Corticosteroid

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.[1]

Some common naturally occurring steroid hormones are cortisol (C
21H
30O
5), corticosterone (C
21H
30O
4), cortisone (C
21H
28O
5) and aldosterone (C
21H
28O
5). (Note that aldosterone and cortisone share the same chemical formula but the structures are different.) The main corticosteroids produced by the adrenal cortex are cortisol and aldosterone.[2]

Contents

  • 1 Classes
  • 2 Medical uses
  • 3 Pharmacogenetics
    • 3.1 Asthma
  • 4 Adverse effects
  • 5 Biosynthesis
  • 6 Classification
    • 6.1 By chemical structure
      • 6.1.1 Group A – Hydrocortisone type
      • 6.1.2 Group B – Acetonides (and related substances)
      • 6.1.3 Group C – Betamethasone type
      • 6.1.4 Group D – Esters
        • 6.1.4.1 Group D1 – Halogenated (less labile)
        • 6.1.4.2 Group D2 – Labile prodrug esters
    • 6.2 By route of administration
      • 6.2.1 Topical steroids
      • 6.2.2 Inhaled steroids
      • 6.2.3 Oral forms
      • 6.2.4 Systemic forms
  • 7 History
    • 7.1 Etymology
  • 8 See also
  • 9 References

Classes[edit]

Cortisol

Corticosterone

Cortisone

Aldosterone

  • Glucocorticoids such as cortisol affect carbohydrate, fat, and protein metabolism, and have anti-inflammatory, immunosuppressive, anti-proliferative, and vasoconstrictive effects.[3] Anti-inflammatory effects are mediated by blocking the action of inflammatory mediators (transrepression) and inducing anti-inflammatory mediators (transactivation).[3] Immunosuppressive effects are mediated by suppressing delayed hypersensitivity reactions by direct action on T-lymphocytes.[3] Anti-proliferative effects are mediated by inhibition of DNA synthesis and epidermal cell turnover.[3] Vasoconstrictive effects are mediated by inhibiting the action of inflammatory mediators such as histidine.[3]
  • Mineralocorticoids such as aldosterone are primarily involved in the regulation of electrolyte and water balance by modulating ion transport in the epithelial cells of the renal tubules of the kidney.[3]

Medical uses[edit]

Synthetic pharmaceutical drugs with corticosteroid-like effects are used in a variety of conditions, ranging from brain tumors to skin diseases. Dexamethasone and its derivatives are almost pure glucocorticoids, while prednisone and its derivatives have some mineralocorticoid action in addition to the glucocorticoid effect. Fludrocortisone (Florinef) is a synthetic mineralocorticoid. Hydrocortisone (cortisol) is typically used for replacement therapy, e.g. for adrenal insufficiency and congenital adrenal hyperplasia.

Medical conditions treated with systemic corticosteroids:[3][4]

  • Allergy and respirology medicine
    • Asthma (severe exacerbations)
    • Chronic obstructive pulmonary disease (COPD)
    • Allergic rhinitis
    • Atopic dermatitis
    • Hives
    • Angioedema
    • Anaphylaxis
    • Food allergies
    • Drug allergies
    • Nasal polyps
    • Hypersensitivity pneumonitis
    • Sarcoidosis
    • Eosinophilic pneumonia
    • Some other types of pneumonia (in addition to the traditional antibiotic treatment protocols)
    • Interstitial lung disease
  • Dermatology
    • Pemphigus vulgaris
    • Contact dermatitis
  • Endocrinology (usually at physiologic doses)
    • Addison’s Disease
    • Adrenal insufficiency
    • Congenital adrenal hyperplasia
  • Gastroenterology
    • Ulcerative colitis
    • Crohn’s disease
    • Autoimmune hepatitis
  • Hematology
    • Lymphoma
    • Leukemia
    • Hemolytic anemia
    • Idiopathic thrombocytopenic purpura
    • Multiple Myeloma
  • Rheumatology/Immunology
    • Rheumatoid arthritiseas
    • Systemic lupus erythematosus
    • Polymyalgia rheumatica
    • Polymyositis
    • Dermatomyositis
    • Polyarteritis
    • Vasculitis
  • Ophthalmology
    • Uveitis
    • Keratoconjunctivitis
  • Other conditions
    • Multiple sclerosis
    • Organ transplantation
    • Nephrotic syndrome
    • Chronic hepatitis (flare ups)
    • Cerebral edema
    • IgG4-related disease
    • Prostate cancer
    • Tendinosis
    • Lichen planus

Topical formulations are also available for the skin, eyes (uveitis), lungs (asthma), nose (rhinitis), and bowels. Corticosteroids are also used supportively to prevent nausea, often in combination with 5-HT3 antagonists (e.g. ondansetron).

Typical undesired effects of glucocorticoids present quite uniformly as drug-induced Cushing’s syndrome. Typical mineralocorticoid side-effects are hypertension (abnormally high blood pressure), hypokalemia (low potassium levels in the blood), hypernatremia (high sodium levels in the blood) without causing peripheral edema, metabolic alkalosis and connective tissue weakness.[5] Wound healing or ulcer formation may be inhibited by the immunosuppressive effects.

Clinical and experimental evidence indicates that corticosteroids can cause permanent eye damage by inducing central serous retinopathy (CSR, also known as central serous chorioretinopathy, CSC).[6] A variety of steroid medications, from anti-allergy nasal sprays (Nasonex, Flonase) to topical skin creams, to eye drops (Tobradex), to prednisone have been implicated in the development of CSR.[7][8]

Corticosteroids have been widely used in treating people with traumatic brain injury.[9] A systematic review identified 20 randomised controlled trials and included 12,303 participants, then compared patients who received corticosteroids with patients who received no treatment. The authors recommended people with traumatic head injury should not be routinely treated with corticosteroids.[10]

Pharmacogenetics[edit]

Asthma[edit]

Patients’ response to inhaled corticosteroids has some basis in genetic variations. Two genes of interest are CHRH1 (corticotropin-releasing hormone receptor 1) and TBX21 (transcription factor T-bet). Both genes display some degree of polymorphic variation in humans, which may explain how some patients respond better to inhaled corticosteroid therapy than others.[11][12]

Adverse effects[edit]

Lower arm of a 47-year-old female showing skin damage caused by topical corticosteroid use.

Use of corticosteroids has numerous side-effects, some of which may be severe:

  • Severe amebic colitis: Fulminant amebic colitis is associated with high case fatality and can occur in patients infected with the parasite Entamoeba histolytica after exposure to corticosteroid medications [13].
  • Neuropsychiatric: steroid psychosis,[14] and anxiety,[15] depression. Therapeutic doses may cause a feeling of artificial well-being (“steroid euphoria”).[16] The neuropsychiatric effects are partly mediated by sensitization of the body to the actions of adrenaline. Therapeutically, the bulk of corticosteroid dose is given in the morning to mimic the body’s diurnal rhythm; if given at night, the feeling of being energized will interfere with sleep. An extensive review is provided by Flores and Gumina.[17]
  • Cardiovascular: Corticosteroids can cause sodium retention through a direct action on the kidney, in a manner analogous to the mineralocorticoid aldosterone. This can result in fluid retention and hypertension.
  • Metabolic: Corticosteroids cause a movement of body fat to the face and torso, resulting respectively in “moon face” and “buffalo hump”. and away from the limbs. Due to the diversion of amino-acids to glucose, they are considered anti-anabolic, and long term therapy can cause muscle wasting[18]
  • Endocrine: By increasing the production of glucose from amino-acid breakdown and opposing the action of insulin, corticosteroids can cause hyperglycemia,[19] insulin resistance and diabetes mellitus.[20]
  • Skeletal: Steroid-induced osteoporosis may be a side-effect of long-term corticosteroid use. Use of inhaled corticosteroids among children with asthma may result in decreased height.[21]
  • Gastro-intestinal: While cases of colitis have been reported, corticosteroids are often prescribed when the colitis, although due to suppression of the immune response to pathogens, should be considered only after ruling out infection or microbe/fungal overgrowth in the gastrointestinal tract. While the evidence for corticosteroids causing peptic ulceration is relatively poor except for high doses taken for over a month,[22] the majority of doctors as of 2010[update] still believe this is the case, and would consider protective prophylactic measures.[23]
  • Eyes: chronic use may predispose to cataract and retinopathy.
  • Vulnerability to infection: By suppressing immune reactions (which is one of the main reasons for their use in allergies), steroids may cause infections to flare up, notably candidiasis.[24]
  • Pregnancy: Corticosteroids have a low but significant teratogenic effect, causing a few birth defects per 1,000 pregnant women treated. Corticosteroids are therefore contraindicated in pregnancy.[25]
  • Habituation: Topical steroid addiction (TSA) has been reported in long-term users of topical steroids (users who applied topical steroids to their skin over a period of weeks, months, or years).[26][27] TSA is characterised by uncontrollable, spreading dermatitis and worsening skin inflammation which requires a stronger topical steroid to get the same result as the first prescription. When topical steroid medication is lost, the skin experiences redness, burning, itching, hot skin, swelling, and/or oozing for a length of time. This is also called ‘red skin syndrome’ or ‘topical steroid withdrawal'(TSW). After the withdrawal period is over the atopic dermatitis can cease or is less severe than it was before.[28]
  • In children the short term use of steroids by mouth increases the risk of vomiting, behavioral changes, and sleeping problems.[29]

Biosynthesis[edit]

Steroidogenesis, including corticosteroid biosynthesis.

The corticosteroids are synthesized from cholesterol within the adrenal cortex.[1] Most steroidogenic reactions are catalysed by enzymes of the cytochrome P450 family. They are located within the mitochondria and require adrenodoxin as a cofactor (except 21-hydroxylase and 17α-hydroxylase).

Aldosterone and corticosterone share the first part of their biosynthetic pathway. The last part is mediated either by the aldosterone synthase (for aldosterone) or by the 11β-hydroxylase (for corticosterone). These enzymes are nearly identical (they share 11β-hydroxylation and 18-hydroxylation functions), but aldosterone synthase is also able to perform an 18-oxidation. Moreover, aldosterone synthase is found within the zona glomerulosa at the outer edge of the adrenal cortex; 11β-hydroxylase is found in the zona fasciculata and zona glomerulosa.

Classification[edit]

By chemical structure[edit]

In general, corticosteroids are grouped into four classes, based on chemical structure. Allergic reactions to one member of a class typically indicate an intolerance of all members of the class. This is known as the “Coopman classification”.[30][31]

The highlighted steroids are often used in the screening of allergies to topical steroids.[32]

Group A – Hydrocortisone type[edit]

Hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone (short- to medium-acting glucocorticoids).

Group B – Acetonides (and related substances)[edit]

Amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, and triamcinolone acetonide.

Group C – Betamethasone type[edit]

Beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, and mometasone.

Group D – Esters[edit]
Group D1 – Halogenated (less labile)[edit]

Alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, and mometasone furoate.

Group D2 – Labile prodrug esters[edit]

Ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, prednicarbate, and tixocortol pivalate.

By route of administration[edit]

Topical steroids[edit]
Main article: Topical steroid

For use topically on the skin, eye, and mucous membranes.

Topical corticosteroids are divided in potency classes I to IV in most countries (A to D in Japan). Seven categories are used in the United States to determine the level of potency of any given topical corticosteroid.

Inhaled steroids[edit]

For nasal mucosa, sinuses, bronchii, and lungs.[33] This group includes:

  • Flunisolide[34]
  • Fluticasone furoate[34]
  • Fluticasone propionate[34]
  • Triamcinolone acetonide[34]
  • Beclomethasone dipropionate[34]
  • Budesonide[34]

There also exist certain combination preparations such as Advair Diskus in the United States, containing fluticasone propionate and salmeterol (a long-acting bronchodilator), and Symbicort, containing budesonide and formoterol fumarate dihydrate (another long-acting bronchodilator)[34]. They are both approved for use in children over 12 years old.

Oral forms[edit]

Such as prednisone, prednisolone, methylprednisolone, or dexamethasone.[35]

Systemic forms[edit]

Available in injectables for intravenous and parenteral routes.[35]

History[edit]

Tadeusz Reichstein, Edward Calvin Kendall. and Philip Showalter Hench were awarded the Nobel Prize for Physiology and Medicine in 1950 for their work on hormones of the adrenal cortex, which culminated in the isolation of cortisone.[41]

Initially hailed as a miracle cure and liberally prescribed during the 1950s, steroid treatment brought about adverse events of such a magnitude that the next major category of anti-inflammatory drugs, the nonsteroidal anti-inflammatory drugs (NSAIDs), was so named in order to demarcate from the opprobrium.[42] Corticosteroids were voted Allergen of the Year in 2005 by the American Contact Dermatitis Society.[43]

Lewis Sarett of Merck & Co. was the first to synthesize cortisone, using a 36-step process that started with deoxycholic acid, which was extracted from ox bile.[44] The low efficiency of converting deoxycholic acid into cortisone led to a cost of US $200 per gram. Russell Marker, at Syntex, discovered a much cheaper and more convenient starting material, diosgenin from wild Mexican yams. His conversion of diosgenin into progesterone by a four-step process now known as Marker degradation was an important step in mass production of all steroidal hormones, including cortisone and chemicals used in hormonal contraception.[45]

In 1952, D.H. Peterson and H.C. Murray of Upjohn developed a process that used Rhizopus mold to oxidize progesterone into a compound that was readily converted to cortisone.[46] The ability to cheaply synthesize large quantities of cortisone from the diosgenin in yams resulted in a rapid drop in price to US $6 per gram, falling to $0.46 per gram by 1980. Percy Julian’s research also aided progress in the field.[47] The exact nature of cortisone’s anti-inflammatory action remained a mystery for years after, however, until the leukocyte adhesion cascade and the role of phospholipase A2 in the production of prostaglandins and leukotrienes was fully understood in the early 1980s.

Etymology[edit]

The cortico- part of the name refers to the adrenal cortex, which makes these steroid hormones. Thus a corticosteroid is a “cortex steroid”.

See also[edit]

  • List of corticosteroids
  • List of corticosteroid cyclic ketals
  • List of corticosteroid esters
  • List of steroid abbreviations

References[edit]

  • ^ a b Nussey, S.; Whitehead, S. (2001). Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers. 
  • ^ Nussey, Stephen; Whitehead, Saffron (2001-01-01). The adrenal gland. BIOS Scientific Publishers. 
  • ^ a b c d e f g Liu, Dora; Ahmet, Alexandra; Ward, Leanne; Krishnamoorthy, Preetha; Mandelcorn, Efrem D; Leigh, Richard; Brown, Jacques P; Cohen, Albert; Kim, Harold (2013-08-15). “A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy”. Allergy, Asthma, and Clinical Immunology. 9 (1): 30. doi:10.1186/1710-1492-9-30. ISSN 1710-1484. PMC 3765115 . PMID 23947590. 
  • ^ Mohamadi, Amin; Chan, Jimmy J.; Claessen, Femke M. A. P.; Ring, David; Chen, Neal C. (2017-01-01). “Corticosteroid Injections Give Small and Transient Pain Relief in Rotator Cuff Tendinosis: A Meta-analysis”. Clinical Orthopaedics and Related Research. 475 (1): 232–243. doi:10.1007/s11999-016-5002-1. ISSN 0009-921X. PMC 5174041 . PMID 27469590. 
  • ^ Werner R (2005). A massage therapist’s guide to Pathology (3rd ed.). Pennsylvania: Lippincott Williams & Wilkins. 
  • ^ Abouammoh, Marwan A. (2015). “Advances in the treatment of central serous chorioretinopathy”. Saudi Journal of Ophthalmology. 29 (4): 278–286. doi:10.1016/j.sjopt.2015.01.007. ISSN 1319-4534. PMC 4625218 . PMID 26586979. 
  • ^ Carvalho-Recchia, CA; Yannuzzi, LA; Negrão, S; Spaide, RF; Freund, KB; Rodriguez-Coleman, H; Lenharo, M; Iida, T (2002). “Corticosteroids and central serous chorioretinopathy”. Ophthalmology. 109 (10): 1834–7. doi:10.1016/S0161-6420(02)01117-X. PMID 12359603. 
  • ^ “The New York Times :: A Breathing Technique Offers Help for People With Asthma”. buteykola.com. Retrieved 2012-11-30. 
  • ^ Alderson P, Roberts I. “Plain Language Summary”. Corticosteroids for acute traumatic brain injury. The Cochrane Collaboration. p. 2. 
  • ^ Alderson, P.; Roberts, I. (2005). Alderson, Phil, ed. “Corticosteroids for acute traumatic brain injury”. Cochrane Database Syst Rev (1): CD000196. doi:10.1002/14651858.CD000196.pub2. PMID 15674869. 
  • ^ Tantisira KG, Lake S, Silverman ES, Palmer LJ, Lazarus R, Silverman EK, Liggett SB, Gelfand EW, Rosenwasser LJ, Richter B, Israel E, Wechsler M, Gabriel S, Altshuler D, Lander E, Drazen J, Weiss ST (2004). “Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids”. Human Molecular Genetics. 13 (13): 1353–9. doi:10.1093/hmg/ddh149. PMID 15128701. 
  • ^ Tantisira KG, Hwang ES, Raby BA, Silverman ES, Lake SL, Richter BG, Peng SL, Drazen JM, Glimcher LH, Weiss ST (Dec 2004). “TBX21: A functional variant predicts improvement in asthma with the use of inhaled corticosteroids”. PNAS. 101 (52): 18099–18104. Bibcode:2004PNAS..10118099T. doi:10.1073/pnas.0408532102. PMC 539815 . PMID 15604153. 
  • ^ Shirley, Debbie-Ann; Moonah, Shannon; Meza, Isaura (28 July 2016). “Fulminant Amebic Colitis after Corticosteroid Therapy: A Systematic Review”. PLOS Neglected Tropical Diseases. 10 (7): e0004879. doi:10.1371/journal.pntd.0004879. 
  • ^ Hall, Richard. “Psychiatric Adverse Drug Reactions: Steroid Psychosis”. Director of Research Monarch Health Corporation Marblehead, Massachusetts. 
  • ^ Korte SM (2001). “Corticosteroids in relation to fear, anxiety and psychopathology”. Neurosci Biobehav Rev. 25 (2): 117–42. doi:10.1016/S0149-7634(01)00002-1. PMID 11323078. 
  • ^ Swinburn CR, Wakefield JM, Newman SP, Jones PW (December 1988). “Evidence of prednisolone induced mood change (‘steroid euphoria’) in patients with chronic obstructive airways disease”. Br J Clin Pharmacol. 26 (6): 709–713. doi:10.1111/j.1365-2125.1988.tb05309.x. PMC 1386585 . PMID 3242575. 
  • ^ Benjamin H. Flores and Heather Kenna Gumina. The Neuropsychiatric Sequelae of Steroid Treatment. URL:http://www.dianafoundation.com/articles/df_04_article_01_steroids_pg01.html
  • ^ Hasselgren PO, Alamdari N, Aversa Z, Gonnella P, Smith IJ, Tizio S (July 2010). “CORTICOSTEROIDS AND MUSCLE WASTING ROLE OF TRANSCRIPTION FACTORS, NUCLEAR COFACTORS, AND HYPERACETYLATION”. Curr Opin Clin Nutr Metab Care. 13 (4): 423–428. doi:10.1097/MCO.0b013e32833a5107. PMC 2911625 . PMID 20473154. 
  • ^ Donihi AC, Raval D, Saul M, Korytkowski MT, DeVita MA (2006). “Prevalence and predictors of corticosteroid-related hyperglycemia in hospitalized patients”. Endocr Pract. 12 (4): 358–62. doi:10.4158/ep.12.4.358. PMID 16901792. 
  • ^ Blackburn D, Hux J, Mamdani M (2007). “Quantification of the risk of corticosteroid-induced diabetes mellitus among the elderly”. Journal of General Internal Medicine. 17 (9): 717–720. doi:10.1046/j.1525-1497.2002.10649.x. PMC 1495107 . PMID 12220369. 
  • ^ Zhang, L; Prietsch, SO; Ducharme, FM (Jul 17, 2014). “Inhaled corticosteroids in children with persistent asthma: effects on growth”. The Cochrane Database of Systematic Reviews. 7: CD009471. doi:10.1002/14651858.CD009471.pub2. PMID 25030198. 
  • ^ Pecora PG, Kaplan B (1996). “Corticosteroids and ulcers: is there an association?”. Ann Pharmacother. 30 (7–8): 870–2. doi:10.1177/106002809603000729. PMID 8826575. 
  • ^ Martínek J, Hlavova K, Zavada F, et al. (June 2010). “”A surviving myth” —corticosteroids are still considered ulcerogenic by a majority of physicians”. Scand J Gastroenterol. 45 (10): 1156–61. doi:10.3109/00365521.2010.497935. PMID 20569095. 
  • ^ Fukushima, C.; Matsuse, H.; Tomari, S.; Obase, Y.; Miyazaki, Y.; Shimoda, T.; Kohno, S. (2003). “Oral candidiasis associated with inhaled corticosteroid use: Comparison of fluticasone and beclomethasone”. Annals of Allergy, Asthma & Immunology. 90 (6): 646–651. doi:10.1016/S1081-1206(10)61870-4. PMID 12839324. 
  • ^ Shepard, TH.; Brent, RL.; Friedman, JM.; Jones, KL.; Miller, RK.; Moore, CA.; Polifka, JE. (April 2002). “Update on new developments in the study of human teratogens”. Teratology. 65 (4): 153–61. doi:10.1002/tera.10032. PMID 11948561. 
  • ^ Nnoruka, Edith; Daramola, Olaniyi; Ike, Samuel (2007). “Misuse and abuse of topical steroids: implications”. Expert Review of Dermatology. 2 (1): 31–40. doi:10.1586/17469872.2.1.31. Retrieved 2014-12-18. 
  • ^ Sanjay, Rathi; D’Souza, Paschal (2012). “Rational and ethical use of topical corticosteroids based on safety and efficacy”. Indian Journal of Dermatology. 57 (4): 251–259. doi:10.4103/0019-5154.97655. 
  • ^ Fukaya, M; Sato, K; Sato, M; Kimata, H; Fujisawa, S; Dozono, H; Yoshizawa, J; Minaguchi, S (2014). “Topical steroid addiction in atopic dermatitis”. Drug, Healthcare and Patient Safety. 6: 131–8. doi:10.2147/dhps.s69201. PMC 4207549 . PMID 25378953. 
  • ^ Aljebab, F; Choonara, I; Conroy, S (April 2016). “Systematic review of the toxicity of short-course oral corticosteroids in children”. Archives of Disease in Childhood. 101 (4): 365–70. doi:10.1136/archdischild-2015-309522. PMC 4819633 . PMID 26768830. 
  • ^ Rietschel, Robert L. (2007). Fisher’s Contact Dermatitis, 6/e. Hamilton, Ont: BC Decker Inc. p. 256. ISBN 1-55009-378-9. 
  • ^ Coopman S, Degreef H, Dooms-Goossens A (July 1989). “Identification of cross-reaction patterns in allergic contact dermatitis from topical corticosteroids”. Br. J. Dermatol. 121 (1): 27–34. doi:10.1111/j.1365-2133.1989.tb01396.x. PMID 2757954. 
  • ^ Wolverton, SE (2001). Comprehensive Dermatologic Drug Therapy. WB Saunders. p. 562. 
  • ^ “Asthma Steroids: Inhaled Steroids, Side Effects, Benefits, and More”. Webmd.com. Retrieved 2012-11-30. 
  • ^ a b c d e f g Mayo Clinic Staff (September 2015). “Asthma Medications: Know your options”. MayoClinic.org. Retrieved 2018-02-27. 
  • ^ a b “Systemic steroids (corticosteroids). DermNet NZ”. . DermNet NZ. 2012-05-19. Retrieved 2012-11-30. 
  • ^ Khan MO, Park KK, Lee HJ (2005). “Antedrugs: an approach to safer drugs”. Curr. Med. Chem. 12 (19): 2227–39. doi:10.2174/0929867054864840. PMID 16178782. 
  • ^ CALVERT DN (1962). “Anti-inflammatory steroids”. Wis. Med. J. 61: 403–4. PMID 13875857. 
  • ^ Alberto Conde-Taboada (2012). Dermatological Treatments. Bentham Science Publishers. pp. 35–36. ISBN 978-1-60805-234-9. 
  • ^ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1642–1643. ISBN 978-0-8155-1856-3. 
  • ^ Kyu-Won Kim; Jae Kyung Roh; Hee-Jun Wee; Chan Kim (14 November 2016). Cancer Drug Discovery: Science and History. Springer. pp. 169–. ISBN 978-94-024-0844-7. 
  • ^ http://nobelprize.org/nobel_prizes/medicine/laureates/1950/kendall-lecture.pdf
  • ^ Buer JK (Oct 2014). “Origins and impact of the term ‘NSAID'” (PDF). Inflammopharmacology. 22 (5): 263–7. doi:10.1007/s10787-014-0211-2. PMID 25064056. 
  • ^ “Contact Allergen of the Year: Corticosteroids: Introduction”. Medscape.com. 2005-06-13. Retrieved 2012-11-30. 
  • ^ Sarett, Lewis H. (1947). “Process of Treating Pregnene Compounds”, U. S. Patent 2,462,133
  • ^ Marker, Russell E.; Wagner, R. B.; Ulshafer, Paul R.; Wittbecker, Emerson L.; Goldsmith, Dale P. J.; Ruof, Clarence H. (1947). “Steroidal Sapogenins”. J. Am. Chem. Soc. 69 (9): 2167–2230. doi:10.1021/ja01201a032. PMID 20262743. 
  • ^ Peterson DH, Murray HC (1952). “Microbiological Oxygenation of Steroids at Carbon 11”. J. Am. Chem. Soc. 74 (7): 1871–2. doi:10.1021/ja01127a531. 
  • ^ Julian, Percy L., Cole, John Wayne, Meyer, Edwin W., and Karpel, William J. (1956) “Preparation of Cortisone”. U. S. Patent 2,752,339
  • Sex steroids

    Neurosteroids

    • Cholestanes: 24S-Hydroxycholesterol
    • Cholesterol
    • Pregnanes: 3α-Dihydroprogesterone
    • 3β-Dihydroprogesterone
    • 5α-Dihydrocorticosterone
    • 5α-Dihydroprogesterone
    • 5β-Dihydroprogesterone
    • Allopregnanolone
    • Corticosterone
    • DHC
    • DHDOC
    • 11-Deoxycorticosterone
    • Epipregnanolone
    • Isopregnanolone
    • Pregnanolone
    • Pregnenolone
    • Pregnenolone sulfate
    • Progesterone
    • THB
    • THDOC
    • Androstanes: 3α-Androstanediol
    • 3α-Androstenol
    • 7-Keto-DHEA
    • 7α-Hydroxy-DHEA
    • 7β-Hydroxy-DHEA
    • 7α-Hydroxyepiandrosterone
    • 7β-Hydroxyepiandrosterone
    • Androsterone
    • DHEA
    • DHEA sulfate
    • Etiocholanolone
    • Pheromones: 3α-Androstenol
    • 3β-Androstenol
    • Androstadienol
    • Androstadienone
    • Androstenone
    • Androsterone
    • Estratetraenol

    Others

    • Vitamin D: 7-Dehydrocholesterol
    • Calcidiol/Calcifediol
    • Calcitriol
    • Cholecalciferol
    • Others: 7α-Hydroxycholesterol
    • 11α-Hydroxyprogesterone
    • 11β-Hydroxyprogesterone
    • Cholesterol sulfate

    Antiglucocorticoids

    • Antagonists: Aglepristone
    • Ketoconazole
    • Mifepristone
    • Ulipristal acetate

    Synthesis modifiers

    • Acetoxolone
    • Aminoglutethimide
    • Carbenoxolone
    • Enoxolone
    • Ketoconazole
    • Metyrapone
    • Mitotane
    • Trilostane
    • #WHO-EM
    • ‡Withdrawn from market
    • Clinical trials:
      • †Phase III
      • §Never to phase III

    See also
    Glucocorticoid receptor modulators
    Mineralocorticoids and antimineralocorticoids
    List of corticosteroids

    See also
    Receptor/signaling modulators
    Glucocorticoids and antiglucocorticoids
    Mineralocorticoid receptor modulators
    List of corticosteroids

    See also
    Receptor/signaling modulators
    Mineralocorticoids and antimineralocorticoids
    Glucocorticoid receptor modulators
    List of corticosteroids


    Serum Sickness

    Serum Sickness

    Serum sickness is a reaction that is similar to an allergy. The immune system reacts to medications that contain injected proteins used to treat immune conditions. Or it can react to antiserum, the liquid part of blood that contains antibodies giv…

    Read More…

    The Effect of Immunosuppressive Drugs on MDSCs in Transplantation

    <h1>The Effect of Immunosuppressive Drugs on MDSCs in Transplantation</h1>

    The Effect of Immunosuppressive Drugs on MDSCs in Transplantation

    Review Article The Effect of Immunosuppressive Drugs on MDSCs in Transplantation
    1 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China 2 University of Chinese Academy of Sciences, Beijing, China 3 Center of Organ Transplantation, Second Xiangya Hospital of Central South University, Changsha, China
    Correspondence should be addressed to Yong Zhao ;
    Received 24 March 2018; Accepted 5 June 2018; Published 3 July 2018
    Academic Editor: Paulina Wlasiuk
    Copyright © 2018 Fan Yang et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract
    Myeloid-derived suppressor cells (MDSCs) are a group of innate immune cells that regulates both innate and adaptive immune responses. In recent years, MDSCs were shown to play an important negative regulatory role in transplant immunology even upstream of regulatory T cells. In certain cases, MDSCs are closely involved in transplantation immune tolerance induction and maintenance. It is known that some immunosuppressant drugs negatively regulate MDSCs but others have positive effects on MDSCs in different transplant cases. We herein summarized our recent insights into the regulatory roles of MDSCs in transplantation specially focusing on the effects of immunosuppressive drugs on MDSCs and their mechanisms of action. Studies on the effects of immunosuppressive drugs on MDSCs will significantly expand our understanding of immunosuppressive drugs on immune regulatory cells in transplantation and offer new insights into transplant tolerance. We hope to emphasize our concern for the negative effects of immunosuppressive agents on MDSCs, which may potentially attenuate the immune tolerance induction in transplanted recipients. 1. Introduction
    Since the introduction of powerful immunosuppressive drugs like calcineurin inhibitors into treatment of allograft rejection, excellent short-term graft survival has been achieved. But chronic rejection and side effects of immunosuppressant like infection, malignancy, and drug toxicity still need to be solved urgently [ 1 ]. Cellular immunotherapy has made great achievements in cancer recently [ 2 ]. So, there is increasing interest in the potential of immune regulatory cells as cell therapy for transplant rejection. This is also a very promising solution for getting the “holy grail” of transplantation. Myeloid-derived suppressor cells (MDSCs) are immune regulatory cells studied most extensively in cancer; now, we know that MDSCs can also exert immune modulatory effects in transplantation [ 3 ]. In this review, we will discuss how these cells are induced and activated during different types of transplantation and the mechanism they employed to protect the graft or induce tolerance. Recently, there are already some attempts to induce MDSCs in vitro for administration to organ transplant recipients to promote graft survival and induce immune tolerance in animal transplant models. Nowadays, there are no clinical trials for MDSC-based cell therapy in transplantation. It is promising to further improve MDSC-inducing strategy with enhanced function for their clinical application. It will also be helpful for us if these cells can be manipulated in vivo to exert stronger and more specific suppressive function. Targeting MDSCs in transplant recipients for long-term survival even tolerance is promising but also challenging. Understanding how currently used immunosuppressive drugs acting on MDSCs will give lots of benefits for the future clinical medication, which may reduce side effects of high doses of immunosuppressive drugs and promote graft survival in transplantation. More importantly, it may shed lights on new treatment strategy targeting MDSCs to enhance their alloimmune suppressive capacity and promote tolerance in transplantation. 2. MDSCs
    MDSCs are a class of immune-negative regulatory cells, with the earliest found in the late 70s of the last century. BCG inoculation or systemic irradiation of mice can result in inflammatory response, which will induce a group of abnormally proliferating myeloid cells with the ability to inhibit the activation and function of cytotoxic T cells, known as natural suppressor cells [ 4 ]. In recent years, MDSCs have been reported mainly in a variety of tumor animal models and patients, and the concept introduction of MDSC is mainly to describe these myeloid cells under the conditions of abnormal activation. But many other inflammatory microenvironments, such as trauma, chronic infections, acute infection-induced sepsis, tissue damage caused by radiation, and autoimmune diseases, also have similar cells. Under different activation conditions, MDSCs mediate immune-negative regulation through different mechanisms [ 5 ]. MDSCs are essentially a heterogeneous population of early myeloid progenitors, immature granulocytes, macrophages, and dendritic cells (DCs) at different stages of differentiation. Usually, MDSCs were divided into two subgroups: monocytic (M-MDSCs) and granulocytic (G-MDSCs) [ 6 ]. Since G-MDSCs actually had less granules and low density, also with a distinctive phenotype from neutrophils, it is recommended to be named as polymorphonuclear- (PMN-) MDSCs recently as the standard nomenclature [ 7 ]. These two subsets can be distinguished by surface markers [ 8 ]. In mice, M-MDSCs were characterized by phenotypic markers as CD11b + Ly6G − Ly6C high and PMN-MDSCs as CD11b + Ly6G + Ly6C low . In humans, M-MDSCs were defined as CD11b + CD14 + CD15 − HLA-DR −/low and PMN-MDSCs as CD11b + CD14 − CD15 + (or CD66b + ). Both of them were from human peripheral blood mononuclear cells (PBMCs) to exclude mature neutrophils. In human PBMCs, lin − (including CD3, CD14, CD15, CD19, and CD56) HLA-DR − CD33 + cells containing mixed groups of MDSCs with more immature progenitors have been defined as early-stage MDSCs (e-MDSCs), which have no equivalent in mice [ 7 ]. It should be pointed out that we do not have specific markers to define MDSCs and their subpopulations so far. This important issue requires to be addressed in the future.
    Two major groups of MDSCs often use different mechanisms to mediate immunosuppression in tumor models, with high levels of nitric oxide synthase 2 (NOS2 or iNOS) for M-MDSCs and reactive oxygen species (ROS) for PMN-MDSCs. But both of them can rely on arginase 1 (Arg1) for suppression. Arg1 and iNOS deplete L-arginine from microenvironments, and either together, or separately, they subsequently block the translation of the T cell CD3 ζ chain, inhibit T cell proliferation, and promote T cell apoptosis [ 9 ]. ROS produced by PMN-MDSCs reacts with NO to induce nitration and nitrosylation of amino acid in molecules of T cell signaling for functional inhibition [ 10 ]. Other mechanisms are also involved in immunosuppression in addition to the ones mentioned above. Indoleamine 2,3-dioxygenase (IDO) is an important immune regulatory enzyme for environmental tryptophan consumption to induce T cell dysfunction, which has been well documented in DCs and macrophages [ 11 , 12 ]. MDSCs can also induce IDO expression in cancer [ 13 ]. LPS-induced MDSCs suppress immune response by heme oxygenase-1 (HO-1) through IL-10 [ 14 ]. TGF- β and IL-10 produced by MDSCs can mediate the cytotoxic NK cell inhibition and Treg cell induction. ADAM metallopeptidase domain 17 on MDSCs can cut CD62L and thus inhibit the recognition of T cells with antigen-presenting cells (APCs) in lymph nodes [ 15 ]. Galectin 9 (GAL9) on MDSCs can act directly on T cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM3) on T cells to mediate their apoptosis [ 16 ]. Upregulating prostaglandin E2 (PGE2) by cyclooxygenase-2 (COX2) expression was also employed by MDSCs for immune suppression in tumor condition [ 17 ].
    The development and accumulation of MDSCs are mainly dependent on two types of signals. The first signal is responsible for immature myeloid cell expansion, and the second is for their pathologic activation in emergency myelopoiesis [ 18 ]. MDSCs arise from lineage-committed progenitors including common myeloid progenitors (CMPs) and granulocyte-monocyte progenitor (GMP) downstream of hematopoietic stem and progenitor cells [ 19 ]. Recently, it was found that monocyte-dendritic cell progenitors (MDPs) arose from CMPs independently of GMPs, GMP-, and MDP- produced monocytes via similar but distinct monocyte-committed progenitors [ 20 ]. It is interesting to clarify the developed pathway of M-MDSCs from each progenitor. Studies also showed that epigenetic silencing of the retinoblastoma (Rb) gene controlled by histone deacetylase 2 (HDAC-2) promotes monocyte preferential differentiation towards PMN-MDSCs (Figure 1 ) [ 21 , 22 ]. Growth factors like GM-CSF, G-CSF, and M-CSF work as expansion signals, and cytokines like IFN- γ , IL-1 β , IL-6, IL-10, IL-12, and IL-13 are responsible for their pathologic activation. The first group of signals activated downstream transcription factors or pathways like STAT3, IRF8, C/EBP β , RB1, Notch, adenosine receptors A2b signaling, and NLRP3 for MDSC expansion [ 23 ]. The second group of signals employs NF- κ B pathway, STAT1, STAT6, PGE2, and COX2 for full function [ 24 ]. Figure 1: The development, subsets, and phenotypes of MDSCs. MDSCs arise from CMP in the presence of several growth factors and cytokines during emergency myelopoiesis under inflammatory conditions. Growth factors (signal 1) drive the expansion of myeloid cell progenitors. Subsequent activation signal (signal 2) via cytokines endows these progenitors with immunosuppressive function to give rise to e-MDSCs, M-MDSCs, and PMN-MDSCs. Recently, it was found that GMP and MDP yielded distinct monocyte-committed progenitors which differentiated into different monocyte subsets at steady-state, respectively. Which of the two monocyte-committed progenitors can give rise to functional M-MDSCs and further acquiring the ability to differentiate into PMN-MDSCs during emergency myelopoiesis is unclear. The phenotype markers of different MDSC subsets are illustrated here. CMP, common myeloid progenitor; GMP, granulocyte-monocyte progenitor; MDP, monocyte-dendritic cell progenitor; MP, monocyte-committed progenitor; cMoP, common monocyte progenitor; GP, granulocyte-committed progenitor; G-mono, GMP-derived monocyte; M-mono, MDP-derived monocyte. 3. MDSCs in Transplantation and Mechanisms of Immune Suppression 3.1. MDSCs in Organ Transplantation
    The concept of MDSCs was introduced into transplantation field to describe similar phenotypic cells found in cancers where they were intensively studied. Under tumor conditions, MDSCs can be divided into M-MDSCs and PMN-MDSCs; these two groups of MDSCs have some differences in development, phenotype, and mechanisms mediating immune suppression [ 6 ]. This is also true in different transplant models (Table 1 ). In most cases, M-MDSCs play more important roles in transplant tolerance induction and graft protection. For example, CD11b + CD115 + Gr1 + M-MDSCs promote tolerance by iNOS through IFN- γ and STAT-1 in a mouse heart transplant model [ 25 ]. CD11b + CD33 + HLA-DR − CD14 + M-MDSCs from kidney-transplanted patients can inhibit CD4 + T cell proliferation and expand Treg cells in mixed leukocyte reactions in vitro [ 26 ]. Table 1: MDSCs in transplantation.
    Clinical significance of MDSCs in human renal transplantation with acute T cell-mediated rejection was confirmed by comparing patients with higher MDSCs in PBMCs to the lower ones. Patients with high levels of MDSCs had better graft function and longer organ survival time [ 27 ]. In intestinal transplantation, MDSCs accumulate in the recipient PBMCs and the grafted intestinal mucosa, and MDSC numbers decreased in intestinal transplant recipients suffering from acute cellular rejection, which suggests that MDSC may regulate acute cellular rejection [ 28 ].
    In animal transplant models, whether or not MDSCs can be induced in the absence of any immunosuppressive treatment is controversial. In our group, we found that MDSCs with suppressive capacity can be induced in mouse spleen by alloskin transplantation [ 29 ]. But data from other groups using mouse heart transplantation model supports that functional MDSCs cannot be induced by transplantation alone [ 25 , 30 ]. This may be due to the different intensity of the alloimmune response in different models. The earliest report on the role of MDSCs in organ transplantation is in the rat kidney transplant model treated with anti-CD28 mAb. MDSCs expressing CD11b and Sirp α in blood and bone marrow inhibit T cell proliferation, but the counterparts in lymph nodes and spleen cannot [ 31 ]. The mechanism of these MDSC-mediated inhibitions is through the iNOS, since the addition of iNOS inhibitor rescues T cell proliferation in vitro and restores the survival time of the graft in vivo [ 31 ]. Subsequent study from the same group demonstrated that expression of CCL5 by MDSCs in the blood was downregulated, while the expression level in the graft was unchanged, which promoted the recruitment of Treg cells into the graft and supported graft survival [ 32 ]. In a mouse heart transplant model, donor-specific transfusion (DST) + anti-CD40L treatment induced accumulation of CD11b + Gr-1 + CD115 + MDSCs in blood and bone marrow and CD11b + Gr-1 + MDSCs in allografts. But only MDSCs in allograft can suppress T cell proliferation in MLR. Using Ccr2 −/− mice which cannot induce tolerance by DST + anti-CD40L, it was found that a transfer of CD115 + CD11b + Gr1 + bone marrow monocytes can restore tolerance but not monocytes from Ifngr −/− , Nos2 −/− , Stat1 −/− , or Irf-1 −/− mice. This demonstrated that IFN- γ to iNOS signaling pathway was necessary for MDSC function [ 25 ].
    Immunoglobulin-like transcript 2 (ILT2) is an inhibitory receptor that is widely expressed on white blood cells. In ILT2 transgenic mice (ILT2 constitutively activated by mouse H2-D b ), the ratio of CD11b + Gr-1 + MDSCs increased in both spleens and peripheral blood. Wild-type B6 mice and ILT2 transgenic mice were transplanted with bm2 mouse skin which had only one mismatch locus in MHC class II molecules. Six days later, MDSCs in spleens were sorted and transferred to B6 recipients transplanted with bm2 skin. MDSCs from ILT2 mice could promote graft survival significantly [ 33 ]. Our laboratory reported that Smad3-deficient mice were defective for skin and cardiac graft rejection with reduced T cell infiltration in the graft comparing to WT mice, but the numbers and function of MDSCs were upregulated. Functional enhancement for MDSCs in Smad3-deficient mice mainly relies on iNOS. MDSC depletion antibody RB6-8C5 reversed the protective effect on the graft survival for Smad3-deficient mice [ 34 ]. LPS tolerance-induced MDSCs have the ability to inhibit T cell proliferation in vitro. After transfer to recipient B6 mice grafted with bm12 skin, MDSCs prolong the graft survival through HO-1-dependent IL-10 production [ 14 ]. Peritonitis induced by cecal ligation and puncture results in MDSC accumulation in the bone marrow. After transfer to recipient mice, these cells reduced corneal neovascularization and promote graft survival in allocorneal transplantation model [ 35 ]. IL-33 treatment can prolong graft survival with increased CD11b + Gr-1 int MDSCs in allografts, spleens, and bone marrow in the bm12 to B6 heart transplant model. But whether IL-33 can directly induces MDSC expansion or activation needs to be illustrated [ 36 ]. Donor IL-6 deficiency also significantly prolongs graft survival with increased CD11b + Gr-1 low splenic MDSCs and graft infiltration of CD11b + Gr-1 low/int MDSCs in the B6 to BALB/c heart transplant model [ 37 , 38 ]. G-CSF treatment in BALB/c mice can induce functional MDSCs in spleens which can suppress T cell proliferation in vitro. G-CSF can also prolong allograft survival in a bm12 to B6 skin transplant model with increased CD11b + Gr-1 + MDSCs in blood and spleen [ 39 ]. Hepatic stellate cells cotransplanted with alloislets can prolong graft survival with increased CD11b + CD11c − MDSCs in spleen [ 40 ]. 3.2. MDSCs in Transplant Tolerance
    There are many ways to induce transplant tolerance in rodent animal models like costimulatory blockades or donor-specific transfusion [ 41 ]. Although it is difficult to repeat in large animals probably because of the presence of more memory T cells, these results are important for understanding the mechanisms of tolerance induction. MDSCs may be a key factor for transplant tolerance maintenance. In a renal transplant model, anti-CD28 treatment-induced tolerance can be interrupted by iNOS inhibitor, which suggests the role of MDSCs in tolerance maintenance [ 31 ]. Studies using a heart transplant model support this idea. In this model, graft tolerance was induced by anti-CD154 and DST treatment. Different types of myeloid cells were depleted during the transplantation by using anti-Gr-1, anti-Ly6G antibody, CD11b-DTR, and MaFIA mice, and the results showed that CD115 + CD11b + Gr-1 + MDSCs recruited to heart grafts from bone marrow played a key role on tolerance maintenance [ 25 ]. Tolerance was independent of splenic MDSCs because mice with splenectomy can also induce tolerance. Treg cell induction and maintenance were dependent on MDSCs by monocyte depletion in vivo [ 25 ]. Further study showed that DC-SIGN signaling on M-MDSC-derived macrophages was required for tolerance induction in mouse heart transplantation by costimulatory blockade for tolerance induction [ 42 ]. Using anti-CD154 mAb and DST treatment for heart transplant tolerance induction, another study showed that Listeria monocytogenes infection can break the tolerance and cause acute graft rejection [ 43 ]. But the donor-specific tolerant state reemerges, allowing spontaneous acceptance of a donor-matched heart after the secondary transplantation [ 43 ]. As MDSCs play important roles for tolerance in this model, infection may disturb the function of MDSCs and lead to rejection. Spontaneous tolerance by secondary transplantation may also depend on the recovery of MDSC function. Transfusion of donor splenocytes treated with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (ECDI-SPs) provides donor-specific tolerance of islet allografts. ECDI-SPs also significantly prolong cardiac allograft survival, and depletion of MDSCs or inhibition of IDO reversed this effect [ 44 ]. ECDI-SPs treatment increased both M-MDSCs and PMN-MDSCs in the spleen of allograft-transplanted recipients. Both of them can suppress T cell proliferation in vitro, and their protective effect for allograft was mediated in part by intrinsic IFN- γ -dependent mechanisms [ 45 ]. 3.3. MDSCs in Hematopoietic Stem Cell Transplantation
    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important therapeutic procedure to treat hematologic malignancies, which can cause graft-versus-host disease (GVHD). It is reported that circulating CD14 + HLA-DR −/low M-MDSCs with suppressive function mediated by IDO were increased in patients after allo-HSCT with GVHD [ 46 ]. Further study showed that the M-MDSCs in GVHD patient expressed CD1d and CD226, and CD1d + M-MDSC exerted strong immune-suppressive effect [ 47 ]. MDSC subsets were recovered between 2 and 4 weeks after allo-HSCT; they can suppress T cell proliferation and promote Treg cell development [ 48 ]. In human haploidentical-HSCT, G-CSF plays an important role in MDSC induction. M/PMN/e-MDSCs expanded in bone marrow and peripheral blood of donors after G-CSF treatment, and M/e-MDSCs are important factors associated with the low risk of acute GVHD [ 49 ]. Early studies in mouse GVHD models support this idea. In a murine model of allogeneic bone marrow transplantation (BMT), GVHD was induced by donor lymphocyte infusions immediately after BMT. MDSCs expanded in this model with the ability to suppress alloreactive T cell proliferation in MLR via iNOS [ 50 ]. It was reported that CpG + IFA treatment of donor mice can induce the accumulation of MDSCs in peripheral blood and spleens, which then protected mice from GVHD [ 51 ]. MDSCs isolated from G-CSF subcutaneously injected mice can inhibit acute GVHD through an IDO-independent mechanism [ 52 ]. G-CSF treatment also generates a population of suppressive neutrophils with less granule content and low density (features of PMN-MDSCs), which reduce acute GVHD in an alloantigen-specific manner through IL-10 and Treg generation [ 53 ]. Mice with SHIP deficiency accept allo-HSCT without serious GVHD, which was due to the accumulation of MDSCs impairing alloreactive T cell priming [ 54 ]. Transplantation of bone marrow cells from MyD88-deficient C57BL/6 (B6) mice together with B6 T cells into MHC-matched allogeneic BALB.B strain mice can induce more serious GVHD than transfer with WT bone marrow cells. The aggravation of GVHD was associated with impaired expansion of CD11b + Gr1 + MDSCs from the MyD88-deficient bone marrow cells during the GVHD development [ 55 ]. The in vitro induced MDSCs by G-CSF + GM-CSF + IL-13 from bone marrow cells inhibit lethality caused by GVHD through Arg1 [ 56 ]. GM-CSF + G-CSF-induced MDSCs attenuate GVHD by skewing T cells toward type 2 T cells [ 57 ]. The function of these induced MDSCs can be further improved by inhibiting their inflammasome activation to inhibit GVHD lethality [ 58 ]. To investigate the regulatory role of myeloid cells in GVHD, subclinical GVHD model was constructed in nonirradiated F1 hybrids by transfer of parental splenocytes [ 59 ]. Both M-MDSC and PMN-MDSC subsets suppressed alloreactive T cell proliferation in vitro and in vivo [ 60 ]. These results collectively suggested that MDSCs may play immune regulatory roles in allo-HSCT to suppress GVHD. 3.4. Induction of MDSCs In Vitro
    MDSCs can be induced in vitro for potential clinical application such as in organ transplantation. Early study reported that GM-CSF + LPS + IFN- γ can induce functional MDSCs in vitro and in vivo [ 61 ]. It is reported that the combination of GM-CSF and IL-6 was sufficient to induce MDSCs which prolonged alloislet graft survival after transfer to recipient mice [ 62 ]. These two cytokines can also induce functional MDSCs from human PBMCs [ 63 ]. This combination was further confirmed in a skin transplantation model. Repeated injection of MDSCs or a single injection of activated MDSCs by LPS stimulation resulted in prolonged allograft survival by short-term T cell exhaustion [ 64 ]. GM-CSF + IL-4 + PGE 2 induce the differentiation of MDSCs with enhanced function from human monocyte isolated from human PBMCs [ 65 ]. MDSCs induced by GM-CSF alone or M-MDSCs induced by M-CSF + TNF α can also prolong the survival of skin grafts with HY antigen [ 29 , 66 ]. Functional MDSCs induced by GM-CSF + IL-4 prolonged alloislet survival after cotransplantation via iNOS [ 67 , 68 ]. B7-H1 was required for MDSCs to exert immune regulatory activity and induction of Treg cells in this model [ 69 ]. 4. Clinically Used Immunosuppressive Drugs and Their Effects on MDSCs
    There are five major categories of clinical immunosuppressive agents (Table 2 ). Herein, we briefly discuss their mechanism of action to mediate immunosuppression and their effects on MDSCs. Table 2: Immunosuppressive drugs on MDSCs. 4.1. Corticosteroids (CS)
    CS including glucocorticoids (GC) and mineralocorticoids (MC) are the product of adrenal cortex, with broad-spectrum immunosuppressive and anti-inflammatory effects. Clinically applied CS are mainly GC which can activate gluconeogenesis. GC can enter the cell membrane in two ways. Unbound GC can passively diffuse into cell membrane, and they can also enter the cell via membrane receptor after binding with corticosteroid-binding globulin (CBG) [ 70 ]. GC can bind to glucocorticoid receptors (GR) then promote many gene activation by binding to glucocorticoid response element DNA sequence. Different chromatin accessibility determined that GR regulated different genes in different cell types [ 71 ]. GR regulate the immune response by interacting with other transcription factors without its own direct DNA binding. Many proinflammatory transcription factors like nuclear factor­ κ B (NF­ κ B), activator protein 1 (AP­1), the signal transducer and activator of transcription (STAT), CCAAT/enhancer­binding protein (C/EBP), and nuclear factor of activated T cells (NFAT) can interact with GR [ 72 ]. GC inhibit the initiation of inflammation and cell recruitment to inflammatory sites and promote the resolution of inflammation [ 73 ]. At the initial stage of the inflammation, GC can inhibit downsteam signaling of pattern recognition receptors. For example, GC can upregulate dual­specificity protein phosphatase 1 (DUSP1) to inhibit mitogen­activated protein kinase 1 (MAPK1) and IL­1 receptor­associated kinase 3 (IRAK3) signaling downstream of TLR and IL-1 receptor signaling [ 74 ]. GC inhibit eicosanoid production by macrophages to reduce vascular permeability [ 75 ]. Ligated GR can bind to mRNA of CCL2 and CCL7 to promote their degradation [ 76 ]. GC promote phagocytosis of macrophages and monocytes for apoptotic cells and debris to accelerate the resolution of inflammation [ 77 ]. For adaptive immunity, GC influence T cell activation by inhibiting DC maturation and upregulating IL-10 expression [ 78 ]. GC directly inhibit TCR signaling by disturbing the activity of AP­1, NF­ κ B, and NFAT [ 79 ]. But GC increase peripheral Treg cell frequency by targeting glucocorticoid-induced leucine zipper (GILZ) [ 80 , 81 ].
    CS are important immunosuppressive drugs for organ transplant medication at early times, which are now often used in early induction therapy stages. Prednisone and methyl-prednisolone were CS commonly used in clinics, and they were also the earliest drug used to inhibit transplant rejection. CS can directly target monocytes/macrophages to inhibit IL-12 production, which subsequently redirects T cell polarization from Th1 to Th2 cells [ 82 , 83 ]. CS also strongly inhibit the production of IL-12p70, TNF- α , and IL-6 by LPS-stimulated monocyte-derived immature DCs (iDCs) in vitro [ 84 ]. GC did not cause a global effector function suppression of monocyte but result in differentiation of monocytes with a specific anti-inflammatory phenotype [ 77 ]. Dexamethasone- (Dex-) treated monocytes can upregulate CD163 and Gr-1 with a phenotype like M-MDSCs [ 85 ]. Dex profoundly modulates CD40-dependent DC activation by downregulating costimulatory, adhesion, and MHC class I and II molecules and without expressing the maturation marker CD83. Dex also suppressed the production of the proinflammatory cytokine IL-12 and potentiated the secretion of the anti-inflammatory cytokine IL-10 without affecting antigen uptake [ 86 ]. Dex inhibits the development and maturation of BMDCs from human monocytes treated with GM-CSF and IL-4 for 7 days [ 87 ]. In a mouse immunological hepatic injury model by LPS shock, MDSCs display significantly lower levels of GR. Dex treatment can restore GR expression in MDSCs and enhance the suppressive function by suppressing HIF1 α and glycolysis [ 88 ]. In a mouse skin transplant model, Dex can relieve graft rejection. By upregulating the expression of CXCL1 and CXCL2 chemokines in the graft, more CD11b + Gr-1 + MDSCs were recruited into skin grafts. Removal of these cells with anti-Gr-1 depletion antibodies or glucocorticoid receptor antagonist treatment reversed the mitigation effect of Dex on skin graft rejection, indicating that binding of Dex directly to glucocorticoid receptor mediated the accumulation and inhibitory function of MDSCs to promote graft survival. Dex-treated MDSCs promote Th2 cell differentiation to alleviate graft rejection through iNOS [ 89 ]. MDSCs from Dex-treated mice transferred to unmanipulated recipients can prolong alloskin graft survival, but MDSCs from untreated alloskin-grafted mice cannot. Thus, Dex can initiate the accumulation of MDSCs in spleens of alloskin-grafted mice and endow these cells with the immunosuppressive function. In another study, it was found that Dex treatment on GM-CSF-induced MDSCs in vitro increase the number of CD11b + Gr-1 int/low MDSCs with an enhanced immunosuppressive function. Adoptive transfer of these MDSCs significantly prolonged heart allograft survival and also favored the expansion of Treg cells in vivo. Mechanistic studies showed that iNOS signaling was required for suppressive function of MDSCs. GR signaling played a critical role in the recruitment of transferred MDSCs into allografts through upregulating CXCR2 expression on MDSCs [ 90 ]. In PBMCs of intestinal transplant recipients, MDSC numbers were positively correlated with serum IL-6 levels and the glucocorticoid administration index. IL-6 and methylprednisolone treatment enhanced the differentiation of bone marrow cells to MDSCs in vitro [ 28 ]. Therefore, CS exert positive modulatory effects on MDSCs in transplanted recipients (Figure 2 ). Figure 2: The modulatory effects of corticosteroids and calcineurin inhibitors on MDSCs. The effects of corticosteroids and calcineurin inhibitors on MDSCs were illustrated here. Targeting GR and calcineurin by corticosteroids and CsA, respectively, altered MDSC differentiation, suppressive function, and recruitment. MP, methylprednisolone; Dex, dexamethasone; GR, glucocorticoid receptors; HIF1 α , hypoxia-inducible factor 1 α ; iNOS, inducible nitric oxide synthase; IDO, indoleamine 2,3-dioxygenase; CsA, cyclosporin A. 4.2. Calcineurin Inhibitors (CNIs)
    CNIs include a class of drugs targeting at calcineurin, and the most commonly used ones are cyclosporin A (CsA) and tacrolimus (FK506). CNIs become the mainstream medication for organ transplantation since the introduction of CsA to this field [ 91 ]. CsA and FK506 bind to different immunophilins as cyclophilins and FK-binding proteins, respectively. Then the complex binds to an intracellular molecule calcineurin, which is a protein phosphatase for cytoplasmic NFAT dephosphorylation and its subsequent translocation to nucleus to perform function. NFAT is a key transcription factor by upregulating many cytokines and costimulatory molecules, like IL-2, IL-4, TNF- α , and CD40 ligand, for full activation of T cells [ 92 ]. However, CNIs also have a negative effect on the proliferation and function of Treg cells due to impaired function of NFAT [ 93 , 94 ].CNIs also regulate innate immune cells. CsA inhibits the activation of neutrophils stimulated by angiotensin II through the MAPK and ERK pathways [ 95 ]. Calcineurin inhibition by FK506 leads to decreased responsiveness to LPS in macrophages and dendritic cells [ 96 ]. CNIs inhibit expression of iNOS in macrophage cell lines [ 97 ]. CNIs also have effect on parenchymal cells, and it is well known that CNIs have toxicity to endothelial cells [ 98 ].
    Because targets of CNIs are NFAT and MAPK pathways, which are widely used signaling by myeloid cells, it is not surprising that CNIs affect myeloid cell functions including MDSCs. Tacrolimus impairs clearance of fungal pathogen Aspergillus fumigatus from the airway by targeting TLR9-BTK-calcineurin-NFAT pathway in macrophage [ 99 ]. Treatment of bone marrow-derived macrophages (BMDMs) with tacrolimus significantly inhibited LPS and LPS plus IFN- γ -induced IL-12p40 mRNA and protein expression [ 100 ]. After coculture with increasing concentrations of CsA for 24 h, the number of live splenic MDSCs decreased significantly in a dose-dependent manner by calcineurin inhibition [ 101 ]. In the mouse skin transplant model, a daily dose of 15–30 mg/kg of CsA can promote the accumulation of CD11b + Gr-1 + MDSCs in the graft, draining lymph nodes, spleen, peripheral blood, and bone marrow with the prolonged survival time of grafts [ 102 ]. The expression of CXCR2 was upregulated on splenic MDSCs [ 102 ]. Blocking this receptor or removal of these cells by anti-Gr-1 depletion antibody reverses the mitigation effect of CsA on transplant rejection [ 102 ]. Adoptive transfer of MDSCs from spleens of CsA-treated skin-grafted mice to newly transplanted mice promotes graft survival [ 102 ]. CsA promotes the immunosuppressive function by downregulating NFATc1 in MDSCs, thereby promoting the differentiation of Th cells into Th2 cells. MDSC depletion reverses the tendency of T cell polarization [ 102 ]. Finally, the authors demonstrated that CsA regulated MDSC function via calcineurin-NFAT-IDO axis [ 102 ]. In our group, the effects of CsA on MDSC differentiation and development were explored in vitro and in vivo [ 103 ]. CsA treatment significantly increases the number, phenotype, and function of GM-CSF-induced MDSCs by in vitro assays. Similar results were obtained in alloskin-grafted mice with CsA administration. The enhanced immunosuppressive function of MDSCs is related to the upregulation of iNOS and CD274 [ 103 ]. Thus, CNIs may regulate MDSC differentiation and immunosuppressive function by NFAT (Figure 2 ). 4.3. mTOR Inhibitors (mTORi)
    mTORi is targeting at the protein named mTOR (mechanistic target of rapamycin). mTOR is a serine, threonine protein kinase, which is the main component of two complexes that mediate different signal transduction named mTORC1 and mTORC2. Rapamycin can bind to FK506-binding protein 12 (FKBP12) to form an immunosuppressive complex to inhibit mTOR. mTORC1 plays a central role in regulating cell processes for anabolism in response to environmental conditions. mTORC1 promotes protein synthesis largely through the phosphorylation of p70S6 kinase 1 (S6K1) and eIF4E-binding protein (4EBP). mTORC1 promotes lipid and nucleotide synthesis by different mechanism. mTORC1 provides substrates for anabolism by promoting glycolysis. mTORC2 controls cell proliferation and survival by downstream effector molecules like protein kinase PKA/PKG/PKC to regulate cytoskeletal remodeling. Akt can be phosphorylated and activated by mTORC2 to promote cell survival and proliferation through FoxO1/3a, GSK3 β , and TSC2 downstream of Akt. mTORC2 also phosphorylates and activates SGK1 to control ion transport and cell survival. The role of mTOR in innate and adaptive immunity has been well reviewed [ 104 – 106 ], so we will not discuss it excessively here.
    The mTOR signaling significantly affects the development of myeloid cells. It masters monocyte/macrophage development at the early stages through regulating STAT5-IRF8-dependent CD115 expressing pathway [ 107 , 108 ]. Inhibition of mTOR by rapamycin promotes inflammatory cytokine production through NF- κ B but blocks IL-10 via STAT3 on human monocyte [ 109 ]. mTOR inhibition by rapamycin interferes GC signaling and prevents the anti-inflammatory potency of GC in human monocytes [ 110 ]. We found that rapamycin treatment reduced cell number of M-MDSCs in a skin transplantation model [ 29 ]. The suppressive function of M-MDSCs from spleens of recipients in vitro was also impaired by rapamycin treatment [ 29 ]. Using myeloid-specific mTOR-deficient mice, we obtained similar results with rapamycin treatment [ 29 ]. Rapamycin treatment also undermines the differentiation, proliferation, and function of GM-CSF-induced MDSCs in vitro [ 29 ]. Finally, it was demonstrated that inhibition of glycolysis and subsequent downregulation of iNOS were the main mechanisms of rapamycin affecting MDSCs [ 29 ]. In murine immunological hepatic injury model by injection of ConA, inhibition of mTOR by rapamycin enhanced suppressive function of liver MDSCs and promoted MDSC recruitment to inflammatory site via iNOS [ 111 ]. Mechanism studies show that MDSCs suppress T cell activation and modulate T cell differentiation by targeting the HIF1 α -dependent glycolytic pathway [ 112 ]. It is also reported that SIRT1 can regulate MDSC differentiation to M2 phenotype by blocking HIF1 α -dependent glycolysis and rapamycin recovers MDSC suppressive function by blocking glycolytic activity in SIRT1 KO cells [ 113 ]. In the acute kidney injury mouse model, inhibition of mTOR signaling by rapamycin promotes MDSC recruitment and enhances PMN-MDSC development and suppressive function of MDSCs to ameliorate acute kidney injury [ 114 ]. In another study, rapamycin treatment in the mouse heart transplant model increased the number and function of MDSCs, and depletion of these cells by anti-Gr-1 antibody reversed the mitigation effect of rapamycin. M-MDSCs and PMN-MDSCs were isolated from the spleen of transplant recipients. Both subsets of MDSCs treated with rapamycin had the ability to inhibit T cell proliferation, and the immunosuppression was mediated by upregulation of iNOS and Arg1, respectively [ 30 ]. In untreated group, MDSCs have no suppressive function. PMN-MDSCs or M-MDSCs from rapamycin-treated mice were administered to newly heart-transplanted recipient via the inferior vena cava or the aorta of the transplanted heart, and both of them prolong graft survival and the effect of M-MDSCs was more pronounced. But MDSCs from PBS-treated mice have no effect [ 30 ]. Current reports on the roles of mTORi on MDSCs are not consistent. The reason for this inconsistency is whether caused by different transplant models or different treatment protocols which need further elucidation (Figure 3 ). Figure 3: The different modulatory effects of mTOR inhibitors on MDSCs. The regulatory effects of mTOR inhibition on MDSCs were controversial so far. The positive and negative effects of rapamycin on MDSCs were both illustrated here. This inconsistency may be due to different animal models or different doses and modes of rapamycin administration. Rapa, rapamycin; Arg1, arginase 1; iNOS, inducible nitric oxide synthase; HK, hexokinase; PFK, phosphofructokinase; PKM, pyruvate kinase muscle isozyme; LDHA, lactate dehydrogenase- α . 4.4. Purine Analogues
    Purine analogues are compounds structurally similar to DNA and RNA synthetic substrates that can interfere with the synthesis of DNA, RNA, and other nucleic acids to inhibit cell proliferation and immune responses. Azathioprine (AZA) and 6-mercaptopurine (6-MP) are widely used immunosuppressive agents to prevent transplant rejection. Actually from the early 60s to the early 80s, AZA and steroids are the main medication for transplant rejection [ 115 ]. Mycophenolate mofetil (MMF) is another drug acting on purine synthesis pathway with mycophenolic acid as its active metabolite of MMF. Through inhibiting inosine monophosphate dehydrogenase (IMPDH), which mediated the only pathway for lymphocyte guanosine nucleotide synthesis, MMF can suppress lymphocyte proliferation specially. So MMF has substituted AZA for transplant medication in recent years [ 116 ].
    There are no reports on the role of antiproliferative drugs on MDSCs so far. But this drug might potentially inhibit the development of MDSCs, because MPA has been reported to suppress granulopoiesis [ 117 ]. In kidney transplant recipients with long-term stable graft function, MMF treatment reduces the production of IL-1 β , IL-10, and TNF- α by monocytes [ 118 ]. MMF also inhibits upregulation of ICAM-1 and MHC-II expression on human monocytes by LPS or IFN- γ stimulation and the adhesion of monocyte to endothelial cells [ 119 ]. Human monocyte-derived DCs can be induced by GM-CSF + IL-4 treatment in vitro. MMF can impair their differentiation, maturation, and allostimulatory function [ 120 ]. MPA inhibits IL-1 β production by human CD14 + monocytes stimulated by PMA/ionomycin [ 121 ]. The effects of MMF on MDSCs should be addressed in the near future. 4.5. Costimulatory Blockade
    Costimulatory blockade is a common method to induce tolerance in animal models of transplantation. Belatacept is the first and only currently used immunosuppressive drug for treatment of rejection in renal transplantation as a costimulatory blocker. CD28-mediated costimulatory signals are essential for the survival, proliferation, and cytokine production of T cells. B7-1 (CD80) and B7-2 (CD86) expressed on the surface of APCs are the main ligands of CD28. CTLA-4 is a negative regulatory molecule sharing the same ligands with CD28 on T cell surface. CTLA-4 expression is lagging behind CD28 but with more affinity than CD28 to B7. CTLA-4 has a stronger affinity for B7-1 which is also expressed at a later phase of T cell activation on APCs [ 122 ]. CTLA-4 and IgG Fc fragment were fused into CTLA-4Ig, which can block CD28 signaling with higher affinity for B7-1/2. Two amino acids were mutated in CTLA-4Ig for enhancing the binding ability to B7-2 which resulted in the generation of belatacept [ 123 ]. The 7-year-phase-III clinical trial found that the use of belatacept-based renal transplantation therapy was associated with lower nephrotoxicity compared to CNI-based group, and the proportion of patients who produced anti-HLA antibodies after transplantation was lower than CNI treatment group [ 124 ]. Recently, ASP2409, a next-generation of CTLA4-Ig with 14-fold higher binding affinity with CD86 than belatacept in vitro had exhibited potent suppressive effects on the monkey renal transplantation model without serious side effects [ 125 ]. FR104, an antagonist anti-CD28 monovalent Fab antibody, was proved to show preclinical efficacy and immunological safety in 2012 [ 126 ]. FR104 prevented acute rejection and alloantibody development with low doses of tacrolimus in the nonhuman primate renal transplantation in 2015 [ 127 ]. FR104 and belatacept exert different effects on mechanisms of renal allograft rejection in baboons [ 128 ]. Study in healthy human subjects with FR104 reported in 2016 and results showed that FR104 has potential to use in clinics for transplantation [ 129 ]. In mouse and nonhuman primate transplant models, blocking CD40/CD40L pathway is more effective for allograft survival and tolerance induction comparing to CD28 blockade [ 130 ]. Unfortunately, anti-CD40L in clinical trials showed a number of thromboembolic complications. Recently, it is reported that a novel anti-CD154 mAb that lacks Fc-binding activity was safe without evidence of thromboembolism. It is equally as potent as previous anti-CD154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model [ 131 ]. Thus, it is promising that the costimulatory blockades will be widely used in clinics to avoid graft rejection and even immune tolerance induction in transplanted patients.
    Costimulatory blockade can effectively inhibit T cell activation by blocking the secondary signals, which can promote T cell deletion and anergy and have the ability to induce Treg cells. Both anti-CD28 and anti-CD154 treatments can significantly increase the number and function of MDSCs, suggesting that costimulatory blockade has a positive regulatory effect on MDSCs [ 25 , 31 ]. Abatacept (CTLA-4Ig), the basis for the second-generation belatacept, was commonly used for treatment of patients with rheumatoid arthritis (RA) [ 132 ]. Previous studies showed that CTLA4-Ig downregulates the production of proinflammatory cytokines in synovial macrophages from RA patients or monocyte-derived macrophages from healthy donor cocultured with activated T cells [ 133 , 134 ]. It also increases the absolute numbers of monocytes in RA patients after treatment. Monocytes from these patients showed reduced expression of adhesion molecules and displayed reduction in endothelial adhesion and transendothelial migration. Monocytes from healthy donors pretreated with CTLA-4Ig showed similar results [ 135 ]. We have no knowledge about belatacept or CTLA-4Ig on MDSCs so far, which requires to be studied. 5. Conclusion
    MDSCs can be induced in different transplant animal models and clinical transplant cases. More importantly, the prolonged graft survival or transplant tolerance by immune modulation in some cases is all or partially dependent on MDSCs. This suggests that MDSCs play an important role in the maintenance of immune suppression and tolerance in certain situations, and targeting MDSCs may promote transplant tolerance induction. Some immunosuppressive agents enhance the function of MDSCs in transplantation significantly, but some will impair MDSC number and function. Considering the critical roles of MDSCs in transplant immune tolerance, we should put caution to the negative effects of certain immunosuppressive drugs on MDSCs, which may potentially block the tolerance induction in transplanted recipients. Understanding the impacts of immunosuppressive drugs on MDSCs may provide scientific guidance on the clinical optimal application of immunosuppressive agents. Conflicts of Interest
    The authors herein declare that all authors have no competing financial interests. Authors’ Contributions
    Fan Yang and Yang Li contributed equally to this work. Acknowledgments
    The authors appreciated Drs. Yuzhu Hou and Peng Wang for their critical reviewing of their manuscript and Mrs. Ling Li for her excellent laboratory management. This work was supported by grants from the National Key Research and Development Program of China (2017YFA0105002 and 2017YFA0104402, Yong Zhao), the National Natural Science Foundation for General and Key Programs (81130055 and 31470860, Yong Zhao), the Knowledge Innovation Program of Chinese Academy of Sciences (XDA04020202-19, Yong Zhao), and The China Manned Space Flight Technology Project (TZ-1). References T. van Gelder, R. H. van Schaik, and D. A. Hesselink, “Pharmacogenetics and immunosuppressive drugs in solid organ transplantation,” Nature Reviews Nephrology , vol. 10, no. 12, pp. 725–731, 2014. View at Publisher · View at Google Scholar · View at Scopus A. D. Fesnak, C. H. June, and B. L. Levine, “Engineered T cells: the promise and challenges of cancer immunotherapy,” Nature Reviews Cancer , vol. 16, no. 9, pp. 566–581, 2016. View at Publisher · View at Google Scholar · View at Scopus J. R. Scalea, Y. S. Lee, E. Davila, and J. S. Bromberg, “Myeloid-derived suppressor cells and their potential application in transplantation,” Transplantation , vol. 102, no. 3, pp. 359–367, 2018. View at Publisher · View at Google Scholar · View at Scopus J. E. Talmadge and D. I. Gabrilovich, “History of myeloid-derived suppressor cells,” Nature Reviews Cancer , vol. 13, no. 10, pp. 739–752, 2013. View at Publisher · View at Google Scholar · View at Scopus D. I. Gabrilovich and S. Nagaraj, “Myeloid-derived suppressor cells as regulators of the immune system,” Nature Reviews Immunology , vol. 9, no. 3, pp. 162–174, 2009. View at Publisher · View at Google Scholar · View at Scopus V. Kumar, S. Patel, E. Tcyganov, and D. I. Gabrilovich, “The nature of myeloid-derived suppressor cells in the tumor microenvironment,” Trends in Immunology , vol. 37, no. 3, pp. 208–220, 2016. View at Publisher · View at Google Scholar · View at Scopus V. Bronte, S. Brandau, S. H. Chen et al., “Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards,” Nature Communications , vol. 7, article 12150, 2016. View at Publisher · View at Google Scholar · View at Scopus E. Peranzoni, S. Zilio, I. Marigo et al., “Myeloid-derived suppressor cell heterogeneity and subset definition,” Current Opinion in Immunology , vol. 22, no. 2, pp. 238–244, 2010. View at Publisher · View at Google Scholar · View at Scopus V. Bronte and P. Zanovello, “Regulation of immune responses by L-arginine metabolism,” Nature Reviews Immunology , vol. 5, no. 8, pp. 641–654, 2005. View at Publisher · View at Google Scholar · View at Scopus C. A. Corzo, M. J. Cotter, P. Cheng et al., “Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells,” The Journal of Immunology , vol. 182, no. 9, pp. 5693–5701, 2009. View at Publisher · View at Google Scholar · View at Scopus D. H. Munn, E. Shafizadeh, J. T. Attwood, I. Bondarev, A. Pashine, and A. L. Mellor, “Inhibition of T cell proliferation by macrophage tryptophan catabolism,” The Journal of Experimental Medicine , vol. 189, no. 9, pp. 1363–1372, 1999. View at Publisher · View at Google Scholar · View at Scopus G. Mondanelli, R. Bianchi, M. T. Pallotta et al., “A relay pathway between arginine and tryptophan metabolism confers immunosuppressive properties on dendritic cells,” Immunity , vol. 46, no. 2, pp. 233–244, 2017. View at Publisher · View at Google Scholar · View at Scopus J. Yu, W. du, F. Yan et al., “Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer,” The Journal of Immunology , vol. 190, no. 7, pp. 3783–3797, 2013. View at Publisher · View at Google Scholar · View at Scopus V. De Wilde, N. Van Rompaey, M. Hill et al., “Endotoxin-induced myeloid-derived suppressor cells inhibit alloimmune responses via heme oxygenase-1,” American Journal of Transplantation , vol. 9, no. 9, pp. 2034–2047, 2009. View at Publisher · View at Google Scholar · View at Scopus E. M. Hanson, V. K. Clements, P. Sinha, D. Ilkovitch, and S. Ostrand-Rosenberg, “Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4 + and CD8 + T cells,” The Journal of Immunology , vol. 183, no. 2, pp. 937–944, 2009. View at Publisher · View at Google Scholar · View at Scopus K. Sakuishi, P. Jayaraman, S. M. Behar, A. C. Anderson, and V. K. Kuchroo, “Emerging Tim-3 functions in antimicrobial and tumor immunity,” Trends in Immunology , vol. 32, no. 8, pp. 345–349, 2011. View at Publisher · View at Google Scholar · View at Scopus T. Condamine, I. Ramachandran, J.-I. Youn, and D. I. Gabrilovich, “Regulation of tumor metastasis by myeloid-derived suppressor cells,” Annual Review of Medicine , vol. 66, no. 1, pp. 97–110, 2015. View at Publisher · View at Google Scholar · View at Scopus F. Veglia, M. Perego, and D. Gabrilovich, “Myeloid-derived suppressor cells coming of age,” Nature Immunology , vol. 19, no. 2, pp. 108–119, 2018. View at Publisher · View at Google Scholar · View at Scopus W.-C. Wu, H. W. Sun, H. T. Chen et al., “Circulating hematopoietic stem and progenitor cells are myeloid-biased in cancer patients,” Proceedings of the National Academy of Sciences of the United States of America , vol. 111, no. 11, pp. 4221–4226, 2014. View at Publisher · View at Google Scholar · View at Scopus A. Yáñez, S. G. Coetzee, A. Olsson et al., “Granulocyte-monocyte progenitors and monocyte-dendritic cell progenitors independently produce functionally distinct monocytes,” Immunity , vol. 47, no. 5, pp. 890–902.e4, 2017. View at Publisher · View at Google Scholar · View at Scopus J.-I. Youn, V. Kumar, M. Collazo et al., “Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer,” Nature Immunology , vol. 14, no. 3, pp. 211–220, 2013. View at Publisher · View at Google Scholar A. J. Casbon, D. Reynaud, C. Park et al., “Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils,” Proceedings of the National Academy of Sciences of the United States of America , vol. 112, no. 6, pp. E566–E575, 2015. View at Publisher · View at Google Scholar · View at Scopus T. Condamine, J. Mastio, and D. I. Gabrilovich, “Transcriptional regulation of myeloid-derived suppressor cells,” Journal of Leukocyte Biology , vol. 98, no. 6, pp. 913–922, 2015. View at Publisher · View at Google Scholar · View at Scopus D. I. Gabrilovich, “Myeloid-derived suppressor cells,” Cancer Immunology Research , vol. 5, no. 1, pp. 3–8, 2017. View at Publisher · View at Google Scholar · View at Scopus M. R. Garcia, L. Ledgerwood, Y. Yang et al., “Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice,” The Journal of Clinical Investigation , vol. 120, no. 7, pp. 2486–2496, 2010. View at Publisher · View at Google Scholar · View at Scopus Y. Luan, E. Mosheir, M. C. Menon et al., “Monocytic myeloid-derived suppressor cells accumulate in renal transplant patients and mediate CD4(+) Foxp3(+) Treg expansion,” American Journal of Transplantation , vol. 13, no. 12, pp. 3123–3131, 2013. View at Publisher · View at Google Scholar · View at Scopus F. Meng, S. Y. Chen, X. Guo et al., “Clinical significance of myeloid-derived suppressor cells in human renal transplantation with acute T cell-mediated rejection,” Inflammation , vol. 37, no. 5, pp. 1799–1805, 2014. View at Publisher · View at Google Scholar · View at Scopus S. Okano, K. Abu-Elmagd, D. D. Kish et al., “Myeloid-derived suppressor cells increase and inhibit donor-reactive T cell responses to graft intestinal epithelium in intestinal transplant patients,” American Journal of Transplantation , 2018. View at Publisher · View at Google Scholar T. Wu, Y. Zhao, H. Wang et al., “mTOR masters monocytic myeloid-derived suppressor cells in mice with allografts or tumors,” Scientific Reports , vol. 6, no. 1, article 20250, 2016. View at Publisher · View at Google Scholar · View at Scopus T. Nakamura, T. Nakao, N. Yoshimura, and E. Ashihara, “Rapamycin prolongs cardiac allograft survival in a mouse model by inducing myeloid-derived suppressor cells,” American Journal of Transplantation , vol. 15, no. 9, pp. 2364–2377, 2015. View at Publisher · View at Google Scholar · View at Scopus A. S. Dugast, T. Haudebourg, F. Coulon et al., “Myeloid-derived suppressor cells accumulate in kidney allograft tolerance and specifically suppress effector T cell expansion,” The Journal of Immunology , vol. 180, no. 12, pp. 7898–7906, 2008. View at Publisher · View at Google Scholar · View at Scopus N. Dilek, N. Poirier, C. Usal, B. Martinet, G. Blancho, and B. Vanhove, “Control of transplant tolerance and intragraft regulatory T cell localization by myeloid-derived suppressor cells and CCL5,” The Journal of Immunology , vol. 188, no. 9, pp. 4209–4216, 2012. View at Publisher · View at Google Scholar · View at Scopus W. Zhang, S. Liang, J. Wu, and A. Horuzsko, “Human inhibitory receptor immunoglobulin-like transcript 2 amplifies CD11b+Gr1+ myeloid-derived suppressor cells that promote long-term survival of allografts,” Transplantation , vol. 86, no. 8, pp. 1125–1134, 2008. View at Publisher · View at Google Scholar · View at Scopus T. Wu, C. Sun, Z. Chen et al., “Smad3-deficient CD11b + Gr1 + myeloid-derived suppressor cells prevent allograft rejection via the nitric oxide pathway,” The Journal of Immunology , vol. 189, no. 10, pp. 4989–5000, 2012. View at Publisher · View at Google Scholar · View at Scopus Y. He, B. Wang, B. Jia, J. Guan, H. Zeng, and Z. Pan, “Effects of adoptive transferring different sources of myeloid-derived suppressor cells in mice corneal transplant survival,” Transplantation , vol. 99, no. 10, pp. 2102–2108, 2015. View at Publisher · View at Google Scholar · View at Scopus S. M. Brunner, G. Schiechl, W. Falk, H. J. Schlitt, E. K. Geissler, and S. Fichtner-Feigl, “Interleukin-33 prolongs allograft survival during chronic cardiac rejection,” Transplant International , vol. 24, no. 10, pp. 1027–1039, 2011. View at Publisher · View at Google Scholar · View at Scopus F. Ge, S. Yuan, L. Su et al., “Alteration of innate immunity by donor IL-6 deficiency in a presensitized heart transplant model,” PLoS One , vol. 8, no. 10, article e77559, 2013. View at Publisher · View at Google Scholar · View at Scopus W. Gong, D. Shou, F. Cheng, J. Shi, F. Ge, and D. Liu, “Tolerance induced by IL-6 deficient donor heart is significantly involved in myeloid-derived suppressor cells (MDSCs),” Transplant Immunology , vol. 32, no. 2, pp. 72–75, 2015. View at Publisher · View at Google Scholar · View at Scopus D. Adeegbe, P. Serafini, V. Bronte, A. Zoso, C. Ricordi, and L. Inverardi, “In vivo induction of myeloid suppressor cells and CD4 + Foxp3 + T regulatory cells prolongs skin allograft survival in mice,” Cell Transplantation , vol. 20, no. 6, pp. 941–954, 2011. View at Publisher · View at Google Scholar · View at Scopus C.-H. Chen, L. M. Kuo, Y. Chang et al., “ In vivo immune modulatory activity of hepatic stellate cells in mice,” Hepatology , vol. 44, no. 5, pp. 1171–1181, 2006. View at Publisher · View at Google Scholar · View at Scopus S. Ryzhov, S. V. Novitskiy, A. E. Goldstein et al., “Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b + Gr1 + cells,” The Journal of Immunology , vol. 187, no. 11, pp. 6120–6129, 2011. View at Publisher · View at Google Scholar · View at Scopus P. Conde, M. Rodriguez, W. van der Touw et al., “DC-SIGN + macrophages control the induction of transplantation tolerance,” Immunity , vol. 42, no. 6, pp. 1143–1158, 2015. View at Publisher · View at Google Scholar · View at Scopus M. L. Miller, M. D. Daniels, T. Wang et al., “Spontaneous restoration of transplantation tolerance after acute rejection,” Nature Communications , vol. 6, no. 1, p. 7566, 2015. View at Publisher · View at Google Scholar · View at Scopus G. Chen, T. Kheradmand, J. Bryant et al., “Intragraft CD11b + IDO + cells mediate cardiac allograft tolerance by ECDI-fixed donor splenocyte infusions,” American Journal of Transplantation , vol. 12, no. 11, pp. 2920–2929, 2012. View at Publisher · View at Google Scholar · View at Scopus J. Bryant, N. M. Lerret, J. J. Wang et al., “Preemptive donor apoptotic cell infusions induce IFN- γ –producing myeloid-derived suppressor cells for cardiac allograft protection,” The Journal of Immunology , vol. 192, no. 12, pp. 6092–6101, 2014. View at Publisher · View at Google Scholar · View at Scopus D. Mougiakakos, R. Jitschin, L. von Bahr et al., “Immunosuppressive CD14+HLA-DRlow/neg IDO+ myeloid cells in patients following allogeneic hematopoietic stem cell transplantation,” Leukemia , vol. 27, no. 2, pp. 377–388, 2013. View at Publisher · View at Google Scholar · View at Scopus B. An, J. Y. Lim, S. Jeong et al., “CD1d is a novel cell-surface marker for human monocytic myeloid-derived suppressor cells with T cell suppression activity in peripheral blood after allogeneic hematopoietic stem cell transplantation,” Biochemical and Biophysical Research Communications , vol. 495, no. 1, pp. 519–525, 2018. View at Publisher · View at Google Scholar · View at Scopus Q. Guan, A. R. Blankstein, K. Anjos et al., “Functional myeloid-derived suppressor cell subsets recover rapidly after allogeneic hematopoietic stem/progenitor cell transplantation,” Biology of Blood and Marrow Transplantation , vol. 21, no. 7, pp. 1205–1214, 2015. View at Publisher · View at Google Scholar · View at Scopus M. Lv, X. S. Zhao, Y. Hu et al., “Monocytic and promyelocytic myeloid-derived suppressor cells may contribute to G-CSF-induced immune tolerance in haplo-identical allogeneic hematopoietic stem cell transplantation,” American Journal of Hematology , vol. 90, no. 1, pp. E9–E16, 2015. View at Publisher · View at Google Scholar · View at Scopus A. D. Billiau, S. Fevery, O. Rutgeerts, W. Landuyt, and M. Waer, “Transient expansion of Mac1 + Ly6-G + Ly6-C + early myeloid cells with suppressor activity in spleens of murine radiation marrow chimeras: possible implications for the graft-versus-host and graft-versus-leukemia reactivity of donor lymphocyte infusions,” Blood , vol. 102, no. 2, pp. 740–748, 2003. View at Publisher · View at Google Scholar · View at Scopus S. Morecki, Y. Gelfand, E. Yacovlev, O. Eizik, Y. Shabat, and S. Slavin, “CpG-induced myeloid CD11b + Gr-1 + cells efficiently suppress T cell-mediated immunoreactivity and graft-versus-host disease in a murine model of allogeneic cell therapy,” Biology of Blood and Marrow Transplantation , vol. 14, no. 9, pp. 973–984, 2008. View at Publisher · View at Google Scholar · View at Scopus Y. D. Joo, S. M. Lee, S. W. Lee et al., “Granulocyte colony-stimulating factor-induced immature myeloid cells inhibit acute graft-versus-host disease lethality through an indoleamine dioxygenase-independent mechanism,” Immunology , vol. 128, 1Part2, pp. e632–e640, 2009. View at Publisher · View at Google Scholar · View at Scopus S. M. Perobelli, A. C. T. Mercadante, R. G. Galvani et al., “G-CSF–induced suppressor IL-10 + neutrophils promote regulatory T cells that inhibit graft-versus-host disease in a long-lasting and specific way,” The Journal of immunology , vol. 197, no. 9, pp. 3725–3734, 2016. View at Publisher · View at Google Scholar · View at Scopus T. Ghansah, K. H. T. Paraiso, S. Highfill et al., “Expansion of myeloid suppressor cells in SHIP-deficient mice represses allogeneic T cell responses,” The Journal of Immunology , vol. 173, no. 12, pp. 7324–7330, 2004. View at Publisher · View at Google Scholar · View at Scopus Y.-K. Lee, J.-M. Ju, M.-S. Kang et al., “Impairment of myeloid-derived suppressor cell expansion and enhancement of dendritic cell differentiation of MyD88-deficient bone marrow cells in graft-versus-host disease,” The Journal of Immunology , vol. 198, 1 Supplement, p. 140.2, 2017. View at Google Scholar S. L. Highfill, P. C. Rodriguez, Q. Zhou et al., “Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1–dependent mechanism that is up-regulated by interleukin-13,” Blood , vol. 116, no. 25, pp. 5738–5747, 2010. View at Publisher · View at Google Scholar · View at Scopus J. J. Messmann, T. Reisser, F. Leithauser, M. B. Lutz, K. M. Debatin, and G. Strauss, “In vitro-generated MDSCs prevent murine GVHD by inducing type 2 T cells without disabling antitumor cytotoxicity,” Blood , vol. 126, no. 9, pp. 1138–1148, 2015. View at Publisher · View at Google Scholar · View at Scopus B. H. Koehn, P. Apostolova, J. M. Haverkamp et al., “GVHD-associated, inflammasome-mediated loss of function in adoptively transferred myeloid-derived suppressor cells,” Blood , vol. 126, no. 13, pp. 1621–1628, 2015. View at Publisher · View at Google Scholar · View at Scopus B. Sprangers, B. van Wijmeersch, A. Luyckx et al., “Subclinical GvHD in non-irradiated F1 hybrids: severe lymphoid-tissue GvHD causing prolonged immune dysfunction,” Bone Marrow Transplantation , vol. 46, no. 4, pp. 586–596, 2011. View at Publisher · View at Google Scholar · View at Scopus A. Luyckx, E. Schouppe, O. Rutgeerts et al., “Subset characterization of myeloid-derived suppressor cells arising during induction of BM chimerism in mice,” Bone Marrow Transplantation , vol. 47, no. 7, pp. 985–992, 2012. View at Publisher · View at Google Scholar · View at Scopus V. Greifenberg, E. Ribechini, S. Rößner, and M. B. Lutz, “Myeloid-derived suppressor cell activation by combined LPS and IFN- γ treatment impairs DC development,” European Journal of Immunology , vol. 39, no. 10, pp. 2865–2876, 2009. View at Publisher · View at Google Scholar · View at Scopus I. Marigo, E. Bosio, S. Solito et al., “Tumor-induced tolerance and immune suppression depend on the C/EBP β transcription factor,” Immunity , vol. 32, no. 6, pp. 790–802, 2010. View at Publisher · View at Google Scholar · View at Scopus M. G. Lechner, D. J. Liebertz, and A. L. Epstein, “Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells,” The Journal of Immunology , vol. 185, no. 4, pp. 2273–2284, 2010. View at Publisher · View at Google Scholar · View at Scopus L. Drujont, L. Carretero-Iglesia, L. Bouchet-Delbos et al., “Evaluation of the therapeutic potential of bone marrow-derived myeloid suppressor cell (MDSC) adoptive transfer in mouse models of autoimmunity and allograft rejection,” PLoS One , vol. 9, no. 6, article e100013, 2014. View at Publisher · View at Google Scholar · View at Scopus N. Obermajer, R. Muthuswamy, J. Lesnock, R. P. Edwards, and P. Kalinski, “Positive feedback between PGE 2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells,” Blood , vol. 118, no. 20, pp. 5498–5505, 2011. View at Publisher · View at Google Scholar · View at Scopus F. Yang, Y. Li, T. Wu et al., “TNF α -induced M-MDSCs promote transplant immune tolerance via nitric oxide,” Journal of Molecular Medicine , vol. 94, no. 8, pp. 911–920, 2016. View at Publisher · View at Google Scholar · View at Scopus Y. Arakawa, J. Qin, H. S. Chou et al., “Cotransplantation with myeloid-derived suppressor cells protects cell transplants: a crucial role of inducible nitric oxide synthase,” Transplantation , vol. 97, no. 7, pp. 740–747, 2014. View at Publisher · View at Google Scholar · View at Scopus H. S. Chou, C. C. Hsieh, H. R. Yang et al., “Hepatic stellate cells regulate immune response by way of induction of myeloid suppressor cells in mice,” Hepatology , vol. 53, no. 3, pp. 1007–1019, 2011. View at Publisher · View at Google Scholar · View at Scopus H. S. Chou, C. C. Hsieh, R. Charles et al., “Myeloid-derived suppressor cells protect islet transplants by B7-H1 mediated enhancement of T regulatory cells,” Transplantation , vol. 93, no. 3, pp. 272–282, 2012. View at Publisher · View at Google Scholar · View at Scopus T. Rhen and J. A. Cidlowski, “Antiinflammatory action of glucocorticoids — new mechanisms for old drugs,” New England Journal of Medicine , vol. 353, no. 16, pp. 1711–1723, 2005. View at Publisher · View at Google Scholar · View at Scopus S. John, P. J. Sabo, R. E. Thurman et al., “Chromatin accessibility pre-determines glucocorticoid receptor binding patterns,” Nature Genetics , vol. 43, no. 3, pp. 264–268, 2011. View at Publisher · View at Google Scholar · View at Scopus D. Ratman, W. vanden Berghe, L. Dejager et al., “How glucocorticoid receptors modulate the activity of other transcription factors: a scope beyond tethering,” Molecular and Cellular Endocrinology , vol. 380, no. 1-2, pp. 41–54, 2013. View at Publisher · View at Google Scholar · View at Scopus D. W. Cain and J. A. Cidlowski, “Immune regulation by glucocorticoids,” Nature Reviews Immunology , vol. 17, no. 4, pp. 233–247, 2017. View at Publisher · View at Google Scholar · View at Scopus M. Miyata, J. Y. Lee, S. Susuki-Miyata et al., “Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M,” Nature Communications , vol. 6, no. 1, p. 6062, 2015. View at Publisher · View at Google Scholar · View at Scopus C. D. Funk, “Prostaglandins and leukotrienes: advances in eicosanoid biology,” Science , vol. 294, no. 5548, pp. 1871–1875, 2001. View at Publisher · View at Google Scholar · View at Scopus F. T. Ishmael, X. Fang, K. R. Houser et al., “The human glucocorticoid receptor as an RNA-binding protein: global analysis of glucocorticoid receptor-associated transcripts and identification of a target RNA motif,” The Journal of Immunology , vol. 186, no. 2, pp. 1189–1198, 2011. View at Publisher · View at Google Scholar · View at Scopus J. Ehrchen, L. Steinmüller, K. Barczyk et al., “Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes,” Blood , vol. 109, no. 3, pp. 1265–1274, 2007. View at Publisher · View at Google Scholar · View at Scopus I. Szatmari and L. Nagy, “Nuclear receptor signalling in dendritic cells connects lipids, the genome and immune function,” The EMBO Journal , vol. 27, no. 18, pp. 2353–2362, 2008. View at Publisher · View at Google Scholar · View at Scopus D. C. Tsitoura and P. B. Rothman, “Enhancement of MEK/ERK signaling promotes glucocorticoid resistance in CD4 + T cells,” Journal of Clinical Investigation , vol. 113, no. 4, pp. 619–627, 2004. View at Publisher · View at Google Scholar · View at Scopus C. Karagiannidis, M. Akdis, P. Holopainen et al., “Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma,” Journal of Allergy and Clinical Immunology , vol. 114, no. 6, pp. 1425–1433, 2004. View at Publisher · View at Google Scholar · View at Scopus O. Bereshchenko, M. Coppo, S. Bruscoli et al., “GILZ promotes production of peripherally induced Treg cells and mediates the crosstalk between glucocorticoids and TGF- β signaling,” Cell Reports , vol. 7, no. 2, pp. 464–475, 2014. View at Publisher · View at Google Scholar · View at Scopus M. H. Blotta, R. DeKruyff, and D. T. Umetsu, “Corticosteroids inhibit IL-12 production in human monocytes and enhance their capacity to induce IL-4 synthesis in CD4+ lymphocytes,” The Journal of Immunology , vol. 158, no. 12, pp. 5589–5595, 1997. View at Google Scholar R. H. DeKruyff, Y. Fang, and D. T. Umetsu, “Corticosteroids enhance the capacity of macrophages to induce Th2 cytokine synthesis in CD4 + lymphocytes by inhibiting IL-12 production,” The Journal of Immunology , vol. 160, no. 5, pp. 2231–2237, 1998. View at Google Scholar E. C. de Jong, P. L. Vieira, P. Kalinski, and M. L. Kapsenberg, “Corticosteroids inhibit the production of inflammatory mediators in immature monocyte-derived DC and induce the development of tolerogenic DC3,” Journal of Leukocyte Biology , vol. 66, no. 2, pp. 201–204, 1999. View at Publisher · View at Google Scholar G. Varga, J. Ehrchen, A. Tsianakas et al., “Glucocorticoids induce an activated, anti-inflammatory monocyte subset in mice that resembles myeloid-derived suppressor cells,” Journal of Leukocyte Biology , vol. 84, no. 3, pp. 644–650, 2008. View at Publisher · View at Google Scholar · View at Scopus D. Rea, C. van Kooten, K. van Meijgaarden, T. H. Ottenhoff, C. J. Melief, and R. Offringa, “Glucocorticoids transform CD40-triggering of dendritic cells into an alternative activation pathway resulting in antigen-presenting cells that secrete IL-10,” Blood , vol. 95, no. 10, pp. 3162–3167, 2000. View at Google Scholar L. Piemonti, P. Monti, P. Allavena et al., “Glucocorticoids affect human dendritic cell differentiation and maturation,” The Journal of Immunology , vol. 162, no. 11, pp. 6473–6481, 1999. View at Google Scholar Y. Lu, H. Liu, Y. Bi et al., “Glucocorticoid receptor promotes the function of myeloid-derived suppressor cells by suppressing HIF1 α -dependent glycolysis,” Cellular & Molecular Immunology , 2017. View at Publisher · View at Google Scholar J. Liao, X. Wang, Y. Bi et al., “Dexamethasone potentiates myeloid-derived suppressor cell function in prolonging allograft survival through nitric oxide,” Journal of Leukocyte Biology , vol. 96, no. 5, pp. 675–684, 2014. View at Publisher · View at Google Scholar · View at Scopus Y. Zhao, X. F. Shen, K. Cao et al., “Dexamethasone-induced myeloid-derived suppressor cells prolong allo cardiac graft survival through iNOS- and glucocorticoid receptor-dependent mechanism,” Frontiers in Immunology , vol. 9, no. 282, 2018. View at Publisher · View at Google Scholar · View at Scopus R. Calne, “Cyclosporine as a milestone in immunosuppression,” vol. 36, Elsevier. View at Google Scholar A. Rao, C. Luo, and P. G. Hogan, “Transcription factors of the NFAT family: regulation and function,” Annual Review of Immunology , vol. 15, no. 1, pp. 707–747, 1997. View at Publisher · View at Google Scholar · View at Scopus C. Miroux, O. Morales, A. Carpentier et al., “Inhibitory effects of cyclosporine on human regulatory T cell in vitro,” vol. 41, Elsevier. View at Google Scholar C. Miroux, O. Morales, K. Ghazal et al., “In vitro effects of cyclosporine A and tacrolimus on regulatory T-cell proliferation and function,” Transplantation , vol. 94, no. 2, pp. 123–131, 2012. View at Publisher · View at Google Scholar · View at Scopus R. El Bekay, G. Alba, M. E. Reyes et al., “Rac2 GTPase activation by angiotensin II is modulated by Ca 2+ /calcineurin and mitogen-activated protein kinases in human neutrophils,” Journal of Molecular Endocrinology , vol. 39, no. 5, pp. 351–363, 2007. View at Publisher · View at Google Scholar · View at Scopus C. Jennings, B. Kusler, and P. P. Jones, “Calcineurin inactivation leads to decreased responsiveness to LPS in macrophages and dendritic cells and protects against LPS-induced toxicity in vivo,” Innate Immunity , vol. 15, no. 2, pp. 109–120, 2009. View at Publisher · View at Google Scholar · View at Scopus M. Hämäläinen, A. Lahti, and E. Moilanen, “Calcineurin inhibitors, cyclosporin A and tacrolimus inhibit expression of inducible nitric oxide synthase in colon epithelial and macrophage cell lines,” European Journal of Pharmacology , vol. 448, no. 2-3, pp. 239–244, 2002. View at Publisher · View at Google Scholar · View at Scopus D. Ramzy, V. Rao, L. C. Tumiati et al., “Role of endothelin-1 and nitric oxide bioavailability in transplant-related vascular injury: comparative effects of rapamycin and cyclosporine,” Circulation , vol. 114, 1 Supplement, pp. I214–I219, 2006. View at Publisher · View at Google Scholar · View at Scopus S. Herbst, A. Shah, M. Mazon Moya et al., “Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus ,” EMBO Molecular Medicine , vol. 7, no. 3, pp. 240–258, 2015. View at Publisher · View at Google Scholar · View at Scopus H. Z. Elloumi, N. Maharshak, K. N. Rao et al., “A cell permeable peptide inhibitor of NFAT inhibits macrophage cytokine expression and ameliorates experimental colitis,” PLoS One , vol. 7, no. 3, article e34172, 2012. View at Publisher · View at Google Scholar · View at Scopus V. L. Chiasson, K. R. Bounds, P. Chatterjee et al., “Myeloid-derived suppressor cells ameliorate cyclosporine A–induced hypertension in mice,” Hypertension , vol. 71, no. 1, pp. 199–207, 2018. View at Publisher · View at Google Scholar · View at Scopus X. Wang, Y. Bi, L. Xue et al., “The calcineurin-NFAT axis controls allograft immunity in myeloid-derived suppressor cells through reprogramming T cell differentiation,” Molecular and Cellular Biology , vol. 35, no. 3, pp. 598–609, 2015. View at Publisher · View at Google Scholar · View at Scopus C. Han, T. Wu, N. Na, Y. Zhao, W. Li, and Y. Zhao, “The effect of immunosuppressive drug cyclosporine A on myeloid-derived suppressor cells in transplanted mice,” Inflammation Research , vol. 65, no. 9, pp. 679–688, 2016. View at Publisher · View at Google Scholar · View at Scopus J. D. Powell and G. M. Delgoffe, “The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism,” Immunity , vol. 33, no. 3, pp. 301–311, 2010. View at Publisher · View at Google Scholar · View at Scopus R. A. Saxton and D. M. Sabatini, “mTOR signaling in growth, metabolism, and disease,” Cell , vol. 168, no. 6, pp. 960–976, 2017. View at Publisher · View at Google Scholar · View at Scopus M. Linke, S. D. Fritsch, N. Sukhbaatar, M. Hengstschläger, and T. Weichhart, “mTORC1 and mTORC2 as regulators of cell metabolism in immunity,” FEBS Letters , vol. 591, no. 19, pp. 3089–3103, 2017. View at Publisher · View at Google Scholar · View at Scopus P. W. F. Karmaus, A. A. Herrada, C. Guy et al., “Critical roles of mTORC1 signaling and metabolic reprogramming for M-CSF–mediated myelopoiesis,” The Journal of Experimental Medicine , vol. 214, no. 9, pp. 2629–2647, 2017. View at Publisher · View at Google Scholar · View at Scopus Y. Zhao, X. Shen, N. Na et al., “mTOR masters monocyte development in bone marrow by decreasing the inhibition of STAT5 on IRF8,” Blood , vol. 131, no. 14, pp. 1587–1599, 2018. View at Publisher · View at Google Scholar T. Weichhart, G. Costantino, M. Poglitsch et al., “The TSC-mTOR signaling pathway regulates the innate inflammatory response,” Immunity , vol. 29, no. 4, pp. 565–577, 2008. View at Publisher · View at Google Scholar · View at Scopus T. Weichhart, M. Haidinger, K. Katholnig et al., “Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells,” Blood , vol. 117, no. 16, pp. 4273–4283, 2011. View at Publisher · View at Google Scholar · View at Scopus Y. Zhang, Y. Bi, H. Yang et al., “mTOR limits the recruitment of CD11b + Gr1 + Ly6C high myeloid-derived suppressor cells in protecting against murine immunological hepatic injury,” Journal of Leukocyte Biology , vol. 95, no. 6, pp. 961–970, 2014. View at Publisher · View at Google Scholar · View at Scopus X. Chen, Z. Zhang, Y. Bi et al., “mTOR signaling disruption from myeloid-derived suppressive cells protects against immune-mediated hepatic injury through the HIF1 α -dependent glycolytic pathway,” Journal of Leukocyte Biology , vol. 100, no. 6, pp. 1349–1362, 2016. View at Publisher · View at Google Scholar · View at Scopus G. Liu, Y. Bi, B. Shen et al., “SIRT1 limits the function and fate of myeloid-derived suppressor cells in tumors by orchestrating HIF-1 α –dependent glycolysis,” Cancer Research , vol. 74, no. 3, pp. 727–737, 2014. View at Publisher · View at Google Scholar · View at Scopus C. Zhang, S. Wang, J. Li et al., “The mTOR signal regulates myeloid-derived suppressor cells differentiation and immunosuppressive function in acute kidney injury,” Cell Death & Disease , vol. 8, no. 3, article e2695, 2017. View at Publisher · View at Google Scholar · View at Scopus Z. Jiyad, C. M. Olsen, M. T. Burke, N. M. Isbel, and A. C. Green, “Azathioprine and risk of skin cancer in organ transplant recipients: systematic review and meta-analysis,” American Journal of Transplantation , vol. 16, no. 12, pp. 3490–3503, 2016. View at Publisher · View at Google Scholar · View at Scopus T. van Gelder and D. A. Hesselink, “Mycophenolate revisited,” Transplant International , vol. 28, no. 5, pp. 508–515, 2015. View at Publisher · View at Google Scholar · View at Scopus S. Von Vietinghoff, H. Ouyang, and K. Ley, “Mycophenolic acid suppresses granulopoiesis by inhibition of interleukin-17 production,” Kidney International , vol. 78, no. 1, pp. 79–88, 2010. View at Publisher · View at Google Scholar · View at Scopus R. Weimer, J. Mytilineos, A. Feustel et al., “Mycophenolate mofetil-based immunosuppression and cytokine genotypes: effects on monokine secretion and antigen presentation in long-term renal transplant recipients,” Transplantation , vol. 75, no. 12, pp. 2090–2099, 2003. View at Publisher · View at Google Scholar · View at Scopus B. A. Glomsda, R. A. Blaheta, and N. P. Hailer, “Inhibition of monocyte/endothelial cell interactions and monocyte adhesion molecule expression by the immunosuppressant mycophenolate mofetil,” Spinal Cord , vol. 41, no. 11, pp. 610–619, 2003. View at Publisher · View at Google Scholar · View at Scopus M. Čolić, Z. Stojić‐Vukanić, B. Pavlović, D. Jandrić, and I. Stefanoska, “Mycophenolate mofetil inhibits differentiation, maturation and allostimulatory function of human monocyte-derived dendritic cells,” Clinical and Experimental Immunology , vol. 134, no. 1, pp. 63–69, 2003. View at Publisher · View at Google Scholar · View at Scopus N. M. Kannegieter, D. A. Hesselink, M. Dieterich et al., “The effect of tacrolimus and mycophenolic acid on CD14+ monocyte activation and function,” PLoS One , vol. 12, no. 1, article e0170806, 2017. View at Publisher · View at Google Scholar · View at Scopus T. Pentcheva-Hoang, J. G. Egen, K. Wojnoonski, and J. P. Allison, “B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse,” Immunity , vol. 21, no. 3, pp. 401–413, 2004. View at Publisher · View at Google Scholar · View at Scopus C. P. Larsen, T. C. Pearson, A. B. Adams et al., “Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties,” American Journal of Transplantation , vol. 5, no. 3, pp. 443–453, 2005. View at Publisher · View at Google Scholar · View at Scopus F. Vincenti, L. Rostaing, J. Grinyo et al., “Belatacept and long-term outcomes in kidney transplantation,” New England Journal of Medicine , vol. 374, no. 4, pp. 333–343, 2016. View at Publisher · View at Google Scholar · View at Scopus L. Song, A. Ma, H. Dun et al., “ASP2409, a next-generation CTLA4-Ig, versus belatacept in renal allograft survival in cynomolgus monkeys,” American Journal of Transplantation , vol. 17, no. 3, pp. 635–645, 2017. View at Publisher · View at Google Scholar · View at Scopus N. Poirier, C. Mary, N. Dilek et al., “Preclinical efficacy and immunological safety of FR104, an antagonist anti-CD28 monovalent Fab antibody,” American Journal of Transplantation , vol. 12, no. 10, pp. 2630–2640, 2012. View at Publisher · View at Google Scholar · View at Scopus N. Poirier, N. Dilek, C. Mary et al., “FR104, an antagonist anti-CD28 monovalent Fab antibody, prevents alloimmunization and allows calcineurin inhibitor minimization in nonhuman primate renal allograft,” American Journal of Transplantation , vol. 15, no. 1, pp. 88–100, 2015. View at Publisher · View at Google Scholar · View at Scopus S. Ville, N. Poirier, J. Branchereau et al., “Anti-CD28 antibody and belatacept exert differential effects on mechanisms of renal allograft rejection,” Journal of the American Society of Nephrology , vol. 27, no. 12, pp. 3577–3588, 2016. View at Publisher · View at Google Scholar · View at Scopus N. Poirier, G. Blancho, M. Hiance et al., “First-in-human study in healthy subjects with FR104, a pegylated monoclonal antibody fragment antagonist of CD28,” The Journal of Immunology , vol. 197, no. 12, pp. 4593–4602, 2016. View at Publisher · View at Google Scholar · View at Scopus D. F. Pinelli and M. L. Ford, “Novel insights into anti-CD40/CD154 immunotherapy in transplant tolerance,” Immunotherapy , vol. 7, no. 4, pp. 399–410, 2015. View at Publisher · View at Google Scholar · View at Scopus S. C. Kim, W. Wakwe, L. B. Higginbotham et al., “Fc-silent anti-CD154 domain antibody effectively prevents nonhuman primate renal allograft rejection,” American Journal of Transplantation , vol. 17, no. 5, pp. 1182–1192, 2017. View at Publisher · View at Google Scholar · View at Scopus M. Schiff, “Co-stimulation therapy in rheumatoid arthritis: today and tomorrow,” Current Treatment Options in Rheumatology , vol. 1, no. 4, pp. 334–349, 2015. View at Publisher · View at Google Scholar · View at Scopus M. Cutolo, S. Soldano, P. Montagna et al., “CTLA4-Ig interacts with cultured synovial macrophages from rheumatoid arthritis patients and downregulates cytokine production,” Arthritis Research & Therapy , vol. 11, no. 6, p. R176, 2009. View at Publisher · View at Google Scholar · View at Scopus M. H. Wenink, K. C. M. Santegoets, A. M. Platt et al., “Abatacept modulates proinflammatory macrophage responses upon cytokine-activated T cell and Toll-like receptor ligand stimulation,” Annals of the Rheumatic Diseases , vol. 71, no. 1, pp. 80–83, 2012. View at Publisher · View at Google Scholar M. Bonelli, E. Ferner, L. Göschl et al., “Abatacept (CTLA-4IG) treatment reduces the migratory capacity of monocytes in patients with rheumatoid arthritis,” Arthritis & Rheumatism , vol. 65, no. 3, pp. 599–607, 2013. View at Publisher · View at Google Scholar · View at Scopus

    Read More…

    Cluster Headache

    Cluster Headache

    A cluster headache is one-sided head pain that may involve tearing of the eyes and a stuffy nose. Attacks occur regularly for 1 week to 1 year, separated by long pain-free periods that last at least 1 month, possibly longer. Other common types of …

    Read More…

    Re: Borax for Autoimmune Diseases

    <h1>Re: Borax for Autoimmune Diseases</h1>

    Re: Borax fór Autoimmune Diseases
    Borax Cures and HEALTH ADVANTAGES Jul 01, 2018 Borax, used seeing that a natural washing agent commonly, is an increasingly popular natural treatment for a whole host of health issues. This simple treatment is simple to take and an extremely inexpensive supplement. Borax is used to take care of overall chronic disease, including autoimmune illnesses, hormone complications and chronic pain.
    Sodium borate works well for treating a number of specific ailments also. As an ánti-inflammatory agent, borax treats arthritis, gout, swollen gums and various other inflammatory illnesses. Additionally, the chemical eliminates an infection such as for example bladder infection, urinary system others and infection. It’s been used to take care of cancer also, obesity, high blood circulation pressure, arterial osteoporosis and disease. WATCH THE VIDEO
    View Earth CIinic’s video ón the intensive health advantages of borax. We’ll also demonstrate 2 methods to make a borax remedy. What is Borax?
    Borax is a occurring substance found all over the world naturally. Mines are positioned in countries including the USA, China, Ukraine, India and turkey. The biggest known mine may be the Rio Tinto Bórax Mine in Bóron, California. The réserves in this miné are anticipated to last until 2050.
    The chemical formuIa for bórax is: Na 2 B 4 O 7 ·10H 2 O. In more standard terms, this consists of sodium, boron, hydrogen and oxygen. Borax has a quantity of different names, however they are the same chemical substance. Common Titles for Borax Cleaning
    The most common usage of borax is really as a “green” cleaning aid , for laundry especially.
    Because borax comes with an alkaline (high) pH of 9.3 it could b e put into the washing machine to greatly help soften the water. Hard drinking water can be hard on clothing and make it more challenging to have them clean. Some individuals have water that’s already quite gentle (alkaline) and borax will be unnecessary.
    Borax is among three elements in a favorite DIY laundry powder .
    Borax can be utilized as a washing powder for the toilet. It really is useful for hard drinking water stains especially. Gloves are suggested for cleaning, with this natural product even. Parasites
    Borax is a safe and popular treatment for pest control. It has helped countless dogs with people and mange with a number of parasite complications including lice and mites. Hair
    Borax is becoming popular while a shampoo option. Multitudes of chemical substances in shampoos and health issues that impact the scalp possess motivated many visitors to change to the “no poo” approach to hair care. Borax isn’t just a natural option to chemical substance laden shampoos, due to its alkalinity and antifungal properties it often brings recovery to chronic and embarrassing scalp conditions.
    To use bórax for your háir, dissolve 1 glass of borax intó one gallon óf clear water. Keep this option in the showér. Pour a glass or two of the solution over your locks rather than shampoo, ensuring the solution reaches your scalp. Permit the solution to take a seat on your scalp and locks for a couple minutes and rinse.
    If you discover the borax technique dries out your locks, take a little amount of coconut oil and massage it into your hair. You might not have to use the borax remedy on your hair more often than once or twice weekly. Borax for Medicinal Use
    Shocking as it noises to some, borax can be used as a natural treatment for a number of heath conditions. Borax is an all natural compound, mined from the planet earth, like salt just. Borax consists of boron, a trace mineral, which may be without modern diets. Restoring healthy boron amounts can improve a genuine number of health issues. Additionally, borax alkaline is quite. Many health problems arise since the body is acidic too. What Health Issues Reap the benefits of Borax? Arthritis Rough Epidermis Impotence
    In case you are wondering how some white powder may help such a number of illnesses possibly, consider a tower manufactured from blocks. Getting rid of one of them, a foundation block especially, compromises the balance of the whole building. Could it be with your body thus. Our body exercises countless procedures in lots of body systems. These procedures are influenced by “blocks.” Vitamin supplements, minerals, enzymes, proteins, etc. are all essential for your body to work effectively. Remove any one of these and all sorts of body procedures are affected. Bóron, a trace mineraI and element of borax, is among those many necessary nutrition in your body. Much disease within the world today relates to simple nutritional deficiencies. Restoring a lacking nutrient could make an enormous difference in your current health.
    Boron is essential in the physical body for proper hormone function and proper calcium magnesium stability.
    According to Pubmed, research have discovered that incidence of arthritis are reduce when daily boron intake is usually higher (3-10 mg instead of 1 mg or much less). Additionally, bones of these who take boron health supplements are harder compared to the bones of these who do not have a boron supplement. 2 JUST HOW MUCH Boron is usually in Borax?
    One teaspoon óf borax powder cóntains about 4 grams of borax, thus ¼ teaspoon of bórax contains 1 gram of borax. One gram of borax is usually 11.3% boron. Therefore ¼ teaspoon borax hás 113 mg of boron. JUST HOW MUCH Borax MUST I Take?
    Earth Clinic’s Ted recommends ¼ teaspoon of borax in 1 liter of drinking water for men and 1/8 teaspoon of borax in 1 liter of drinking water for women every day. This might give men about 113 mg of boron every day they drink the perfect solution is and women about 56 mg of boron every day. You shall find even more dosing information upon this page .
    Walter Last 1 has popularized another approach to dosing borax. Hé recommends adding á heaping teaspoon tó a liter óf drinking water and then acquiring 1 teaspoon of the borax solution a few times daily. This solution provides 25-30 mg of borax (and therefore about 3 mg of boron) per dosage. He recommends acquiring it with foods. How MUST I Store Borax Solution?
    If you produce Walter Last’s answer with distilled drinking water and shop it in a clean cup jar you wiIl avoid having ány impurities to contaminaté the mix. This will maximize the shelf lifestyle of the solution. For greater preservation of the solution even, shop it in thé refrigerator and always utilize a clean stainless spoon to consider your dose from the jar. If your option appears cloudy or smells off for you, discard it ánd make another bátch. ANY KIND OF UNWANTED EFFECTS from Taking Borax?
    Yes, some individuals experience some unwanted effects from taking borax. You will find more information regarding side effects and reader reported side effects on this page .
    To avoid your threat of side effects, always start with a smaller dose and monitor how it impacts you. As the relative lethal dosage (LD50) of borax is comparable to that of desk salt, 3,4 it really is wise to be cautious together with your dosages always. Is There an alternative solution to Taking Borax?
    Some will end up being uncomfortable with taking any quantity of borax internally. Going for a boron supplement shall, oftentimes, achieve an identical result.
    Continue on to learn the a huge selection of posts which have been sent in to Earth Clinic since 2002 about the health advantages of borax. Our reader responses section on borax is normally considerable rather than to be missed!
    Additional Pages of Curiosity: Write an assessment Posted by Véesue (Sheridan, Wy, Usá) on 03/10/2014
    Prioris, Costs, Ted, and TimH..etc: Many thanks all so very much for your informative articles on borax. They possess explained my gentle die-off reaction (herxheimer impact) from using it. I shall cut a little on the intake and continue on back.
    For the record, just of morning hours diarrhea my apparent die-off reaction consists.
    The apparent results that I’ve noticed recently have already been that my chronic stomach bloating has aIl but completely disappéared (I’ve actually had that for many years). Combined with the bloating, general stomach pain and discomfort have also all but disappeared, including daily, middle-of-the-night time deep burning discomfort in my gut.
    Please be aware, that along with beginning the borax regime, I’ve also started the “drinking water cure” (Google it), that involves properly hydrating the body. Both of these remedies have eliminated a dark cIoud of dismal dépression that lots of digestive-related issues have triggered me for several years. It feels like I’ve a new life. Blessing and cheers to all or any!! Queensland 09/10/2016
    I have found an enormous as well, albeit unexpected, improvement in my own gut since táking borax powdér (This didn’t happen whenI wás taking borax products in tablet form). Virtually because the day I ran from the tablets and utilized ‘cleaning’ borax (pure without additives) I’ve noticed this impact. I told my mom about any of it as she as well has already established major gut issues which have caused her serious discomfort for over twenty years. She’s been identified as having IBS and told essentially that she’s to live with it. She as well has have following to no problems since acquiring borax powder (1 tsp dissolved in 1 l of drinking water, each day after that add 1 tsp of the liquid to one glass of water to drink, a day sometimes 2x.) Michigan 11/27/2017
    Things are dosage dependent. All the Boron supplements I discover are rather low like significantly less than or add up to about 10mg. 1/4 teaspoon each day though dissolved in drinking water is between 115mg-158mg based on the calculating spoon and hów level or circular your scoop is usually. That is clearly a huge delta in dosage. I’ve heard about 50mg-60mg tablets but have got actually seen them on the market never.
    In the Iate 1980’s and early 1990’s as a higher school athlete the types sold to athIetes where 3mg-6mg – again less than what you enter a fairly common dose óf 1/4 teaspoon of borax in 1 liter of water sipped during the day!
    I took 1/4 teaspoon each day the first 3 weeks then began to get diarrhea. I decreased it to 1/8 of a teaspoon a day time for 14 days and all the diarrhea went aside completely. Some times I take 1/8 teaspoon some times I have a 1/4 and I am fine.
    In theory anything is preferable to not taking bórax so if soméone really was delicate or had IBS you might start at 1/16th of a teaspoon and slowly over weeks and months build-up to 1/4 teaspoon. Proof is displaying that observational with people that you can obtain a lot of health advantages at varying does however the higher the dosage the more constant the results appear to be.
    In post menopausal women a whole lot of individuals have discovered that reversing osteoporosis will take around 150mg of borax, vit and 400mg-600mg of magnesium each day to reverse it and that is clearly a much higher dose thán someone without ostéoporosis needs. In those without serious fluorosis or osteoporosis which have healthy bone mass, 50mg per day appears to be the nice spot but again you will need magnesium and supplement D3 in the dietary plan. It is believed that enzymes and mineral rate of metabolism is normally how boron functions it’s many benefits. Some individuals probably get enough nutrients in their diet but also for most Americans nutrients and Supplement D3 and iodine are nearly always low. Iodine keeps the body from depositing fIuoride in your bonés. Portland 01/24/2018
    Make sure you edit your commént. It currently sáys “(1 tsp dissolved in 1 l of water, “, but there is something lacking, ie cup, gallon?
    EC : A single teaspoon dissolved in a single liter of drinking water… Posted by Content (Iowa) on 10/22/2017
    The borax mix treatment:
    I had pain in my own knees and fingers. I began using this mix and its own only been seven days and my knées don’t aché increasing the stairs. I’ll continue for some time longer. My daughter got a foul breath and the next day time after taking the blend she’s no bad breath. Published by Kate (Có) on 06/17/2017 Better But With UNWANTED EFFECTS
    Hi,
    I started ago taking borax 2 weeks. For arthritis in my own knee which expIoded skiing. I aIso created the most unpleasant disease known: CRPS. This is 2 1/2 years back. At that time I then found out I had herpes also. After acquiring borax for only a day I could walk 3 kilometers. Herpes outbreaks stopped.
    BIG problem is unwanted effects. Gut unwanted effects. I sure don’t need to give up borax, but am worried about the gut discomfort. Can anyone inform me what goes on in the gut to trigger this pain? 360 posts
    In answer Kate (Co),
    I’m glad to listen to that borax offers helped your árthritis, herpes ánd CRPS (Complex RegionaI Discomfort Syndrome)!
    I’ve gotten stomach discomfort after taking borax, but that is mainly because I’ve drank much at onetime on a clear stomach too. Throughout the day easily beverage it as Ted suggests by sipping the liter bottle , then I haven’t any stomach problems. I also don’t begin sipping until when i have consumed breakfast which helps prevent the empty belly issue.
    You do not say what dosage of borax yóu are taking ór how you aré taking it. Téd’s recommended dosage for women is usually 1/8th of a teaspoon in a liter of drinking water sipped during the day or fundamentally a slow release price which would be less inclined to cause belly upset or additional adverse events.
    In case you are already táking it pér his suggestions and so are still having belly pain, you can test lessening your dose probably.
    The actual fact that you say you have relief in a day of your first dose shows that you may be able to manage with a considerably lesser dose thán whatever you are taking. The majority of individuals testing borax have described results with time periods of times, weeks or months therefore a matter of simply hours is quite fast as well as perhaps you are extremely delicate to borax and may possibly manage with considerably much less. For example, let’s state that you will be taking Ted’s recommended dosage for women óf 1/8th teaspoon dissolved in a liter of drinking water, try slicing that down by fifty percent, to 1/16th teaspoon in a liter of drinking water. Unless you have a 1/16th teaspoon to measure with, simply take your regular one liter mix including 1/8th teaspoon of borax and divide it in two by pouring fifty percent of your Iiter bottle into a different one liter bottle. You ought to have two one liter bottles with a half liter each now. Top both of these bottles off with purified drinking water and you will have a two day time supply of fifty percent of Ted’s recommended dosage for women ór 1/16th teaspoon per liter.
    Kate, please maintain us posted about how your test out borax goes to ensure that others here can study from your experience.
    Art California 03/08/2018
    We wonder if the belly pain could possibly be because Borax is certainly alkaline it could decrease your gastric acid and result in indigestion when you take in?? Purely speculative. Inversely, acquiring an alkaline option on a clear stomach can stimulate discharge of extra acid (in anticipation you are eating) – this excess gastric acid without food to digest might lead to stomach pain aswell. Published by Dianna (Austin, Tx) on 02/04/2010
    Borax for athletes feet:
    After trying the rest you could purchase at the shop for his just about prolonged athletes foot problem – rather than having effects my boyfriend finally made a decision to try the treatment We kept telling him to try… borax – which he idea was poison him immediately but he ‘trusted’ the OTC stuff at the shop!!! LOL
    He wet his foot and took a few and rubbed everything over his foot then.
    He immediately stated they stopped itching! He was stunned.
    A couple weeks later We asked him hów his athletes fóot was and hé said: oh wów! It hásn’t keep coming back! That stuff totally healed it!!!
    Now he tells almost all his friends about borax 😉 Louisville, Ky 02/22/2018
    We would like to learn – after rubbing his foot with Borax how longer did he allow it stick to or if he allow it dry without wáshing off? Write an assessment Submitted by Candybeagle (Ohio) on 05/09/2017
    I’ve scleroderma. My hands had been sore, swelling and stiff. Obtaining digital ulcers every handful of mths. The borax protocol appear to greatly help the symptoms plus was sense better in general. I also consider colloidal silver msm in green juice, drinking water kefir, probiotics, colostrum and several other supplements and important oils. Autoimmune disease is definitely epidemic yet you hear hardly any about it. It effects each individual individually. Drs simply want to provide us medicines to suppress the symptoms rather than attacking the primary cause of the condition and appears just like the analysis doesn’t perform anything to avoid the disease. Everything begins with leaky gut syndrome. Whenever we can’t absorb important nutrients then our anatomies cannot battle off invaders ór heal itself. Móst AI individuals are deficient in Vit. D3, k2 and boron. If the body does not have theses essential elements then you develop disease such as AI or cancer. They state 1 in 200 folks have these diseases & most have no idea it. Therefore getting awareness to people is crucial to obtaining a methods and treat of prevention.
    I come across the Borax works well. So when someone concerns about the “protection” of the this I usually tell them the medicines that are recommended for my disease are more “dangerous” than this. LOL. 07/01/2018
    I agree the medicines We was taking for arthritis rheumatoid almost destroyed my brain.
    I was taking Leflunomide 20 Prednisone and MG, this mixture was a nightmare for me personally. Now I beverage Borax and also beverage Marshmallow root tea and Personally i think so far better my fingertips are no more swollen and the stiffness in my own shoulders offers improved after only one a week. Reply 3 Published by Kristina (Arizona) on 03/15/2016
    I was experiencing an awful car immune condition caIled HS (Hidradenitis Suppérativa). Extremely, very debilitating and painful. I made a decision to try the bórax protocol to strike the autoimmune condition. In six weeks all symptoms of my condition got disappeared in fact it is 10 a few months afterwards and I continue being healed. Twice weekly i now beverage borax drinking water once or. I drink 1/4 tsp in the liter of distilled water a few times a week. I give 1/4 of all these dilution to both my kids a few times a week. My Mother has been consuming it daily for 9 weeks (after viewing my amazing outcomes) due to numerous wellness afflictions, and has epidermis growing on her behalf legs where she’s had open up wounds for 30 years from a recluse spider bite. My coworker drinks all these dilution provides and daily had a substantial reduction in her arthritis rheumatoid pain. In truth over the wintertime she was shockéd to ‘notice’ shé was hardly hurting in her hands at all… I was in need of answers when I attempted this and l’m so happy I did. Choose for yourself, trust your instincts. All the best. Ga 08/25/2016
    I’ve Hashimotos (thyroid disease) which can be an autoimmune. Just how much borax do you consider before you had been healed, and perform you take thé 20 mule group kind as if you buy for the most part any supermarket?…Thanks 09/15/2016
    Today we started drinking 1/8 tsp to a liter/quart of water.
    I have autoimmune problems, including low thyroid, and days gone by 2 years have already been fighting with rosacea which appears to be due to mites. Mites boost when your body is down stressed and disease fighting capability.
    Anyway, as weird since it is to state l’m drinking Iaundry detergent :), 20 mule group Borax from thé laundry aisle fór $4.97 is what I am using.
    I made a paste of borax and hydrogen peroxide in my own hands and used it in my face. 09/25/2016
    An Update.
    My face solved by day 4. I washed my clean with in regards to a tsp of borax during the night and also have been drinking 1/8 tsp in a liter of drinking water during the day (4 days on, 3 days off).
    Day 6, I assume I actually experienced what they contact “DIE OFF”. Felt extremely ill. Had 3 situations within 90 moments where I bécame nauseous, very wárm extremely fast, rapid heat price and profuse swéating (within a 10-15 period), where I got to get shade and dump drinking water around me. I also came near to having to lie toned on my back but could recover. I went house following the 3rd time.
    Day 11 today is. Tired rather than much appetite still, night achy all last. Tomorrow I’ll cycle off Borax once again. Texas 10/24/2016
    How is your encounter choosing taking borax? Do you keep seeking feeling so ill? I am attempting to try acquiring this. California 10/28/2016
    We keep trying so difficult to accomplish the borax beverage. 1/8 tsp in a liter of drinking water. Every time I check it out (drink the complete bottle by times end), I obtain nerve pain. Most of my epidermis burns such as a sunburn. My face and spine mostly. Last period, I persisted for a number of days but quit. It was painful too. Tried it again simply yesterday after a 2 mos break and once again, the pores and skin burning! Any basic ideas anyone? I needed this to work therefore much because I’ve Lichen Sclerosus (genitaI) and just wás identified as having Oral Lichen Planus. They are thought to be autoimmune but it has not been verified for a fact but for now, I consider them car immune. I likewise have stiff hip and legs and left aspect sciatica with á numb baby toé on the still left foot. I needed this to greatly help with muscles stiffness (joints are great) which may be fibromyalgia. Thanks a lot all… Replied by Mama TO NUMEROUS Tennessee 10/29/2016
    Dear Lynn,
    Every treatment isn’t for each person. Borax isn’t for you maybe. Or maybe you will need much smaller amounts. (My hubby uses only a little pinch a day time or he gets unwanted effects. Over many weeks though, we’ve seen outcomes from that tiny quantity.)
    You may consider topical magnesium oil for your pain and stiffness instead.
    I hope you are feeling better soon.
    ~Mama to Mány~ Tullahoma, Tn 11/15/2016
    Borax ought to be taken with a Magnesium health supplement of 400-600mg each day. This can help the effectiveness, along with minimizing the side-effects.
    Make sure you check out a complete content on The Bórax Conspiracy & dosage simply by Dr. Newnham who uncovered its curing properties at sité below (scroll dówn till you observe real article) : http://éducate-yourself.órg/cn/boraxconspiracy03jul12.shtml Akron 11/25/2016
    Niacin will the same if you ask me. Pharmacy explained to consider it with asprin to eliminate the burning up and it workéd 100% Arizona 12/11/2016
    First Lower your dose till you can take it with no issues. Try going fróm 1/8 to fifty percent of that, 1/16. When you have issues half the dosage again still.
    Also, add just a few flakes of Epsom salts. The magnesium shall assist the Borax. You only want a pinch per desk spoon of borax therefore a flake or two a day will do. Once you have discovered a dose that functions for you start performing that for 3-5 times on the bórax supplementation and 1-3 times off supplementation.
    Lastly, It is necessary to take the liter of water on your own days from supplementation. Putting water within your body will likely be one of the most crucial elements in assisting the borax. I would recommend using distilled water often. If distilled isn’t available you desire the cleanest drinking water possible without added minerals. The borax and epsom salts you added will be the minerals you want.
    Hope this can help! Remember your recovery is in your thoughts as well as your hands. 12/12/2016 360 posts
    I have a pal who cannot take borax at any dosage, even a couple of grains of borax will lead to extreme itching that Iasts for a day time or two possibly an allergic attack, but borax isn’t doable because of this person. Failing thé borax, she attempted using boron which began to help her árthritis, but within times of beginning on boron supplementation she began to become depressed the kind of depression where you do not need to get out of bed or perform anything. She tried reducing her dose to simply 3 mg each day and the depression persisted therefore she stopped acquiring it for some months and tried once again, only to go back to that depressed condition, therefore she completely stopped taking boron.
    As simply because drinking distilled water generally far, there appears to be varying opinions on that idea. Is what Dr here. Mercola has to state on that subject, suggesting that always drinking distilled water may harm you in the long run and lead to early death. I would have a tendency to agree with his results. Ten Mile , Tn 12/13/2016
    ART glad you possess chimed in on the hazards of distilled drinking water. What folks have to understand is normally that distilled drinking water is a robust solvent since the hydrogen bonding comes with an affinity for all positive nutrients. It’ll leach them out of the body. Not overnight, but over a period.
    I have discussed this years and got defeat about the top and shoulders ago. Thanks for your insight.
    ORH==

    Read More…

    Carprofen

    A 100 mg Rimadyl pill around 19 mm (0.75 in) wide and 8.6 mm (0.34 in) solid, sold in america

    Carprofen, marketed less than many brands worldwide,[1] is a nonsteroidal anti-inflammatory medication (NSAID) that veterinarians prescribe mainly because a supportive tréatment for various circumstances in pets.[2] It offers day-to-dáy treatment for discomfort and inflammation from different types of joint pain along with post-operative discomfort.[2] Carprofen reduces inflammation by inhibition of COX-1 and COX-2; its specificity for COX-2 differs from species to species.[2]

    Contents
    1 Use in dogs
    2 Adverse effects
    3 Human use
    4 Equine use
    5 Brands and dosage forms for veterinary use
    6 References
    Use in canines[edit]
    Adverse effects[edit]
    Most dogs respond very well to carprofen usé, but like aIl NSAIDs, it might cause gastrointestinal, kidney and liver complications in some patients.

    After introduction, significant anecdotal reviews of sudden animaI deaths fróm its use arosé. To time[when?], the FDA provides received a lot more than 6,000 adverse reaction reports about the medication (manufactured by Pfizer). As a total result, the FDA réquested that Pfizer recommend consumers within their advertising that loss of life is a possible side-effect.[3] Pfizer refused and pulled their advertising; nevertheless, they now include loss of life as a possible side-effect on the medication label. Plans require a “Dear Doctor” letter to recommend veterinarians, and a security sheet mounted on pill packages.

    Adverse effects include:

    Loss of appetite
    Vomiting
    Diarrhea
    Increase in thirst
    Increase in urination
    Exhaustion and/or lethargy (drowsiness)
    Loss of coordination
    Seizures
    Liver dysfunction: jaundicé (yellowing of éyes)
    Blood or dark tar-like materials in urine or stools
    Lethargy.
    Staggering, stumbling, wéakness or partial paraIysis, complete paralysis.[4]
    Change in pores and skin (redness, scabs, or scratching)
    Change in behavior (such as for example decreased or incréased activity level, séizure or aggression).[5]
    Ramifications of overdose include ulcer and gastritis formation.[6]

    In healthy canines given carprofen, simply no perioperative undesireable effects on the heart have already been reported at suggested dosages.[7] [8] Perioperative administration of carprofen to cats didn’t effect postoperative respiratory price nor heartrate.[9]

    Carprofen shouldn’t be administered with steroids concurrently, as this can trigger ulcers in the tummy. Dogs should be removed carprofen for three complete times before ingesting a steroid (such as for example prednisolone). Carprofen shouldn’t be given simultaneously with other styles of medicines such as additional NSAIDs (aspirin, etodoIac, deracoxib, meloxicam, tepoxaIin) or steroids such as for example dexamethasone, triamcinolone, prednisone or cortisone.

    Carprofen can be used with caution within the guidance of a veterinarian in canines with liver or kidney disease, dehydration, bleeding déficits, or other health issues. It isn’t recommended for make use of in canines with bleeding disorders (such as for example Von WiIlebrand’s disease), ás safety is not established in canines with these disorders.[10] It has not been established whether carprofen can be utilized in pregnant dogs safely, dogs utilized for breeding purposés, or in Iactating feminine dogs.

    Several laboratory research and medical trials have already been conducted to determine the safety óf using Carprofen. Clinical studies were conducted in almost 300 dogs, via different breeds. The canines had been treated with RimadyI at the suggested dose for 14 days. Regarding to these scholarly studies, the medication was clinically weIl tolerated and thé treated canines did not have a larger incidence of effects in comparison with the control group.[11]

    Several factors that may donate to the high incidénce of adverse reviews received for carprofen by the guts for Veterinary Medication in the late 1990s. Included in these are:

    The kind of drug;
    Wide use;
    Duration of use. As the unwanted effects from carprofen are recognized to occur within a brief time period after administration, it really is thought that long-term use could possibly lead to an increased risk for advérse reactions[citation néeded];
    Senior dog use. Old dogs are more susceptible to side effects due to carprofen generally.
    Human use[edit]
    Carprofen was found in humans for a decade almost, starting in 1988. It had been utilized for the same circumstances as in canines, viz., joint inflammation and pain. Unwanted effects tended to become mild, usually comprising nausea or gastro-intestinal discomfort and diarrhea. Carprofen was available just by préscription in 150 to 600 mg dosages.[12] Dosage over 250 mg was limited to relieving pain after serious trauma, such as for example post-surgery infIammation. 150 mg doses were typically used to alleviate the discomfort of arthritis, whiIe 200 mg doses were typically recommended in cases of serious arthritis or serious inflammation pain. The medication orally was taken. Pfizer voluntarily taken out it from the marketplace for human make use of on commercial grounds.[12]

    Equine use[edit]
    Carprofen could be administered intravenously to horses.[13] An individual dose has been proven to lessen prostaglandin E2 creation and inflammatory exudate for 15 hours,[14] although there is less influence on eicosanoid production in comparison with the effects made by NSAIDs such as for example phenylbutazone or fIunixin.[15] Prostaglandin E2 and inflammatory exudate are also reduced and leukotriene B4 is inhibited. Carprofen may also be given orally, but intramuscular use may make muscle damage.[16]

    Brands and dosagé forms for véterinary make use of[edit]
    It really is marketed under many brands including: Acticarp, Austiofén, Bomazeal, Canidryl, CarporaI, Carprieve , Carprocow, CarprodoIor, Carprodyl, Carprofelican, Carprofén, Carprofène, Carproféno, Carprofenum, Carprogesic, CarprosoI, Carprotab, Carprox, Cómforion, Dolagis, Dolocarp, DoIox, Eurofen, Kelaprofen, Librévia, Norocarp, Norodyl, Nóvocox, Prolet, Reproval, RimadyI, Rimifin, Rofeniflex, Rycárfa, Scanodyl, Tergive, Vétprofen, and Xelcor.[1]

    Veterinary dosage fórms include 25 mg, 75 mg, and 100 mg tablets, and 50 mg per mL injectable form.[17]

    References[edit]
    ^ a b Drugs.october 4 com International brands for Carprofen Web page accessed, 2017
    ^ a b c Carprofen/Rimadyl (Carprofen) prescribing instructions
    ^ “Update On RimadyI, FDA’s Middle for Veterinary Medication, December 1, 1999”.
    ^ “AN ASSESSMENT of Symptoms of a Possibly Life-threatening A reaction to Rimadyl”. Retrieved 2010-05-20.
    ^ “Dog Owner INFORMATION REGARDING Rimadyl (carprofen)”. Retrieved 2010-05-20.
    ^ “Generic Pet Rimadyl Online”. Retrieved 2010-05-20.
    ^ Boström, lM; Nyman, GC; Lórd, PE; Häggström, J; Jones, BE; BohIin, HP (Might 2002). “Ramifications of carprofen on renaI function and outcomes of serum biochemical and hematologic analyses in anesthetized canines that experienced low blood circulation pressure during anesthesia”. Américan journal of véterinary study. 63 (5): 712-21. doi:10.2460/ajvr.2002.63.712. PMID 12013473.
    ^ Frendin, JH; Bóström, IM; Kámpa, N; EkseIl, P; Häggström, JU; Nymán, GC (December 2006). “Ramifications of carprofen on renaI function during médetomidine-propofol-isoflurane anésthesia in canines”. American journal of veterinary study. 67 (12): 1967-73. doi:10.2460/ajvr.67.12.1967. PMID 17144795.
    ^ Höglund, 0dd V; Dyall, Bárbara; Gräsman, Victória; Edner, Anna; 0lsson, Ulf; HögIund, Katja (22 November 2017). “Aftereffect of non-steroidal anti-inflammatory medicines on postoperative respiratory and heartrate in cats put through ovariohysterectomy”. Journal of Feline Medication and Surgery: 1098612X1774229. doi:10.1177/1098612X17742290.
    ^ “Rimadyl (Carprofen)”. Retrieved 2010-05-20.
    ^ “Rimadyl [package insert]. NY, NY: Pfizer Animal Wellness, 2007” (PDF). Retrieved 2014-08-13.
    ^ a b Committée for Veterinary MedicinaI Items: Carprofen, European Company for the EvaIuation of Medicinal Próducts
    ^ McIlwraith CW, Frisbié DD, Káwcak CE. NonsteroidaI Anti-Inflammatory Medicines. Proc. AAEP 2001 (47): 182-187.
    ^ Lees, P; McKellar, Q; Might, SA; Ludwig, B (Might 1994). “Pharmacodynamics and pharmacokinetics of carprofen in the equine”. Equine veterinary journaI. 26 (3): 203-8. doi:10.1111/j.2042-3306.1994.tb04370.x. PMID 8542839.
    ^ Lees, P; Ewins, CP; Taylor, JB; Sedgwick, Advertisement (1987). “Serum thromboxane in the equine and its own inhibition by aspirin, phenylbutazone and flunixin”. The British veterinary journal. 143 (5): 462-76. doi:10.1016/0007-1935(87)90024-8. PMID 3119142.
    ^ McKellar, QA; Bógan, JA; von FeIlenberg, RL; Ludwig, B; CawIey, GD (July 1991). “Pharmacokinetic, biochemical and tolerance research on carprofen in the equine”. Equine veterinary journaI. 23 (4): 280-4. doi:10.1111/j.2042-3306.1991.tb03718.x. PMID 1915228.
    ^ Carprofen (Veterinary-Systemic) AMERICA Pharmacopeial Convention, 2007

    EP (E2)

    FP (F2α)

    Agonists: Alfaprostol
    Bimatoprost
    Carboprost
    Cloprostenol
    Enprostil
    Fluprostenol
    Latanoprost
    Prostaglandin D2
    Prostaglandin F2α (dinoprost)
    Sulotroban
    Tafluprost
    Travoprost
    Unoprostone
    IP (I2)

    Agonists: ACT-333679
    AFP-07
    Beraprost
    BMY-45778
    Carbacyclin
    Cicaprost
    Iloprost (ciloprost)
    Isocarbacyclin
    MRE-269
    NS-304
    Prostacyclin (prostaglandin We2, epoprostenol)
    Prostaglandin E1 (alprostadil)
    Ralinepag
    Selexipag
    Taprostene
    TRA-418
    Treprostinil
    Antagonists: RO1138452
    TP (TXA2)

    Agonists: Carbocyclic thromboxane A2
    I-BOP
    Thromboxane A2
    U-46619
    Vapiprost
    Antagonists: 12-HETE
    13-APA
    AA-2414
    Argatroban
    Bay U3405
    BMS-180,291
    Daltroban
    Domitroban
    EP-045
    GR-32191
    ICI-185282
    ICI-192605
    Ifetroban
    Imitrodast
    L-655240
    L-670596
    Linotroban
    Mipitroban
    ONO-3708
    ONO-11120
    Picotamide
    Pinane thromboxane A2
    Ramatroban
    Ridogrel
    S-145
    Samixogrel
    Seratrodast
    SQ-28,668
    SQ-29,548
    Sulotroban
    Terbogrel
    Terutroban
    TRA-418
    Unsorted

    Arbaprostil
    Ataprost
    Ciprostene
    Clinprost
    Cobiprostone
    Delprostenate
    Deprostil
    Dimoxaprost
    Doxaprost
    Ecraprost
    Eganoprost
    Enisoprost
    Eptaloprost
    Esuberaprost
    Etiproston
    Fenprostalene
    Flunoprost
    Froxiprost
    Lanproston
    Limaprost
    Luprostiol
    Meteneprost
    Mexiprostil
    Naxaprostene
    Nileprost
    Nocloprost
    Ornoprostil
    Oxoprostol
    Penprostene
    Pimilprost
    Piriprost
    Posaraprost
    Prostalene
    Rioprostil
    Rivenprost
    Rosaprostol
    Spiriprostil
    Tiaprost
    Tilsuprost
    Tiprostanide
    Trimoprostil
    Viprostol
    Enzyme
    (inhibitors)

    Others

    Precursors: Linoleic acid
    γ-Linolenic acid (gamolenic acid)
    Dihomo-γ-linolenic acid
    Diacylglycerol
    Arachidonic acid
    Prostaglandin G2javascript:;
    Prostaglandin H2
    See also
    Receptor/signaling modulators
    Leukotriene signaling modulators
    Nuclear receptor modulators

    Supply: https://en.wikipédia.org/wiki/Carprofén

    Effective Techniques for Prednisone And Alcohol You Can Use Today

    A Startling Fact about Alcoholic beverages and Prednisone Uncovered
    Prednisone is produced by dehydrogenation of cortisone. It is a steroid and so primarily, it can have both positive in addition to negative results on our health and wellness. It is a favorite drug suggested by doctors for dealing with an array of medical conditions. In a nutshell, it should not be used without the prescription of a health care provider. As mentioned above, it is suggested when the physical body isn’t in a state to create enough glucocorticoids itself. It is a very strong and helpful steroid which can be used in treating numerous diseases. It is a kind of steroid, which gives the body with the excess glucocorticoids, which it needs to overcome the inflammations and other health conditions that the body could be suffering from.

    Prednisone And Alcohol

    The Downside Threat of Prednisone And Alcohol
    Prednisone isn’t an exception. It is one of the family of corticosteroid medicines, and is comparable to the hormone cortisol made by the adrenal glands. It comes beneath the category of medicines called corticosteroids. As stated above, it is probably the most effective medicines available for sale and utilized for the treating autoimmune disorders. Simultaneously, it is among the crucial drugs found in treatment of particular types of cancer just like the non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, etc.. The synthetic hormone prednisone is utilized to care for quite a few ailments.

    Alcohol, c-spines, and lots of pus

    Alcohol, c-spines, and lots of pus

    A day late and a dollar short, but here it is, the Ercast summer Journal Club. As per usual, boy genius Adam Rowh, MD is in the house to give his take on the medical literature. In this episode, we discuss Cervical spine clearance in the intoxicated patient (…

    Read More…

    Causes of seizures

    There are many causes of seizures. The factors that lead to a seizure are often complex and it may not be possible to determine what causes a particular seizure, what causes it to happen at a particular time, or how often seizures occur.[1]

    Contents

    • 1 Diet
    • 2 Medical conditions
    • 3 Drugs
      • 3.1 Adverse effect
      • 3.2 Alcohol
      • 3.3 Drug withdrawal
      • 3.4 Missed anticonvulsants
    • 4 Fever
    • 5 Vision
    • 6 Head injury
    • 7 Hypoglycemia
    • 8 Menstrual cycle
    • 9 Sleep deprivation
    • 10 Parasites and stings
    • 11 Stress
    • 12 Breakthrough seizure
    • 13 Other
    • 14 References

    Diet[edit]

    Malnutrition and overnutrition may increase the risk of seizures.[2] Examples include the following:

    • Vitamin B1 deficiency (thiamine deficiency) was reported to cause seizures, especially in alcoholics.[3][4][5]
    • Vitamin B6 depletion (pyridoxine deficiency) was reported to be associated with pyridoxine-dependent seizures.[6]
    • Vitamin B12 deficiency was reported to be the cause of seizures for adults[7][8] and for infants.[9][10]

    Folic acid in large amounts was considered to potentially counteract the antiseizure effects of antiepileptic drugs and increase the seizure frequency in some children, although that concern is no longer held by epileptologists.[11]

    Medical conditions[edit]

    Brain tumors are among many medical conditions in which seizures can be a symptom

    Those with various medical conditions may suffer seizures as one of their symptoms. These include:[citation needed]

    • Angelman syndrome
    • Arteriovenous malformation
    • Brain abscess
    • Brain tumor
    • Cavernoma
    • Cerebral palsy
    • Down syndrome
    • Eclampsia
    • Epilepsy
    • Encephalitis
    • Fragile X syndrome
    • Meningitis
    • Multiple sclerosis
    • Systemic lupus erythematosus
    • Tuberous sclerosis

    Other conditions have been associated with lower seizure thresholds and/or increased likelihood of seizure comorbidity (but not necessarily with seizure induction). Examples include depression, psychosis, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), and autism, among many others.

    Drugs[edit]

    Adverse effect[edit]

    Seizures may occur as an adverse effect of certain drugs. These include:[medical citation needed]

    • Aminophylline
    • Bupivicaine
    • Bupropion
    • Butyrophenones
    • Caffeine (in high amounts of 500 mgs and above could increase the occurrence of seizures,[12] particularly if normal sleep patterns are interrupted)
    • Chlorambucil
    • Ciclosporin
    • Clozapine
    • Corticosteroids
    • Diphenhydramine
    • Enflurane
    • Estrogens
    • Fentanyl
    • Insulin
    • Lidocaine
    • Maprotiline
    • Meperidine
    • Olanzapine
    • Pentazocine
    • Phenothiazines (such as chlorpromazine)
    • Prednisone
    • Procaine
    • Propofol
    • Propoxyphene
    • Quetiapine
    • Risperidone
    • Sevoflurane
    • Theophylline
    • Tramadol
    • Tricyclic antidepressants (especially clomipramine)
    • Venlafaxine
    • The following antibiotics: isoniazid, lindane, metronidazole, nalidixic acid, and penicillin, though vitamin B6 taken along with them may prevent seizures; also, fluoroquinolones and carbapenems

    Use of certain recreational drugs may lead to seizures in some, especially when used in high doses or for extended periods. These include amphetamines (such as amphetamine, methamphetamine, MDMA (“ecstasy”), and mephedrone), cocaine, methylphenidate, psilocybin, psilocin, and GHB.

    If treated with the wrong kind antiepileptic drugs (AED), seizures may increase, as most AEDs are developed to treat a particular type of seizure.

    Convulsant drugs (the functional opposites of anticonvulsants) will always induce seizures at sufficient doses. Examples of such agents — some of which are used or have been used clinically and others of which are naturally occurring toxins — include strychnine, bemegride, flumazenil, cyclothiazide, flurothyl, pentylenetetrazol, bicuculline, cicutoxin, and picrotoxin.

    Alcohol[edit]

    There are varying opinions on the likelihood of alcoholic beverages triggering a seizure. Consuming alcohol may temporarily reduce the likelihood of a seizure immediately following consumption. But, after the blood alcohol content has dropped, chances may increase. This may occur, even in non-epileptics.[13]

    Heavy drinking in particular has been shown to possibly have some effect on seizures in epileptics. But studies have not found light drinking to increase the likelihood of having a seizure at all.[citation needed] EEGs taken of patients immediately following light alcohol consumption have not revealed any increase in seizure activity.[14]

    Consuming alcohol with food is less likely to trigger a seizure than consuming it without.[15]

    Consuming alcohol while using many anticonvulsants may reduce the likelihood of the medication working properly. In some cases, it may trigger a seizure. Depending on the medication, the effects vary.[16]

    Drug withdrawal[edit]

    Some medicinal and recreational drugs can dose-dependently precipitate seizures in withdrawal, especially when withdrawing from high doses and/or chronic use. Examples include drugs that affect GABAergic and/or glutamatergic systems, such as alcohol (see alcohol withdrawal),[17] benzodiazepines, barbiturates, and anesthetics, among others.

    Sudden withdrawal from anticonvulsants may lead to seizures. It is for this reason that if a patient’s medication is changed, the patient will be weaned from the medication being discontinued following the start of a new medication.

    Missed anticonvulsants[edit]

    A missed dose or incorrectly timed dose of an anticonvulsant may be responsible for a breakthrough seizure, even if the person often missed doses in the past, and has not had a seizure as a result.[18] Missed doses are one of the most common reasons for a breakthrough seizure. A single missed dose is capable of triggering a seizure in some patients.[19]

    • Incorrect dosage amount: A patient may be receiving a sub-therapeutic level of the anticonvulsant.[20]
    • Switching medicines: This may include withdrawal of anticonvulsant medication without replacement, replaced with a less effective medication, or changed too rapidly to another anticonvulsant. In some cases, switching from brand to a generic version of the same medicine may induce a breakthrough seizure.[21][22]

    Fever[edit]

    In children between the ages of 6 months and 5 years, a fever of 38 °C (100.4 °F) or higher may lead to a febrile seizure.[23] About 2-5% of all children will experience such a seizure during their childhood.[24] In most cases, a febrile seizure will not indicate epilepsy.[24] Approximately 40% of children who experience a febrile seizure will have another one.[24]

    In those with epilepsy, fever can trigger a seizure. Additionally, in some, gastroenteritis, which causes vomiting and diarrhea, can lead to diminished absorption of anticonvulsants, thereby reducing protection against seizures.[25]

    Vision[edit]

    Main article: Photosensitive epilepsy

    Flashing light, such as that from a disco ball, can cause seizures in some people

    In some epileptics, flickering or flashing lights, such as strobe lights, can be responsible for the onset of a tonic clonic, absence, or myoclonic seizure.[26] This condition is known as photosensitive epilepsy and, in some cases, the seizures can be triggered by activities that are harmless to others, such as watching television or playing video games, or by driving or riding during daylight along a road with spaced trees, thereby simulating the “flashing light” effect. Some people can suffer a seizure as a result of blinking one’s own eyes.[27] Contrary to popular belief, this form of epilepsy is relatively uncommon, accounting for just 3% of all cases.[28]

    A routine part of the EEG test involves exposing the patient to flickering lights to attempt to induce a seizure, to determine if such lights may be triggering a seizure in the patient, and to be able to read the wavelengths when such a seizure occurs.[27]

    In rare cases seizures may be triggered by not focusing.[29]

    Head injury[edit]

    A severe head injury, such as one suffered in a motor vehicle accident, fall, assault, or sports injury, can result in one or more seizures that can occur immediately after the fact or up to a significant amount of time later.[30] This could be hours, days, or even years following the injury.

    A brain injury can cause seizure(s) because of the unusual amount of energy that is discharged across of the brain when the injury occurs and thereafter. When there is damage to the temporal lobe of the brain, there is a disruption of the supply of oxygen.[31]

    The risk of seizure(s) from a closed head injury is about 15%.[32] In some cases, a patient who has suffered a head injury is given anticonvulsants, even if no seizures have occurred, as a precaution to prevent them in the future.[33]

    Hypoglycemia[edit]

    Hypoglycemia, or low blood sugar, can result in seizures. The cause is an inadequate supply of glucose to the brain, resulting in neuroglycopenia. When brain glucose levels are sufficiently low, seizures may result.

    Hypoglycemic seizures are usually a complication of treatment of diabetes mellitus with insulin or oral medications. Less commonly, it can be the result of excessive insulin produced by the body (hyperinsulinemia) or other causes.

    Menstrual cycle[edit]

    In catamenial epilepsy, seizures become more common during a specific period of the menstrual cycle.

    Sleep deprivation[edit]

    Sleep deprivation is the second most common trigger of seizures.[13] In some cases, it has been responsible for the only seizure a person ever suffers.[34] However, the reason for which sleep deprivation can trigger a seizure is unknown. One possible thought is that the amount of sleep one gets affects the amount of electrical activity in one’s brain.[35]

    Patients who are scheduled for an EEG test are asked to deprive themselves of some sleep the night before to be able to determine if sleep deprivation may be responsible for seizures.[36]

    In some cases, patients with epilepsy are advised to sleep 6-7 consecutive hours as opposed to broken-up sleep (e.g., 6 hours at night and a 2-hour nap) and to avoid caffeine and sleeping pills in order to prevent seizures.[37]

    Parasites and stings[edit]

    In some cases, certain parasites can cause seizures. The Schistosoma sp. flukes cause Schistosomiasis. Pork tapeworm and beef tapeworm cause seizures when the parasite creates cysts at the brain. Echinococcosis, malaria, toxoplasmosis, African trypanosomiasis, and many other parasitic diseases can cause seizures.

    Seizures have been associated with insect stings. Reports suggest that patients stung by red imported fire ants (Solenopsis invicta) and Polistes wasps suffered seizures because of the venom.[38][39]

    Stress[edit]

    Stress can induce seizures in people with epilepsy, and is a risk factor for developing epilepsy. Severity, duration, and time at which stress occurs during development all contribute to frequency and susceptibility to developing epilepsy. It is one of the most frequently self-reported triggers in patients with epilepsy.[40][41]

    Stress exposure results in hormone release that mediates its effects in the brain. These hormones act on both excitatory and inhibitory neural synapses, resulting in hyper-excitability of neurons in the brain. The hippocampus is known to be a region that is highly sensitive to stress and prone to seizures. This is where mediators of stress interact with their target receptors to produce effects.[42]

    ‘Epileptic fits’ as a result of stress are common in literature and frequently appear in Elizabethan texts, where they are referred to as the ‘falling sickness’.[43]

    Breakthrough seizure[edit]

    A breakthrough seizure is an epileptic seizure that occurs despite the use of anticonvulsants that have otherwise successfully prevented seizures in the patient.[44]:456 Breakthrough seizures may be more dangerous than non-breakthrough seizures because they are unexpected by the patient, who may have considered themselves free from seizures and, therefore, not take any precautions.[45] Breakthrough seizures are more likely with a number of triggers.[46]:57 Often when a breakthrough seizure occurs in a person whose seizures have always been well controlled, there is a new underlying cause to the seizure.[47]

    Breakthrough seizures vary. Studies have shown the rates of breakthrough seizures ranging from 11–37%.[48] Treatment involves measuring the level of the anticonvulsant in the patient’s system and may include increasing the dosage of the existing medication, adding another medication to the existing one, or altogether switching medications.[49] A person with a breakthrough seizure may require hospitalization for observation.[44]:498

    Other[edit]

    • Acute illness: Some illnesses caused by viruses or bacteria may lead to a seizure, especially when vomiting or diarrhea occur, as this may reduce the absorption of the anticonvulsant.[46]:67
    • Malnutrition: May be the result of poor dietary habits, lack of access to proper nourishment, or fasting.[46]:68 In seizures that are controlled by diet in children, a child may break from the diet on their own.[50]
    • Music (as in musicogenic epilepsy) [51][52][53]

    References[edit]

  • ^ “Epilepsy Foundation”. 
  • ^ Jonathan H. Pincus; Gary J. Tucker (27 September 2002). Behavioral Neurology. Oxford University Press. p. 4. ISBN 978-0-19-803152-9. 
  • ^ 100 Questions & Answers About Epilepsy, Anuradha Singh, page 79
  • ^ Keyser, A.; De Bruijn, S.F.T.M. (1991). “Epileptic Manifestations and Vitamin B1Deficiency”. European Neurology. 31 (3): 121–5. doi:10.1159/000116660. PMID 2044623. 
  • ^ Fattal-Valevski, A.; Bloch-Mimouni, A.; Kivity, S.; Heyman, E.; Brezner, A.; Strausberg, R.; Inbar, D.; Kramer, U.; Goldberg-Stern, H. (2009). “Epilepsy in children with infantile thiamine deficiency”. Neurology. 73 (11): 828–33. doi:10.1212/WNL.0b013e3181b121f5. PMID 19571254. 
  • ^ Vitamin B-6 Dependency Syndromes at eMedicine
  • ^ Matsumoto, Arifumi; Shiga, Yusei; Shimizu, Hiroshi; Kimura, Itaru; Hisanaga, Kinya (2009). “Encephalomyelopathy due to vitamin B12 deficiency with seizures as a predominant symptom”. Rinsho Shinkeigaku. 49 (4): 179–85. doi:10.5692/clinicalneurol.49.179. PMID 19462816. 
  • ^ Kumar, S (2004). “Recurrent seizures: an unusual manifestation of vitamin B12 deficiency”. Neurology India. 52 (1): 122–3. PMID 15069260. 
  • ^ Mustafa TAŞKESEN; Ahmet YARAMIŞ; Selahattin KATAR; Ayfer GÖZÜ PİRİNÇÇİOĞLU; Murat SÖKER (2011). “Neurological presentations of nutritional vitamin B12 deficiency in 42 breastfed infants in Southeast Turkey” (PDF). Turk J Med Sci. TÜBİTAK. 41 (6): 1091–1096. 
  • ^ Yavuz, Halûk (2008). “‘Vitamin B12 deficiency and seizures'”. Developmental Medicine and Child Neurology. 50 (9): 720. doi:10.1111/j.1469-8749.2008.03083.x. PMID 18754925. 
  • ^ Morrell, Martha J. (2002). “Folic Acid and Epilepsy”. Epilepsy Currents. 2 (2): 31–34. doi:10.1046/j.1535-7597.2002.00017.x. PMC 320966 . PMID 15309159. 
  • ^ Devinsky, Orrin; Schachter, Steven; Pacia, Steven (2005). Complementary and Alternative Therapies for Epilepsy. New York, N.Y.: Demos Medical Pub. ISBN 9781888799897. 
  • ^ a b Engel, Jerome; Pedley, Timothy A.; Aicardi, Jean (2008). Epilepsy: A Comprehensive Textbook. Lippincott Williams & Wilkins. pp. 78–. ISBN 978-0-7817-5777-5. 
  • ^ Wilner, Andrew N. (1 November 2000). Epilepsy in Clinical Practice: A Case Study Approach. Demos Medical Publishing. pp. 92–. ISBN 978-1-888799-34-7. 
  • ^ “Epilepsy Foundation”. 
  • ^ Wilner, Andrew N. (1 November 2000). Epilepsy in Clinical Practice: A Case Study Approach. Demos Medical Publishing. pp. 93–. ISBN 978-1-888799-34-7. 
  • ^ Orrin Devinsky (1 January 2008). Epilepsy: Patient and Family Guide. Demos Medical Publishing, LLC. p. 63. ISBN 978-1-934559-91-8. 
  • ^ Orrin Devinsky (1 January 2008). Epilepsy: Patient and Family Guide. Demos Medical Publishing, LLC. p. 120. ISBN 978-1-934559-91-8. 
  • ^ Steven S. Agabegi; Elizabeth D. Agabegi (2008). Step-up to medicine. Lippincott Williams & Wilkins. p. 230. ISBN 978-0-7817-7153-5. 
  • ^ Crain, Ellen F.; Gershel, Jeffrey C. (2003). Clinical manual of emergency pediatrics (4th ed.). New York: McGraw-Hill, Medical Publishing Division. ISBN 9780071377508. 
  • ^ Singh, Anuradha (2009). 100 Questions & Answers About Your Child’s Epilepsy. 100 Questions & Answers. Sudbury, Massachusetts: Jones and Bartlett. ISBN 9780763755218. 
  • ^ MacDonald, J. T. (December 1987). “Breakthrough seizure following substitution of Depakene capsules (Abbott) with a generic product”. Neurology. 37 (12): 1885. doi:10.1212/wnl.37.12.1885. PMID 3120036. 
  • ^ Greenberg, David A.; Michael J. Aminoff; Roger P. Simon (2012). “12”. Clinical neurology (8th ed.). New York: McGraw-Hill Medical. ISBN 978-0071759052. 
  • ^ a b c Graves, RC; Oehler, K; Tingle, LE (Jan 15, 2012). “Febrile seizures: risks, evaluation, and prognosis”. American Family Physician. 85 (2): 149–53. PMID 22335215. 
  • ^ Orrin Devinsky (1 January 2008). Epilepsy: Patient and Family Guide. Demos Medical Publishing, LLC. p. 67. ISBN 978-1-934559-91-8. 
  • ^ Thomas R. Browne; Gregory L. Holmes (2008). Handbook of Epilepsy. Jones & Bartlett Learning. p. 129. ISBN 978-0-7817-7397-3. 
  • ^ a b Graham F A Harding; Peter M Jeavons (10 January 1994). Photosensitive Epilepsy. Cambridge University Press. p. 16. ISBN 978-1-898683-02-5. 
  • ^ [1]
  • ^ Wallace, Sheila J.; Farrell, Kevin (2004). Epilepsy in Children, 2E. CRC Press. p. 246. ISBN 9780340808146. 
  • ^ Overview of Head Injuries: Head Injuries Merck Manual Home Edition
  • ^ Diane Roberts Stoler (1998). Coping with Mild Traumatic Brain Injury. Penguin. p. 124. ISBN 978-0-89529-791-4. 
  • ^ Donald W. Marion (1999). Traumatic Brain Injury. Thieme. p. 107. ISBN 978-0-86577-727-9. 
  • ^ “Head Injury as a Cause of Epilepsy”. Archived from the original on 2011-06-23. Retrieved 2011-06-23. CS1 maint: BOT: original-url status unknown (link) Epilepsy Foundation
  • ^ “Can sleep deprivation trigger a seizure?”. Archived from the original on 2013-10-29. Retrieved 2013-10-29. CS1 maint: BOT: original-url status unknown (link)
  • ^ Orrin Devinsky (1 January 2008). Epilepsy: Patient and Family Guide. Demos Medical Publishing, LLC. p. 61. ISBN 978-1-934559-91-8. 
  • ^ Ilo E. Leppik, MD (24 October 2006). Epilepsy: A Guide to Balancing Your Life. Demos Medical Publishing. p. 136. ISBN 978-1-932603-20-0. 
  • ^ Orrin Devinsky (1 January 2008). Epilepsy: Patient and Family Guide. Demos Medical Publishing, LLC. p. 62. ISBN 978-1-934559-91-8. 
  • ^ Candiotti, Keith A.; Lamas, Ana M. (1993). “Adverse neurologic reactions to the sting of the imported fire ant”. International Archives of Allergy and Immunology. 102 (4): 417–420. doi:10.1159/000236592. PMID 8241804. 
  • ^ Gonzalo Garijo, M.A.; Bobadilla González, P.; Puyana Ruiz, J. (1995). “Epileptic attacks associated with wasp sting-induced anaphylaxis”. Journal of Investigational Allergology & Clinical Immunology. 6 (4): 277–279. PMID 8844507. 
  • ^ Nakken, Karl O.; Solaas, Marit H.; Kjeldsen, Marianne J.; Friis, Mogens L.; Pellock, John M.; Corey, Linda A. “Which seizure-precipitating factors do patients with epilepsy most frequently report?”. Epilepsy & Behavior. 6 (1): 85–89. doi:10.1016/j.yebeh.2004.11.003. 
  • ^ Haut, Sheryl R.; Hall, Charles B.; Masur, Jonathan; Lipton, Richard B. (2007-11-13). “Seizure occurrence: precipitants and prediction”. Neurology. 69 (20): 1905–1910. doi:10.1212/01.wnl.0000278112.48285.84. ISSN 1526-632X. PMID 17998482. 
  • ^ Gunn, B.G.; Baram, T.Z. “Stress and Seizures: Space, Time and Hippocampal Circuits”. Trends in Neurosciences. 40 (11): 667–679. doi:10.1016/j.tins.2017.08.004. 
  • ^ “Medscape Log In”. 
  • ^ a b American Academy of Orthopaedic Surgeons (2006). Emergency care and transportation of the sick and injured (9th ed.). Sudbury, Massachusetts: Jones and Bartlett. pp. 456, 498. ISBN 9780763744052. 
  • ^ Ettinger, Alan B.; Adiga, Radhika K. (2008). “Breakthrough Seizures—Approach to Prevention and Diagnosis”. US Neurology. 4 (1): 40–42. 
  • ^ a b c Devinsky, Orrin (2008). Epilepsy: Patient and Family Guide (3rd ed.). New York: Demos Medical Publishing. pp. 57–68. ISBN 9781932603415. 
  • ^ Lynn, D. Joanne; Newton, Herbert B.; Rae-Grant, Alexander D. (2004). The 5-Minute Neurology Consult. LWW medical book collection. Philadelphia: Lippincott Williams & Wilkins. p. 191. ISBN 9780683307238. 
  • ^ Pellock, John M.; Bourgeois, Blaise F.D.; Dodson, W. Edwin; Nordli, Jr., Douglas R.; Sankar, Raman (2008). Pediatric Epilepsy: Diagnosis and Therapy. Springer Demos Medicical Series (3rd ed.). New York: Demos Medical Publishing. p. 287. ISBN 9781933864167. 
  • ^ Engel, Jr., Jerome; Pedley, Timothy A.; Aicardi, Jean (2008). Epilepsy: A Comprehensive Textbook (2nd ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 9780781757775. 
  • ^ Freeman, John M.; Kossoff, Eric; Kelly, Millicent (2006). Ketogenic Diets: Treatments for Epilepsy. Demos Health Series (4th ed.). New York: Demos. p. 54. ISBN 9781932603187. 
  • ^ Stern, John (2015). “Musicogenic epilepsy”. Handbook of Clinical Neurology. 129: 469–477. doi:10.1016/B978-0-444-62630-1.00026-3. ISSN 0072-9752. PMID 25726285. 
  • ^ “music and epilepsy”. Epilepsy Society. 2015-08-10. Retrieved 2017-09-16. 
  • ^ Maguire, Melissa Jane (21 May 2012). “Music and epilepsy: a critical review”. Epilepsia. 53 (6): 947–61. doi:10.1111/j.1528-1167.2012.03523.x. 
  • Related disorders

    • Sudden unexpected death in epilepsy
    • Todd’s paresis
    • Landau-Kleffner syndrome
    • Epilepsy in animals

    Epilepsy
    organizations

    • Citizens United for Research in Epilepsy
    • Epilepsy Action
    • Epilepsy Action Australia
    • Epilepsy Foundation (USA)
    • Epilepsy Outlook (UK)
    • Epilepsy Research UK
    • Epilepsy Society


    Source: https://en.wikipedia.org/wiki/Causes_of_seizures