Positive Health Online

“The first inference deducible from the experiments, according to my reading of them, is, that lactic acid has the power, when existing in an animal body in excess, of producing a class of symptoms attaching themselves mainly to the fibroserous textures, and which, regarded in all points of view, are essentially the symptoms of acute rheumatic inflammation.” Benjamin Ward Richardson -- ‘The Effect of Lactic Acid on Animal Bodies’ (P. 389), 1856 [1,2]

Abstract

The major focus of the present article is Rheumatoid Arthritis (RA).

It tells about:

1. The history of discovery of the autonomic dysfunction as the precursor of Rheumatoid Arthritis;
2. The forgotten theory of the accumulation of lactic acid as the cause of arthritis and rheumatism, and its renaissance in the case of RA;
3. A new hypothesis for the cause of RA that links autonomic dysfunction to the development of increased lactic acid production with its  accumulation in the body;
4. The risk factors for RA based in this new hypothesis, covering almost all of those already know and in use;
5.  An old and inexpensive drug comply with the new perspectives above mentioned, representing an adequate and potential solution for prevention and treatment of RA.

Introduction

Aretaeus, who lived in Cappadocia in Asia Minor during the first century AD and was ranked by some next to Hippocrates as a clinician, described a polyarthritis in phrases reminiscent of features of rheumatoid arthritis: “a general pain of all the joints-the disease lies concealed for a long time, when the pain and the disease are kindled up by any slight cause-it is incredible how far the mischief spreads.”[3]

Sir Alfred Baring Garrod, physician to the West London Hospital, coined the name Rheumatoid Arthritis (RA), in 1859, wishing, as he stated, “to imply an inflammatory affection of the joints, not unlike rheumatism in some of its characters, but differing materially from it.“ At that time rheumatism was the common designation for rheumatic fever: the term rheumatoid arthritis thus may be freely translated as joint inflammation resembling that seen in rheumatic fever.”[3]

RA is considered today as a chronic autoimmune disorder, estimated to affect approximately 1% of the world’s population. It may affect more than the joints, damaging other parts of the body, like the lungs, heart and blood vessels.

Some of the etiological theories presented for RA, through the ages, were neurogenic, vascular, infectious, hypersensitivity, metabolic, endocrine, psychogenic[4] and Selye’s disease of adaptation.[5] More recently other etiological theories for RA were developed as of genetic origin and environment triggers (including smoking).[6] Although, some of the etiologies above mentioned for RA are not really causes, but rather risk factors for RA.

Elapsed many centuries from its initial description by Aretaeus [3], the causative factor of rheumatoid arthritis remains unknown, On the other hand, the cure for RA was not found until today. Existing treatments may only improve symptoms and slow the progress of the disease.

A New Hypothesis

In this paper we postulate a new hypothesis for the cause of RA which has autonomic dysfunction as precursor, by stimulating an increased lactate/lactic acid production and its accumulation in the body.

Also, we present a compatible and fundamental drug, according this hypothesis, for the prevention or in management of RA, eventually with a cure, of some patients.

Notes:

A.  There are many risk factors leading to dysregulation of the autonomic nervous system, which is related with sympathetic dominance, through sympathetic over-activity or withdrawal of the parasympathetic system. Among these risk factors are stress, smoking, age, high carbohydrate diets and genetic predisposition (ex: familial dysautonomia);

B.  Dysautonomia or autonomic dysfunction is a condition in which the autonomic nervous system (ANS) does not work properly;

C.  Autonomic neuropathies are a collection of syndromes and diseases affecting the autonomic neurons, either parasympathetic or sympathetic, or both;

D.  The vagus nerve is the main component of the parasympathetic nervous system;

E.  Hyperlactatemia is defined here as a mild to moderate persistent increase in blood lactate concentration (2-4 mmol/L) without metabolic acidosis, whereas lactic acidosis is characterized by persistently increased blood lactate levels (usually >4-5 mmol/L) in association with metabolic acidosis; Lactic acidosis results from increased production of lactate, the final product in the pathway of glucose metabolism. Lactate and lactic acid are not synonymous. Lactic acid is a strong acid which, at physiological pH, is almost completely ionized to lactate. The measurement of lactate concentration can also be made in cerebrospinal fluid, synovial fluid and other fluids and tissues of the body.

The Autonomic Dysfunction in RA

Related to this topic a fundamental theory is the Selye’s diseases of adaptation, developed in 1936, when he coined the term stress.[5] This theory from Hans Selye involves a complex neurohormonal model of stress that implicates pituitary and adrenal function in the etiology of many chronic diseases, including rheumatism. [6]

L. J. Michotte, in a presentation occurred in 1953 at the 7th International Congress at Geneva, has linked the autonomic nervous system to RA. He found that the spleen of patients with rheumatoid arthritis does not contract under the action of adrenaline injected intravenously, This led to his proposition of the hypothesis that RA may be a perturbation of the autonomous nervous system bearing on the chemical transmitters noradrenaline and adrenaline. [7, 8]

Edmonds and colleagues have written in 1979[9]: “Peripheral neuropathy is a well-described complication of rheumatoid arthritis, but few reports on autonomic neuropathy exist. In 1963 Kalliomaki et al showed a deficient sweating response to an intradermal injection of nicotine in patients with RA. In 1965 Bennett and Scott found areas of deficient sweating corresponding to cutaneous sensory disease in patients with seropositive RA with peripheral neuropathy but did not examine seronegative patients. In three of their patients a deficient sweating response was found in the absence of peripheral neuropathy, suggesting the presence of a lone autonomic neuropathy.”

In the same paper from 1979, Edmonds and colleagues have written about their investigation involving 68 subjects which were divided into four groups: patients with classical and definite RA, both seropositive and seronegative (mean age 54-6 (range 22-67) years); patients with osteoarthritis (mean age 54-2 (range 4265) years); old controls (mean age 51-0 (range 41-67) years); and young controls (mean age 24-6 (range 2028) years).

The summary on their investigation[9] presented the following results:

“Significantly more patients with RA had abnormal autonomic function, suggesting that autonomic neuropathy occurs more commonly in RA than hitherto suspected. The existence of an autonomic neuropathy may be an important complicating factor in rheumatoid disease and may lead to increased morbidity and mortality.”

A study published in 2004 found that cardiac sympathetic nervous system activity is elevated in RA, whereas cardiac parasympathetic activity remains at a normal level.[10]

A study by Koopman et al, published in 2016, made the postulation that autonomic dysfunction precedes the development of RA, which would suggest that it plays a role in its etiopatogenesis.[11]

Lactic Acid Accumulation in the Body and RA

In 1856, Benjamin Ward Richardson, a famous British physician, published the results of extensive experiments  on dogs in which the injection of large quantities of lactic acid, intraperitoneally , was followed by severe joint involvement. The condition of the joints showed in his studies were similar to that seen in acute arthritis. These results led Richardson to suggest that the acute arthritis was due to an accumulation of lactic acid in the body (pages 371 - 396).[1, 2]

In 1874, Balthazar Foster found that the administration of lactic acid by the mouth to two diabetic patients resulted in painful and swollen joints. These manifestation persisted so long as the lactic acid was continued and disappeared when it was discontinued [12]. This discovery by Foster gave some support to the Richardson’s theory at that time.[1]

In 1922, the theory that arthritis is characterized by an excessive accumulation of lactic acid in the body was revived by Percy Wilde, mainly on the clinical area.[13]

In 1924, a study by Cajori and colleagues[14] presented findings that conflicted with the idea that arthritis and rheumatism are caused or characterized by abnormal production or disposal of lactic acid. According to their study the lactic acid contents of the blood, urine and sweat of patients suffering from arthritis and rheumatic disabilities has been determined and the results have been compared with the respective lactic acid contents from nonarthritic persons. The lactic acid was determined also in the synovial fluid from a case of joint effusion. In no case have they observed abnormal quantities of lactic acid in the arthritic patients. Therefore, to the authors, their findings lend no support to the idea that arthritis, at least of the types studied, is caused or characterized by abnormal production or disposal of lactic acid.

However, the study by Cajori and colleagues was based in insufficient measurements of lactic acid in synovial fluid (just one case), for their judgement on the Richardson’s medical theory.[1]

This is because, years later, starting in the seventies, many studies have shown accumulation of lactic acid in synovial fluid of patients with rheumatoid arthritis, These later studies demonstrated that the measurement of lactic acid or lactate in synovial fluid is the correct place for analysis and determination of cases with RA.

So, in practice, the precipitated conclusion of the study from Cajori et al[14] led the lactic acid theory, as cause of arthritis and rheumatism, to be erroneously abandoned and almost forgotten until the present day.

For example, a study from 1971 by Lindy and colleagues measured total lactate dehydrogenase activity in the synovial tissue from 19 patients with rheumatoid arthritis and from 13 control subjects. It found that total enzyme activity in synovium was increased about two-fold in rheumatoid arthritis when compared to controls. It suggested an increased glycolytic metabolism in the RA synovial joints.[15]

Also, in a study by Gobelet et al, published in 1984, lactate concentration was measured in 383 synovial fluid specimens from patients with various arthritides. The highest concentrations of lactate occurred in nongonococcal septic synovial fluids. High values were recorded in seropositive rheumatoid arthritis and crystal induced arthritides, medium values in synovial fluids from seronegative rheumatoid arthritis, seronegative spondylarthritides, gonococcal arthritis and haemarthrosis, and the lowest values in aspirates from osteoarthritic joints. There was a positive correlation between synovial pH and lactic acid concentration with the finding of high values of lactate in seropositive RA and crystal-induced arthritides.[16]

In their paper from 2011 Chang and Wei said in conclusion: “Studies to date regarding the roles of glucose metabolism in RA have confirmed the increased glycolytic activity and autoimmune responses to some enzymes involved in glycolysis, which provides new perspectives to understand the pathogenesis of RA. In view of the important roles of glycolysis in RA pathogenesis, we suggest inhibiting the activity of glycolysis as a means of treating RA.”[17]

Some risk factors for RA, based in our hypothesis:

• Stress [18, 19];
• Age [20, 21, 22];
• High carbohydrate diets [23-30];*
• Smoking [31-34];
• Obesity [35-37];
• Air pollution [38,39];
• Vitamin D deficiency [40, 41].

* Some Important Facts about High Carbohydrate Diets as Risk Factors for RA:

1. Old studies have already show that patients with chronic arthritis do best when their intake of vitamins is increased and their intake of carbohydrate reduced [23];
2. After the intake of refined sugar and sweets there is an aggravation of symptoms in RA, what may be explained by metabolic changes, such as an increased concentration of blood glucose; [24];
3. Evidence of high carbohydrate diets in the stool of patients with RA compared to controls. Starch in stools is prone to occur in patients with chronic arthritis, and adds further evidence that diets low in starch are of use in this disease;[25];
4. High carbohydrate diets cause greater sympathetic nervous system activation while fat ingestion does not result in any appreciable changes; [26];
5. High carbohydrate diets may increase significantly the activity of serum lactate; [27];
6. The Ingestion of monosaccharides (simple sugars like glucose, fructose and galactose) may have the effect to raise blood lactic acid with this increase being most marked and lasting longest after fructose, that is largely used today as sweetener in soft drinks, fruit punches, pastries and processed foods; [28,29];
7. Sweetened soda have been associated with an increased risk of RA. When compared to no consumption of sugar sweetened soda or  <1 soda per month, consumption of ≥1 sugar-sweetened soda per day has 63% increased risk of developing seropositive RA [30].

Autonomic Dysfunction and the Development of Lactate / Lactic Acid

The sympathetic dominance leads to a raised catecholamine (adrenaline/epinephrine and noradrenaline) release, accelerating glycolysis metabolism, therefore increasing lactic acid and lactate concentration in blood and tissues.

We hypothesize that a raised catecholamine release may equally produce the same effects of lactic acid measurements in cerebrospinal and synovial fluids

The first to observe the influence of adrenaline on lactic acid production was Carl F Cori in 1925. Together with his wife Gerty Cori, received a Nobel Prize in 1947 for their discovery of how glycogen - a derivative of glucose - is broken down and resynthesized in the body.[42, 43]

John R Williamson confirmed in 1964 the effects of adrenaline infusion on the increased production of lactate in isolated heart tissue, up to five times the normal production.[44]

An article published in 1982 by Schade[45] supported the following points for a direct participation of catecholamines in the development and/or maintenance of lactic acidosis:

1. The common association of stress and lactic acidosis;
2. The rise in plasma lactate concentration during adrenaline infusion;
3. The precipitation of lactic acidosis by adrenaline intoxication and phaeochromocytoma;
4. The vasoconstrictor effects of catecholamines leading to tissue anoxia and lactic acid production.

However, according to new findings, hyperlactatemia is not a consequence of anaerobic glycolysis, tissue hypoperfusion, or cellular hypoxia, as believed in the past. Such hyperlactatemia is probably indicative of a stress response, with increased metabolic rate and sympathetic nervous system activity.[46]

The relationship between the autonomic dysfunction and increased lactic acid/lactate concentration was recently discussed by us as having a causal role for atherosclerosis,[47, 48] acute myocardial infarction,[49] cancer [50, 51] and stroke [52].

Cardiac Glycosides, the Fundamental Drugs for RA

The fundamental therapeutic for prevention and management of RA, according to our hypothesis, are old drugs called cardiac glycosides. The cardiac glycosides family include digitalis (foxglove plants) from which are derived the drugs digitoxin and digoxin.

Digitalis was used for more than 200 years in the treatment of heart failure and more than 100 years in the treatment of atrial fibrillation.

Recent studies have confirmed that low doses of digoxin (< 0.25 mg daily, by oral route) are associated with better outcomes for both heart failure and atrial fibrillation.

Remembering  the words of August M. Watanabe, from 1985 [53]:

“Although there is not total agreement on the nature and clinical significance of the effects of digitalis on the autonomic nervous system, the following points seem well established and generally accepted:

1. The actions of digitalis on the autonomic nervous system are very important clinically and play a major role in determining the clinical pharmacodynamic effects of the drug;
2. With therapeutic concentrations of the drug, the predominant effect is activation of vagal tone; and;
3. With toxic concentrations of the drug there may be activation of sympathetic tone.”

In recent articles, where we have presented an equivalent hypothesis for the cause of other diseases, was shown the information that cardiac glycosides at low concentration doses may also be beneficial in the prevention and in the treatment of atherosclerosis/ischemic heart disease [47, 49], cancer [51] and stroke [52].

Cardiac glycosides like digoxin and Lanatoside C are drugs approved by the US Federal Drugs Administration (FDA), and by other similar organizations around the world, with some of these having also approval for the use of digitoxin and other CGs . Therefore, these drugs can be prescribed for prevention and in the management of rheumatoid arthritis, with no major obstacles, by a well-informed physician.

Cardiac Glycosides and Sympatho-Inhibitory Effects

Evidences that the following cardiac glycosides have a sympatho-inhibitory response:

• Cedilanid* [54];
• Digoxin  [55-56];
• Digitoxin [57];
• Ouabain [58].

*Cedilanid is the trade name. The active ingredient is Lanatoside C

Cardiac Glycosides in Reduction of Lactate Production

A recent paper has demonstrated that inhibiting the overproduction of catecholamine by digoxin, digitoxin and ouabain may induce a potent inhibition of glycolysis (glucose consumption and lactate).[59] It confirms the results of old studies on this matter. [60]

The “Anti-inflammatory” Effects of Cardiac Glycosides

Beneficial effects of cardiac glycosides have also been observed through anti-inflammatory pathways.[61 - 67] Among these, a recent study has investigated whether digoxin would supress pathogenic Th17 and consequently ameliorate arthritis and joint damage in the collagen-induced arthritis (CIA) model, a prototype animal of RA. As result, digoxin regulated pathogenic Th17 differentiation and suppressed autoimmune arthritis in mice, appearing to be able to prevent the incidence and ameliorate the severity of CIA.[67]

Note:

However, inflammation is a result of an injury, not its cause.

According to a study published in 2014: “Over the past decades evidence has accumulated clearly demonstrating a pivotal role for the sympathetic nervous system (SNS) and its neurotransmitters in regulating inflammation”[68] A study from 2013 suggested that acidic environment represents a novel endogenous danger signal alerting the innate immunity. Low pH may thus contribute to inflammation in acidosis-associated pathologies, such as atherosclerosis and post-ischemic inflammatory responses.[69]

Also, a study published in 2016 has demonstrated that moderate extracellular acidosis which is a common finding in different pathological conditions such as inflammation, ischemia or in solid growing tumours affects the functional behaviour of monocytes and macrophages and can therefore modulate the immune response.[70]

And, a study published in 2016 has shown that vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. [71]

Acidosis and Bone Loss in RA

Finally, studies have shown a strong evidence that osteoclasts may be the primary effectors of the bone erosions that are typical in RA. So, to prevent the progression of the erosive damage of bones seems to be an important initiative in RA.[72,73]

Moreover, we must take into account the proposition from A. Wachman and DS. Bernstein, made in 1968, that the body draws minerals from the bones to neutralize acid challenges.[74]

References:

1. Richardson, B. W.: The Cause of the Coagulation of the Blood. The Astley Cooper Prize Essay for 1856, London, John Churchill, Chapter: The Effect of Lactic Acid on Animal Bodies. Pages 371 – 396. 1858 at https://play.google.com/books/reader?id=8VtEAAAAcAAJ&hl=pt&pg=GBS.PA1  
2. https://en.wikipedia.org/wiki/Benjamin_Ward_Richardson
3. Charles L. Short, The Antiquity of Rheumatoid Arthritis.  Arthritis and Rheumatism, Vol. 17: No. 3.1974 at https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780170302  
4. Charles L. Short, Rheumatoid Arthritis, J. Chron. Dis., Vol10: N 5, 1959 at https://www.jclinepi.com/article/0021-9681(59)90106-7/fulltext  
5. Selye Hans. A Syndrome Produced by Diverse Nocuous Agents. Nature,138: 32, July 4, 1936
6. Rheumatic Disease As Diseases Of Adaptation: Professor Hans Selye's Heberden Oration. The British Medical JournalVol. 1: N. 4666 pp. 1362-1364. 1950 at https://www.jstor.org/stable/25357315  
7. Michotte, L.: Septiéme Congrés International du Rheumatisme, Geneve, 1953
8. Michotte, L. J, Reversal of the Urinary Excretion Ratio Noradrenaline/Adrenaline in Rheumatoid Arthritis. Acta Medica 7, Scandinavia, 162: (S341), 101–106, 1958 at doi:10.1111/j.0954-6820.1958.tb19094.x 
9. Edmonds ME et al. Autonomic neuropathy in rheumatoid arthritis. British Medical Journal, 2: 173-175, 1979 at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1595852/
10. Dekkers JC et al. Elevated sympathetic nervous system activity in patients with recently diagnosed rheumatoid arthritis with active disease. Clin Exp Rheumatol. 22: (1):63-70. Jan-Feb 2004
11. Koopman FA et al.  Autonomic Dysfunction Precedes Development of Rheumatoid Arthritis: A Prospective Cohort Study. EbioMedicine. 6: 231-237, April 2016 at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856742/  
12. Foster, B.: Clinical Medicine, London, J. and A. Churchill, p. 143, 1874 at https://play.google.com/books/reader?id=mdfQnXKC_S4C&printsec=frontcover&output=reader&hl=pt_BR&pg=GBS.PA206
13. Wilde, P.: Physiology of Gout, Rheumatism and Arthritis, New York, William Wood & Co., 1922.
14. Cajori F. A, et al. The Alleged Role of Lactic Acid In Arthritis And Rheumatoid Conditions. Arch Intern Med ,34: (4). 566-572, 1924 at https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/534620
15. Lindy, S.et al, Lactate dehydrogenase in the synovial tissue in rheumatoid arthritis: total activity and isoenzyme composition. Clin. Chim. Acta 31: 19–23, 1971 at https://www.sciencedirect.com/science/article/pii/0009898171903573
16. Gobelet C and Gerster J. C.. Synovial fluid lactate levels in septic and non-septic arthritides. Ann Rheum Dis. 43: (5), 1984  at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1001519/  
17. Chang X. and Wei C.. Glycolysis and rheumatoid arthritis. International Journal of Rheumatic Diseases 14: 2011 at https://onlinelibrary.wiley.com/doi/full/10.1111/j.1756-185X.2011.01598.x  
18. Cutolo M, Straub RH. Stress as a risk factor in the pathogenesis of rheumatoid arthritis. Neuroimmunomodulation.13: (5– 6); 277–82, 2006 at https://www.karger.com/Article/Abstract/104855
19. de Brouwer, S. J. et al. Immune responses to stress in rheumatoid arthritis and psoriasis. Rheumatology (Oxford). 53: 10,  Pages 1844–1848. October, 2014 at https://academic.oup.com/rheumatology/article/53/10/1844/1817665  
20. Shimada et al. Age-related changes of baroreflex function, plasma norepinephrine , and blood pressure. Hypertension 7:113-117, 1985.
21. Narkiewicz et al. Gender-selective interaction between aging, blood pressure and sympathetic nerve activity. Hypertension 45:522-525. 2005
22. Kwoh C.K. et al. Age, Sex, and the Familial Risk of Rheumatoid Arthritis.  American Journal of Epidemiology, Vol. 144, No. 1, 1996
23. Pemberton, R.: Arthritis and Rheumatoid Conditions, Philadelphia, Lea & Febiger, 1930.
24. M. Haugen et al. Diet therapy for the patient with rheumatoid arthritis? Rheumatology, Volume 38, Issue 11, 1 November 1999 at https://academic.oup.com/rheumatology/article/38/11/1039/1783279  
25. Monroe RT, Hall FC. The feces of patients with chronic arthritis. Arch Intern Med, 764 –70, 1931 at https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/537478  
26. Tentolouris et al. Differential effect of high-fat and high carbohydrate isoenergetic meals on cardiac autonomic nervous system activity in lean and obese women. Metabolism 52: 1426-32. 2003 at https://www.metabolismjournal.com/article/S0026-0495(03)00322-6/pdf  
27. Marshall MW and Iacono JM. Changes in lactate dehydrogenase, LDH isoenzymes, lactate, and pyruvate as a result of feeding low fat diets to healthy men and women. Metabolism. 25: (2);169-78.1976 at https://www.sciencedirect.com/science/article/pii/0026049576900470  
28. Harold T. Edwards, Edward H. Bensley, David B. Dill and Thorne M. Carpenter. Human Respiratory Quotients in Relation to Alveolar Carbon Dioxide and Blood Lactic Acid After Ingestion of Glucose, Fructose, or Galactose. Journal of Nutrition. 27: N 3: 241-251, March 1944 at https://academic.oup.com/jn/article-abstract/27/3/241/4725717 
29. Hallfrisch J. Metabolic effects of dietary fructose. FASEB J, V 4; 2652-2660. Jun 1990 at https://www.fasebj.org/doi/abs/10.1096/fasebj.4.9.2189777?journalCode=fasebj  
30. Badsha H. Role of Diet in Influencing Rheumatoid Arthritis Disease Activity. Open Rheumatol J. 12: 19–28, 2018 at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827298/  
31. Niedermaier ON, Smith ML. Influence of cigarette smoking on human autonomic function. Circulation. 88: 562571. 1993 32
32. Adamopoulus D, et al, New insights into the sympathetic, endothelial and coronary effects of nicotine. Clin Exp Pharmacol Physiol 35(4): 458-63. 2008.
33. Yarlioglues M. Kaya MG et al. Dose-dependent acute effects of passive smoking on left ventricular cardiac function in health volunteers. J Investig Med  60 (2): 517-22. Feb 2012
34. Chang K et al. Smoking and Rheumatoid Arthritis. Int J Mol Sci. 15(12): 22279–22295, 2014 at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284707/
35. Guarino D. et al,  The Role of the Autonomic Nervous System in the Pathophysiology of Obesity. Front Physiol. 8: 665, 2017 at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606212/
36. Ali A et al, Evaluation of Autonomic Dysfunction in Obese and Non-Obese Hypertensive Subjects. J Clin Diagn Res.10(6): YC01–YC03, 2016 at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963754/
37. George M. D. et al, The Obesity Epidemic and Consequences for Rheumatoid Arthritis Care. Curr Rheumatol Rep. 18(1): 6, 2016 at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809046/  
38. Essouma M et al. Is air pollution a risk factor for rheumatoid arthritis?. J Inflamm (Lond). 12: 48, 2015 at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518680/
39. Huang W et al. Air Pollution and Autonomic and Vascular Dysfunction in Patients With Cardiovascular Disease: Interactions of Systemic Inflammation, Overweight, and Gender. Am J Epidemiol. 176(2): 117–126, 2012 at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493195/
40. Kostoglou-Athanassiou I. et al. Vitamin D and rheumatoid arthritis. Ther Adv Endocrinol Metab, 3(6): 181–187, 2012 at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539179/
41. Wadhwania R. Is Vitamin D Deficiency Implicated in Autonomic Dysfunction?. J Pediatr Neurosci. 12(2): 119– 123, 2017 at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5588633/
42. Cori CF and Cori GT. The mechanism of epinephrine action IV: The influence of epinephrine on lactic acid production and blood sugar utilization. J Biol Chem, 84: 683-98, 1929 at http://www.jbc.org/content/84/2/683.full.pdf+html
43. The Nobel Prize in Physiology or Medicine 1947 at https://www.nobelprize.org/nobel_prizes/medicine/laureates/1947/  
44. Williamson JR. Metabolic effects of epinephrine in the isolated, perfused rat heart. J Biol Chem, 239: 272129, 1964 at http://www.jbc.org/content/239/9/2721.full.pdf  
45. Schade DS. The role of catecholamines in metabolic acidosis. Ciba Found Symp; 87:235-53: 1982
46. Mercedes Garcia Alvarez, Paul Marik, Rinaldo Bellomo. Stress hyperlactataemia: present understanding and controversy. The Lancet Diabetes & Endocrinology, 2013
47. Carlos ETB Monteiro, Acidity Theory of Atherosclerosis -- History, Pathophysiology, Therapeutics and Risk Factors – A Mini Review. Positive Health Online, Edition 226, November 2015 at http://www.positivehealth.com/article/heart/acidity-theory-of- atherosclerosis-history-pathophysiologytherapeutics-and-risk-factors-a-mini-revie 
48. Carlos ETB Monteiro, 'Stress as Cause of Atherosclerosis – The Acidity Theory' published in Chapter 10 of the book “Fat and Cholesterol Don’t Cause Heart Attacks and Statins Are Not The Solution”, 2016 at https://www.amazon.com/Cholesterol- Cause-Attacks-Statins-Solution-ebook/dp/B01LZHKRD8 
49. Carlos ETB Monteiro, “Stress as Cause of Heart Attacks - The Myogenic Theory”. Published at the Journal Wise Traditions in Food, Farming, and the Healing Arts, Fall 2014. Reproduced by Positive Health Online, Issue 222, May 2015 at http://www.positivehealth.com/article/heart/stress-as-cause-of-heart-attacks-the-myogenic-theory  
50. Carlos ETB Monteiro, “Stress as the Inductive Factor for Increased Lactate Production: The Evolutionary Path to Carcinogenesis”. Positive Health Online, Edition 241, October, 2017 athttp://www.positivehealth.com/article/cancer/stress-inductive-factor-for-increased-lactate-production-evolutionary-path-tocarcinogenesis
51. Carlos ETB Monteiro, “Cardiac Glycosides at Low Concentration Providing Neuro-Hormonal Effects.: The Final Solution Against Cancer?”. Positive Health Online, Edition 241, November, 2017 at http://www.positivehealth.com/article/cancer/cardiac-glycosides-at-low-concentration-providing-neurohormonal-effects-thefinal-solution-against-c
52. Carlos ETB Monteiro, Intense Stress Leading to Raised Production and Accumulation of Lactate in Brain Ischemia – The Ultimate Cause of Acute Stroke: Mechanism, Risk Factors and Therapeutics. Positive Health Online, Edition 247, July 2018 at http://www.positivehealth.com/article/heart/intense-stress-leading-to-accumulation-of-lactate-in-brain-ischemia
53. Watanabe AM. Digitalis and the Autonomic Nervous System. JACC Vol. 5; No.5, 35 A - 42A: May 1985
54. Ferguson DW et al. Sympathoinhibitory responses to digitalis glycosides in heart failure patients, Circulation, V80; N1, July 1980
55. Gheorghiade M. Digoxin, a neurohormonal modulator for heart failure? Circulation V84, N5; Nov 1991.
56. Gheorghiade M, Adams KF, Colucci WS. Digoxin in the Management of Cardiovascular Disorders. Circulation, 109; 29592964: 2004 at http://circ.ahajournals.org/content/109/24/2959.long   
57. Fardin NM et al. Digitoxin improves cardiovascular autonomic control in rats with heart failure. Can J. Pharmacol 94, 18; 2016
58. Gutman Y, Boonyaviroj P. Naunyn Schmiedebergs. Mechanism of inhibition of catecholamine release from adrenal medulla by diphenylhydantoin and by low concentration of ouabain (10 (-10) M). Arch Pharmacol,296(3);293-6: 1977
59. Calderón-Montaño J, Burgos-Morón E, Lopez-Lazaro M. The Cardiac Glycosides Digitoxin, Digoxin and Ouabain Induce a Potent Inhibition of Glycolysis in Lung Cancer Cells. WebmedCentral CANCER,;4(7);WMC004323: 2013 at https://www.webmedcentral.com/wmcpdf/Article_WMC004323.pdf  
60. Kypson J, Triner L, Nahas GG. The effects of cardiac glycosides and their interaction with catecholamines on glycolysis and glycogenolysis in skeletal muscle J Pharmacol Exp Ther,164(1); 22-30:1968 at http://jpet.aspetjournals.org/content/164/1/22.long
61. Jagielska J. et al. Digitoxin elicits anti-inflammatory and vasoprotective properties in endothelial cells: Therapeutic implications for the treatment of atherosclerosis?, Atherosclerosis, 206(2):390-6, 2009
62. Kolkhof P et al. Cardiac glycosides potently inhibits C-reactive protein synthesis in human hepatocytes. Biochem Biophys Res Commun. 26;394(1): 233-9, 2010
63. Ihenetu K et al. Digoxin and digoxin-like immunoreactive factors (DLIF) modulate the release of proinflammatory cytokines.  Inflamm Res. 57(11); 519-23, 2008
64. Shah VO, Ferguson J, Hunsaker LA, Deck LM, Vander Jagt DL. Cardiac Glycosides Inhibit LPS-induced Activation of Proinflammatory Cytokines in Whole Blood through an NF-κB-dependent Mechanism. International Journal of Applied Research in Natural Products Vol. 4 (1), pp. 11-19, Mar-April 2011
65. Yang Q, Huang W, Jozwik C, Lin Y, Glasman M et al. Cardiac glycosides inhibit TNF-alpha/NF-kappaB signaling by blocking recruitment of TNF receptor-associated death domain to the TNF receptor. Proc Natl Acad Sci USA.5;102(27):9631-6, 2005 at http://www.pnas.org/cgi/content/full/102/27/9631 
66. Tani S et al. Digoxin Attenuates Murine Experimental Colitis by Downregulating Th17-related Cytokines. Inflamm Bowel Dis.  23(5):728-738 , 2017
67. Lee J et al, Digoxin ameliorates autoimmune arthritis via suppression of Th17 differentiation. International Immunopharmacology  V 26, Issue 1, 103–111, 2015 athttps://www.sciencedirect.com/science/article/pii/S1567576915001113?via%3Dihub  
68. Pongratz G; Straub RH. The Sympathetic Nervous Response in Inflammation. Arthritis Res Ther.16(504) 2014 at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396833/
69. Rajamäki K et al. Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome. Journal of Biological Chemistry, Manuscript M112.426254, March 25, 2013 at http://www.jbc.org/content/early/2013/03/25/jbc.M112.426254
70. Riemann A et al. Acidosis differently modulates the inflammatory program in monocytes and macrophages. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Vo 1862, Issue 1, Pages 72-81, January 2016 at https://doi.org/10.1016/j.bbadis.2015.10.017
71. Koopman FA.  Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. PNAS: vol. 113; no. 29, July 19, 2016 at http://www.pnas.org/content/113/29/8284.long
72. El-Gabalawy HD and Lipsky PE. Why do we not have a cure for rheumatoid arthritis? Arthritis Res 2002, 4 (suppl 3):S297-S30 at https://arthritis-research.biomedcentral.com/articles/10.1186/ar568
73. Karmakar S et al. Bone Damage in Rheumatoid Arthritis – Mechanistic Insights and Approaches to Prevention at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905601/
74. Wachman A and Bernstein DE. Diet and Osteoporosis, Lancet: V 291 I 7549; P 958-959, 1968 at https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(68)90908-2/fulltext