Herbal Highlight

With a lemony fragrant scent, agrimony has relaxing and calming qualities along with a gentle bitterness and astringency that makes it helpful for toning tissues that have become too relaxed or inflamed. UK herbalist Lucy Jones describes the energetics of agrimony as encouraging “us to reset the balance between tension and relaxation in our bodies.” She says it is for patients who ‘put on a brave face’, ‘hide their worries behind a happy countenance’ and who drive their tension deep inside their body, so that the surface seems relaxed and calm. “This is the classic British ‘stiff-upper-lip’ syndrome. We do not want to bother someone else with our troubles and prefer to keep up a pretence of all being well. This dual reality sets up a lot of tension in the body, so much so that a release valve can be needed. Often this is achieved by the person falling prey to addictive behaviours, such as excessive drug taking or alcohol consumption, or thrill-seeking behaviour patterns such as driving too fast…" Agrimony people “like partying hard” and are addicted to activities that “get their adrenaline flowing”, she says.  

However, agrimony is most often prescribed as a hepatic herb recommended for chronic liver disease, inflammation of the gallbladder and to increase the secretion of the bile in general. Its astringency has led to its use traditionally as an anti-inflammatory and wound healing herb. It is a good choice for a mouthwash for inflamed gums and a gargle for a sore throat. Adding an antispasmodic action to this means it can be helpful in cases of diarrhoea and irritable bowel syndrome. Another attribute is its use as a relaxing diuretic to support the urinary system in cases of cystitis, urinary stones and incontinence. Jones says “agrimony is one of those herbs that is a medicine chest in itself…It surprises me that it is not prescribed more widely by herbalists…” 

 The late matriarch of Australian herbal medicine, Dorothy Hall, concurs saying of agrimony: “all the great herbalists mention this plant: all agree on its major uses. This in itself is rare, but the plant was mostly prescribed then on its own as a ‘simple’ [the use of one herb at a time].” In his eponymous book, Weiss’s Herbal Medicine, the author points out in the chapter on Diseases of the Liver and Biliary Tract that “real success will only be achieved if [agrimony] is used consistently for some time.” Weiss ranks agrimony as a tonic bitter that is a “gentle antidiarrhoeic drug.” It is said to be especially useful in children with irritations and infections in the intestinal tract.

References

Jones L. A Working Herbal Dispensary. Aeon Books:Glasgow. 2023. p40-3

Jones L. A Working Herbal Dispensary. Aeon Books:Glasgow. 2023. p40-3

Hall D. Dorothy Hall’s Herbal Medicine. Sydney:Lothian. 1988. p. 78, 314.

Weiss R. Herbal Medicine.Stuttgart: Thieme, 2001. p. 93

Aloes is a tall, single stemmed plant with a rosette crown of thick and fleshy succulent leaves and striking orange-red flowers that make it a standout specimen along the south-central regions of southern Africa, where it originated. It is widely distributed throughout the tropics and subtropics where it is grown as an ornamental and medicinal plant valued for its colourless leaf 'gel' and bitter brown leaf exudate. 

Aloes leaf exudate was first exported from South Africa in 1761. The centuries-old local tradition of sustainably gathering leaves for this purpose continues in South Africa today. Around 200 to 300 mature leaves are removed from the plants, without harming or destroying them, and stacked around a central well. This usually happens during the rainy season because the exudate is more abundant. The pungent brown exudate drips from the cut surface of the leaves into the well. The leaves are usually cut in the morning and extraction takes about six hours. The exudate is then dried to yield a dark, glossy crystalline mass. Full time aloe harvesters tap and drain the leaves and are commonly referred to as ‘tappers’. Age-old, indigenous, responsible harvesting knowledge, practices and skills have been passed down over generations as a family custom that has changed little over time. 

Aloes is made from the yellow sap or latex found in specialised cells in the margins of the leaves beneath the thick leaf epidermis and the gel of the leaf, which is extracted and dried to make a dark crystalline substance. The word “Aloes” in pharmacopoeias and formularies refers to this herbal substance derived from the dried leaf juice. This has always created confusion due to the fact that the leaves are the source of two products “aloe dried juice” and “aloe gel”, which are quite different in their chemical composition and their therapeutic properties. Aloes is mainly used for its anthraquinone laxative effect. It should be administered for constipation in small doses, for limited periods, due to its side effects and habituating potential. The purgative effects of the dark sap are attributed to the action of reducing water reabsorption into the intestine and by directly stimulating the smooth muscle of the gut. It is recommended to consume it with carminative herbs, such as fennel (Foeniculum vulgare), angelica (Angelica archangelica) or ginger (Zingiber officinale), to prevent intestinal cramping and griping pain. Results can take 12 to 18 hours following consumption. Therefore, it should be consumed early in the evening to obtain results the following morning. 

References

Bhaludra CSS, Bethapudi RR, Murugulla AC, Pullagummi C, Latha T, Venkatesh K, et al. Cultivation, Phytochemical Studies, Biological Activities and Medicinal Uses of Aloe ferox, Grandfather of Aloes an Important Amazing Medicinal Plant. International Journal of Pharmacology. 2013;9: 405-415.

Aloe ferox Mill. Royal Botanic Gardens Kew Plants of the World Online. (accessed Feb 23 2024). Available from https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:529449-1/general-information

Steenkamp V, Stewart MJ. Medicinal Applications and Toxicological Activities of Aloe. Products, Pharmaceutical Biology. 2007;45:5, 411-420, DOI: 10.1080/13880200701215307

Assessment report on Aloe barbadensis Mill. and on Aloe (various species, mainly Aloe
ferox Mill. and its hybrids), folii succus siccatus. Committee on Herbal Medicinal Products (HMPC). Europaean Medicines Agency Science Medicines Health (updated 22 Nov 2016; accessed 25 Jan 2024). Available from https://www.ema.europa.eu/en/documents/herbal-report/final-assessment-report-aloe-barbadensis-mill-and-aloe-various-species-mainly-aloe-ferox-mill-and-its-hybrids-folii-succus-siccatus_en.pdf

Juniper is a small evergreen coniferous tree in the cypress family, with a strong aromatic scent, which makes an attractive ornamental for landscaping. Its “berries” aren’t technically berries at all but are actually seed cones whose fleshy scales merge to create the impression of a smooth, unified surface. The term juniper berry however has become widely accepted. Martini lovers will know juniper berries as being the main flavouring component of gin and they must be lightly crushed and distilled to release the “piney, citrusy, turpentiney flavour” so central to the spirit’s taste. They are also used as a seasoning to enliven game, marinades, poultry and sauerkraut. 

Juniper berries stimulate the functions of the kidney and bladder, making an excellent antiseptic and diuretic for urinary conditions such as cystitis. This diuretic action explains juniper’s traditional use in high blood pressure, congestive heart failure and premenstrual fluid retention. Its bitter action aids digestion and flatulence and stimulates the appetite. Juniper can also assist with rheumatism and arthritis as well as easing the pain in joints and muscles when applied externally. 

Likening the juniper person picture to Santa Claus, herbalist extraordinaire, the late Dorothy Hall, said juniper people are defined by fluid retention: “’Fat and jolly’ may be the personality-summation; a hearty, jovial, fun-loving person who is not only expansive by nature but also by the waistline! Falstaff, Shakespeare’s wine-bibbing, red-faced rotund declaimer of stories and fun, was a classic ‘Juniper’. In later life, dropsy [oedema] would follow.” 

References

O’Connell J. The Book of Spice. Profile Books:London. 2015 p.130

Hoffman D. The New Holistic Herbal. Melbourne:Element. 1990.p. 209

Hall D. Dorothy Hall’s Herbal Medicine. Sydney:Lothian. 1988. p. 207 

From the Leguminosae (Fabaceae: Mimosoideae), or legume, pea or bean family, albizia is native to tropical southern Asia and is widely distributed in Australia, Asia, Africa and Southern America. Commonly known as raintree, siris or Indian siris it is a large, fast growing, deciduous tree with highly scented white flowers in fluffy clusters and flat, thin, light brown pods which rattle in the wind when they brush together. Albizia grows to an average height of 25 metres and for this reason it is widely planted as an impressive shade tree around homesteads. 

Albizia is Ayurveda’s top anti-allergy herb which has been used for centuries for respiratory conditions, including hayfever and asthma, and allergic skin complaints such as eczema and hives. Despite its long use albizia has not been well studied in clinical trials however there is enough evidence to suggest it is an effective medicine, particularly for allergic conditions. Preclinical scientific evidence helps support the traditional use of albizia in inflammation. In one study the alcoholic extract of albizia has been reported to modulate histamine release which plays a major role in allergic diseases. 

In one single blind study 81 participants with asthma were given 50mL of albizia decoction three times daily for six weeks, supported by a light diet. At six weeks there was a significant increase in lung function and a decrease in total leucocyte count (which indicates infection), eosinophil count (which can indicate a parasitic infection, allergy or cancer) and erythrocyte sedimentation rate (helps detect inflammation in the body). Of the 50 participants who completed the trial more than half reported symptom reduction. 

References

Albizia lebbeck. James Cook University Australia c1995-2024. (accessed 13 Feb 2024). Available from https://www.jcu.edu.au/discover-nature-at-jcu/plants/plants-by-scientific-name2/albizia-lebbeck

Keighery GJ. The status of Albizia lebbeck (Fabaceae:Mimosoideae) in Western Australia. Nuytsia —The journal of the Western Australian Herbarium.7 July 2022;33:143-146.

Nurul IM, Mizuguchi H, Shahriar M, Venkatesh P, Maeyama K, Mukherjee PK, Hattori M, Choudhuri MS, Takeda N, Fukui H. Albizia lebbeck suppresses histamine signaling by the inhibition of histamine H1 receptor and histidine decarboxylase gene transcriptions. Int Immunopharmacol. 2011 Nov;11(11):1766-72. doi: 10.1016/j.intimp.2011.07.003. Epub 2011 Jul 21. PMID: 21782040.

Venkatesh P, Mukherjee PK, Kumar NS, Bandyopadhyay A, Fukui H, Mizuguchi H, Islam N. Anti-allergic activity of standardized extract of Albizia lebbeck with reference to catechin as a phytomarker. Immunopharmacol Immunotoxicol. 2010 Jun;32(2):272-6. doi: 10.3109/08923970903305481. PMID: 20109037.

Kumar S, Bansal P, Gupta V, Sannd R, Rao MM. The Clinical Effect of Albizia lebbeck Stem Bark Decoction on Bronchial Asthma. International Journal of Pharmaceutical Sciences and Drug Research. 2010;2(1):48–50.

Not to be confused with a different species in the verbena family, the highly scented lemon verbena (Aloysia citrodora), vervain, like so many other lilac-flowered plants, is primarily a nervine. It is considered specific for long standing nervous tension, especially helpful when a patient has been chronically stressed for an extended time. According to the Dorothy Hall vervain person-picture they are “detail” people, “conscientious, always busy and somewhat irritable.” This is echoed by UK herbalist Lucy Jones who says: “I always think of it for people who make lists…Vervain is specific for those who are perfectionists and carry the weight of the world on their shoulders…” She says another way of viewing this is that they carry most of their tension in their neck and shoulders. 

Vervain is also strongly bitter, which stimulates the liver and bile secretion, enhancing digestion. As a hepatic herb vervain encourages hormone balance meaning it can be helpful for menstrual irregularities, period pain, menopausal symptoms and premenstrual tension. Vervain also plays a role in balancing blood sugar and counteracting depression through its liver supporting action. 

It's no wonder then that Juliette de Bairacli Levy, deemed one of the grandmothers of contemporary herbalism, declared vervain a cure-all which, “along with red clover (Trifolium pratense), is known as God’s gift to man… In the plague years, vervain was one of the herbs recommended as a safeguard.” De Bairacli Levy said that while vervain is beneficial for all “ills” it is especially valuable for fevers. 

References

Hall D. Dorothy Hall’s Herbal Medicine. Sydney:Lothian. 1988. p301

Jones L. A Working Herbal Dispensary. Aeon Books:Glasgow. 2023. p362

Jones L. A Working Herbal Dispensary. Aeon Books:Glasgow. 2023. p362

de Bairacli Levy J. Common Herbs for Natural Health. Ash Tree Publishing:New York. 1997. p.165

Believed to be a hybrid of spearmint (Mentha spicata) and water mint (Mentha aquatica), the highly aromatic, pleasant tasting peppermint is a very popular herbal tea however it is also significantly medicinal and should not be underestimated as a herbal extract. It is often taken after meals because of its carminative properties but it should be avoided by people who are prone to heartburn, acid reflux or hiatus hernia. This is due to the fact that it relaxes the stomach and oesophageal valve, potentially exacerbating these conditions. Therefore it is best drunk as a tea, or taken as a liquid extract, when needed rather than as a daily habit. It is widely known to relieve digestive ailments including indigestion, flatulence, nausea and associated problems. 

It may come as a surprise to some people that while peppermint may be cooling at first it then warms the system and encourages sweating. It has been used in both traditional Chinese medicine and Western herbalism as a diaphoretic to address fevers that accompany colds and influenza. According to UK herbalist, Lucy Jones, although cooling in action superficially peppermint raises the internal heat of the body and encourages sweating but less strongly than some of the other diaphoretic herbs. 

Peppermint is one of the stars of a classic botanical blend of synergistic herbs that is still common today for the onset of colds and influenza. It is a combination of equal parts yarrow (Achillea millefolium), elder flowers (Sambucus nigra) and peppermint, colloquially known as Y.E.P.  Maud Grieve said “An infusion of equal quantities of Peppermint herb and Elder flowers (to which either Yarrow or Boneset may be added) will banish a cold or mild attack of influenza within thirty-six hours, and there is no danger of an overdose or any harmful action on the heart. Peppermint tea is used also for palpitation of the heart.” 

References

Jones L. A Working Herbal Dispensary. Aeon Books:Glasgow. 2023. p.275

Jones L. A Working Herbal Dispensary. Aeon Books:Glasgow. 2023. p.275

Grieve M. A Modern Herbal. Middlesex:Penguin Books. 1978

Rhubarb, also known as Da Huang, has been used medicinally in China for many centuries and is noted for the medicinal properties of its root. The Chinese Materia Medica described the traditional use including: “Purging heat and loosing the bowels, used for retention of the faeces and abdominal pain, fever with constipation and dysentery with inadequate discharge of the bowels…” In her famous book, A Modern Herbal published in 1931, Maud Grieve says R. palmatum, also called turkey rhubarb, can be distinguished from its relation, the familiar garden rhubarb (Rheum rhabarbarum), by its much larger size, the shape of its leaves and the “graceful looseness of its little panicles [cluster of flowers] of greenish-white flowers. The first buds which appear in spring are yellow, not red.” The flowers, however, can become purple-red as they grow. 

The use of rhubarb root as a laxative for use in constipation is recognised and well documented in authoritative texts. It is used for short-term use in cases of occasional constipation by promoting intestinal contraction and movement. The correct individual dose is the smallest required to produce a comfortable soft-formed motion. 

As a mild anthraquinone purgative rhubarb differs from other anthraquinone purgatives in that it exerts an astringent action after evacuation of the bowels. This makes it a true gut cleanser because it can firstly remove debris and then astringe the system with its antiseptic properties. It is therefore used traditionally as both a laxative and an antidiarrhoeal agent. The astringent bitter action predominates with small doses. To avoid any griping it is recommended to take rhubarb with carminatives such as ginger (Zingiber officinale). 

References

Grieve M. A Modern Herbal. Middlesex: Penguin Books; 1973. p. 676

European Medicines Agency. Assessment report on Rheum palmatum L. and Rheum
officinale Baillon, radix. Scientific Medicines Health. Committee on Herbal Medicinal Products (HMPC) (updated September 25 2019;accessed Jan 23 2024). Available from https://www.fitoterapia.net/archivos/201910/draft-assessment-report-rheum-palmatum-l-rheum-officinale-baillon-radix-revision-1_en.pdf?1

Xiang H, Zuo J, Guo F, Dong D. What we already know about rhubarb: a comprehensive review. Chin Med. 2020 Aug 26;15:88. doi: 10.1186/s13020-020-00370-6. PMID: 32863857; PMCID: PMC7448319

European Scientific Cooperative on Phytotherapy (ESCOP) Monographs. Rhei Radix Rhubarb. 2018.
Notaries House:United Kingdom

European Medicines Agency. Assessment report on Rheum palmatum L. and Rheum
officinale Baillon, radix. Scientific Medicines Health. Committee on Herbal Medicinal Products (HMPC) (updated September 25 2019;accessed Jan 23 2024). Available from https://www.fitoterapia.net/archivos/201910/draft-assessment-report-rheum-palmatum-l-rheum-officinale-baillon-radix-revision-1_en.pdf?1

Hoffmann D. Medical Herbalism. Rochester: Healing Arts Press. 2003. p. 577

Blue cohosh is from the Berberidaceae, or barberry, family. The plant has dark blue berries and small, white flowers. Blue cohosh is generally classed as a uterine tonic which has both stimulating and relaxing properties which facilitate childbirth, similar to raspberry (Rubus idaeus) and black cohosh (Actaea racemosa) which is not related despite the similar name. Blue cohosh produces contractions which are regular and effective, interspersed with a good relaxation period. It is said to be most helpful when delay in childbirth is due to weakness, fatigue or ‘lack of uterine power’. It was a favourite remedy amongst Native American women for false pains and after pains. Historically it was used to prepare the uterus for labour (partus praeparator), for period pain and for various ‘inflammations’ of the uterus. It also acts as a relaxant and tonic to the nervous system. Traditionally, blue cohosh has been used as a diaphoretic, diuretic, expectorant and for arthritis, but it is used most commonly in pregnancy and gynaecology, most specifically as a way to avoid conventional methods of induction. 

Case reports of adverse events in recent years, however, have called for an evaluation of the plant’s pharmacological and safety data. Reports of toxicity associated with blue cohosh, combined with its continued popularity as a natural birthing aid, prompted The American Herbal Pharmacopoeia (AHP) to publish a monograph. “Blue cohosh has been implicated in a few cases of toxicity that include neonatal cardiac toxicity and maternal toxicity,” said AHP Executive Director Roy Upton. “Because blue cohosh was the primary herb used in birthing practices of herbalists, integrated medical doctors, and midwives for more than 100 years, we felt it was important to address this concern.” The AHP monograph notes that Eclectic physicians in the latter part of the 19th and early part of the 20th centuries almost always used the herb in combination formulas, “which inherently limits the exposure to potentially toxic substances.” Upton says, ”it may still prove to be a safe and effective induction agent when used by highly trained and experienced birthing professionals, but concern regarding potential toxicity has limited its use in birthing.” A review of the data suggests that blue cohosh is indeed associated with certain adverse events reported, but confounding factors make it impossible to establish a causal relationship. The monograph stressed the “need to use the herb within the context of those most experienced with it and in the context of how it was most widely used traditionally, in combination with other botanicals.” 

A combination of blue and black cohosh has been shown to be effective in ripening the uterus for augmenting labour. There were claims of neurological toxicity in a newborn after using this combination however they were formally disputed on the grounds that the toxic effects suggested would only occur if much higher doses than reported were consumed. Caution is therefore advised with this herb during pregnancy. 

References

McIntyre A. The Complete Woman’s Herbal. Gai Books Limited:London. 1994. p. 26

Blue Cohosh Root & Rhizome monograph. American Herbal Pharmacopoeia. 2012.

Smith T. American Herbal Pharmacopoeia Publishes Blue Cohosh Monograph. HerbalGram Winter 2012;96:18. https://www.herbalgram.org/resources/herbalgram/issues/96/table-of-contents/hg96-orgnews-blkcohosh/

Trickey R. Women, Hormones and the Menstrual Cycle. 3rd edn. Fairfield: Melbourne Holistic Health Group. 2011. p. 293

A large plant belonging to the daisy family (Asteraceae), St. Mary’s thistle has a long-standing reputation as a bitter liver herb used as a preventative measure for liver damage caused by viruses, bacteria, fungi and chemical toxins. Perhaps of even more interest at this time of year, is the fact that the seeds of St. Mary’s thistle are often the first choice of herb to protect the liver from the ill effects of excessive alcohol consumption as they minimise hangovers and reduce toxic fatty degeneration of the liver.  

In practice, St. Mary’s thistle is commonly used for treating digestive disorders and any indication whereby improved liver function or liver protection may be a benefit. As well as being a general ‘liver cleansing’ agent, the seeds have been used traditionally to treat jaundice, hepatitis, haemorrhoids and psoriasis. The specific species name marianum preserves the legend that the white mottling surrounding the venation of the leaves was a result of a single drop of the Virgin Mary's milk as it gently fell onto the leaf surface. This medicinal plant is traditionally used as a galactogogue (stimulating milk production) and as a tonic for nursing mothers, perhaps contributing to the word origins of the other common name, milk thistle, along with the milky sap it exudes.  

There is often a connection between poor liver health and depression and St. Mary’s thistle is specific for depression that follows hepatitis. The British herbalist Gerard referred to it as ‘the best remedy that grows against all melancholy diseases.’ Melancholy, a term that is often equated with depression, derives its name from the Greek words ‘black bile’ and was treated historically with liver herbs, in addition to mood-enhancing plants. 

References

Jones L. A Working Herbal Dispensary. Aeon Books:Glasgow. 2023. p.237

Braun L, Cohen M. Essential Herbs and Natural Supplements. Chatswood:Elsevier. 2017. p. 866

HEC monograph

Known as a Christmas trimming associated with the ‘kissing under the mistletoe’ custom (the fictional young wizard Harry Potter had his first kiss this way), this romantic plant is more than just a holiday decoration. In ancient lore mistletoe signified life-force and fertility, hence the tradition of kissing under it, and it was considered a panacea with exceptional beneficial properties. Ethanolic liquid extracts of mistletoe have been widely used in folk medicine in Europe for blood pressure reduction. It has also been prescribed historically as a nervine for convulsions and epilepsy. In modern herbal medicine it is mostly chosen to help treat hypertension and insomnia. This semi-parasitic plant has also been used for more than 100 years in the complementary therapy of cancer and other immunological disorders. Several lines of evidence indicate that mistletoe improves patient survival, reduces the damage caused by conventional cancer therapies and increases patients’ quality of life. 

The relation between cancer and inflammation has been widely demonstrated. One researcher said, “inflammation and cancer dance together towards disaster”. Inflammation is considered a hallmark of cancer and related to the spread of the disease within the body and the resistance of cancer cells to the treatment. Chronic inflammation is closely related to oxidative stress and immunosuppression. A 2023 study researching the anti-inflammatory activity of mistletoe concluded that, although further data trials need to be performed, the examination of clinical and pharmacological evidence on the majority of oncological patients so far “allows us to consider European mistletoe extracts able to cause various anticancer achievements. This anticancer activity is matched with pro-apoptotic, antiproliferative and immunomodulatory effects, which are considered necessary to reduce the disease.” The researcher also said mistletoe can improve quality of life and treatment-related symptoms. 

In general, mistletoe does not kill its host tree as it needs the host alive for its own survival. It provides many habitat benefits for local native wildlife. The host plant chosen by mistletoe depends on the available flora. It can be found mostly in several deciduous and needle trees such as apple, linden, hawthorn, oak, elm, poplar, pines and firs. In Nigeria and Ghana it can be found on cocoa, kola and cashew trees. Mistletoe produces its own energy through photosynthesis, and can biosynthesise its own compounds, but it can also take some nutrients and water from the host trees. Pharmacologically active compounds pass from the host trees to the parasitic plants. Research from 2022 found that host trees play a key role in the phenolic profile and antioxidant capacity of mistletoe. 

References

Saha C, Das M, Stephen-Victor E, Friboulet A, Bayry J, Kaveri SV. Differential Effects of Viscum album Preparations on the Maturation and Activation of Human Dendritic Cells and CD4⁺ T Cell Responses. Molecules. 2016 Jul 14;21(7). pii: E912. doi: 10.3390/molecules21070912.

Melo MNO, Ochioni AC, Zancan P, Oliveira AP, Grazi M, Garrett R, Holandino C, Baumgartner S. Viscum album mother tinctures: Harvest conditions and host trees influence the plant metabolome and the glycolytic pathway of breast cancer cells. Front Pharmacol. 2022 Oct 31;13:1027931. doi: 10.3389/fphar.2022.1027931. PMID: 36386174; PMCID: PMC9662615.

Jones L. A Working Herbal Dispensary. Aeon Books:Glasgow. 2023. p239

Nicoletti M. The Anti-Inflammatory Activity of Viscum album. Plants (Basel). 2023 Mar 27;12(7):1460. doi: 10.3390/plants12071460. PMID: 37050086; PMCID: PMC10096603.

Nazaruk J, Orlikowski P. Phytochemical profile and therapeutic potential of Viscum album L. Nat Prod Res. 2016;30(4):373-85. doi: 10.1080/14786419.2015.1022776. Epub 2015 Mar 27. PMID: 25813519.