Musculoskeletal pain and the immune system

Posted on October 24, 2010 by Dr. Jonathan

When you experience musculoskeletal pain—back, shoulder, knee, wrist, neck pain, etc.—while biomechanical factors determine the location, the nature of the inflammatory reaction established why it hurts the way it does. A paper just published in the American Journal of Sports Medicine examines this in the context of tendinopathy (pain in the muscle tendons that can occur from the neck down to the feet).

“The authors previously identified increased levels of inflammatory cytokines in an early human model of tendinopathy and sought to extend these studies to the cellular analysis of tissue.”

In this study they set out to…

“…characterize inflammatory cell subtypes in early human tendinopathy, the authors explored the phenotype and quantification of inflammatory cells in torn and control tendon samples.”

The authors biopsied specimens of torn supraspinatus tendon, matched intact subscapularis tendon specimens collected from 20 patients undergoing arthroscopic shoulder surgery, and control specimens from 10 patients undergoing arthroscopic stabilization surgery. They quantified the inflammatory white blood cells present: macrophages, T cells, mast cells, and vascular endothelium (CD34). What did the data show?

“Subscapularis tendon samples obtained from patients with a torn supraspinatus tendon exhibited significantly greater macrophage, mast cell, and T-cell expression compared with either torn supraspinatus samples or control subscapularis-derived tissue.”

There is a clinical gem embedded in the authors’ conclusion. These inflammatory white blood cells express the immune system’s ‘innate’, cell-mediated (versus humoral, antibody) activity. This is modified by numerous factors that can cause the inflammation to be out of proportion to the mechanical aspects of the injury. These factors influence the conditions and circumstances that modify the pain, and can determine whether it subsides or becomes chronic.

“This study provides evidence for an inflammatory cell infiltrate in early mild/moderate human tendinopathy. In particular, the authors demonstrate significant infiltration of mast cells and macrophages, suggesting a role for innate immune pathways in the events that mediate early tendinopathy.”

Clinicians and patients alike should consider the role of the immune system in addition to the biomechanical factors whenever there is musculoskeletal pain.

Carbohydrates and death from inflammatory disease

Posted on September 22, 2010 by Dr. Jonathan

As the authors of research just published in the American Journal of Clinical Nutrition state:

“Several studies suggest that carbohydrate nutrition is related to oxidative stress and inflammatory markers.”

The proceeded to examine whether dietary glycemic index (GI), dietary fiber, and carbohydrate-containing food groups were associated with death due to non-cardiovascular, non-cancer inflammatory disease in 1490 postmenopausal women and 1245 men. What did their data show?

“Over a 13-y period, 84 women and 86 men died of inflammatory diseases. Women in the highest GI tertile had a 2.9-fold increased risk of inflammatory death…Increasing intakes of foods high in refined sugars or refined starches and decreasing intakes of bread and cereals or vegetables other than potatoes also independently predicted a greater risk. In men, only an increased consumption of fruit fiber and fruit conferred an independent decrease in risk of inflammatory death.”

In other words, for postmenopausal women the high glycemic index diet almost tripled the risk of death from inflammatory disease.

Inflammation, mitochondrial dysfunction and neurodegeneration in major depression

Posted on August 21, 2010 by Dr. Jonathan

Is depression mainly a disorder of serotonin regulation? A paper just published in Progress in Neuro-Psychopharmacology and Biological Psychiatry reminds us that, of course, it is not. The authors state:

“For many years, a deficiency of monoamines including serotonin has been the prevailing hypothesis on depression, yet research has failed to confirm consistent relations between brain serotonin and depression.“

They observe that there is a relationship between depression a number of other conditions with a common set of underlying causes:

“…depression is one of a family of related conditions sometimes referred to as the “affective spectrum disorders”, and variably including migraine, irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia and generalized anxiety disorder, among many others.”

What do these disorders have in common?

“…we present data from many different experimental modalities that strongly suggest components of mitochondrial dysfunction and inflammation in the pathogenesis of depression and other affective spectrum disorders. The three concepts of monoamines, energy metabolism and inflammatory pathways are inter-related in many complex manners. For example, the major categories of drugs used to treat depression have been demonstrated to exert effects on mitochondria and inflammation, as well as on monoamines. Furthermore, commonly-used mitochondrial-targeted treatments exert effects on mitochondria and inflammation, and are increasingly being shown to demonstrate efficacy in the affective spectrum disorders.”

In the functional approach, the evaluation and treatment of depression is not complete without addressing the factors that contribute to neuroinflammation, neurodegeneration and mitochondrial dysfunction with the appropriate tests and physiological interventions.

Magnesium reduces inflammation by opposing calcium

Posted on July 31, 2010 by Dr. Jonathan

A paper published last month in the journal Magnesium Research sheds light on the study reported in the last post offering evidence for the link between calcium supplementation and heart attacks. The authors investigated the role of magnesium deficiency in the calcium-activated inflammation of metabolic syndrome.

“The concept that metabolic syndrome is an inflammatory condition may explain the role of Mg [magnesium]. Mg deficiency results in a stress effect and..activates the hypothalamic-pituitary-adrenal axis (HPA) axis and the sympathetic nervous system. The activation of the renin-angiotensin-aldosterone system is a factor in the development of insulin resistance by increasing oxidative stress [and]…leads to an inflammatory phenotype.”

They further describe how this develops an inflammatory milieu in blood vessels:

“One of the earliest events in the acute response to stress is endothelial [blood vessel 'lining'] dysfunction…Experimental Mg deficiency in rats induces a clinical inflammatory syndrome characterized by leukocyte and macrophage activation, synthesis of inflammatory cytokines and acute phase proteins, extensive production of free radicals. An increase in extracellular Mg concentration decreases inflammatory effects, while reduction in extracellular Mg results in cell activation. The effect of Mg deficiency in the development of insulin resistance in the rat model is well documented.”

They then elucidate how magnesium deficiency promotes atherosclerosis with the vascular inflammation characteristic of cardiovascular diseases including heart attacks:

“Inflammation occurring during experimental Mg deficiency is the mechanism that induces hypertriglyceridemia and pro-atherogenic changes in lipoprotein metabolism. The presence of endothelial dysfunction and dyslipidemia triggers platelet aggregability [stickiness], thus increasing the risk of thrombotic events [blood clots]. Oxidative stress contributes to the elevation of blood pressure. The inflammatory syndrome induces activation of several factors, which are dependent on cytosolic [inside the cell] Ca [calcium] activation. Recent findings support the hypothesis that the Mg effect on intracellular Ca 2+ homeostasis may be a common link between stress, inflammation and a possible relationship to metabolic syndrome.“

In other words, as calcium goes up in ratio to magnesium cardiovascular inflammation develops. This is important in light of the previous post on calcium supplementation and heart attacks.

The author of a review in the same issue of Magnesium Research notes:

“Hypomagnesemia is associated with an increased incidence of diabetes mellitus, metabolic syndrome, mortality rate from CAD [coronary artery disease] and all causes. Magnesium supplementation improves myocardial metabolism, inhibits calcium accumulation and myocardial cell death; it improves vascular tone, peripheral vascular resistance, afterload and cardiac output, reduces cardiac arrhythmias and improves lipid metabolism. Magnesium also reduces vulnerability to oxygen-derived free radicals, improves human endothelial function and inhibits platelet function, including platelet aggregation and adhesion, which potentially gives magnesium physiologic and natural effects similar to adenosine-diphosphate inhibitors such as clopidogrel [blood clot prevention].”

If you’re reading this, whether you are a man or woman it is highly likely that you have a functional deficiency of magnesium and should not be taking calcium.

Pro-inflammatory cytokines of rheumatoid arthritis reduced by Vitamin B6

Posted on July 11, 2010 by Dr. Jonathan

We’re always on the lookout for physiological agents that have the potential to calm the activity of pro-inflammatory cytokines when they are elevated in autoimmune disease. An exciting finding was reported in a paper just published in the European Journal of Clinical Nutrition:

“The purpose of this study was to investigate whether vitamin B6 supplementation had a beneficial effect on inflammatory and immune responses in patients with rheumatoid arthritis (RA).”

The control group of patients was given 5 mg/day of folic acid only while the study group was given 100 mg/day of vitamin B6 in addition for 12 weeks. Indicators of inflammation (C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and lymphocyte subsets were measured on day 1 (week 0) and after 12 weeks (week 12) of the intervention.

At the end of twelves the data painted this picture:

“In the group receiving vitamin B6, plasma IL-6 and TNF-α levels significantly decreased at week 12. Plasma IL-6 level remained significantly inversely related to plasma PLP (pyridoxal 5′-phosphate, B6) after adjusting for confounders.”

The bottom line conclusion is worth bearing in mind when evaluating any autoimmune disorder because underlying causal factors are similar regardless of the specific tissue under attack:

“A large dose of vitamin B6 supplementation (100 mg/day) suppressed pro-inflammatory cytokines (that is, IL-6 and TNF-α) in patients with RA.”

One way to prevent having a schizophrenic child

Posted on July 3, 2010 by Dr. Jonathan

An important research article was just published in PLoS One (Public Library of Medicine) that shows a connection between the disruption of dopamine neurons when a maternal infection causes the iron supply of the fetus to drop and schizophrenia. The authors give some background:

“Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring’s dopamine function.”

The authors measured the adverse behavioral and neurochemical changes from challenging the dopamine circuits with turpentine to trigger an inflammatory immune response, both with and without maternal iron supplementation. They demonstrated that…

“Both the behavioral and neurochemical changes were prevented by maternal iron supplementation.“

We already know that iron is a critical nutrient for dopamine production in the adult. Their conclusion sums up why prenatal iron status is important in preventing neurodevelopmental disorders including schizophrenia in the offspring.

Inflammation and insulin resistance genes are activated by surgery

Posted on June 28, 2010 by Dr. Jonathan

This interesting paper recently published in the Journal of Clinical Endocrinology & Metabolism describes one of the reasons why support when undergoing a surgical procedure is so important (and links to the risks for delirium and accelerated dementia after surgery in the elderly). The authors set out to investigate the…

“…mechanisms behind postoperative insulin resistanceand impaired glucose utilization…”

They shrewdly analyzed the expression of 21 target genes in abdominal adipose (fat) tissue from samples taken at the beginning and end of patients undergoing abdominal surgery. What did the data show?

“After surgery, both sc [subcutaneous] and omental adipose tissue mRNA levels of genes involved in the IL6 and nicotinamide phosphoribosyltransferase pathways were increased, whereas mRNA levels of insulin receptor substrate 1 and adiponectin were reduced. TNF pathway genes were differently regulated between sc and omental adipose tissue, and glucose transporter 4 mRNA levels were decreased only in omental adipose tissue.”

In other words, surgery elicits a shift in genetic expression that favors insulin resistance and inflammation. The authors conclude:

“The transcriptional output of pivotal inflammatory and insulin signaling pathway genes is altered after surgery…This could be of importance for the metabolic aberrations associated to postsurgical complications…”

This helps to understand why patients who are lucky enough to receive adjunctive support for the insulin and inflammatory signaling pathways and receptors recover faster and with less complications.

Support for insulin signaling and inflammation after surgery

Posted on June 23, 2010 by Dr. Jonathan

Journal of Clinical Endocrinology & Metabolism Surgeons are routinely surprised at the speed of recovery and reduction of complications and discomfort when they operate on our patients who have a surgical support program based on their individual needs. This interesting study published recently in the Journal of Clinical Endocrinology & Metabolism describes why supporting insulin function and regulation of the inflammatory response help so much.

“The mechanisms behind postoperative insulin resistance and impaired glucose utilization are not fully understood…In this study, we aimed to specifically evaluate the transcription profile of genes in the insulin and adipokine signaling pathways…after surgical injury.”

Adipokines are cytokines such as IL-6 and TNFα secreted by fat cells. The authors measured changes in the messenger RNA (mRNA) levels that code for insulin signaling and inflammatory cytokines to define how genes alter their expression in response to a surgical trauma. Their data showed a signficant effect:

“After surgery…adipose tissue mRNA levels of genes involved in the IL6 and nicotinamide phosphoribosyltransferase pathways were increased, whereas mRNA levels of insulin receptor substrate 1 and adiponectin were reduced.”

Their conclusion is important for surgeons and their patients:

“The transcriptional output of pivotal inflammatory and insulin signaling pathway genes is altered after surgery…This could be of importance for the metabolic aberrations associated to postsurgical complications, such as insulin resistance and hyperglycemia.”

If you are anticipating an elective procedure and your surgeon is not trained to design a supportive protocol based on an evaluation using the appropriate tests, you may wish to seek out a practitioner experienced in the functional approach.

Magnesium for inflammation and vascular dysfunction in postmenopausal women

Posted on June 21, 2010 by Dr. Jonathan

Magnesium participates in hundreds of important functions in the body, but as they authors of this study published recently in the journal Diabetes Care note:

“Although magnesium may favorably affect metabolic outcomes, few studies have investigated the role of magnesium intake in systemic inflammation and endothelial dysfunction in humans.”

The endothelium is the living lining of blood vessels, alive with functions. The authors correlated magnesium intake with plasma concentrations of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor-α receptor 2 (TNF-α-R2), and other markers of inflammation and endothelial function. Their data amounted to this straightforward conclusion:

“High magnesium intake is associated with lower concentrations of certain markers of systemic inflammation and endothelial dysfunction in postmenopausal women.”

Don’t forget that suboptimal magnesium levels are extremely common, become more likely with stress of various kinds (long-haul air travel for example), and magnesium excretion is increased by alcohol consumption. I have observed over thirty years that it is relatively very rare for lower extremity muscle cramps that occur at rest to not subside when magnesium status is restored. When you make the cramps go away with magnesium you’re accomplishing numerous other benefits.

Note: I have found that when the usually well tolerated bioavailable forms such as magnesium glycinate at appropriate dosages cause diarrhea, there is always a pre-existing intestinal inflammation that must be diagnosed and treated.

Laser therapy reduces inflammatory cytokines

Posted on June 14, 2010 by Dr. Jonathan

Photomedicine and Laser Surgery The therapeutic use of non-invasive, low level (cold) laser and and infrared has not crossed the gap into clinical practice to the degree that the rich body of scientific research justifies. The laser and infrared therapies we use here appear to help even though you can’t feel them (at the time of application); but what evidence is there that they really do anything? And by what mechanisms? Consider this study published in the journal Photomedicine and Laser Surgery a few years ago that documents the effect of visible and infrared light on inflammatory cytokines (immune system messenger molecules). The authors state:

“The aim of this randomized, placebo-controlled, double-blind trial was to investigate changes in the content of 10 cytokines in the human peripheral blood after transcutaneous [through the skin] and in vitro [to blood removed from the body] irradiation with polychromatic visible and infrared (IR) polarized light…”

The magnitude of the effect that they observed by just applying the light to the sacral area of the study subjects is surprising:

“A dramatic decrease in the level of pro-inflammatory cytokines TNF-α, IL-6, and IFN-γ was revealed: at 0.5 h after exposure of volunteers (with the initial parameters exceeding the norm), the cytokine contents fell, on average, 34, 12, and 1.5 times. The reduced concentrations of TNF-α and IL-6 were preserved after four daily exposures, whereas levels of IFN-γ and IL-12 decreased five and 15 times. At 0.5 h and at later times, the amount of anti-inflammatory cytokines was found to rise: that of IL-10 rose 2.7–3.5 times (in subjects with normal initial parameters) and of TGF-β1 1.4–1.5 times.”

But if you expose just the area over the sacrum, what happens when that blood mixes with the rest of the circulation?

“Similar regularities of the light effects were recorded after in vitro irradiation of blood, as well as on mixing the irradiated and non-irradiated autologous blood at a volume ratio 1:10 (i.e., at modeling the events in a vascular bed of the exposed person when a small amount of the transcutaneously photomodified blood contacts its main circulating volume).”

In other words, a small limited application causes system-wide effects. Considering how much we need therapies that physiologically modulate the inflammatory response without side effects, the authors’ conclusion is extremely compelling:

“Exposure of a small area of the human body to light leads to a fast decrease in the elevated pro-inflammatory cytokine plasma content and to an increase in the the anti-inflammatory factor concentration, which may be an important mechanism of the anti-inflammatory effect of phototherapy. These changes result from transcutaneous photomodification of a small volume of blood and a fast transfer of the light-induced changes to the entire pool of circulating blood [!].”

Here’s a little more from the large body of research published in the same journal:

By the way, this is interesting in connection with the earlier post on the infrared treatment of depression.