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.