Shorts

briefed by Jule Klotter

Amalgams, CFS, and FM

Toxic metal exposure from dental amalgam fillings may contribute to chronic fatigue syndrome and fibromyalgia in some people, according to a 2014 review led by Janet K. Kern, PhD. The safety of amalgams has been debated for decades. The American Dental Association and FDA assert that amalgam mercury, which makes up about 50%of a filling by weight, is inert and poses little or no hazard. Multiple studies, including this review by Kern et al., indicate that mercury in amalgam fillings is not inert and has numerous detrimental biological effects that can produce a wide variety of symptoms.

Unlike high exposure to mercury, chronic low-level exposure initially produces subtle, nonspecific health effects that progress over years. Kern et al. found that symptoms associated with amalgam toxicity match those that characterize chronic fatigue syndrome (CFS) and fibromyalgia (FM) including abnormal fatigue after physical exertion, muscular discomfort and pain, impaired memory and concentration, impaired sleep, depression, and GI problems. People with CFS and FM, unlike healthy controls, tend to test positive for allergies to nickel, mercury, and other metals found in amalgams. Moreover, careful amalgam removal has been associated with symptom improvement in people with CFS and FM in several studies.

Amalgams emit mercury vapor that is inhaled and also absorbed by structures in the mouth. Animal studies have confirmed that mercury from amalgams accumulates in body tissues. Human studies show a direct dose-dependent correlation between the number of amalgams and the amount of mercury in the kidneys. The kidneys along with the brain are the first organs to show pathological changes after mercury exposure. Once it is absorbed into the bloodstream, mercury can pass through the blood–brain barrier and the placenta. An autopsy study involving 35 infants (age 11–50 weeks) found a correlation between the amount of mercury in their cerebral cortex tissue samples and the number of amalgam fillings in their mothers’ mouths. Studies have also found significant correlation between the number of maternal amalgam fillings and mercury levels in amniotic fluid. Kern et al. point out that urine or blood mercury levels may reflect acute exposure in some people, but the measurements cannot show mercury levels stored in organs and tissue. Moreover, some bodies have more difficulty eliminating mercury, resulting in higher body burden and low urine, blood, or hair test results.

Mercury binds with several important biomolecules, thereby inhibiting their function, including thiol (sulfur-containing) and selenol functional groups found in enzymes, cofactors, receptors, cytokines, ion channels, transport proteins, and transcription factors. Mercury also disrupts the balance between copper and zinc. Zinc is necessary for the function of over 200 enzymes. Mercury has several negative effects on the central nervous system, including the increased production of extracellular glutamate (an excitatory neurotransmitter) and neuroinflammation. In addition, mercury increases oxidative stress and changes gut flora.

Some countries, such as Norway and Sweden, have responded to the growing body of scientific research on mercury amalgam toxicity by banning amalgam use. Although they have not totally banned mercury amalgams, Germany and Canada forbid their use in pregnant women and children – a path that US Food and Drug Administration (FDA) was prepared to follow in January 2012. However, the Department of Health and Human Services (HHS) refused to approve the new guidelines, according to a Medscape article. The stalled guidelines are among plaintiff evidence, submitted on behalf of the International Academy of Oral Medicine and Toxicology (IAOMT) and coplaintiffs, in a lawsuit against FDA and HHS.

Kern JK, Geier DA, Bjørklund G, et al. Evidence supporting a link between dental amalgams and chronic illness, fatigue, depression, anxiety, and suicide. Neuroendocrinol Lett. 2014;35(7):537–552. Available at http://www.nel.edu/archive_issues/o/35_7/NEL35_7_Kern_537-552.pdf. Accessed August 24, 2015.

Lowes R. Did HHS cancel proposed FDA limits on mercury fillings? [online article]. Medscape. July 29, 2015. http://www.medscape.com/viewarticle/848835. Accessed August 26, 2015.

Whole Body Cryotherapy and Fibromyalgia

Whole body cryotherapy (WBC), a treatment used to reduce pain and inflammation in rheumatic patients, was tested on people with fibromyalgia (FM) in a 2013 Italian study led by Lorenzo Bettoni. WBC, first investigated in the 1980s, exposes the entire body to very cold, dehumidified air (−110 to −160 °C) in a cryochamber for just 2 or 3 minutes. The treatment tends to regulate cytokine expression, increasing anti-inflammatory cytokines such as IL-10 and decreasing pro-inflammatory cytokines such as IL-2 and IL-8. People with fibromyalgia have high levels of IL-8 and other pro-inflammatory cytokines in their skin and peripheral blood. IL-8 activates the sympathetic nervous system and increases sensitivity to painful stimuli. FM patients have a lower pain threshold than healthy controls.

The Italian study involved 100 people with fibromyalgia, who were divided into two groups. The first group (46 females and 4 males, aged 17–67 years) was prescribed WBC by their doctors. The second group (46 females and 4 males, ages 19–70 years) acted as the control. People in the WBC group received 15 sessions of WBC over a 3-week period, consisting of a 30-second preconditioning at −60 °C and a 3-minute-long exposure at −140 °C. To avoid frostbite, patients wore bathing suits, socks, clogs or shoes, surgical masks, and hats or headbands to protect the ears. They also kept their fingers moving as they walked in the chamber. Each session was followed by 30 minutes of aerobic exercise (stationary bike or treadmill). It is unclear whether control patients also engaged in 30 minutes of aerobic exercise. All participants were assessed at the beginning and end of the study using the Italian version of the Short Form (SF-16) to measure physical and mental health, the Visual Analogue Scale (VAS) to measure chronic pain intensity, Fatigue Severity Scale (FSS), and Global Health Status (GHS) self-assessment.

Patients in both groups improved according to all four measures, but the WBC group improvement was significantly greater. Patient perception of pain (VAS score) decreased by 58% in the WBC group compared with 22% in the control. Fatigue severity (FSS) and health status (GHS) improved by the same magnitude, according to the authors. The WBC group also showed greater improvement in physical functioning, vitality, social functioning, and mental health, according to SF-36 scores. Is WBC’s pain reduction effect in people with fibromyalgia due to its effect on cytokine levels? Can it “reset” the inflammatory imbalance in FM patients, or is the effect short-term?

Bettoni L, Bonomi FG, Zani V et al. Effects of 15 consecutive cryotherapy sessions on the clinical output of fibromyalgic patients. Clin Rheumatol. 2013;32:1337–1345. Available at http://www.clinicafisioterapiamalaga.es/wp-content/uploads/2013/12/Bettoni-L-Bonomi-F.C_-Effects-of-15-consecutive-cryotherapy-sessions-on-the-clinical-output-of-fibromyalgic-patients.pdf. Accessed September 4, 2015.

New IOM Definition for Chronic Fatigue Syndrome

Systemic exertion intolerance disease (SEID) is the latest name proposed for the condition called chronic fatigue syndrome in the US and myalgic encephalomyelitis in the UK. A 2015 US Institute of Medicine report recommends the name change because CFS/ME patients typically exhibit debility and exhaustion after exerting themselves. The authors hope that emphasizing this symptom will encourage doctors to see this “serious, complex, multisystem disease” as “real,” according to Medscape. Fatigue, even chronic fatigue, is less specific and can be experienced for many physical and emotional reasons. Although myalgic encephalomyelitis (“brain and spinal cord inflammation with muscle pain”) points to a more physiological condition, not all patients experience muscle pain.

The 235-page report, Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining and Illness, defines SEID as “a substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest,” according to Medscape. Postexertional malaise, unrefreshing sleep, and cognitive impairment and/or orthostatic intolerance are the other defining characteristics of SEID. Some patients may also experience sore throat, sensitivity to external stimuli, gastrointestinal and genitourinary problems, and tender axillary/cervical lymph nodes. In addition to new diagnostic criteria, the IOM report recommends that SEID be given a new diagnostic code in the International Classification of Diseases, 10th revision.

The belief that patients’ complaint of fatigue after exertion is simply the result of poor physical conditioning, remedied with exercise, is inaccurate, according to the report authors. Dr. Ellen Wright Clayton, chair of the IOM panel, says that patients with SEID exhibit reproducible signs of decreased exercise capacity with two-day cardiopulmonary testing, orthostatic intolerance, and slowed processing on neuropsychiatric tests. “This is not a figment of their imagination,’” she told David Tuller at the New York Times. Dr. Lucinda Bateman, another member of the IOM panel, told Tuller, “We are hoping [the criteria] provide a very clear path for clinicians to make a diagnosis. … We want to make sure that symptoms that maybe have been overlooked by clinicians have been put front and center.”

The full report is available at http://iom.nationalacademies.org/Reports/2015/ME-CFS.aspx.

Tucker ME. IOM gives chronic fatigue syndrome a new name and definition [online article]. Medscape. February 10, 2015. Available at http://www.medscape.com/viewarticle/839532. Accessed September 2, 2015.

Tuller D. Chronic fatigue syndrome gets a new name. New York Times. February 11, 2015. Available at http://well.blogs.nytimes.com/2015/02/10/chronic-fatigue-syndrome-gets-a-new-name. Accessed September 2, 2015.

Mitochondrial Dysfunction and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

In a 2012 study, Norman E. Booth and colleagues used an ATP Profile Test to identify mitochondrial dysfunction in 138 patients diagnosed with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Test results corresponded with illness severity. The British researchers also noticed that patients exhibited two different ATP compensatory pathways for mitochondrial dysfunction. One group showed increased glycolysis, which produced lactic acid burn, acidosis, and cellular damage. The other group did not exhibit excess lactate. Instead of muscle soreness, their main symptom was delayed fatigue. Booth and colleagues suggest that the delayed fatigue may be due to loss of adenine nucleotides needed to make ATP that occurs during the adenylate kinase reaction.

What produces mitochondrial dysfunction in the first place? Booth and colleagues say one cause is the partial blocking of translocator protein sites – sites where ADP is moved into mitochondria for recycling and ATP is moved out of the mitochondria to the cytosol. The other cause is lack of substrate or essential cofactors – that is, nutrients. Magnesium, for example, is required for ATPase (the enzyme that releases energy from ATP) to function. Most patients with CFS/ME have low intracellular magnesium levels.

Garth L. Nicolson, PhD, discusses several nutrients to treat mitochondrial dysfunction in a 2014 review. In addition to providing magnesium, phosphate, thiamine, and other factors necessary for energy production, he recommends the use of phospholipids to repair mitochondrial membranes damaged by oxidative stress. “The dietary replacement of mitochondrial membrane phospholipids (lipid replacement therapy [LRT] ) using food-derived molecules to remove damaged, mainly oxidized, membrane lipids in mitochondria and other cellular organelles has proved very effective at increasing mitochondrial function and reducing fatigue,” he writes. Phospholipids and vitamins reduced severe chronic fatigue in elderly patients by 40.5% in 8 weeks in a 2003 pilot study led by R. R. Ellithorpe. Other nutrients that support mitochondrial dysfunction and relieve fatigue, according to Nicolson, are CoQ10, microencapsulated NADH, L-carnitine, and alpha-lipoic acid.

Booth NE, Myhill S, McLaren-Howard J. Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Int J Clin Exp Med. 2012:5(3):208–220. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3403556. Accessed August 25, 2015.

Nicolson GL. Mitochondrial dysfunction and chronic disease: treatment with natural supplements. Altern Ther. Winter 2014;20(Suppl. 1):18–25. Available at http://todayspractitioner.com/wp-content/uploads/2014/09/athm_s1_nicolson.pdf. Accessed September 5, 2015.

Metal Oxide Nanoparticles and Gut Microbiota

Metal oxide nanoparticles (NPs) commonly used in foods, cosmetics, drugs, and medical diagnostics significantly affect gut microbiota, according to a 2015 study. The study, led by Alicia A. Taylor, used a custom-built device that simulates the colon to investigate the effects of titanium dioxide (TiO2), zinc oxide (ZnO) and cerium dioxide (CeO2) nanoparticles on microbiota from a healthy 26-year-old female. TiO2 NPs are added to toothpastes, sunscreens, and cosmetics. ZnO and CeO2 NPs are used in coatings, paints, pigments, and cosmetics. These two NPs have species-specific antibacterial effects. They also cause membrane damage in eukaryotic cells (nonbacterial cells with nuclei). “It is estimated that 15,600 metric tons year^-1 of TiO2 nanomaterials, 3700 metric tons year ^-1 of ZnO nanomaterials, and 300 metric tons year^-1 of CeO2 nanomaterials enter water systems with the majority of these NPs discharged from wastewater treatment plants,” say the authors. As a result, these NPs are in drinking water.

Before adding NPs to colon media, the environmental engineering science team ran the simulation device for two 5-day-long experimental trials to determine the bacterial community’s baseline composition. They then ran at least two consecutive 5-day trials for each NP. The researchers used NP concentrations that reflected typical human exposure from drinking water and food. During the 5-day trials, waste samples were taken 3 times a day, at which time the colon was “fed” with sterile media.

Findings indicate that gut bacteria are stressed by NPs and react defensively. All three metal NPs produced significant decreases in bacterial cell size compared with baseline control. Decreased cell size is a survival adaptation that occurs in other stressful situations such as starvation. All three NPs increased cell hydrophobicity compared with the control. With increased hydrophobicity, cells tend to clump together, reducing their surface exposure. Biofilms (aggregates of microorganisms) occur during increased hydrophobicity. All three NPs affected electrophoretic mobility (EPM), an indicator of the relative surface charge associated with microorganism attachment and stability. The EPM indicated more instability during midweek, increasing the possibility of aggregate formation.

The researchers also looked at microbial production of the short-chain fatty acids (SCFAs) butyric acid and acetic acid. (They were unable to measure a third important SCFA, propionic acid, accurately.) For the most part, SCFA levels changed little compared with controls. The one exception was butyric acid production, which decreased during the CeO2 trials. Butyric acid inhibits gut inflammation and supports gut lining integrity. “This indicates that NPs could have a two-fold impact on the intestine by first affecting SCFA production, then leading to systemic circulation of the NPs via an inhibited intestinal barrier,” say the authors.

The authors acknowledge that their study, using microbiota from one woman, cannot give a definitive picture of NPs’ effect on gut microbes in vivo long term. Chemical composition and surface charge of digested food, diet variability, and individual differences in microbiota composition may contribute to the health effects of NP exposure. Still, this study looks at a little-discussed environmental exposure with potential health effects. “To date, this is the first paper analyzing the effects of environmentally relevant concentrations of NPs and their effects on the physical-chemical components of the gut community,” the authors write.

Taylor AA, Marcus IM, Guysi RL, Walker SL. Metal oxide nanoparticles induce minimal phenotypic changes in a model colon gut microbiota. Environ Eng Sci. Epub April 24, 2015. Available at www.silae.it/files/ees_2014_0518.pdf. Accessed August 24, 2015.

Pain, Anger, and Compassion Meditation

Many patients who suffer chronic pain are angry – angry at the pain, angry at their physical limitations, angry with practitioners for not healing them. While this anger is understandable, the stress-induced biochemicals triggered by the emotion contribute to the pain. Anger and frustration correlate with reduced treatment response. Unresolved negative emotions also damage relationships with spouses, adding more stress. Recognizing the need to address anger in people with chronic pain, Heather L. Chapin and colleagues at Stanford University (Palo Alto, CA) recently conducted a pilot study to test compassion meditation. “Compassion meditation,” they explain, “is prescribed as treatment for persistent anger in Eastern cultures.” During the practice, the meditator focuses on the distress of oneself or another person and cultivates the desire to alleviate that distress (compassion). This form of meditation has increased psychological well-being, improved interpersonal relationships, and enhanced immune and stress responses in research studies.

This pilot study used patients’ perceptions and the observations of a spouse, relative, or close friend to evaluate compassion meditation’s effect on pain, anger, and quality of life. Although 28 patients were enrolled initially, only 12 completed the study; the other 14 withdrew or were withdrawn for a variety of reasons. All participants had experienced chronic pain for at least 6 months and an average pain intensity of ≥ 4 on a scale of 0 (no pain) to 10 during the month before enrollment. After an initial interview, all patients took part in a 5-week wait period before receiving group instruction in compassion cultivation training. At the end of the waiting period, patients completed online surveys that measured anger, pain severity, and pain-related functional interference (baseline).

The Compassion Cultivation Training course, used in the study, is a 9-week curriculum develop by Stanford’s Center for Compassion and Altruism Research and Education. Weekly 2-hour classes provide instruction in compassion meditation practices, small and large group discussions, and in-class meditation practice sessions. Patients in the study also received a CD with guided meditations for individual practice and were asked to keep a record of the amount of time that they meditated each day. To avoid influencing the third-party observations, patients were instructed to avoid discussing this training with their significant other who had volunteered to take part in the study.

After the 9-week course, patients completed online questionnaires again as well as a survey with quantitative and open-ended questions. Then, their significant others were asked to complete online surveys that asked them to rate their partner’s pain, quality of life, and possible changes in their relationship. If significant others reported seeing any improvement, they were asked to provide more details and give examples.

Compassion training produced a moderate but “clinically important“ reduction in pain severity, according to patient responses. Anger also decreased about 25%. In addition, significant others observed reduced anger and improved life quality. Even though none of the questions in the posttreatment survey mentioned anger, significant others reported a lessened tendency for the patient to “go off the handle” and faster recovery from anger. The authors state: “Our results indicated that greater change in anger for the chronic pain patients’ correlated with significant others’ ratings for post-treatment improved quality of life in their chronic pain partners (r=.68, n=12, p=.016).”

Larger studies with an active control group (engaged in a group class without a meditation component) are needed to assess the benefits of compassion training for patients with chronic pain. Nonetheless, compassion meditation has a long traditional history and may well benefit people with chronic pain.

Chapin HL, Darnall BD, Seppala EM, Dotay JR, Hah JM, Mackey SC. Pilot study of a compassion meditation intervention in chronic pain. J Compassionate Health Care. 2014;1(4). Available at www.biomedcentral.com/content/pdf/s40639-014-0004-x.pdf. Accessed August 24, 2015.