Cortisol regulation problems, methylation of DNA determining functional expression
This study confirms a lot of what we know clinically about the symptom expression pattern and aggravating factors in ME/Chronic Fatigue Syndrome.
This study highlights the importance of the hypothalamic-pituitary-adrenal control axis, but really the hypothalamic-pituitary-endocrine axis in Chronic Fatigue Syndrome/ME, and how the epigenetics [environmental factors] interact with DNA to determine how our genes are expressed.
Methylation of genes [the function of Vit B12, B6, l-methylfolate, TMG/Betaine, DIM etc.] determines how DNA is translated into health or disease.
One of the problems in objectively diagnosing CFIDS/ME, Fibromyalgia, Lyme disease, MS etc is that we lack reliable biomarkers AND that the known biomarkers are characteristic for many of these named conditions – thus pointing us in the right direction but not being very specific.
Currently we combine a symptomatic analysis of symptoms [see adrenal section of the clinic intake form, page 3] with pituitary trophic hormones and also the adrenal production of cortisol measured [saliva] at 4 different times of the day.
This system is rather accurate and is able to help most patients with CFIDS to a healthier, more stable place. This is measured through quality of life and sense of well being increase over net reduction in symptoms.
W.Vosloo ND MHom.
Genetic Changes and CFS: Identifying the Culprit
Contrary to what some might think, our fate is not set upon conception when the genome is created, nor is our fate determined entirely upon the environment into which we are born and live. Instead, everything we are and everything we will be stems from a complex interaction between our genes and our environment, with the environment influencing which genes turn on and off and when, and our genes influence how we react to the environment.
For decades, scientists believed that while the genome was very plastic and could adapt to the environment in very early life, that window closed as we developed in utero. They also believed that genetic changes could only occur through changes to the underlying DNA. Today, however, an exciting new field called epigenetics has set that thinking on its head and created new possibilities for understanding how diseases develop — and how to prevent and treatment them.
Epigenetics refers to patterns of change in gene expression — not the gene itself — that occur in response to such things as nutrition, infection and physical and mental trauma, not genetic factors. These outside influences trigger a process called methylation that affects gene function but doesn’t change the underlying DNA structure.
“Epigenetics is really a funnel by which the outside environment interacts with the genome,” explains CFIDS Association grantee Patrick O. McGowan, Ph.D., assistant professor in the department of biological sciences at the University of Toronto in Canada. This, in turn, influences how cells work (or don’t work). Already, research shows that epigenetic changes are implicated in numerous diseases, including cancer, asthma and heart disease.
And, if Dr. McGowan is right, they may also play a role in the development of chronic fatigue syndrome (CFS).
Disrupted Signaling in Body’s “Conductor”
To understand where Dr. McGowan and his team hope to go with their research, you first need to understand the hypothalamic-pituitaryadrenal (HPA) axis, often referred to as the “conductor” of our body and its responses.
Dr. McGowan and colleagues at the University of Toronto’s Laboratory for Epigenetic Neuroscience
The HPA is one of the most important communication pathways in the brain. The signals it produces (from hypothalamus to pituitary gland to the adrenal glands and back again) help maintain balance in the neuroendocrine system, which enables communication between various hormones throughout your body and your brain; and the sympathetic nervous system, which regulates the infamous “fight-or-flight” system and determines how the immune system responds to environmental stressors.
This latter component involves cortisol, a glucocorticoid hormone that helps dampen immune system inflammation and keep the body in balance. It also “turns on,” or activates, glucocorticoid receptors that then act on hundreds of genes that control development, metabolism, cognition and inflammation. Think of these receptors as a lock, and cortisol as the “key” that unlocks them to allow the hormone to enter the cell and tell it what to do. Yet one of the most consistent findings in CFS is that patients don’t produce enough cortisol. Without that cortisol, immune system cells called lymphocytes continue to release pro-inflammatory cytokines, keeping the system activated and wreaking all sorts of havoc throughout the body. The whole process likely contributes to many of the symptoms of CFS.
If Dr. McGowan is correct, epigenetic changes may be at the heart of this cortisol/cytokine imbalance.
Dr. McGowan’s research has three main goals:
- Confirm that there is, indeed, altered sensitivity to glucocorticoids and increased inflammatory cytokine production in immune system cells of people with CFS.
- Identify patterns of DNA methylation and the specific epigenetic locations in the genome in people with CFS.
- Analyze the epigenomic and genetic changes in CFS patients in conjunction with symptoms, their severity and medication response — all areas associated with the HPA axis.
To do this, Dr. McGowan and his team will use immune system cells from the SolveCFS BioBank. They will first stimulate the cells with a synthetic glucocorticoid hormone to assess their sensitivity to glucocorticoids and cytokine production. They will also extract DNA from the blood cells to evaluate epigenetic patterns and compare the results to those of cells from people without CFS. They also want to see if cells from different CFS patients respond differently, which would provide evidence of subtypes of CFS, something many researchers suspect exist.
“The exciting thing is that we’re looking across the entire genome, so we’re not making assumptions about what system is influencing the HPA abnormalities,” he says.
In addition to identifying potential epigenetic changes, Dr. McGowan and his team will also try to understand the environmental triggers that likely set about those changes. To do this, they will use disease-specific family history and current health reports for the patients whose cells they are examining.
Unlike genetic differences, which are fixed from conception and remain relatively stable across the lifespan, epigenetic differences are stable but respond to environmental factors; thus, Dr. McGowan said, they may be amenable to therapeutic intervention. For instance, some cancer drugs alter gene expression through epigenetic changes. But there are also potential lifestyle interventions that could have similar results, he said.
“I’m really excited about this grant because we are right at the beginning stages of being able to look at very complex diseases like CFS in a holistic way” by targeting the genome, he said. “If we can start to get biomarkers for this disease that correlate with clusters of symptoms, we will have a better idea of how to approach interventions.” Those biomarkers could also make it easier to study CFS, even aiding in early diagnosis of the disease and, possibly, approaches designed to prevent its development in susceptible individuals, as well as targets for treatment.
Learn more about epigenetics with this primer from The Scientist magazine:
More and more research is being published about the benefits of prolotherapy for numerous musculoskeletal complaints, this particular one on knee osetoarthritis. Prolotherapy is a form of regenerative injection technique that is very effective at treating injuries to tendons and ligaments. It has also been shown to be beneficial for arthritis and discopathy. If you have pain or instability at or around a joint that impairs your daily activities, contact Dr Jarosz for more information.
Effect of Regenerative Injection Therapy on Function and Pain in Patients with Knee Osteoarthritis: A Randomized Crossover Study.
Dumais R, Benoit C, Dumais A, Babin L, Bordage R, de Arcos C, Allard J, Bélanger M. Pain Med. 2012 Jul 3. doi: 10.1111/j.1526-4637.2012.01422.x. [Epub ahead of print]
Dr. Georges-L.-Dumont Regional Hospital, Vitalité Health Network, Moncton, New Brunswick Centre de formation médicale du Nouveau-Brunswick, Moncton, New Brunswick Dieppe Family Medicine Unit, Dieppe, New Brunswick Department of Family Medicine, Université de Sherbrooke, Sherbrooke, Quebec Department of Mathematics and Statistics, Université de Moncton, Moncton, New Brunswick Research Centre, Vitalité Health Network, Moncton, New Brunswick, Canada.
Objective. We assessed the effectiveness of regenerative injection therapy (RIT) to relieve pain and restore function in patients with knee osteoarthritis. Design. Crossover study where participants were randomly assigned to receive exercise therapy for 32 weeks in combination with RIT on weeks 0, 4, 8, and 12 or RIT on weeks 20, 24, 28, and 32. Patients. Thirty-six patients with chronic knee osteoarthritis. Interventions. RIT, which is made up of injections of 1 cc of 15% dextrose 0.6% lidocaine in the collateral ligaments and a 5 cc injection of 20% dextrose 0.5% lidocaine inside the knee joint. Outcome Measures. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index of severity of osteoarthrosis symptoms (WOMAC) score (range: 0-96). Results. Following 16 weeks of follow-up, the participants assigned to RIT presented a significant reduction of their osteoarthritis symptoms (mean ± standard deviation: -21.8 ± 12.5, P < 0.001). WOMAC scores in this group did not change further during the last 16 weeks of follow-up, when the participants received exercise therapy only (-1.2 ± 10.7, P = 0.65). WOMAC scores in the first 16 weeks did not change significantly among the participants receiving exercise therapy only during this period (-6.1 ± 13.9, P = 0.11). There was a significant decrease in this groups’ WOMAC scores during the last 16 weeks when the participants received RIT (-9.3 ± 11.4, P = 0.006). After 36 weeks, WOMAC scores improved in both groups by 47.3% and 36.2%. The improvement attributable to RIT alone corresponds to a 11.9-point (or 29.5%) decrease in WOMAC scores. Conclusions. The use of RIT is associated with a marked reduction in symptoms, which was sustained for over 24 weeks.
The negative impact lead has on our children is becoming more and more dangerous. All recent studies are suggesting that lead is much more of a problem at lower levels, than was previously thought. This will make us rethink the lead pipes in many of our homes. Especially for sensitive children, lead and other toxic metals can threaten their ability to grow and thrive normally.
By Nancy Walsh, Staff Writer, MedPage Today
Published: May 13, 2013: Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Young children exposed to lead — even at low levels — are at risk for not meeting reading readiness benchmarks in kindergarten, a large study of urban children found.
On tests of reading readiness, children with blood lead levels between 5 and 9 mcg/dL scored 4.5 points (95% CI −2.9 to −6.2) lower than those with levels below 5 mcg/dL, according to Pat McLaine, DPH, of the University of Maryland in Baltimore, and colleagues.
And those with lead levels of 10 mcg/dL and higher had scores 10.1 points (95% CI −7 to −13.3) lower, the researchers reported online in Pediatrics.
Almost 25 years ago the CDC established 10 mcg/dL as a “level of concern” for blood lead levels in children, and more recently determined that children whose levels are 5 mcg/dL should be targeted for intervention.
“Learning to read is critical to the entire process of formal education,” McLaine and colleagues stated.
This requires “proficiency in phonologic processing skills (using the sounds of one’s language to process written and oral language) and in the ability to decode new words,” they explained.
A possible association between lead exposure and reading readiness has not previously been examined, but cooperation between school and public health authorities in Providence, R.I., provided an opportunity to consider this.
Using linked data from the Rhode Island Department of Health and Providence’s public school district records, McLaine’s group compared results among 3,406 children who had been tested for blood lead levels an average of three times before entering kindergarten.
Reading readiness was assessed on the Phonological Awareness Literacy Screening-Kindergarten (PALS-K) instrument, which measures reading-relevant cognitive abilities.
The test is given in the fall of kindergarten, and children who score lower than 28 out of a total of 102 are given additional classroom instruction throughout the year, the researchers explained.
The goal is for children to score 81 or higher by the time the test is repeated in the spring.
The study population was diverse and largely low income, with almost 60% being Hispanic and more than 90% qualifying for federal school lunch assistance.
The median blood level of lead in the entire group was 4.2 mcg/dL.
One in five children had had at least one blood level reading of 10 mcg/dL or higher, and more than two-thirds had at least one level of 5 mcg/dL or above.
“These results are markedly higher than [National Health and Nutrition Examination Survey] estimates from the same time and suggest that national population estimates may seriously underestimate the lead problem in urban schools,” the researchers observed.
The highest levels were seen in blacks and children whose first language was not English or Spanish, such as those of Asian descent.
About 35% of the children tested below the cutoff score on the PALS-K in the fall. These low scores were most commonly among boys, Hispanics, those receiving free lunches, and those with blood lead levels of 10 mcg/dL or higher.
Low scores also were seen in children whose mothers hadn’t completed high school or had public insurance at birth.
More than two-thirds of children whose blood levels were below 5 mcg/dL passed the cutoff PALS-K score, compared with only half of those whose levels exceeded 10 mcg/dL.
The prevalence ratio for not meeting the PALS-K benchmark score on the fall test was 1.21 (95% CI 1.19 to 1.23) among children whose blood lead levels fell between 5 and 9 mcg/dL and 1.56 (95% CI 1.51 to 1.60) for those with levels of 10 mcg/dL or higher.
This analysis found a “clear dose-response relationship” between early-life lead exposure and kindergarten reading readiness, even after adjustment for socioeconomic status, language spoken, and other demographic factors.
“Our results suggest the need to evaluate current screening approaches for early reading intervention and to determine whether adding a history of elevated [blood lead levels] could improve targeting of children who are at risk of school failure and are not presently being captured in that system,” the researchers stated.
They plan to follow these children during elementary school “to better understand the long-term impacts of both kindergarten reading readiness and childhood lead exposure on school success.”
These findings offer a caution about children who are exposed to fairly low levels of lead, according to Kevin Chatham-Stephens, MD, of Mount Sinai Medical Center in New York, who was not involved in the study.
“This study reinforces the fact that levels we used to think were safe — up to 5 mcg/dL — actually can impact children’s growth and neurodevelopment,” Chatham-Stephens told MedPage Today.
Limitations of the study included unclear reliability of measures of lead levels and possible residual confounding.
The study was supported by the National Institute for Occupational Safety and Health Education and Research Center for Occupational Safety and Health, the CDC, and the U.S. Department of Health and Human Services.
The authors reported no financial conflicts.
Primary source: Pediatrics
Source reference: McLaine P, et al. “Elevated blood lead levels and reading readiness at the start of kindergarten” Pediatrics 2013; DOI: 10.1542/peds.2012-2277 .
Grapes are already renowned for their abundance of health enhancing polyphenals, vitamins & minerals. They are an antioxidant superfood, known to support the cardiovascular system and provide important nutrients for all tissues of the body. A recent study released by the Journal of Nutritional Biochemistry has taken our understanding of grapes & heart failure prevention further: it’s all about the glutathione.
In patients with heart disease caused by chronic hypertension (high blood pressure), the glutathione enhancing effects of grapes help to reduce heart failure.
Glutathione is the most important antioxidant to your heart, and the most abundant. According to the study, glutathione deficiency is statistically linked to a greater occurrence of heart failure in both human & animals. The ability for grapes to reduce heart failure in patients with hypertension is now believed to be due to the increase in glutathione production. Grapes “turn on antioxidant defense pathways” that lead to higher blood levels of this vital antioxidant.
Grapes Aren’t the Only Way to Enhance Glutathione
Three amino acids are necessary for your body to produce glutathione: L-cysteine, L-glutamic acid & L-glycine. While glutamic acid and glycine are abundant in the body, cysteine is harder to find and is key in supporting glutathione production. Selenium, too, is necessary for activation of the antioxidant. Such nutrients can be supplemented or found naturally in food:
Example Sources of L-cysteine:
Poultry & eggs
Onions & garlic
Example Sources of selenium:
Glutathione supplementation is also available in the form of IV’s, subcutaneous injections and oral forms.
Glutathione Protects More Than Just Your Heart
Glutathione is in nearly every cell of your body. It plays an invaluable role in immune function, reduction of the oxidative effects related to everyday metabolic processes, cleansing the blood through neutralization of toxins for disposal in bile, heavy metal detoxification, DNA repair and more.
To best support your body’s glutathione protection and overall health, enjoy a diet rich in fresh vegetables and fruits (don’t forget your grapes!), nuts, seeds & lean meat. Speak with your healthcare provider to assess your need for further glutathione support.
Dr. Kaley Bourgeois
University of Michigan Health System (2013, May 2). Mechanism for how grapes reduce heart failure associated with hypertension identified. ScienceDaily. Retrieved May 2, 2013, from http://www.sciencedaily.com /releases/2013/05/130502120259.htm