preoptic area (MPO) and periventricular hypothalamic nucleus (Pe) 24–48 hrs after the injection of poly I:C. Pretreatment with minocycline for the consecutive 3 days (40 mg/kg/day), the poly I:C-induced decrease in the running wheel activity recovered to the base line levels, and the activation of microglia was suppressed. Following poly I:C injection, the expression of IL-1β was markedly increased in microglia in the MPO and Pe, since the IL-1β-positive cells were double-labeled with an antibody for the microglia marker, Iba-1. Furthermore, the poly I:C-induced increase in the expression of IL-1β was also prevented by pretreatment with minocycline. These findings, taken together, suggest that the activation of microglia, which is accompanied by the enhanced expression of IL-1β, is involved in the onset of the immunologically induced fatigue.

  • The BPND values of 11C-(R)-PK11195 were low. This result is highly dependent on there being no differences in the reference region. 11C-(R)-PK11195 is known to offer a poorer signal-to-noise ratio than the second-generation radioligands for TSPO such as 11C-PBR28 (37). Therefore, we are currently performing the next-phase international collaboration study using 11C-PBR28 with arterial input function to evaluate neuroinflammation of CFS/ME patients in relation to other neurotransmitter  dysfunctions. Furthermore, we hope that more specific radioligands for TSPO or glial cells, such as 11C-(S)-ketoprofen-methyl ester, which is a good radiotracer for cyclooxygenase-1 imaging in brain microglia activation (38), will provide more information on neuroinflammation in CFS patients
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