Propolis

• How It Works

  A few studies have investigated the efficacy of propolis in treating various conditions. However, further study is needed to determine whether propolis is an effective treatment for any of them.

  Propolis is a mixture of pollen, beeswax, and resin that is collected by honeybees from the buds and sap of certain trees and plants. It has been used in folk medicine and in food and drinks to improve health and prevent disease. Propolis is thought to be effective against cancer, diabetes, heart disease, infections, and inflammation. However, anticancer effects have not been confirmed in humans. Preliminary studies on the effect of topical propolis-containing products for cancer treatment-related oral ulcerations are mixed and more study is needed. In some instances propolis may actually have toxic effects.

  Bee pollen, found in propolis, is a mixture of plant pollens, nectar, and bee secretions that bees form into granules to store as food. It is claimed as a “cure all” by some and is thought to have antiaging and stamina-increasing properties, as well as antioxidant effects. Bee pollen has been used to treat chronic inflammation of the prostate, as well as other conditions. However, aside from its nutritional value, clinical data show that the benefits of bee pollen are limited.

  Allergic reactions to propolis and bee pollen have been reported. Therefore, patients who are allergic to bee venom (ie, bee stings), honey, ragweed, or chrysanthemum should not take either of these supplements. Bee pollen may increase the side effect of warfarin, a blood thinning drug.

• Purported Uses
  • Cancer
    Laboratory studies show that propolis has anticancer properties. One study on propolis supplementation for colon cancer prevention in high-risk patients found no benefit, and actually indicated potential negative effects on muscle tissues including heart muscle cells.
  • Cancer treatment-related oral ulcerations (mucositis)
    A few studies evaluating propolis-containing products have had mixed results. Additional studies are needed.
  • Diabetes
    There is no scientific evidence to support this use.
  • Heart disease
    This claim is not backed by clinical data.
  • Infections
    A few small studies suggest that propolis can be effective in treating ear infections. Larger studies are needed.
  • Inflammation
    Laboratory studies show that propolis has immunomodulatory effects. Human studies are needed.
• Do Not Take If
  • You are taking warfarin: Propolis can increase the time required for blood coagulation.
• Side Effects

  Hypersensitivity reactions

  The increased commercial use of propolis or bee pollen in cosmetics, supplement, food, and other industries, has led to a rise in reports of both skin and systemic reactions:

  Case Reports

   

  • Toxic reaction to sunlight: A 32-year-old woman experienced itching and rash with sun exposure after taking a dietary supplement containing ginseng, goldenseal, and bee pollen.
  • Lip swelling, pain, skin redness and inflammation: In an 18-year-old woman who used propolis spray for gum swelling caused by orthodontic bands.
  • Recurring lesion over a 1-year period: In a 55-year-old man related to the ingestion of bee pollen containing propolis.
  • Fungal infection and recurrent itchy eyelid rash: In a 28-year-old woman related to daily application of beeswax-containing lip gloss using her fingers.
  • Recurrent itchy widespread rash over a 3-year period: In a 65-year-old woman with non-Hodgkin B-cell lymphoma related to the hobby of glass beading which involved contact with beeswax.
  • Life-threatening deep neck infection that traveled into the chest cavity: In an otherwise healthy 40-year-old woman who took liquid propolis 3 times daily for 1 week to relieve common cold symptoms, requiring chest surgery.
  • Tumor mimicking lung cancer: In a 36-year-old woman caused by the inhalation of long-term topically applied propolis on nasal passages to treat asthma. Interestingly, this patient tested negative to pollen allergies both before and after this adverse event occurred, even though this effect was confirmed to be related to the product.
  • Acute kidney failure: In a 59-year-old man requiring dialysis after ingesting propolis for 2 weeks.
• Special Point

  Propolis is not a recommended treatment for ear infections. If an ear infection is suspected, a physician should be immediately consulted for advice regarding appropriate treatment.

• Clinical Summary

  Propolis is a resinous mixture of pollen and beeswax collected by honeybees from the buds and exudates of certain trees and plants ⁽¹⁾. It has been used in folk medicine and in food and beverages to improve health and prevent disease. Propolis is thought to have antibacterial, antiviral, antifungal, anti-inflammatory, antioxidant, immunostimulatory, antiproliferative, vasomodulatory, cardioprotective, and radioprotective properties ^{(2) (3) (15) (16)}.

  In vitro studies demonstrate synergistic antimicrobial effects when propolis is used with honey or ethyl alcohol ⁽¹⁷⁾ . Propolis also enhanced the antitumor effects of temozolomide in human glioblastoma cell lines ⁽¹⁸⁾. Another study found propolis to have greater cytotoxic activity against human lung adenocarcinoma and fibrosarcoma cells compared with 5-fluorouracil ⁽⁷⁾. Propolis and several of its constituents demonstrated anticancer activities in several human cancer cell lines ^{(19) (20) (21) (22) (23)}.

  In animal models, propolis and its constituents have demonstrated cardiovascular ⁽²⁴⁾, wound-healing ^(25) (26), and antitumor activities ^(27) (28).

  Despite the number of laboratory studies, very few clinical trials of propolis have been conducted. Topical propolis extract may be helpful in treat fungal foot infections, but confirmatory studies are needed ⁽²⁹⁾. A pilot study suggests ethanolic propolis extract reduces microbial count and improves symptoms from periodontal treatment ⁽³⁰⁾. Clinical data also show propolis to be an effective adjuvant treatment for asthma ⁽⁴⁾, and to treat plane and common warts ⁽⁵⁾. A propolis/zinc suspension reduced the number of acute otitis media infections in children ⁽⁶⁾.

  Only a few trials evaluate propolis for cancer and treatment-related mucositis. In a pilot randomized placebo-controlled double-blind study, supplemental propolis was not effective for colon cancer prevention and suggested negative effects on muscle tissues including myocardial cells ⁽³¹⁾. The effects of propolis on chemotherapy-induced mucositis are thus far equivocal with results from only two small double-blind controlled trials: one in adults with grade 2/3 mucositis found benefits with both the topical application of honey and a proprietary mixture of honey, olive oil-propolis extract, and beeswax compared with controls ⁽³²⁾, but another in pediatric patients with severe mucositis self-administering topical propolis alone did not find benefit ⁽³³⁾. An open-label study evaluating a mucoadhesive propolis gel for mucositis did find benefit, but confirmatory studies are needed ⁽³⁴⁾.

  Bee pollen, a constituent of propolis, is a mixture of plant pollens, nectar, and bee saliva that bees form into granules to store as food ⁽⁸⁾. It is claimed as a “cure all” by some and is touted for its antiaging and stamina-increasing properties, antioxidant effects, and for chronic prostatitis, among other conditions. Aside from its nutritional value, clinical data show that bee pollen has limited benefits in improving athletic performance ^(9) (10).

  The use of propolis and bee pollen is relatively benign. However, hypersensitivity reactions to each of these supplements have been reported.

  In addition, although a number of laboratory studies indicate anticancer effects, propolis or its constituents may also act as pro-oxidants ⁽³⁵⁾, produce cytotoxic effects in normal cells ^{(31) (36) (37) (38)}, and/or have mutagenic activity ^(39) (40) under certain circumstances indicating that risk versus benefit also needs further evaluation.

• Purported Uses
  • Cancer
  • Mucositis
  • Diabetes
  • Heart disease
  • Infections
  • Inflammation
• Mechanism of Action

  In vitro studies have identified a number of active propolis constituents and their potential mechanisms. Generally, antimicrobial and antioxidant activities are related to total phenolic contents ⁽¹⁵⁾; caffeic acid phenethyl ester (CAPE) and artepillin C are well-known anti-inflammatory components ⁽²⁵⁾; and the main active anticancer constituents are CAPE and chrysin ⁽²³⁾. However, all of these constituents also possess these other characteristics to some degree and vary with geographic origin.

  CAPE specifically inhibits nuclear factor-kappaB (NF-kB) ⁽⁴¹⁾. In human breast cancer cells, it also inhibits MDR gene expression, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) ⁽²⁰⁾. CAPE decreased malignancy potential of breast cancer stem cells via inhibition of self-renewal, progenitor formation, and clonal growth, and significantly decreased CD44 expression ⁽⁴²⁾. CAPE-initiated S- and G2/M-phase cell-cycle arrests and apoptosis in human cervical cancer lines was associated with increased E2F-1 expression ⁽⁴³⁾.

  The flavonoid chrysin demonstrated photoprotective effects by attenuating UVA- and UVB-induced apoptosis, reactive oxygen species (ROS) production, and cyclooxygenase 2 (COX-2) expression ⁽⁴⁴⁾. Chrysin is an inhibitor of aromatase, an enzyme converting testosterone into estrogen ⁽³⁹⁾. It is also a histone deacetylase (HDAC) inhibitor and inhibited HDAC8 enzymatic activity and tumor growth in human breast cancer cell lines ⁽²³⁾. Chrysin may overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance through Mcl-1 downregulation via STAT3 phosphorylation inhibition ⁽⁴⁵⁾. A novel chrysin-organogermanium complex demonstrated inhibitory effects across several human cancer cell lines, with high selectivity between cancer cells and normal cells causing membrane toxicity as demonstrated by decreased cell rigidity and adhesion force, and apoptosis via ROS-dependent mitochondrial pathways ⁽⁴⁶⁾.

  The phenolic compound artepillin C is the major constituent that stimulates pungent taste by activating TRPA1 channels ⁽⁴⁷⁾. Its immune-modulating effects are attributed to suppression of interleukin (IL)-2, interferon (IFN)-gamma and IL-17 expression in alloreactive CD4 T cells, suggesting its potential in treating graft versus host disease ⁽⁴⁸⁾. Artepillin C also sensitizes prostate cancer cells to TRAIL-induced apoptosis by engaging both extrinsic receptor-mediated and intrinsic mitochondrial apoptotic pathways ⁽²¹⁾. In different tumor cell lines, artepillin C and baccharin were found to be more cytotoxic than propolis, without additive or synergistic effects when combined ⁽⁴⁹⁾.

  Induction and/or inhibition of hypoxia-inducible factor-1alpha (HIF-1) and HIF-1 target genes also been demonstrated with other constituents, including polyphenols, cinnamic acid derivatives baccharin and drupanin, and the flavonoids beturetol and isosakuranetin ^(50) (51). Baccharin plus drupanin particularly exerted synergistic growth-inhibitory effects, via intrinsic and extrinsic apoptotic signaling transduction and by modulating miRNA expression ⁽²²⁾. Baccharin demonstrates highly selective inhibition of human aldo-keto reductase superfamily (AKR1C3), and suppressed proliferation of PC3 prostate cancer cells stimulated by AKR1C3 overexpression ⁽⁵²⁾. A synthesized baccharin derivative also demonstrated AKR1C3 inhibition ⁽⁵³⁾.

  Several compounds mostly belonging to the polycyclic polyprenylated acylphloroglucinols class demonstrated selective targeting of chemotherapy-refractory neuroblastoma cancer stem cells by acting in a pleiotropic manner, including strong disruption of tubulin polymerization and inhibition of replicative enzymes like toposimerases I/II and DNA polymerase ⁽⁵⁴⁾.

  In vitro studies of propolis as a whole demonstrate significant free-radical scavenging activity and anti-inflammatory effects by modulating key inflammatory mediators of mRNA transcription, inhibiting specific inflammatory cytokines, and blocking NF-kB activation ⁽⁵⁵⁾. Propolis was also found to inhibit proliferation and induce apoptosis in human leukemia cells through activation of caspase-3 via the mitochondrial pathway ⁽²⁾. Apoptotic induction in human breast cancer cells occurs partly through endoplasmic reticulum stress-related signaling ⁽¹⁹⁾, and synergy between propolis and temozolomide in human glioblastoma cell lines is also partly attributed to reduced NF-kB activity ⁽¹⁸⁾.

  In animal models, an ethanolic propolis extract may enhance reverse cholesterol transport via stimulated plasma HDL levels and hepatic ABCA1 and ABCG1 expression ⁽²⁴⁾. Propolis promotes wound-healing by exerting effects on mast cells that result in downregulation of type I allergy and inflammation ⁽²⁵⁾ and modifying fibronectin metabolism ⁽²⁶⁾. Immunomodulatory effects occurred through increased toll-like receptor expression and IL-1beta and IL-6 production ⁽¹²⁾. Pretreatment with orally-administered propolis extract reduced doxorubicin-induced oxidative damage to heart mitochondria ⁽³⁾. Diabetic hepatorenal damage was attentuated via antioxidant activity including free-radical scavenging, and was more pronounced in ethanol than water extracts ⁽⁵⁶⁾. In human colon cancer models, oral propolis at doses that caused no detectable toxicity was associated with a decrease in mitotic cells and Ki-67 expression as well as increased endoreduplications and p53 expression, and apoptosis in leukemia cells was associated with downregulation of Bcl-2 and Bax activation ⁽²⁷⁾.

• Contraindications

  Patients allergic to bee stings (bee venom), intolerance to honey, or allergic to ragweed/chrysanthemums should avoid products containing bee pollen, such as propolis ⁽⁸⁾.

• Adverse Reactions

  Hypersensitivity reactions

  Propolis has strong sensitizing properties and is well documented as an occupational contact allergen. However, due to its increased use in cosmetics, supplement, food, and other industries, there has also been a rise in nonoccupational contact allergy reports as well as systemic reactions:

  Case Reports

  • Photosensitivity reaction: Itching and rash in a 32-year-old woman after taking a dietary supplement containing ginseng, goldenseal and bee pollen ⁽¹⁴⁾.
  • Contact cheilitis and perioral dermatitis: Lip edema, perioral skin erythema accompanied by lip burning pain in an 18-year-old woman with self-prescribed topical use of propolis spray as a medication for gingival swelling caused by orthodontic molar bands ⁽⁵⁷⁾.
  • 1-year history of a recurrent lesion: In a 55-year-old man attributed to ingestion of bee pollen containing propolis. The lesion eventually cleared with cessation of the natural product used and erupted again with subsequent substance re-challenge, confirming product reaction ⁽⁵⁸⁾.
  • Ectopic periorbital dermatitis and mycosis: In a 28-year-old woman with a 4-month history of recurrent itchy rash of the eyelids. Patch testing included positive reactions to propolis. Daily application of beeswax-containing lip gloss using her fingers implicated propolis in beeswax as the relevant allergen ⁽⁵⁹⁾.
  • Fungoides-like dermatitis: In a 65-year-old woman with non-Hodgkin B-cell lymphoma and 3-year history of a recurrent itchy widespread rash. Patch testing included positive reactions to propolis. Her reaction was related to the hobby of glass beading which involved contact with beeswax ⁽⁵⁹⁾.
  • Descending necrotizing mediastinitis and aspiration pneumonia: In an otherwise healthy 40-year-old woman who took liquid propolis 3 times daily for 1 week to relieve common cold symptoms. Severe sore throat, difficulty swallowing, easy choking, and fever and chills developed. Thoracoscopic surgery to achieve immediate and adequate drainage was necessary for this life-threatening reaction ⁽⁶⁰⁾.
  • Propolis aspiration mimicking lung cancer: In a 36-year-old woman who presented with a pulmonary tumor with high carcinoembryonic antigen titer caused by chronic aspiration from propolis topically applied on nasal mucosa as 6 months’ adjuvant therapy for her asthma. Interestingly, this patient had negative allergen-specific IgE assay results for all common inhalant allergens, including pollen, before and after this adverse event ⁽⁶¹⁾.
  • Acute renal failure requiring hemodialysis: In a 59-year-old man requiring hemodialysis after ingestion of propolis for 2 weeks ⁽⁶²⁾.
• Herb-Drug Interactions
  • Warfarin: A published case report described a probable interaction between warfarin and honeybee pollen, which caused an increase in the international normalized ratio (INR) ⁽⁸⁾.
• Herb Lab Interactions

  Bee pollen in propolis contains flavonoids that are known to inhibit cytochrome P450 (CYP) isoenzyme 2C9 in vitro. Because this isoenzyme is responsible for much of the hepatic metabolism of warfarin, its inhibition may elevate the International Normalized Ratio (INR) ⁽⁸⁾.

• References

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  2. Eom HS, Lee EJ, Yoon BS, et al. Propolis inhibits the proliferation of human leukaemia HL-60 cells by inducing apoptosis through the mitochondrial pathway. Nat Prod Res. 2010 Mar;24(4):375-86.

  3. Alyane M, Kebsa LB, Boussenane HN, et al. Cardioprotective effects and mechanism of action of polyphenols extracted from propolis against doxorubicin toxicity. Pak J Pharm Sci. 2008 Jul;21(3):201-9.

  4. Khayyal MT, el-Ghazaly MA, el-Khatib AS, et al. A clinical pharmacological study of the potential beneficial effects of a propolis food product as an adjuvant in asthmatic patients. Fundam Clin Pharmacol. 2003 Feb;17(1):93-102.

  5. Zedan H, Hofny ER, Ismail SA. Propolis as an alternative treatment for cutaneous warts. Int J Dermatol. 2009 Nov;48(11):1246-9.

  6. Marchisio P, Esposito S, Bianchini S, et al. Effectiveness of a propolis and zinc solution in preventing acute otitis media in children with a history of recurrent acute otitis media. Int J Immunopathol Pharmacol. 2010 Apr-Jun;23(2):567-75.

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  19. Kamiya T, Nishihara H, Hara H, et al. Ethanol extract of Brazilian red propolis induces apoptosis in human breast cancer MCF-7 cells through endoplasmic reticulum stress. J Agric Food Chem. Nov 7 2012;60(44):11065-11070.

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  24. Yu Y, Si Y, Song G, et al. Ethanolic extract of propolis promotes reverse cholesterol transport and the expression of ATP-binding cassette transporter A1 and G1 in mice. Lipids. Sep 2011;46(9):805-811.

  25. Chirumbolo S. Flavonoids in propolis acting on mast cell-mediated wound healing. Inflammopharmacology. Apr 2012;20(2):99-101.

  26. Olczyk P, Komosinska-Vassev K, Wisowski G, et al. Propolis modulates fibronectin expression in the matrix of thermal injury. Biomed Res Int. 2014;2014:748101.

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  31. Ishikawa H, Goto M, Matsuura N, et al. A pilot, randomized, placebo-controlled, double-blind phase 0/biomarker study on effect of artepillin C-rich extract of Brazilian propolis in frequent colorectal adenoma polyp patients. J Am Coll Nutr. Oct 2012;31(5):327-337.

  32. Abdulrhman M, Elbarbary NS, Ahmed Amin D, et al. Honey and a mixture of honey, beeswax, and olive oil-propolis extract in treatment of chemotherapy-induced oral mucositis: a randomized controlled pilot study. Pediatr Hematol Oncol. Apr 2012;29(3):285-292.

  33. Tomazevic T, Jazbec J. A double blind randomised placebo controlled study of propolis (bee glue) effectiveness in the treatment of severe oral mucositis in chemotherapy treated children. Complement Ther Med. Aug 2013;21(4):306-312.

  34. Noronha VR, Araujo GS, Gomes RT, et al. Mucoadhesive propolis gel for prevention of radiation-induced oral mucositis. Curr Clin Pharmacol. 2014;9(4):359-364.

  35. Tsai YC, Wang YH, Liou CC, et al. Induction of oxidative DNA damage by flavonoids of propolis: its mechanism and implication about antioxidant capacity. Chem Res Toxicol. Jan 13 2012;25(1):191-196.

  36. Markiewicz-Zukowska R, Car H, Naliwajko SK, et al. Ethanolic extract of propolis, chrysin, CAPE inhibit human astroglia cells. Adv Med Sci. 2012;57(2):208-216.

  37. Calhelha RC, Falcao S, Queiroz MJ, et al. Cytotoxicity of Portuguese propolis: the proximity of the in vitro doses for tumor and normal cell lines. 2014;2014:897361.

  38. Pardo Andreu GL, Reis FH, Dalalio FM, et al. The cytotoxic effects of brown Cuban propolis depend on the nemorosone content and may be mediated by mitochondrial uncoupling. Chem Biol Interact. Feb 25 2015;228:28-34.

  39. Oliveira GA, Ferraz ER, Souza AO, et al. Evaluation of the mutagenic activity of chrysin, a flavonoid inhibitor of the aromatization process. J Toxicol Environ Health A. 2012;75(16-17):1000-1011.

  40. Montoro A, Soriano JM, Barquinero JF, et al. Assessment in vitro of cytogenetic and genotoxic effects of propolis on human lymphocytes. Food Chem Toxicol. Feb 2012;50(2):216-221.

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  43. Hsu TH, Chu CC, Hung MW, et al. Caffeic acid phenethyl ester induces E2F-1-mediated growth inhibition and cell-cycle arrest in human cervical cancer cells. FEBS J. Jun 2013;280(11):2581-2593.

  44. Wu NL, Fang JY, Chen M, et al. Chrysin protects epidermal keratinocytes from UVA- and UVB-induced damage. J Agric Food Chem. Aug 10 2011;59(15):8391-8400.

  45. Lirdprapamongkol K, Sakurai H, Abdelhamed S, et al. Chrysin overcomes TRAIL resistance of cancer cells through Mcl-1 downregulation by inhibiting STAT3 phosphorylation. Int J Oncol. Jul 2013;43(1):329-337.

  46. Yang F, Jin H, Pi J, et al. Anti-tumor activity evaluation of novel chrysin-organogermanium(IV) complex in MCF-7 cells. Bioorg Med Chem Lett. Oct 15 2013;23(20):5544-5551.

  47. Hata T, Tazawa S, Ohta S, et al. Artepillin C, a major ingredient of Brazilian propolis, induces a pungent taste by activating TRPA1 channels. PLoS One. 2012;7(11):e48072.

  48. Cheung KW, Sze DM, Chan WK, et al. Brazilian green propolis and its constituent, Artepillin C inhibits allogeneic activated human CD4 T cells expansion and activation. J Ethnopharmacol. Nov 18 2011;138(2):463-471.

  49. de Oliveira PF, de Souza Lima IM, Munari CC, et al. Comparative evaluation of antiproliferative effects of Brazilian green propolis, its main source Baccharis dracunculifolia, and their major constituents artepillin C and baccharin. Planta Med. Apr 2014;80(6):490-492.

  50. Hattori H, Okuda K, Murase T, et al. Isolation, identification, and biological evaluation of HIF-1-modulating compounds from Brazilian green propolis. Bioorg Med Chem. Sep 15 2011;19(18):5392-5401.

  51. Daleprane JB, Schmid T, Dehne N, et al. Suppression of hypoxia-inducible factor-1alpha contributes to the antiangiogenic activity of red propolis polyphenols in human endothelial cells. J Nutr. Mar 2012;142(3):441-447.

  52. Endo S, Matsunaga T, Kanamori A, et al. Selective inhibition of human type-5 17beta-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis. J Nat Prod. Apr 27 2012;75(4):716-721.

  53. Endo S, Hu D, Matsunaga T, et al. Synthesis of non-prenyl analogues of baccharin as selective and potent inhibitors for aldo-keto reductase 1C3. Bioorg Med Chem. Oct 1 2014;22(19):5220-5233.

  54. Diaz-Carballo D, Acikelli AH, Bardenheuer W, et al. Identification of compounds that selectively target highly chemotherapy refractory neuroblastoma cancer stem cells. Int J Clin Pharmacol Ther. Sep 2014;52(9):787-801.

  55. Wang K, Zhang J, Ping S, et al. Anti-inflammatory effects of ethanol extracts of Chinese propolis and buds from poplar (Populus x canadensis). J Ethnopharmacol. Aug 8 2014;155(1):300-311.

  56. Orsolic N, Sirovina D, Koncic MZ, et al. Effect of Croatian propolis on diabetic nephropathy and liver toxicity in mice. BMC Complement Altern Med. 2012;12:117.

  57. Budimir V, Brailo V, Alajbeg I, et al. Allergic contact cheilitis and perioral dermatitis caused by propolis: case report. Acta Dermatovenerol Croat. 2012;20(3):187-190.

  58. Ramien ML, Pratt MD. Fixed drug eruption to ingested propolis. Dermatitis. Jul-Aug 2012;23(4):173-175.

  59. Baker L, Litzner B, Le EN, et al. Ectopic periorbital dermatitis and mycosis fungoides-like dermatitis due to propolis. Dermatitis. Nov-Dec 2013;24(6):328-329.

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  61. Lin WC, Tseng YT, Chang YL, et al. Pulmonary tumour with high carcinoembryonic antigen titre caused by chronic propolis aspiration. Eur Respir J. Dec 2007;30(6):1227-1230.

  62. Li YJ, Lin JL, Yang CW, et al. Acute renal failure induced by a Brazilian variety of propolis. Am J Kidney Dis. Dec 2005;46(6):e125-129.