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Over 4.5 billion people are at risk of infection with soil transmitted helminths and there are concerns about the development of resistance to the handful of frontline nematocides in endemic populations. We investigated the anti-nematode efficacy of a series of polypyridylruthenium(II) complexes and showed they were active against L3 and adult stages of Trichuris muris , the rodent homologue of the causative agent of human trichuriasis, T. trichiura . One of the compounds, Rubb 12 -mono, which was among the most potent in its ability to kill L3 (IC 50 = 3.1 ± 0.4 μM) and adult (IC 50 = 5.2 ± 0.3 μM) stage worms was assessed for efficacy in a mouse model of trichuriasis by administering 3 consecutive daily oral doses of the drug 3 weeks post infection with the murine whipworm Trichuris muris . Mice treated with Rubb 12 -mono showed an average 66% reduction ( P = 0.015) in faecal egg count over two independent trials. The drugs partially exerted their activity through inhibition of acetylcholinesterases, as worms treated in vitro and in vivo showed significant decreases in the activity of this class of enzymes. Our data show that ruthenium complexes are effective against T. muris , a model gastro-intestinal nematode and soil-transmitted helminth. Further, knowledge of the target of ruthenium drugs can facilitate modification of current compounds to identify analogues which are even more effective and selective against Trichuris and other helminths of human and veterinary importance. [ABSTRACT FROM AUTHOR]

Bhutanese traditional medicine (BTM) is an integral part of the mainstream health care system in Bhutan. It uses more than 230 species of medicinal plants, including the Meconopsis species. Although traditional BTM methods are used to check the quality of medicinal plants, these methods have limitations in differentiating the closely related species. There is a need for integrating traditional methods with modern analytical techniques to efficiently monitor the quality and safety of medicinal plants. Here, we studied two closely related Meconopsis species using both traditional and modern analytical approaches. Meconopsis horridula Hook. F & Thompson and Meconopsis simplicifolia (D. Don) Walpers were collected from Lingzhi, Bhutan. The samples were tested and compared for physicochemical properties and extractive values. Their microscopy and High-Performance Thin-Layer Chromatography (HPTLC) profiles were also compared. A literature review was performed to document isolated phytochemicals and their biological activities. Two Meconopsis species revealed distinct macro-and microscopic characteristics. The physicochemical analysis and the HPTLC fingerprinting generated adequate data to authenticate these two species while preparing 16 essential traditional medicine drugs (ETMDs) in BTM. A literature review revealed that the two Meconopsis species contain alkaloids and flavonoids, which can be used as biomarker compounds for quality screening. M. horridula and M. simplicifolia could be differentiated based on their taxonomical features, macroscopic and microscopic characteristics, HPTLC fingerprint profiles, and physicochemical values. The accomplished pharmacognostic properties of the two species can be used as important parameters in ensuring the quality and safety of BTM. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: The aerial components of Meconopsis simplicifolia (D. Don) Walpers are indicated in Bhutanese traditional medicine for treating malaria, coughs and colds, and the infections of the liver, lung and blood. This study is to validate the ethnopharmacological uses of this plant and also identify potent antimalarial drug leads through bioassays of its crude extracts and phytochemical constituents. Materials and methods: Meconopsis simplicifolia (D. Don) Walpers was collected from Bhutan and its crude MeOH extract was subjected to acid-base fractionation. Through repeated extractions, separations and spectroscopic analysis, the alkaloids obtained were identified and tested for their antimalarial and cytotoxicity activities. Results: Phytochemical studies resulted in the isolation of one new protoberberine type alkaloid which we named as simplicifolianine and five known alkaloids: protopine, norsanguinarine, dihydrosanguinarine, 6-methoxydihydrosanguinarine and oxysanguinarine. Among the five of the alkaloids tested, simplicifolianine showed the most potent antiplasmodial activities against the Plasmodium falciparum strains, TM4/8.2 (chloroquine–antifolate sensitive strain) and K1CB1 (multidrug resistant strain) with IC 50 values of 0.78μg/mL and 1.29μg/mL, respectively. The compounds tested did not show any significant cytotoxicity activities against human oral carcinoma KB cells and normal Vero cells of African kidney epithelial cells. Conclusions: This study validated the traditional uses of the plant for the treatment of malaria and identified a new alkaloid, simplicifolianine as a potential antimalarial drug lead. [Copyright &y& Elsevier]

Bhutanese Sowa Rigpa Medicine (BSM) uses two species of Aconitum in 25 important multi-ingredient formulations. The formulations are used for treating chronic disoders, parasitic and microbial infections, inflammatory diseases, bilious fever, or high fever related to bile disorders, including colds and flu. Some Aconitum species are toxic, and there is a need for stringent quality control measures. Aconitum orochryseum Stapf and Aconitum laciniatum (Bruehl) Stapf, were collected from Lingzhi, which is geographically located under Thimphu district, Bhutan, between the altitudes of 4000–4900 meters above sea level (masl), between July and September. Their comparative pharmacognostic properties were evaluated by: 1) using physicochemical parameters, such as foreign matter and moisture contents, total ash, acid-insoluble ash and alcohol-soluble extracts values and loss on drying of individual crude drugs; 2) developing a comparative High-Performance Thin Layer Chromatography (HPTLC) fingerprint, at Menjong Sorig Pharmaceuticals Corporation Limited (MSCPL), - Bhutan and 3) conducting a literature review to identify the nature and toxicity of alkaloids present in two Aconitum species. Two Aconitum species possess distinct macros- and micros-copic characteristic features (including colour, taste, smell, appearance, and shape). The physicochemical analysis and the HPTLC fingerprinting of their methanol extracts yielded adequate data to differentiate and validate these two species' identities, before adding them to 25 essential traditional medicine drugs (ETMDs) or polyherbal formulations in BSM. A literature review revealed that the two Aconitum species contained two distinct types of alkaloids. Two Aconitum species could be differentiated based on their botanical features, macros- and micros-copic characteristics, physicochemical values and HPTLC fingerprint profiles. These pharmacognostic properties can be used as quality control parameters to confirm the two species' identity, thereby ensuring the quality and safety of BSM. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Seven studied medicinal plants; Aconitum laciniatum, Ajania nubigena, Codonopsis bhutanica, Corydalis crispa, Corydalis dubia, Meconopsis simplicifolia and Pleurospermum amabile, are currently used in the Bhutanese Traditional Medicine (BTM) for the management of different types of disorders including the diseases that bore relevance to various inflammatory conditions. Aims of the study: This study aimed to evaluate the inhibition of TNF-α production in LPS-activated THP-1 monocytic cells by the crude extracts of seven selected Bhutanese medicinal plants. It is expected to; (a) generate a scientific basis for their use in the BTM and (b) form a basis for prioritization of the seven plants for further phytochemical and anti-inflammatory studies. Materials and methods: Seven plants were selected using an ethno-directed bio-rational approach and their crude extracts were prepared using four different solvents (methanol, hexane, dichloromethane and chloroform). The TNF-α inhibitory activity of these extracts was determined by cytokine-specific sandwich quantitative enzyme-linked immunosorbent assays (ELISAs). The results were quantified statistically and the statistical significance were evaluated by GraphPad Prism version 5.01 using Student's t-test with one-tailed distribution. A p-value ≤0.05 was considered statistically significant. Results: Of the seven plants studied, the crude extracts of six of them inhibited the production of pro-inflammatory cytokine, TNF-α in LPS-activated THP-1 monocytic cells. Amongst the six plants, Corydalis crispa gave the best inhibitory activity followed by Pleurospermum amabile, Ajania nubigena, Corydalis dubia, Meconopsis simplicifolia and Codonopsis bhutanica. Of the 13 extracts that exhibited statistically significant TNF-α inhibitory activity (p<0.05; p<0.01), five of them showed very strong inhibition when compared to the DMSO control and RPMI media. Conclusions: Six medicinal plants studied here showed promising TNF-α inhibitory activity. These findings rationalize the traditional use of these selected medicinal plants in the BTM as an individual plant or in combination with other ingredients for the treatment of disorders bearing relevance to the inflammatory conditions. The results forms a good preliminary basis for the prioritization of candidate plant species for an in-depth phytochemical study and anti-inflammatory activity screening of the pure compounds contained within those seven plants. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: : This study involves the assessment of the Bhutanese traditional medicine (BTM) which was integrated with the mainstream biomedicine in 1967 to provide primary health care services in the country. It caters to 20–30% of the daily out-patients within 49 traditional medicine units attached to 20 district modern hospitals and 29 Basic Health Units in the country. Aim of the study: : This study presents the ethnopharmacological, ethnobotanical and the ethnoquality concepts in relation to mainstream Tibetan medicine and describes the current practices of BTM. Materials and methods: : Experienced BTM practitioners (Drung-tshos and Smen-pas) were selected using a convenience sampling method and were interviewed using an open questionnaire followed by informal discussions. The corpus of BTM, Tibetan and scientific literature was obtained and the information on ethnopharmacological, ethnoquality and ethnobotanical concepts and current practices of BTM was extracted. Results: : This study found that the BTM shares many similarities in terms of materia medica, pharmacopoeia and the principles and concepts of ethnopharmacology and ethnobotany with its mainstream Tibetan medicine. However, the resourceful Bhutanese Drung-tshos and Smen-pas have adapted this medical system based on the local language, culture, disease trend, health care needs and their familiarity with the locally available medicinal ingredients making it particular to the country. A number of notable distinctions observed in the current practices include a code of classification of diseases (only 79 of 404 types of disorders recognized), formulations (currently used only 103 of thousands formulation types), usage of medicinal plants (only 229 species of thousands described) and selected treatment procedures (golden needle and water therapy). This BTM was found to cater to 20–30% of daily out-patients visiting 49 modern hospitals and basic health units in the country. Conclusions: : The BTM has been evolved from the Tibetan medicine. While the pharmacopoeia, ethnopharmacology, ethnobotany and the ethnoquality aspects shares commonalities with the mainstream Tibetan medicine, there are some practices unique to BTM. Such uniqueness observed in the current practices of BTM include formulations, medicinal plants collection and usage, and the treatment procedures including golden needle and water therapy. This could be a promising source of information for the rediscovery of useful remedies, the development of modern phytotherapeutics and the establishment of efficient quality control measures. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Corydalis dubia is used in Bhutanese traditional medicine as a febrifuge and for treating infections in the blood, liver and bile which correlate to the signs and symptoms of malarial and microbial infections. Aim of the study: To validate the ethnopharmacological uses of the plant and to discover potential new therapeutic drug leads. Materials and methods: C. dubia was collected from Bhutan and the alkaloids were obtained using acid–base fractionation and separation by repeated column and preparative plate chromatography. The alkaloids were identified from analysis of their physiochemical and spectroscopic data and were tested for antiplasmodial, antimicrobial and cytotoxicity activities. Results: A systematic extraction and isolation protocol yielded one new natural product, dubiamine, and seven known isoquinoline alkaloids, scoulerine, cheilanthifoline, protopine, capnoidine, bicuculline, corydecumbine and hydrastine. Among the four alkaloids tested, scoulerine showed the best antiplasmodial activity with IC50 values of 5.4μM and 3.1μM against the antifolate sensitive and the multidrug resistant P. falciparum strains: TM4/8.2 and K1CB1, respectively. None of the alkaloids tested showed significant antimicrobial or cytotoxicity activities. Conclusions: The antiplasmodial test results, of the isolated alkaloid components, are commensurated with the ethnopharmacological uses of this plant. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: As many as 229 medicinal plants have been currently used in the Bhutanese Traditional Medicine (BTM) as a chief ingredient of polyherbal formulations and these plants have been individually indicated for treating various types of infections including malaria, tumor, and microbial. We have focused our study only on seven species of these plants. Aim of the study: We aim to evaluate the antiplasmodial, antimicrobial, anti-Trypanosoma brucei rhodesiense and cytotoxicity activities of the seven medicinal plants of Bhutan selected using an ethno-directed bio-rational approach. This study creates a scientific basis for their use in the BTM and gives foundation for further phytochemical and biological evaluations which can result in the discovery of new drug lead compounds. Materials and methods: A three stage process was conducted which consisted of: (1) an assessment of a pharmacopoeia and a formulary book of the BTM for their mode of plant uses; (2) selecting 25 anti-infective medicinal plants based on the five established criteria, collecting them, and screening for their major classes of phytochemicals using appropriate test protocols; and (3) finally analyzing the crude extracts of the seven medicinal plants, using the standard test protocols, for their antiplasmodial, antimicrobial, anti-Trypanosoma brucei rhodesiense and cytotoxicity activities as directed by the ethnopharmacological uses of each plant. Results: Out of 25 medicinal plants screened for their major classes of phytochemicals, the majority contained tannins, alkaloids and flavonoids. Out of the seven plant species investigated for their biological activities, all seven of them exhibited mild antimicrobial properties, five plants gave significant in vitro antiplasmodial activities, two plants gave moderate anti-Trypanosoma brucei rhodesiense activity, and one plant showed mild cytotoxicity. Meconopsis simplicifolia showed the highest antiplasmodial activity with IC50 values of 0.40μg/ml against TM4/8.2 strain (a wild type chloroquine and antifolate sensitive strain) and 6.39μg/ml against K1CB1 (multidrug resistant strain) strain. Significantly the extracts from this plant did not show any cytotoxicity. Conclusions: These findings provide the scientific basis for the use of seven medicinal plants in the BTM for the treatment of malaria, microbial infections, infectious fevers, and the Trypanosoma brucei rhodesiense infection. The results also form a good preliminary basis for the prioritization of candidate plant species for further in-depth phytochemical and pharmacological investigations toward our quest to unearth lead antiparasitic, anticancer and antimicrobial compounds. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: The Bhutanese form of g.so-ba-rig-pa medicine, which is a scholarly medical system, belongs to a larger system of medicinal corpus that spreads from Mongolia to India. It uses medicinal plants as a bulk ingredient but only ‘Higher Elevation Medicinal Plants’ have been botanically identified so far. Our study reports the botanical identification of ‘Lower Elevation Medicinal Plants’ and their ethnomedical uses. Aim of the study: To botanically identify the ‘Lower Elevation Medicinal Plants’ used in Bhutanese traditional medicine. Materials and methods: A five stage process was conducted which consisted of: (1) a survey of specialized ancient ethnomedical literatures (Pharmacopoeias and formularies); (2) freely listing the ‘Lower Elevation Medicinal Plants’ reported in the ancient Bhutanese medical texts and translating their ethnomedical uses in equivalent terms of English; (3) making field visits, collecting herbarium specimens and photographs, and spot identification of plants; (4) double blind testing of Bhutanese traditional medicine practitioners for authentication and standardization of Bhutanese g.so-ba-rig-pa names; (5) organising workshops for open forum discussions on medicinal plants involving Traditional Physicians and other professional participants of the relevant areas. Results: We identified the botanical names of 113 ‘Lower Elevation Medicinal Plants’ belonging to 68 families and 104 genera. Out of 113 medicinal plant species identified, 92 species are currently used in Bhutan and the remaining 21 species were not used in the current formulation, but described in the Bhutanese traditional medical texts. The identification of these 21 species was achieved both ethnomedically and botanically for the first time. Out of the 28 plant species that are currently imported from India, we found for the first time, even to the knowledge of Traditional Physicians, that 16 of them are actually growing abundantly in Bhutan. Among the plant parts collected, seeds were the most prominent followed by fruits and then roots. Conclusions: Our study identified 113 ‘Lower Elevation Medicinal Plants’ out of which 92 of them are used daily in formulating 102 multi-ingredient prescription medicines in Bhutan. [Copyright &y& Elsevier]

Ethnopharmacological relevance: The plant Aconitum orochryseum Stapf. (Ranunculaceae) is employed together with other plants in Bhutanese traditional medicine and is indicated for malaria-associated fever. Aim of the study: To study the in vitro antiplasmodial activity of atisinium chloride, the major alkaloid from Aconitum orochryseum. Materials and methods: Atisinium chloride was extracted and purified from aerial parts of Aconitum orochryseum and its structure and absolute configuration confirmed by single crystal X-ray crystallography. The crude methanol extract, crude alkaloid fraction, and atisinium chloride were tested for in vitro antiplasmodial activity against the malarial Plasmodium falciparum strains TM4/8.2 (TM4; wild type) and K1CB1 (K1; chloroquine and antifolate resistant). Results: The diterpenoid alkaloid atisinium chloride was shown to have moderate antiplasmodial activities with IC50 values of 4μM and 3.6μM, respectively against the TM4 strain and the K1 strain of Plasmodium falciparum. Conclusions: Our studies provide the first evidence in support of one of the indicated treatments with Aconitum orochryseum in Bhutanese traditional medicine. This alkaloid also represents a potential new antimalarial structural lead. [Copyright &y& Elsevier]

• Quality control of Bhutanese herbal medicines is important for providing safe and effective treatments to the patients. • There is an urgent need to develop reliable analytical quality parameters to differentiate three Corydalis species. • Literature review revealed a comprehensive traditional and scientific information on three Corydalis species. • Six major quality parameters checklist for authenticating three Corydalis species has been identified and described. Herbal medicines including the scholarly Bhutanese Sowa Rigpa medicine (BSM) contribute significantly to primary health care services and play a considerable part in modern drug discovery. BSM, which was integrated with modern health care system in 1967, currently uses more than 200 species of medicinal plants including three closely related members of the Corydalis species; Corydalis calliantha , C. crispa , and C. dubia. Maintaining the quality of these medicinal plants has been always challenging due to adulterants and also due to lack of traditional quality control parameters that could distinguish closely related species. Therefore there is an urgent need to develop reliable analytical methods and quality parameters. Given the significant medicinal properties attributed to the three Corydalis species which are extensively used in BSM, a thorough literature review was performed to investigate their existing quality control parameters including: 1) morphological assessment, 2) habitat and ecological evaluation, 3) macroscopical and microscopical examination, 4) physiochemical limit setting and comparative high-performance thin layer chromatography (HPTLC) profiling, and 5) phytochemical and biological activities. The study revealed that there are distinct species-specific features including ecological adaptation, micromorphology, anatomy, phytochemical values and HPTLC profiles presented by each Corydalis species, and that these quality parameters support traditional quality screening processes in BSM. [ABSTRACT FROM AUTHOR]

Bhutanese Sowa Rigpa medicine (BSM) has established unique pharmacopoeias that describe ethnotaxonomical concepts, classification systems and descriptions of medicinal plants. BSM was integrated with modern health care system in 1967. BSM uses medicinal plants, minerals and animal products as the main ingredients of the formulations used for treating various disorders. This study was aimed to highlight interesting ethnotaxonomical concepts of BSM and identify and document medicinal plants from the two remotest regions of eastern Himalayas of Bhutan – Merak and Sakteng. Ethnopharmacological data was gathered from the pharmacopoeias, published monographs and research papers on Bhutanese medicinal plants. Medicinal plants diversity was surveyed using the convenience sampling methods. A literature review on the phytochemical content of the medicinal plants and their pharmacological activities was carried out using plant databases, PubMed, SciFinder and Google Scholar. A very interesting ethnotaxonomical concept of BSM has been translated into English terminologies from the traditional pharmacopoeia. A total of 50 alpine medicinal plants belonging to 25 families and 39 genera in 13 study sites between Merak and Sakteng were documented. Only 12 medicinal species were identified as priority species or are currently used at Menjong Sorig Pharmaceuticals for formulating 48 different medicines. This study described the ethnotaxonomical concepts, classification and description of medicinal plants in Bhutan and botanically identified 50 alpine medicinal plants from 13 different study sites under Merak and Sakteng regions. About 12 of them were currently used as ingredients in BSM formulations and 35 species were studied for their phytochemical and pharmacological properties. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance The Bhutanese Sowa Rigpa medicine (BSM) uses animal parts in the preparation of numerous polyingredient traditional remedies. Our study reports the taxonomical identification of medicinal animals and the description of traditional uses in English medical terminologies. Aim of the study To taxonomically identify the medicinal animals and their derived natural products used as a zootherapeutic agents in BSM. Materials and methods First, the traditional textbooks were reviewed to generate a list of animal products described as ingredients. Second, animal parts that are currently used in Bhutan were identified. Third, the ethnopharmacological uses of each animal ingredients were translated into English medical terminologies by consulting Traditional Physicians, clinical assistants, pharmacognosists, and pharmacists in Bhutan. Fourth, the animal parts were taxonomically identified and their Latin names were confirmed by crosschecking them with online animal databases and relevant scientific literature. Results The study found 73 natural products belonging to 29 categories derived from 45 medicinal animals (36 vertebrates and 9 invertebrates), comprising of 9 taxonomic categories and 30 zoological families. Out of 116 formulations currently produced, 87 of them contain one or more extracts and products obtained from 13 medicinal animals to treat more than 124 traditionally classified illnesses. Only five animal ingredients were found available in Bhutan and rest of the animal parts are being imported from India. Conclusions Out of 73 natural products described in the traditional textbooks, only 13 of them (some omitted and few substituted by plants) are currently included in 87 formulations of BSM. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Geological materials, such as minerals, have a long history of usage as ingredients in multicompound formulations of Himalayan Sowa Rigpa medicine – as well as in its localized form of Bhutanese traditional medicine (BTM) – for treating various disorders for over thousand years. Yet, hardly any scientific research has been done on their ethnopharmacological efficacy and chemistry. Aim of the study This study documents and correlates the rarely explored ethnopharmacological and chemical identification of various minerals and their ethnomedicinal uses in BTM formulations for the first time. Material and methods A five stage cross-disciplinary process was conducted as follows: (1) a review of classical literature of Sowa Rigpa texts (Tibetan medical texts, pharmacopoeias and formularies) that are still in use today; (2) listing of mineral ingredients according to Sowa Rigpa names, followed by identification with common English and chemical names, as well as re-translating their ethnomedical uses; (3) cross-checking the chemical names and chemical composition of identified Sowa Rigpa minerals with various geological mineral databases and mineral handbooks; (4) authentication and standardization of Sowa Rigpa names through open forum discussion with diverse BTM practitioners; (5) further confirmation of the chemical names of identified minerals by consulting different experts and pharmacognosists. Results Our current study lists 120 minerals as described in Sowa Rigpa medical textbooks most of which we were able to chemically identify, and of which 28 are currently used in BTM herbo-mineral formulations. Out of these 28 mineral ingredients, 5 originate from precious metal and stone, 10 stem from earth, mud and rocks, 8 are salts, and 5 concern ‘essences’ and exudates. Conclusions Our study identified 120 mineral ingredients described in Sowa Rigpa medical textbooks, out of which 28 are currently used. They are crucial in formulating 108 multicompound prescription medicines in BTM presently in use for treating more than 135 biomedically defined ailments. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance The traditional uses of Corydalis dubia, Ajania nubigena and Pleurospermum amabile in the Bhutanese traditional medicine for treating disorders related to inflammatory conditions and the in vitro anti-inflammatory activity of their crude extracts inspired the isolation and the investigation of anticolitic properties of four pure compounds. Materials and methods Three medicinal plants were collected from Himalayan Mountains of Bhutan. Capnoidine and scoulerine were isolated from C. dubia, linalool oxide acetate from A. nubigena and isomyristicin from P. amabile using natural product isolation protocols. Four compounds were investigated for their anti-inflammatory activities against IBD-colitis using chemically induced (TNBS) mice model of colitis. Capnoidine conferred the best preliminary protection against TNBS-induced colitis in mice and we have conducted in-depth pharmacological investigation of this compound including clinical symptoms, pathological signs, cytokine profiles, histological structure and inflammasomes using relevant bioassay protocols. Results Capnoidine-treated mice had significantly: a) improved clinical symptoms (body weight loss, mobility, piloerection and faecal consistency); b) reduced colon pathology (adhesion, oedema, ulceration, and colon length); c) altered inflammatory cytokines profiles within the colons; d) reduced levels of p-IκB-α (Ser32) and p-NF-κB p65 (Ser536) and e) reduced histological inflammation in the colon when compared with mice administered TNBS only. Conclusion Capnoidine presents as a potential new anti-inflammatory drug lead candidate for diseases where current standard-of-care often fails and is associated with major side effects. It also validates the traditional uses of C. dubia against inflammatory conditions and underlines the value of pursuing bioactive compounds derived from traditionally used ethnobotanical medicines. [ABSTRACT FROM AUTHOR]