Study Confirms Decreases in Immune Function in CFS/ME Patients, Suggests Biomarker
via ProHealth.com • February 21, 2013
Editor’s Note: Natural killer (NK) cells are part of our body’s innate immune system. Their primary function is to reject tumor and virus infected cells. They do this by releasing granzyme and perforin, which are small protein granules that target cells to be destroyed. This process is called apoptosis or programmed cell death.
Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis
~Source: J Transl Med. 2012; 10: 88
By Ekua W. Brenu et al.
Background: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is an etiologically unexplained disorder characterised by irregularities in various aspects of the immunological function. Presently, it is unknown whether these immunological changes remain consistent over time. This study investigates Natural Killer (NK) cell cytotoxic activity, NK cell subsets (CD56 bright CD16- and CD56 dim CD16+) and cytokines, over the course of a 12-month period in patients with CFS/ME.
Methods: The participants in the study comprised 65 (47.2 ± 11.5 years) CFS/ME participants and 21 (45.2 ±9.3 years) non-fatigued controls. Flow cytometry protocols were used to assess NK subsets and NK cytotoxic activity at various time points that included baseline (T1), 6 (T2) and 12 months (T3). Cytokine secretions were measured following mitogenic stimulation of peripheral blood mononuclear cells.
Results: NK cytotoxic activity was significantly decreased in the CFS/ME patients at T1, T2 and T3 compared to the non-fatigued group. Additionally, in comparison to the non-fatigued controls, the CFS/ME group had significantly lower numbers of CD56 bright CD16- NK cells at both T1 and T2. Interestingly, following mitogenic stimulation, cytokine secretion revealed significant increases in IL-10, IFN-gamma and TNF-alpha at T1 in the CFS/ME group. A significant decrease was observed at T2 in the CFS/ME group for IL-10 and IL-17A while at T3, IL-2 was increased in the CFS/ME group in comparison to the non-fatigued controls. Overall cytotoxic activity was significantly decreased at T3 compared to T1 and T2. CD56 bright CD16- NK cells were much lower at T2 compared to T1 and T3. IL-10 and IL-17A secretion was elevated at T2 in comparison to T1 and T3.
Conclusion: These results confirm decreases in immune function in CFS/ME patients, suggesting an increased susceptibility to viral and other infections. Furthermore, NK cytotoxic activity may be a suitable biomarker for diagnosing CFS/ME as it was consistently decreased during the course of the 12 months study
Source: J Transl Med. 2012; 10: 88 doi: 10.1186/1479-5876-10-88. Ekua W Brenu, Mieke L van Driel, Donald R Staines, Kevin J Ashton, Sharni L Hardcastle, James Keane, Lotti Tajouri, Daniel Peterson, Sandra B Ramos, and Sonya M Marshall-Gradisnik.
Dr Alison C Bested named Medical Director of Chronic Disease Clinic in British Columbia, Canada
Vancouver – A new clinic focused on treating people who suffer from a group of complex chronic diseases has appointed its first Medical Director - Dr Alison Bested- to lead the Complex Chronic Disease Clinic, which will be located at BC Women’s Hospital and Health Centre in Vancouver. The clinic is the first of its kind in the province.
Dr. Bested is expected to start on October 1, 2012, after closing up her current medical practice in Toronto where she treats patients with complex medical illnesses.
In March 2011 the Ministry of Health announced a $2 million investment to study cases and best practices for patients with complex chronic diseases.
The clinic will focus on diseases such as Lyme disease, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia Syndrome. Clinic staff will work with patients and doctors from across the province to provide care and to learn more about these complex diseases.
Bested is a medical specialist who has worked with complex medical illnesses for the past 21 years. She is the Medical Specialist Liaison at the Environmental Health Clinic at Women’s College Hospital in Toronto, and also lectures at the Department of Family and Community Medicine at the University of Toronto.
Dr. Alison Bested, MD, FRCPC
“I’m looking forward to continuing my work in the field of complex chronic diseases in British Columbia,” said Bested. “This clinic will be an excellent way for us to focus our resources and energy on patients dealing with very complex medical illnesses that require specialized treatments.”
Alain Gagnon, Senior Medical Director, BC Women’s Hospital:
We are thrilled to have recruited one of Canada’s premiere physicians in this field, said Alain Gagnon. “Her passion for knowledge translation as well as her dedication to patients will advance the care for people all across British Columbia.”
Dr. Alison Bested's Biography
Dr. Alison Bested is a Haematological Pathologist who has held a private practice in Toronto for the past 21 years where she treated patients with complex medical illnesses including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Fibromyalgia and Multiple Chemical Sensitivities.
Dr. Bested is the Medical Specialist Liaison at the Environmental Health Clinic at Women’s College Hospital in Toronto. She is a lecturer in the Department of Family and Community Medicine at the University of Toronto.
Dr. Bested uses Telemedicine to outreach individual patients in Ontario and also with her Education and Support Group.
Dr. Bested co-authored the Canadian ME/CFS consensus definition that was published in the Journal of Chronic Fatigue Syndrome in 2003.
The second edition of her book “Hope and Help for Chronic Fatigue Syndrome and Fibromyalgia” was published by Sourcebooks House in 2008. It was co-authored by Alan Logan ND and lawyer Russ Howe.
Booth, Myhill, McLaren-Howard Comment on ME/CFS Mitochondrial Dysfunction Paper
By Norman E. Booth, Sarah Myhill, John McLaren-Howard • ProHealth.com • July 4, 2012
Source: Press Release, July 4, 2012
Dr. Norman E. Booth, Dr. Sarah Myhill and Dr. John McLaren Howard are pleased to announce the publication of a second paper concerning the link between mitochondrial dysfunction and ME/CFS. [“Mitochondrial Dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)", published June 30, 2012]
In 2009 we published our first paper looking at mitochondrial function in ME/CFS patients. What we found is that those patients with the worst mitochondrial function had the worst levels of fatigue and vice versa. There was a very clear relationship between the two. The importance of this paper was that it gave backing to certain treatment interventions and also that it clearly established ME/CFS as a physical condition with physical causes. The mitochondrial function can be used as an objective assessment of fatigue and of course this has obvious practical implications.
Hitherto any assessment of the level of disability had to be subjective and this created great difficulties for patients in cases where their physicians disbelieved the serious nature of their symptoms. For a detailed explanation of the clinical issues please see http://www.drmyhill.co.uk/wiki/CFS_-_The_Central_Cause:_Mitochondrial_Failure.
This second paper further explores the above ideas. In this second paper the size of the patient group is much larger with 138 ME/CFS patients involved. Their mitochondrial function tests were compared with 53 normal healthy controls.
The findings of the first paper were repeated and confirmed, but the analysis of this second paper was carried out slightly differently.
It was found on careful inspection of the biochemistry that there were various sub-groups of ME/CFS patients with their own characteristic biochemical pattern. In particular, one of the five parameters measured, namely translocator protein function IN, can be higher as well as lower for patients as compared with controls.
This second paper also attempts to explain what is happening at the biochemical level to result in such an abnormality.
To this end, Dr. Booth provides an alternative method of assessing mitochondrial function. He noticed that the percentage inhibition of ATP closely correlates with TL-in factor – this is probably because the biochemistry of these two measured quantities is so closely associated.
So instead of using TL-in to calculate the mitochondrial energy score, he used percentage ATP inhibited – this provided a solution to the problem of translocator protein IN being higher in some patients than in controls, a factor which in itself is abnormal.
Dr. Booth then went on to plot the relationship between mitochondrial energy score and the number of factors within the normal region to achieve an extremely close correlation.
Importantly this test identifies a clean separation between the ME/CFS cases and the healthy controls.
So this first part of the paper very much confirms the work of the first paper published in 2009 which is that those patients with the worst ME/CFS had the worst mitochondrial function and vice versa.
It must be remembered that patients attending a clinic for ME/CFS are usually the most severely fatigued – no mildly ill patients were tested. Within these limitations the ATP profile is an exclusive and sensitive test for ME/CFS. However, we cannot claim that it is specific to ME/CFS because there are many other neurological illnesses and metabolic syndrome also associated with mitochondrial dysfunction.
Dr. Booth went on to analyze sub-groups within the main group.
When mitochondria are stressed, i.e., energy demand exceeds energy delivery, in the short term they can switch into an alternative means of making ATP, of which there are 2 possibilities identified. Dr. Booth called these patients cohort 1 and cohort 2.
• In cohort 1, the mitochondria switch into anaerobic metabolism with increased glycolosis in order to produce ATP.
• In cohort 2 there was an alternative process to supply additional ATP. This alternative process involves the adenylate kinase reaction in which two molecules of ADP combine to make one of ATP and one of AMP. The problem with this reaction is that for every molecule of ATP generated, so is one of AMP. This is not recycled, but mainly lost in the urine. So there may be short term metabolic benefits here, but in the longer term metabolic disaster ensues as the energy molecules literally leak away. It takes time to replace these leaked molecules of ADP (leaked in the form of a ‘lost’ AMP molecule) and so this may explain one of the clinical features of ME/CFS, namely delayed fatigue.
A vital feature of ATP studies is that they identify the mechanisms by which mitochondria ‘go slow’. Essentially they can ‘go slow’ for one of three common reasons:
• Either there is substrate deficiency, i.e. lack of essential co-factors for mitochondria to work such as Co-enzyme Q10, magnesium, vitamin B3, or acetyl-L-carnitine,
• Or secondly, because mitochondria are blocked by toxins. Typically the blockage can be of oxidative phosphorylation and/or translocator protein function. Dr. John McLaren Howard has developed several further tests to look at the nature of these blockages. These tests include microrespirometry studies, translocator protein function studies, intracellular calcium studies and so on.
• The third possible mechanism for mitochondria malfunctioning has to do with membrane function. The membranes of mitochondria need to be of just the right consistency in order to hold the bundle of enzymes in the correct 3D configuration to allow efficient movement of substrate from one enzyme complex to another. To this end, again Dr. John McLaren Howard has developed cardiolipin studies which look in more detail at mitochondrial membrane structure and function.
Many of the above tests have been available in research laboratories, some John has developed through his own brilliance and initiative. What is so wonderful is how he has given these cutting edge research tests a clinical application.
This is extremely helpful for patients and clinicians because we can see exactly why mitochondria are ‘going slow’ and thereby correct deficiencies using both nutritional supplements, correct gut function, as well as being able to tailor detoxification regimes to individual patients.
This second paper also goes on to look at cell free DNA in ME/CFS patients.
Cell free DNA is a measure of DNA in the bloodstream that is not bound up within cell membranes. It can only, therefore, come from damaged cells and therefore is a measure of cell damage within the body.
What we found is a strong negative correlation with mitochondrial energy scores, ATP levels and the rate of oxidative phosphorylation. What this means is that those patients with mitochondria that perform extremely poorly have the highest level of cell damage and vice versa. This makes perfect biochemical sense – if mitochondria ‘go slow’ one can expect there to be the production of free radicals which have the potential to damage tissues.
Therefore addressing these issues of poor antioxidant status is an essential part of the package of treatment for ME/CFS patients.
These abnormal results clearly show that the effect on mitochondria is a systemic effect, not just confined to the neutrophils that are being tested. Very often we see levels of cell free DNA of a similar magnitude to those in patients who are experiencing a serious illness such as cancer, stroke, autoimmunity, or severe viral infection. Again this underpins the fact that ME/CFS is a physical condition with clear indications of marked cell damage.
This puts ME/CFS firmly in the realm of major organic pathology.
IMPLICATIONS FOR THE TREATMENT OF ME/CFS
These bio-medical tests have been extremely helpful in the diagnosis and management of ME/CFS patients. This is because they clearly identify the biochemical lesions that underpin the cause of this illness. Furthermore, identification of these lesions has clear implications for management using the standard methods of nutritional and environmental medicine.
We are currently preparing a third paper which looks at the efficacy of these interventions in patients by measuring mitochondrial function tests before and after such interventions and correlating these with the clinical picture.
For further information as to what these interventions are please see http://www.drmyhill.co.uk/wiki/CFS_-_CFS_Book_published_by_Dr_Sarah_Myhill, which is available on line without charge.
It bears repeating that this paper would not have been remotely possible without the brilliance of Dr. John McLaren Howard at Acumen Laboratory, who has developed these wonderful tests for looking at mitochondrial function, together with the analytical mind of Dr. Norman Booth, who has analyzed the data in detail to identify the biochemical metabolic pathways involved.
- July 4, 2012
Though ASD (Autism spectrum disorder) is mentioned a lot in this piece, the information it presents relates to all neuro-immune disorders, including ME/CFS.
From the Canadian ME/FM Action Network, here's a useful offering to assist teachers assist their students with ME/CFS by helping them understand the illness and the special needs that it entails.A SOURCEBOOK FOR TEACHERS OF YOUNG PEOPLE with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia Syndrome (FMS) with Dr. David S. Bell world authority and researcher on ME/CFS and FMS in young people Dr. Bruce M. Carruthers lead author of the Canadian ME/CFS Consensus Document Co-Editor of the Canadian FMS Consensus Document and the TEACH-ME Task Force Second Edition.
104 pages, Available in English and French (click below):Teach-ME Sourcebook
A Twitter tweet from the June 1 London 'Invest in ME Conference' has Dr. Daniel Peterson announcing that the Lipkin study is completed, with an expected release date of June 30, 2012. Virus hunter Ian Lipkin, MD, at Columbia has been heading up what he calls "the XMRV/MLV/CFS/ME study" to search for evidence of viruses in blood samples from a well-characterized, geographically-distributed US cohort of ME/CFS patients, using cutting edge virus-detecting technology.
We'll keep you posted!
Six Types of Tissue That Can Be Regenerated Through Nutrition
by Sayer Ji*
May 30, 2012
Nutrition research writer Sayer Ji is founder and chair of GreenMedInfo.com
– a not-for-profit consumer advocacy site offering 'the world’s largest natural medicine database,’ with a searchable index linking to more than 18,000 biomedical study abstracts. This article, first published May 23, 2012, is reproduced with kind permission from Sayer Ji’s blog
. ©2012 GreenMedInfo.com all rights reserved.
The tissues discussed are nerves, liver, beta cells (pancreas), hormones, heart, and cartilage/joint/spine.
6 Bodily Tissues That Can Be Regenerated Through Nutrition
It may come as a surprise to some, especially those with conventional medical training, but the default state of the body is one of ceaseless regeneration. Without the flame-like process of continual cell turnover within the body - life and death ceaselessly intertwined - the miracle of the human body would not exist.
Consider the fact that every two days the enterocytes lining your intestines are completely replaced, and that within 100 days almost every atom and molecule within your body has been excreted, breathed out, or sloughed off, only to be replaced by new ones from the food you ate, the water you drank or the air you breathed in, in the interim.
In times of illness, however, regenerative processes are overcome by degenerative ones.
This is where [wholistic] medicine may perform its most noble feat, nudging the body back into balance with foods, herbs, nutrients, healing energies; i.e., healing intention.
Today, however, drug-based medicine invariably uses chemicals that have not one iota of regenerative potential; to the contrary, they almost always interfere with bodily self-renewal in order to suppress the symptoms against which they are applied.
Despite the outright heretical nature of things which stimulate healing and regeneration vis-à-vis the conventional medical system which frowns upon, or is incredulous towards, spontaneous remission in favor of symptom suppression and disease management - over the course of the past few years of trolling MEDLINE we have collected a series of remarkable studies on the topic.
There are actually a broad range of natural compounds with proven nerve-regenerative effects. A 2010 study published in the journal Rejuvenation Research, for instance, found a combination of blueberry, green tea and carnosine have neuritogenic (i.e., promoting neuronal regeneration) and stem-cell regenerative effects in an animal model of neurodegenerative disease.(1)
Other researched neuritogenic substances include:
1. Curcumin (compound in turmeric)
2. Lion’s Mane Mushroom
3. Apigenin (compound in vegetables like celery)
6. Huperzine (from ‘fir moss’)
7. Natto (from fermented soybeans)
8. Red Sage (compound in root of a type of salvia native to China and Japan).
9. Resveratrol (compound in grapes, red wine, purple grape juice, peanuts, some berries)
10. Royal Jelly
11. Theanine (amino acid derived most commonly in Camellia sinensis teas, esp green tea)
12. Ashwaganda (‘Indian ginseng’)
13. Coffee (trigonelline)
There is another class of nerve-healing substances, known as remyelinating compounds, which stimulate the repair of the protective sheath around the axon of the neurons known as myelin, and which is often damaged in neurological injury and/or dysfunction, especially autoimmune and vaccine-induced demyelination disorders.
It should also be noted that even music and falling in love have been studied for possibly stimulating neurogenesis, regeneration and/or repair of neurons, indicating that regenerative medicine does not necessary require the ingestion of anything.
Rather, a wide range of therapeutic actions may be employed to improve health and well-being, as well.
(To view the first-hand biomedical citations on these neuritogenic substances, visit the GreenMedInfo Neuritogenic Research page on the topic.)
Glycyrrhizin, a compound found within licorice, and which we recently featured as a powerful anti-SARS virus agent, has also been found to stimulate the regeneration of liver mass and function in the animal model of hepatectomy. Other liver regenerative substances include:
1. Carvacrol (a volatile compound in oregano)
3. Korean Ginseng
4. Rooibos (aka ‘bush tea’)
5. Vitamin E
[Note: another substance in this category that Sayer Ji may discuss in future is Milk Thistle.]
(View the first-hand biomedical citations on the GreenMedInfo Liver Regeneration research page.)
Unfortunately, the medical community has yet to harness the diabetes-reversing potential of natural compounds.
Whereas expensive stem cell therapies, islet cell transplants, and an array of synthetic drugs in the developmental pipeline are the focus of billions of dollars of research annually, our kitchen cupboards and backyards may already contain the long sought-after cure for type 1 diabetes.
The following compounds have been demonstrated experimentally to support regeneration of the insulin-producing beta cells, which are destroyed in insulin dependent diabetes, and which once restored, may (at least in theory) help restore the health of the patient to the point where they no longer require insulin replacement.
1. Gymenna Sylvestre ("the sugar destroyer")
2. Nigella Sativa ("black cumin")
3. Vitamin D
4. Curcumin (from the spice turmeric)
5. Arginine (amino acid)
7. Berberine (found in bitter herbs such as Goldenseal and Barberry)
8. Bitter Melon
9. Chard (yes, the green leafy vegetables)
10. Corn Silk
12. Sulforaphane (especially concentrated in broccoli sprouts).
(View the first-hand biomedical citations on the Beta Cell Regeneration research page.)
There are secretagogues, which increase the endocrine glands' ability to secrete more hormone.
And there are substances that truly support regeneration of hormones which have degraded (by emitting electrons) into potentially carcinogenic "transient hormone" metabolites.
One of these substances is vitamin C. A powerful electron donor, this vitamin has the ability to contribute electrons to help resurrect the form and function of estradiol (estrogen; E2), progesterone, testosterone, for instance.(2)
In tandem with foods that are able to support the function of glands, such as the ovaries, vitamin C may represent an excellent complement or alternative to hormone replacement therapy.
Cardiac Cell Regeneration
Not too long ago, it was believed that cardiac tissue was uniquely incapable of being regenerated.
A new, but rapidly growing body of experimental research now indicates that this is simply not true, and there is a class of heart-tissue regenerating compounds known as neocardiogenic substances.
Neocardiogenic substances are able to stimulate the formation of cardiac progenitor cells which can differentiate into healthy heart tissue, and they include the following:
2. Siberian Ginseng (Eleuthero)
3. Red Wine Extract
4. Geum Japonicum
Another remarkable example of cardiac cell regeneration is through what is known as fetomaternal trafficking of stem cells through the placenta.
In a recent article we discussed the amazing process known as "fetal microchimerism" by which the fetus contributes stem cells to the mother which are capable of regenerating her damaged heart cells, and possibly a wide range of other cell types.
Cartilage / Joint / Spine Regeneration
As for the spinal cord, curcumin and resveratrol have been shown to support improved recovery from spinal cord injury.
(Over a dozen other natural compounds hold promise in this area, which can be viewed on our Spinal Cord Injury research page.)
As for degenerative joint disease, i.e., osteoarthritis, there is a broad range of potentially regenerative substances.
(With 50 listed on our osteoarthritis research page.)
* * * *
Ultimately, regenerative medicine threatens to undermine the very economic infrastructure that props up the modern, drug-based and quite candidly degenerative medical system.
Symptom suppression is profitable because it guarantees both the perpetuation of the original underlying disease, and the generation of an ever-expanding array of additional, treatment-induced symptoms.
This is the non-sustainable, infinite growth model which shares features characteristic of the process of cancer itself - a model, which by its very nature, is doomed to fail and eventually collapse.
Cultivating diets, lifestyles and attitudes conducive to bodily regeneration can interrupt this pathological circuit, and help us to attain the bodily freedom that is a precondition for the liberation of the human soul and spirit, as well.
- Sayer Ji
1. “NT-020, a natural therapeutic approach to optimize spatial memory performance and increase neural progenitor cell proliferation and decrease inflammation in the aged rat,”
Rejuvenation Res. 2010 Jun 29. Epub 2010 Jun 29. PMID: 20586644
2. “Photo-induced regeneration of hormones by electron transfer processes: Potential biological and medical consequences.”
Radiat Phys Chem Oxf Engl 1993. Updated 2011 Aug ;80(8):890-894. PMID: 21814301 Disclaimer: This information (©2012 GreenMedInfo.com. All Rights Reserved) has not been reviewed by the FDA. It is general information, based on the research of Sayer Ji unless otherwise noted; and does not necessarily reflect the views of GreenMedInfo or its staff, or that of ProHealth, Inc. It is not intended as medical advice, or for prevention, diagnosis or treatment for any condition, illness or disease; and is not meant to replace a one-on-one relationship with a qualified healthcare professional. It is always very important that you make no change in your healthcare plan or health support regimen without researching and discussing it in collaboration with your professional healthcare team
Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis
Ekua W Brenu, Mieke L van Driel, Donald R Staines, Kevin J Ashton, Sharni L Hardcastle, James Keane, Lotti Tajouri, Daniel Peterson, Sandra B Ramos and Sonya M Marshall-Gradisnik
For all author emails, please log on.
Journal of Translational Medicine 2012, 10:88 doi:10.1186/1479-5876-10-88
Published: 9 May 2012
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is an etiologically unexplained disorder characterised by irregularities in various aspects of the immunological function. Presently, it is unknown whether these immunological changes remain consistent over time. This study investigates Natural Killer (NK) cell cytotoxic activity, NK cell subsets (CD56brightCD16- and CD56dimCD16+) and cytokines, over the course of a12 month period in patients with CFS/ME.
The participants in the study comprised 65 (47.2+/-11.5 years) CFS/ME participants and 21 (45.2 +/-9.3 years) non-fatigued controls. Flow cytometry protocols were used to assess NK subsets and NK cytotoxic activity at various time points that included baseline (T1), 6 (T2) and 12 months (T3). Cytokine secretions were measured following mitogenic stimulation of peripheral blood mononuclear cells.
NK cytotoxic activity was significantly decreased in the CFS/ME patients at T1, T2 and T3 compared to the non-fatigued group. Additionally, in comparison to the non-fatigued controls, the CFS/ME group had significantly lower numbers of CD56brightCD16- NK cells at both T1 and T2. Interestingly, following mitogenic stimulation, cytokine secretion revealed significant increases in IL-10, IFN-gamma and TNF-alpha at T1 in the CFS/ME group. A significant decrease was observed at T2 in the CFS/ME group for IL-10 and IL-17A while at T3, IL-2 was increased in the CFS/ME group in comparison to the non- fatigued controls. Overall cytotoxic activity was significantly decreased at T3 compared to T1 and T2. CD56brightCD16- NK cells were much lower at T2 compared to the T1 and T3. IL-10 and IL-17A secretion was elevated at T2 in comparison to the T1 and T3.
These results confirm decreases in immune function in CFS/ME patients, suggesting an increased susceptibility to viral and other infections. Furthermore NK cytotoxic activity may be a suitable biomarker for diagnosing CFS/ME as it was consistently decreased during the course of the 12 months study.
The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.