Puzzling statement from Professor Michael Sharpe on sense about science ...

In this statement on the 28th of October 2015 Lead author of the study, Michael Sharpe, Professor of Psychological Medicine, University of Oxford says:

"The study did not contradict the view that ME/CFS is a chronic illness. These treatments, which we have found previously to be moderately helpful, are not a cure, and they do not benefit everyone. But the good news is, the benefit of these treatments is still apparent two years later, and they do not lead to a relapse of the illness. This new finding should reassure patients who want to try these treatments."

 So he confirms that "These treatments," ie CBT and GET ... "are not a cure" yet in the PACEtrial recovery article they claim that they cure 22% with these treatments. (The percentages (number/total) meeting trial criteria for recovery were 22% (32/143) after CBT, 22% (32/143) after GET, (31 January 2013, Psychological Medicine (2013), 43, 2227–2235) This sounds like a case of serious back peddling ...

 - See more at: http://www.senseaboutscience.org/for_the_record.php/214/response-to-headlines-suggesting-me-is-all-in-the-mind

Investigative Reporter Shreds PACE Trial: Calls Mount for Retraction

Investigative Journalist and public health expert David Tuller, academic coordinator of the concurrent masters degree program in public health and journalism at the University of California, Berkeley, published his investigation into the UK’s £5 million PACE trial, on the well known Virology Blog (see Parts 1 and 2, Part 3 and Part 4).

TRIAL BY ERROR: The Troubling Case of the PACE Chronic Fatigue Syndrome Study

SUMMARY

This examination of the PACE trial of chronic fatigue syndrome identified several major flaws:

*The study included a bizarre paradox: participants’ baseline scores for the two primary outcomes of physical function and fatigue could qualify them simultaneously as disabled enough to get into the trial but already “recovered” on those indicators–even before any treatment. In fact, 13 percent of the study sample was already “recovered” on one of these two measures at the start of the study.

*In the middle of the study, the PACE team published a newsletter for participants that included glowing testimonials from earlier trial subjects about how much the “therapy” and “treatment” helped them. The newsletter also included an article informing participants that the two interventions pioneered by the investigators and being tested for efficacy in the trial, graded exercise therapy and cognitive behavior therapy, had been recommended as treatments by a U.K. government committee “based on the best available evidence.” The newsletter article did not mention that a key PACE investigator was also serving on the U.K. government committee that endorsed the PACE therapies.

*The PACE team changed all the methods outlined in its protocol for assessing the primary outcomes of physical function and fatigue, but did not take necessary steps to demonstrate that the revised methods and findings were robust, such as including sensitivity analyses. The researchers also relaxed all four of the criteria outlined in the protocol for defining “recovery.” They have rejected requests from patients for the findings as originally promised in the protocol as “vexatious.”

*The PACE claims of successful treatment and “recovery” were based solely on subjective outcomes. All the objective measures from the trial—a walking test, a step test, and data on employment and the receipt of financial information—failed to provide any evidence to support such claims. Afterwards, the PACE authors dismissed their own main objective measures as non-objective, irrelevant, or unreliable.

*In seeking informed consent, the PACE authors violated their own protocol, which included an explicit commitment to tell prospective participants about any possible conflicts of interest. The main investigators have had longstanding financial and consulting ties with disability insurance companies, having advised them for years that cognitive behavior therapy and graded exercise therapy could get claimants off benefits and back to work. Yet prospective participants were not told about any insurance industry links and the information was not included on consent forms. The authors did include the information in the “conflicts of interest” sections of the published papers.

Top researchers who have reviewed the study say it is fraught with indefensible methodological problems. Here is a sampling of their comments:

Dr. Bruce Levin, Columbia University: “To let participants know that interventions have been selected by a government committee ‘based on the best available evidence’ strikes me as the height of clinical trial amateurism.”

Dr. Ronald Davis, Stanford University: “I’m shocked that the Lancet published it…The PACE study has so many flaws and there are so many questions you’d want to ask about it that I don’t understand how it got through any kind of peer review.”

Dr. Arthur Reingold, University of California, Berkeley: “Under the circumstances, an independent review of the trial conducted by experts not involved in the design or conduct of the study would seem to be very much in order.”

Dr. Jonathan Edwards, University College London: “It’s a mass of un-interpretability to me…All the issues with the trial are extremely worrying, making interpretation of the clinical significance of the findings more or less impossible.”

Dr. Leonard Jason, DePaul University: “The PACE authors should have reduced the kind of blatant methodological lapses that can impugn the credibility of the research, such as having overlapping recovery and entry/disability criteria.”

The PACE trial and the beauty of subjective outcome measures ...

Study finds Cognitive Behavioral Treatment exacerbates CFS/ME symptoms

@ pubmed

J Child Adolesc Psychiatr Nurs. 2015 Oct 16. doi: 10.1111/jcap.12125. [Epub ahead of print]

The Cognitive Behavioral Treatment of Depression and Low Self-Esteem in the Context of Pediatric Chronic Fatigue Syndrome (CFS/ME): A Case Study.

Loades M1.

Author information

Abstract

PROBLEM:

Up to one in three young people with chronic fatigue syndrome (CFS/ME) also has depressive symptoms. It is not known how best to treat young people with this comorbidity.

METHOD:

This case report seeks to describe and discuss the use of a cognitive behavioral approach for depression and low self-esteem in a 16-year-old girl with CFS/ME.

FINDINGS/CONCLUSION:

Therapy was effective in remediating the young person's mood difficulties, but appeared to exacerbate their CFS/ME symptoms. Therefore, it is crucial that CFS/ME and mood treatments are designed and trialed to ensure a complementary approach. Good communication and joint working between involved professionals is also important, and ideally, treatments for mood and for CFS/ME would be provided by the same team to facilitate this.

Discovered: the underlying metabolic problem in ME

@ sciforschenonline:


The Aerobic Energy Production and the Lactic Acid Excretion are both Impeded in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Mark Vink, Family Physician/GPwSI, Soerabaja Research Center, The Netherlands
E-mail: markvink.md@outlook.com

Abstract
Background: In this study the muscle bioenergetic function in response to exercise in severe ME was explored to see if the underlying metabolic problem in ME, responsible for the severe difficulties with trivial exercise, and the severe loss of muscle power, could be discovered.

Methods: Inorganic phosphate, creatine kinase and lactate were measured in a former Dutch National Field Hockey Champion, who is now a patient bedridden with severe ME, before and 5 minutes after very trivial “exercise”, from which his muscles needed 12 hours to recover.

Results: Inorganic phosphate and creatine kinase were both normal, however, lactate after this trivial exercise was very high, and further testing showed that a second batch of lactic acid was excreted after the same exercise with a 6-fold delay, showing that the lactic acid excretion was impaired and split into two. And this was delayed up to 11- fold by eating closer to the exercise.

Conclusion: This study found that in severe ME, both the oxidative phosphorylation and the lactic acid excretion are impaired, and the combination of these two is responsible for the main characteristic of ME, the abnormally delayed muscle recovery after doing trivial things. The muscle recovery is further delayed by immune changes, including intracellular immune dysfunctions, and by lengthened and accentuated oxidative stress, but also by exercise metabolites, which work on the sensitive receptors in the dorsal root ganglions, which in severe ME are chronically inflamed, and are therefore much more sensitive to these metabolites, which are produced in high quantities in response to trivial exercise, which for ME patients, due to the underlining metabolic problem, is strenuous exercise. And a similar problem is most likely responsible for the abnormally delayed brain recovery after doing trivial things.

This study also shows that the two metabolic problems are the result of an impaired oxygen uptake into the muscle cells or their mitochondria and in combination with the Norwegian Rituximab studies, which suggest that ME is an autoimmune disease, it is suggestive that antibodies are directly or indirectly blocking the oxygen uptake into the muscle cells or their mitochondria.

Characteristics of ME/CFS Responders to Rintatolimod (Ampligen)

@sciforschenonline:


Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME): Characteristics of Responders to Rintatolimod

David R Strayer1
Bruce C Stouch2
Staci R Stevens3
Lucinda Bateman4
Charles W Lapp5
Daniel L Peterson6
William A Carter1
William M Mitchell7*

1Hemispherx Biopharma, Inc., Philadelphia, Pennsylvania, United States of America
2BCS Statistical Solutions LLC, Philadelphia, Pennsylvania, United States of America
3Workwell Foundation, Ripon, California, United States of America
4Fatigue Consultation Clinic, Salt Lake City, Utah, United States of America
5Hunter-Hopkins Center, Charlotte, North Carolina, United States of America
6Sierra Internal Medicine Associates, Incline Village, Nevada, United States of America
7Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America


*Corresponding author: William M. Mitchell, Department of Pathology, Microbiology & Immunology, Vanderbilt University, Nashville, TN 37205, USA, Tel: 615-322-3238;
E-mail: bill.mitchell@vanderbilt.edu

Abstract

Background: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a debilitating disease of unknown pathogenesis consisting of a variety of flu-like symptoms including severe fatigue. Initial analysis of the use of rintatolimod (Poly I: Poly C₁₂U), a selective TLR3 agonist, in a Phase III, double-blind, randomized, placebo-controlled trial of CFS/ME demonstrated statistical significance (p<0.05) in the reduction of fatigue as measured by exercise tolerance (ET) as the primary endpoint using a modified Bruce protocol with reduced physical exertion in patients with severe CFS/ME as defined by a Karnofsky performance score (KPS) of 40-60.

Methods and Findings: In order to better identify responders to rintatolimod, primary and secondary endpoints have been reexamined post hoc as a function of a pre-specified study baseline ET duration >9 minutes. Analysis of improvement in exercise performance at the ≥ 25% and ≥ 50% levels using ET at 40 weeks compared to baseline was performed for the intent-to-treat (ITT) population (n=208) using the pre-specified baseline exercise stratum (baseline ET duration >9 minutes). For this subset of patients (n=126), 33% (n=20), and 12% (n=8) of rintatolimod vs. placebo patients, respectively, improved ET duration by ≥ 25% (p=0.004) while 23% (n=14) compared to 4.5% (n=3) of rintatolimod vs. placebo patients, respectively improved ET duration by ≥ 50% (p=0.003). This corresponds to increases of ≥ 186 and ≥ 373 seconds for patients receiving rintatolimod, respectively, at ≥ 25% and ≥ 50% improvement responses. A frequency distribution analysis of ≥ 25% improvement, <25% change, and ≥ 25% deterioration in ET from baseline at 40 weeks for the baseline >9 minutes cohort showed net improvement to be 18.3% for the rintatolimod cohort vs. 4.6% deterioration for placebo (p=0.015). A continuous responder analysis using 5% increments from ≥ 25% to ≥ 50% provided a robust clinical enhancement in ET effect in the rintatolimod cohorts as compared to placebo. The KPS and Vitality (SF-36 subscale) quality of life secondary endpoints demonstrated similar clinically significant improvements for the rintatolimod cohort as a function of the same ET dichotomization. Rintatolimod was generally well-tolerated in this CFS/ME population.

Conclusions: Using a modified Bruce ET protocol with reduced physical exertion allowed clear identification of patient responders to rintatolimod with severe CFS/ME syndrome. Rintatolimod produced significant enhancement in ET and quality of life indicators in patients able to complete >9 minutes in a modified Bruce ET test. Rintatolimod also reduced deterioration in ET compared to placebo in patients with the poorest initial ET. Exercise endurance >9 minutes in a Bruce protocol modified for patients with CFS/ME provides a method to identify patients most likely to respond to rintatolimod.

Brain fMRI scan demonstrates that cognitive dysfunction in CFS is due to an energy-inefficient process in the frontal cortex

@ sciencedirect.com:

Less efficient and costly processes of frontal cortex in childhood chronic fatigue syndrome

Kei Mizunoa, b, , , Masaaki Tanakac, Hiroki C. Tanabed, e, Takako Joudoif, Junko Kawatanif, Yoshihito Shigiharac, Akemi Tomodaf, g, Teruhisa Miikef, h, Kyoko Imai-Matsumurai, Norihiro Sadatod, Yasuyoshi Watanabea, c

Highlights
• Decrease in divided attention was related to fatigue in childhood and adolescence.
• Left frontal cortex of healthy students activated in verbal divided attention task
• Right MFG and ACG were additionally activated in CCFS patients.
• CCFS is characterized as an energy-inefficient process in frontal cortex.

Abstract
The ability to divide one's attention deteriorates in patients with childhood chronic fatigue syndrome (CCFS). We conducted a study using a dual verbal task to assess allocation of attentional resources to two simultaneous activities (picking out vowels and reading for story comprehension) and functional magnetic resonance imaging.

Patients exhibited a much larger area of activation, recruiting additional frontal areas: 1)

The right middle frontal gyrus (MFG), which is included in the dorsolateral prefrontal cortex, of CCFS patients was specifically activated in both the single and dual tasks; this activation level was positively correlated with motivation scores for the tasks and accuracy of story comprehension; and 2) In patients, the dorsal anterior cingulate gyrus (dACC) and left MFG were activated only in the dual task, and activation levels of the dACC and left MFG were positively associated with the motivation and fatigue scores, respectively.

Patients with CCFS exhibited a wider area of activated frontal regions related to attentional resources in order to increase their poorer task performance with massive mental effort. This is likely to be less efficient and costly in terms of energy requirements. It seems to be related to the pathophysiology of patients with CCFS and to cause a vicious cycle of further increases in fatigue.

Echocardiography objectifies Central nervous system dysfunction responsible for good and bad days in Myalgic Encephalomyelitis

Original Article, Heart and Vessels, pp 1-7 First online: 15 September 2015:

 
  Variability of postural orthostatic tachycardia in patients with myalgic encephalomyelitis and orthostatic intolerance
  Kunihisa Miwa 
  Author information
  Department of Internal Medicine, Miwa Naika Clinic, 1-4-3 Shintomicho, Toyama, 930-0002, Japan,
  info@miwa-naika.com

  Abstract
  Central nervous system dysfunction with myalgic encephalomyelitis (ME) has been suggested as the main cause of chronic fatigue syndrome. Fluctuation of the symptom severity and hierarchy is a characteristic feature in ME patients.

  The characteristics of the sympathetic activation may differ between the “good days” and “bad days” in them. Twenty-four ME patients with orthostatic intolerance underwent a conventional 10-min active standing test and echocardiography both on a “good day” and a “bad day”, defined according to the severity of their symptoms.

  The mean heart rate at rest was significantly higher on the “bad days” than on the “good days”. During the standing test on a “bad day”, 5 patients (21 %) failed to maintain an upright posture for 10 min, whereas on a “good day” all the 24 patients maintained it. Postural orthostatic tachycardia (POT) (increase in heart rate ≥30 beats/min) or severe POT (heart rate ≥120 beats/min) was observed on the “bad days” in 10 patients (43 %) who did not suffer from the severe tachycardia on the “good days”, suggesting the exaggerated sympathetic nervous activation.

  In contrast, POT did not occur or severe POT was attenuated on the “bad days” in 5 patients (21 %) who developed POT or severe POT on the “good days”, suggesting the impaired sympathetic activation.

  Echocardiography revealed significantly lower mean values of both the left ventricular end-diastolic diameter and stroke volume index on the “bad days” compared with the “good days”.

  In conclusion, in ME patients with orthostatic intolerance, the exaggerated activation of the sympathetic nervous system while standing appears to switch to the impaired sympathetic activation after the system is loaded with the additional accentuated stimuli associated with the preload reduction.

Low Natural killer (NK) cells in CFS is associated with increased symptom severity

@ J Clin Cell Immunol:


Low NK Cell Activity in Chronic Fatigue Syndrome (CFS) and Relationship to Symptom Severity

David Strayer, Victoria Scott and William Carter

1617 JFK Boulevard, Suite 500, Philadelphia, PA 19103, USA

Corresponding Author :David Strayer 1617 JFK Boulevard, Suite 500 Philadelphia, PA 19103, USA Tel: + 215-988-0080 Fax: + 215-988-1739 E-mail: annmarie@hemispherx.net

Received: April 29, 2015 Accepted: July 22, 2015 Published: July 29, 2015

Citation: Strayer D, Scott V, Carter W (2015) Low NK Cell Activity in Chronic Fatigue Syndrome (CFS) and Relationship to Symptom Severity. J Clin Cell Immunol 6:348. doi:10.4172/2155-9899.1000348

Copyright: © 2015 Strayer D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.



Abstract
Background:
Natural killer (NK) cells act as an immune surveillance against invading pathogens and tumors. NK cell cytotoxicity (NKCC) has been reported to be decreased in patients with CFS.

Methods:
The objective of this review was to conduct an analysis of available publications that reported NKCC data in CFS in order to evaluate any relationships to case definitions used to define CFS and symptom severity.

Results:
Of 17 studies that evaluated NKCC in patients with CFS, defined using the CDC 1988 and/or 1994 case definition (CD), 88% (15/17) concluded that NKCC was decreased in CFS patients compared to normal controls.
The NKCC decrease was seen using two established methods, 51Cr release (11/13) and flow cytometry (4/4). The mean percent decrease in NKCC using the CDC 1988 CD (66.3%) was significantly greater than that using the CDC 1994 CD (49.7%) (p<0 data-blogger-escaped-.01="" data-blogger-escaped-br=""> This result is consistent with that of six publications showing a greater decrease in NKCC associated with increased CFS symptom severity based on the lower symptom requirement for the CDC 1994 vs. 1988 CD. In contrast, there was no significant difference in the mean percent decrease in NKCC seen comparing the CDC 1994 CD defined population using the 51Cr release (48.3%) vs. flow cytometry (50.7%) assays (p>0.5).
Finally, seven studies investigating the ability of various agents to augment NKCC in patients with CFS showed increases of NKCC with both in vitro exposure (4/5) and in vivo exposure using randomized trials (2/2).

Conclusions:
Low NKCC is commonly seen in CFS and is associated with increase symptom severity.

ME made worse by Rituximab ? You might actually have seronegative borreliosis and not ME

Was your ME/CFS made worse by Rituximab? Well you might actually have seronegative borreliosis and not ME/CFS


  CASE 1:
  @ PubMed:

  van Dop WA, Kersten MJ, de Wever B, Hovius JW. BMJ Case Rep. 2013 Feb 14;2013. pii: bcr2012007627. doi: 10.1136/bcr-2012-007627. Seronegative lyme neuroborreliosis in a patient using rituximab.

  Abstract
  A 66-year-old woman presented with severe shooting pains throughout her back and legs, followed by progressive deafness, weight loss and headache. She had a history of marginal zone B-cell lymphoma stage IV-B, for which she was successfully treated with immunochemotherapy and rituximab maintenance therapy.

  A relapse was suspected, but chemotherapy was not administered, since, despite elaborate investigations, malignancy could not be proven.

  Because of a history of tick bites she was tested for antibodies against Borrelia burgdorferi in serum and cerebrospinal fluid (CSF), which were negative.

  However, a B burgdorferi PCR on CSF came back positive. The patient was treated for seronegative Lyme neuroborreliosis with ceftriaxone intravenously and dramatically improved.

  This case presentation demonstrates that, in immunocompromised patients, it is important not to solely rely on antibody testing and to use additional diagnostic tests to avoid missing or delaying the diagnosis.

 

  CASE 2:
  @ PubMed:

  Harrer T, Geissdörfer W, Schoerner C, Lang E, Helm G., Infection. 2007 Apr;35(2):110-3. Seronegative Lyme neuroborreliosis in a patient on treatment for chronic lymphatic leukemia.

  Abstract
  We report on a patient who developed seronegative Lyme neuroborreliosis complicating chemotherapy for chronic lymphatic leukemia. After the fifth cycle of chemotherapy (FCR: fludarabine, cyclophosphamide, rituximab and prednisone) the 63-year-old patient developed night sweat, arthralgia in elbows, wrists, proximal interphalangeal joints (PIPs) and strong neuropathic pain in both legs, followed by paresthesia and hypesthesia in the feet, arms and face.

  Laboratory analysis revealed an elevated C-reactive protein (CRP), a slight elevation of liver enzymes and decreased IgG levels. Cerebrospinal fluid (CSF) analysis showed a lymphomononuclear pleocytosis and an elevation of protein.

  A broad diagnostic work-up was negative including a negative Borrelia IgG and IgM ELISA.

  The patient did not remember recent tick bites, but after specific questioning he recollected a transient erythema on his leg developing just before the start of the last cycle of chemotherapy.

  As the combination of neuropathic pain and arthralgia, the transient erythema and the lymphomononuclear pleocytosis raised the suspicion of Lyme neuroborreliosis, the patient was treated for 3 weeks with ceftriaxone. On therapy all symptoms resolved and CRP normalized. Retrospective PCR analysis of a CSF sample confirmed the clinical diagnosis by detecting Borrelia garinii DNA.

  This case demonstrates that in immunosuppressed patients borrelial serology may be negative and that additional diagnostic approaches (including tests for direct Borrelia detection) may be needed to demonstrate borrelial infection.

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Researchers’ discovery may explain difficulty in treating Lyme disease

June 1, 2015 by Greg St. Martin @ northeastern.edu:

North­eastern Uni­ver­sity researchers have found that the bac­terium that causes Lyme dis­ease forms dor­mant per­sister cells, which are known to evade antibi­otics. This sig­nif­i­cant finding, they said, could help explain why it’s so dif­fi­cult to treat the infec­tion in some patients.

“It hasn’t been entirely clear why it’s dif­fi­cult to treat the pathogen with antibi­otics since there has been no resis­tance reported for the causative agent of the dis­ease,” explained Uni­ver­sity Dis­tin­guished Pro­fessor Kim Lewis, who led the North­eastern research team.

In other chronic infec­tions, Lewis’ lab has tracked the resis­tance to antibi­otic therapy to the pres­ence of per­sister cells—which are drug-​​tolerant, dor­mant vari­ants of reg­ular cells. These per­sister cells are exactly what they’ve iden­ti­fied here in Bor­relia burgdor­feri, the bac­terium that causes Lyme disease.

The researchers have also reported two approaches—one of them quite promising—to erad­i­cate Lyme dis­ease, as well as poten­tially other nasty infections.

Lewis and his col­leagues pre­sented their find­ings in a paper pub­lished online last week in the journal Antimi­cro­bial Agents and Chemotherapy. He co-​​authored the paper with North­eastern doc­toral stu­dents Bijaya Sharma and Autumn Brown, both PhD’16; recent grad­uate Nicole Matluck, S’15, who received her Bach­elor of Sci­ence in Behav­ioral Neu­ro­science; and Linden T. Hu, a pro­fessor of mol­e­c­ular biology and micro­bi­ology at Tufts University.

The research was sup­ported by grants from the Lyme Research Alliance and the National Insti­tutes of Health.

Lyme dis­ease affects 300,000 people annu­ally in the U.S., according to the Cen­ters for Dis­ease Con­trol and Pre­ven­tion, and is trans­mitted to people via bites from infected black­legged ticks. If caught early, patients treated with antibi­otics usu­ally recover quickly. How­ever, about 10 to 20 per­cent of patients, par­tic­u­larly those diag­nosed later, who have received antibi­otic treat­ment may have per­sis­tent and recur­ring symp­toms including arthritis, muscle pain, fatigue, and neu­ro­log­ical prob­lems. These patients are diag­nosed with Post-​​treatment Lyme Dis­ease Syndrome.

In addi­tion to iden­ti­fying the pres­ence of these per­sister cells, Lewis’ team also pre­sented two methods for wiping out the infection—both of which were suc­cessful in lab tests. One involved an anti-​​cancer agent called Mit­o­mycin C, which com­pletely erad­i­cated all cul­tures of the bac­terium in one fell swoop. How­ever, Lewis stressed that, given Mit­o­mycin C’s tox­i­city, it isn’t a rec­om­mended option for treating Lyme dis­ease, though his team’s find­ings are useful to helping to better under­stand the disease.

The second approach, which Lewis noted is much more prac­tical, involved pulse-​​dosing an antibi­otic to elim­i­nate per­sis­ters. The researchers intro­duced the antibi­otic a first time, which killed the growing cells but not the dor­mant per­sis­ters. But once the antibi­otic washed away, the per­sis­ters woke up, and before they had time to restore their pop­u­la­tion the researchers hit them with the antibi­otic again. Four rounds of antibi­otic treat­ments com­pletely erad­i­cated the per­sis­ters in a test tube.

“This is the first time, we think, that pulse-​​dosing has been pub­lished as a method for erad­i­cating the pop­u­la­tion of a pathogen with antibi­otics that don’t kill dor­mant cells,” Lewis said. “The trick to doing this is to allow the dor­mant cells to wake up.”

He added: “This gives you an idea that you could, in prin­ciple, estab­lish a sim­ilar reg­i­ment for treating patients for this and other chronic diseases.”

Lewis is a fac­ulty member in the biology depart­ment and directs Northeastern’s Antimi­cro­bial Dis­covery Center. Over the past decade he has led pio­neering work on this spe­cial­ized class of cells pro­duced by all pathogens known as per­sis­ters. Ear­lier this year, Lewis, biology pro­fessor Slava Epstein, and other col­leagues pub­lished ground­breaking researchin Nature pre­senting a new antibi­otic that kills pathogens without encoun­tering any detectable resistance.

In pre­vious work, Lewis’ lab iden­ti­fied a com­pound called ADEP that causes dor­mant per­sister cells in MRSA to self-​​destruct. This com­pound was among the first options the researchers tried out to combat Lyme dis­ease. But it didn’t work, and nei­ther did com­bi­na­tions of stan­dard antibi­otics used to treat the dis­ease. The team thought it had hit a dead end yet remained vig­i­lant in its quest to iden­tify promising alter­na­tive options.

“What we came up with was the pulse-​​dosing reg­imen, which worked beau­ti­fully,” Lewis explained. “I think this could be very useful, espe­cially for antibi­otics for which resis­tance doesn’t rapidly develop.”

Though the researchers iden­ti­fied the pres­ence of these per­sister cells, they also note in their paper that the mech­a­nisms by which the per­sis­ters are able to sur­vive remain unknown. More work in this area will be required, they wrote.

Gene expression factors differentiate fibromyalgia, ME/CFS, depression and healthy controls from each other

@ PubMed:

  Arthritis Care Res (Hoboken).  2015 Jun 19. doi: 10.1002/acr.22639. [Epub ahead of print]

  Gene expression factor analysis to differentiate pathways linked to fibromyalgia, chronic fatigue syndrome, and depression in a diverse patient sample.

  Iacob E, Light AR, Donaldson GW, Okifuji A, Hughen RW, White AT, Light KC.

  Abstract

  OBJECTIVE:
  To determine if independent candidate genes can be grouped into meaningful biological factors and if these factors are associated with the diagnosis of chronic fatigue syndrome (CFS) and fibromyalgia (FMS) while controlling for co-morbid depression, sex, and age.

  METHODS:
  We included leukocyte mRNA gene expression from a total of 261 individuals including healthy controls (n=61), patients with FMS only (n=15), CFS only (n=33), co-morbid CFS and FMS (n=79), and medication-resistant (n=42) or medication-responsive (n=31) depression. We used Exploratory Factor Analysis (EFA) on 34 candidate genes to determine factor scores and regression analysis to examine if these factors were associated with specific diagnoses.

  RESULTS:
  EFA resulted in four independent factors with minimal overlap of genes between factors explaining 51% of the variance. We labeled these factors by function as: 1) Purinergic and cellular modulators; 2) Neuronal growth and immune function; 3) Nociception and stress mediators; 4) Energy and mitochondrial function. Regression analysis predicting these biological factors using FMS, CFS, depression severity, age, and sex revealed that greater expression in Factors 1 and 3 was positively associated with CFS and negatively associated with depression severity (QIDS score), but not associated with FMS.

  CONCLUSION:
  Expression of candidate genes can be grouped into meaningful clusters, and CFS and depression are associated with the same 2 clusters but in opposite directions when controlling for co-morbid FMS. Given high co-morbid disease and interrelationships between biomarkers, EFA may help determine patient subgroups in this population based on gene expression.

 

Another clue that ME/CFS might be an autoimmune disease: Increased Risk of ME/CFS for people with allergies

  @ PubMed:

  Medicine (Baltimore). 2015 Jul;94(29):e1211. doi: 10.1097/MD.0000000000001211. Increased Risk of Chronic Fatigue Syndrome Following Atopy: A Population-Based Study.Yang TY1, Kuo HT, Chen HJ, Chen CS, Lin WM, Tsai SY, Kuo CN, Kao CH.

  Author information
  * 1From the Molecular and Genomic Epidemiology Center, China Medical University Hospital, China Medical University, Taichung (T-YY); Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, Changhua (T-YY); Department of Developmental and Behavioral Pediatrics, China Medical University Hospital (H-TK); School of Medicine, China Medical University (H-TK); Management Office for Health Data, China Medical University Hospital (H-JC); Department of Public Health, China Medical University; Asia University (H-JC); Division of Chinese Trauma, China Medical University Hospital, China Medical University, Taichung (C-SC); Department of Diagnostic Radiology, Chang Gung Memorial Hospital, Chiayi (W-ML); Chang Gung University, Taoyuan (W-ML); Department of Laboratory Medicine (Clinical Pathology), Mackay Memorial Hospital, Taipei (S-YT); Department of Health Policy and Management, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD (S-YT); Kau-Tang Traditional Medical Hospital (C-NK); Department of Nuclear Medicine and PET Center, China Medical University Hospital (C-HK); and Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan (C-HK).

  Abstract
  Several hypotheses have been proposed to explain the etiopathogenesis of chronic fatigue syndrome (CFS), including immune dysregulation. However, few population-based prospective cohort studies have been conducted on CFS and atopy. We investigated the relationship between atopy and CFS by using a population-based cohort study.

  In this prospective, population-based cohort study of the National Health Insurance Research Database, we identified 42,558 patients with atopy and 170,232 patients without atopy from 2005 to 2007 with follow-up to 2011. The incidence rates and risks for CFS were estimated using Cox proportion hazards regression.

  The overall incidence rate of CFS was higher in the atopy cohort compared with the nonatopy cohort (1.37 versus 0.87 per 1000 person-year), with an adjusted hazard ratio of 1.48 (95% confidence interval 1.30-1.69).

  The risk of CFS in the atopy cohort increased 1.47- to 1.50-fold for each nonexisting comorbidity. Patients with numerous atopic symptoms exhibited a biological gradient of increasing risk for CFS, and the risk changed significantly after adjustment for age, sex, and comorbidities, increasing from 1.46- to 2.59-fold.

•   We revealed that atopy is associated with CFS, particularly in patients with numerous atopic syndromes. The actual mechanism for CFS development in patients with atopy remains unclear and requires further investigation. We recommend researching the subsequent fatigue symptom in patients with atopy, particularly those with multiple atopic syndromes.

Research shows graded exercise therapy causes exercise intolerance and makes things worse in ME/CFS

@ PubMed:

  Dyn Med. 2005 Oct 28;4:10. Time course of exercise induced alterations in daily activity in chronic fatigue syndrome. Black CD1, McCully KK.

  Author information  * 1Department of Kinesiology, The University of Georgia, Athens, GA, USA. blackcd@uga.edu

  Abstract
In a previous study we demonstrated that while people with CFS had lower daily activity levels than control subjects, they were able to increase daily activity via a daily walking program.

  We reanalyzed our data to determine the time course of activity changes during the walking program. Daily activity assessed via an accelometer worn at the hip was divided into sleep, active, and walking periods. Over the first 4-10 days of walking the subjects with CFS were able to reach the prescribed activity goals each day. After this time, walking and total activity counts decreased.

  Sedentary controls subjects were able to maintain their daily walking and total activity goals throughout the 4 weeks.

  Unlike our previous interpretation of the data, we feel this new analysis suggests that CFS patients may develop exercise intolerance as demonstrated by reduced total activity after 4-10 days.

  The inability to sustain target activity levels, associated with pronounced worsening of symptomology, suggests the subjects with CFS had reached their activity limit.

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