PubMed - Fulltext

Comparison of the antiinflammatory activities of three medicinal plants known as "meiduoluomi" in Tibetan folk medicine.

Yakugaku Zasshi. 2008 May;128(5):805-10

Authors: Zhang Z, Luo P, Li J, Yi T, Wang J, An J, Zhang H

Erigeron breviscapus (Vant.) Hand-mazz (EB), Erigeron multiradiatus (Lindl.) Benth (EM), and Aster brachytrichus Franch (AB), confused under the vernacular name "meiduoluomi" by native people and traditional healers, have been used for the treatment of meningitis, polyneuritis, hepatitis, adenolymphitis, and enteronitis in traditional Tibetan medicine. In this study, the antiinflammatory activity of methanol extracts of all three plants was investigated in the xylene-induced ear edema model, carrageenan-induced paw edema model, and cotton pellet-induced granuloma model. It was found that the methanolic extracts of both EB and EM had strong inhibitory effects on the acute phase of inflammation in carrageenan-induced paw edema in rats. On the other hand, the methanolic extract of EM showed stronger effects than those of EB in xylene-induced ear edema. In the chronic test, the methanolic extracts of EB and EM resulted in a significant reduction in granuloma weight in rats. In addition, myeloperoxidase (MPO) activity was strongly reduced in the EB-treated and EM-treated groups, which indicated that EB and EM can inhibit certain inflammatory modulator factors that cause neutrophil aggregation in inflamed tissue, e.g., nuclear factor-kappaB. However, the methanolic extracts of AB had no antiinflammatory effects in the tested models and MPO assay. The similar effects of EM and EB in tested models provided some scientific basis for the traditional usage of meiduoluomi in inflammatory disease. However, the results also suggest that further study is needed to investigate the antiinflammatory profile of AB and provide a scientific basis for the use of AB in inflammatory diseases.

PMID: 18451629 [PubMed - indexed for MEDLINE]

[Elucidation of structures and functions through Peyer's patches of responsible carbohydrate chains in intestinal immune system modulating polysaccharides from Japanese medicinal herbs]

Yakugaku Zasshi. 2008 May;128(5):709-16

Authors: Kiyohara H, Matsuzaki T, Matsumoto T, Nagai T, Yamada H

Carbohydrate chains in glycoconjugates play important roles in various life phenomena, and there are numerous types of recognition system for carbohydrate chains due to carbohydrate-lectin interactions/carbohydrate-carbohydrate interactions in all higher life forms. It has been proposed that macromolecular polysaccharides isolated from plants, marine organisms, or fungi cross-interact with known and unknown recognition systems in mammals to express their pharmacological activities. Therefore the elucidation of carbohydrate structures related to the activities and functions of these polysaccharide molecules will lead us to utilize the related information in the development of novel carbohydrate-based drugs and functional foods for human health care. Peyer's patches present in the upper intestinal tract play important roles as inductive sites for both protective IgA production and immune tolerance induction in mucosal and systemic immune systems. Dysfunction of the immunocompetent cells of Peyer's patches is thought to induce allergic/autoimmune diseases and down-regulation of the protective system against infectious agents on mucosal sites. We have isolated several Peyer's patch cell-modulating polysaccharides from medicinal herbs used in traditional Japanese herbal remedies, and they have been assumed to comprise the responsible carbohydrate chains with oligosaccharide sizes for expression of modulating activity. Accumulation of knowledge on the structures and functions of these responsible carbohydrate chains in polysaccharide molecules is believed to be important for the development of methodology for logically factitious regulation of functions of immunocompetent cells in Peyer's patches. This review deals with recent results of our study on the structural clarification of responsible carbohydrate chains in modulating polysaccharides against functions of immunocompetent cells in Peyer's patches.

PMID: 18451617 [PubMed - indexed for MEDLINE]

New cytotoxic bicyclic hexapeptides, RA-XXIII and RA-XXIV, from Rubia cordifolia L.

Chem Pharm Bull (Tokyo). 2008 May;56(5):730-3

Authors: Lee JE, Hitotsuyanagi Y, Fukaya H, Kondo K, Takeya K

Two new bicyclic hexapeptides, RA-XXIII and RA-XXIV, were isolated from the roots of Rubia cordifolia L. (Rubiaceae). Their structures were determined by the analysis of their 2D NMR spectra, chemical methods, and X-ray crystallography. The IC50 values of RA-XXIII and RA-XXIV against P-388 leukemia cells were 0.16 and 0.48 microg/ml, respectively.

PMID: 18451569 [PubMed - indexed for MEDLINE]

Three new furoquinoline alkaloids from the leaves of Boninia glabra.

Chem Pharm Bull (Tokyo). 2008 May;56(5):727-9

Authors: Inada A, Ogasawara R, Koga I, Nakatani N, Inatomi Y, Murata H, Nishi M, Nakanishi T

Three novel furoquinoline alkaloid oxogeranyl ethers (1-3) and one known furoquinoline alkaloid (4) were isolated from the leaves of Boninia glabra, an endemic plant of the Bonin Islands. Their structures were elucidated on the basis of spectroscopic analysis.

PMID: 18451568 [PubMed - indexed for MEDLINE]

Myeloperoxidase inhibitory and radical scavenging activities of flavones from Pterogyne nitens.

Chem Pharm Bull (Tokyo). 2008 May;56(5):723-6

Authors: Fernandes DC, Regasini LO, Vellosa JC, Pauletti PM, Castro-Gamboa I, Bolzani VS, Oliveira OM, Silva DH

Two new flavone glucosides, nitensosides A and B (1, 2), together with four known compounds, sorbifolin (3), sorbifolin 6-O-beta-glucopyranoside (4), pedalitin (5), and pedalitin 6-O-beta-glucopyranoside (6) were isolated from Pterogyne nitens. Their structures were elucidated from 1D and 2D NMR analysis, as well as by high resolution mass spectrometry. All the isolated flavones were evaluated for their myeloperoxidase (MPO) inhibitory activity. The most active compound, pedalitin, exhibited IC50 value of 3.75 nM on MPO. Additionally, the radical-scavenging capacity of flavones 1-6 was evaluated towards ABTS and DPPH radicals and compared to standard compounds quercetin and Trolox.

PMID: 18451567 [PubMed - indexed for MEDLINE]

Two new triterpenes from the Rhizome of Dryopteris crassirhizoma, and inhibitory activities of its constituents on human immunodeficiency virus-1 protease.

Chem Pharm Bull (Tokyo). 2008 May;56(5):711-4

Authors: Lee JS, Miyashiro H, Nakamura N, Hattori M

Two new hopane type triterpenes, named dryopteric acids A (1) and B (2), were isolated from the Rhizome of Dryopteris crassirhizoma (Aspiadaceae) together with sixteen known compounds (3-18). Of isolated compounds, ursolic acid (15), and dryopteric acid A (1) and B (2) showed potent inhibitory activities against HIV-1 protease with IC50 values of 8.9-44.5 microM. In addition, acetylated compounds 1 and 2 appreciably increased inhibitory activities with their IC50 values of 1.7 and 10.8 microM, respectively.

PMID: 18451564 [PubMed - indexed for MEDLINE]

Phenolic glycosides from Lindera fruticosa root and their inhibitory activity on osteoclast differentiation.

Chem Pharm Bull (Tokyo). 2008 May;56(5):707-10

Authors: Song MC, Nigussie F, Yang HJ, Kim HH, Kim JY, Chung DK, Baek NI

Two new compounds were found in the phenolic glycosides isolated from the roots of Lindera fruticosa: 5-O-[beta-D-apiofuranosyl-(1''-->2')-O-beta-D-xylopyranosyl]gentisic acid-7,5''-ester (3), named linderofruticoside A; and 5-O-[beta-D-apiofuranosyl-(1''-->3')-O-beta-D-xylopyranosyl]gentisic acid methyl ester (4), linderofruticoside B. Two previously known phenolic glycosides were also identified: beta-D-(3,4-disinapoyl)fructofuranosyl-alpha-D-(6-sinapoyl)glucopyranoside (1) and beta-D-(3-sinapoyl)fructofuranosyl-alpha-D-(6-sinapoyl)glucopyranoside (2). Compounds 1 and 2 inhibited osteoclast differentiation in a dose-dependent manner at concentrations higher than 1.04 microM and 0.132 microM, respectively.

PMID: 18451563 [PubMed - indexed for MEDLINE]

Reinvestigation of absolute stereostructure of (-)-rosiridol: structures of monoterpene glycosides, rosiridin, rosiridosides A, B, and C, from Rhodiola sachalinensis.

Chem Pharm Bull (Tokyo). 2008 May;56(5):695-700

Authors: Yoshikawa M, Nakamura S, Li X, Matsuda H

Three new (-)-rosiridol glycosides, rosiridosides A, B, and C, were isolated from the roots of Rhodiola sachalinensis together with rosiridin [(-)-rosiridol 1-O-beta-D-glucopyranoside]. In the course of the structure elucidation of those new glycosides, the absolute configuration of the 4-position in (-)-rosiridol was reinvestigated. On the basis of the application of the modified Mosher's method for (-)- and (+)-rosiridol derivatives, the absolute configuration of the 4-position in (-)-rosiridol should be revised to be S orientation from the recently assigned R form, so that the absolute stereostructures of rosiridosides A, B, and C and rosiridin were determined.

PMID: 18451561 [PubMed - indexed for MEDLINE]

Sesquiterpenoids isolated from Eupatorium glehnii. Isolation of guaiaglehnin A, structure revision of Hiyodorilactone B, and genetic comparison.

Chem Pharm Bull (Tokyo). 2008 May;56(5):677-81

Authors: Tori M, Morishita N, Hirota N, Saito Y, Nakashima K, Sono M, Tanaka M, Utagawa A, Hirota H

A new sesquiterpenoid substituted with unsaturated ester, guaiaglehnin A (1), along with 15 previously known compounds, were isolated from the methanol extract of the terrestrial part of Eupatorium glehnii (Compositae) collected in Nagano Prefecture, Japan, the results of which supported the previous study by Takahashi et al. The chemical constituents of E. glehnii collected in Nagano Prefecture and those collected in Tokushima or Hokkaido are quite different, depending on collection site, although the species are identical. The base sequences of three different samples were identical. Diversity in the chemical components was detected, though no diversity existed in the DNA sequence. In this study, eupasimplicin A (2) was also isolated, whose presence in the extract of E. chinense simplicifolium was recorded but not in an article. The side chain geometry of hiyodorilactone B (5) was revised to be E.

PMID: 18451557 [PubMed - indexed for MEDLINE]

[Olfactory alterations in allergic rhinitis to pollens and mites]

Acta Otorrinolaringol Esp. 2008 Feb;59(2):47-51

Authors: de Haro J, Benítez P, Alobid I, González JA, Pascual B, Mullol J

INTRODUCTION: In the last 80 years, the presence of allergies has increased among Europeans from 0.28% to 14.2%. Allergic rhinitis is the main presentation, rising from 18% to 40% of cases. The aim of this study is to demonstrate that allergic rhinitis due to pollen and mites has an effect on the olfactory system. MATERIAL AND METHODS: We describe the impairment of olfactory function in two groups of individuals with allergic rhinitis due to mites or pollen (n = 76; 42 with allergy to pollen [48.9%], and 34 with allergy to mites [39%]), compared with a group of healthy volunteers (n = 120). Olfactory ability was measured by the BAST-24 (Barcelona Smell Test) olfactometer comprising 20 odours tested by the forced choice method to compare the levels of odour detection (knowing if there is odour in the environment), and efficacy (identifying what was smelt). RESULTS: The results show firstly that people with allergic rhinitis have a clear, definitive, and significant impairment (P >.05) in olfactory levels; secondly, there is a tendency towards greater olfactory loss in the case of people with pollen-related allergic rhinitis than in those allergic to mites; and thirdly, the different odours are affected differently in the 2 groups. CONCLUSIONS: We propose consideration of the study of olfactory status in the assessment of patients with allergic rhinitis.

PMID: 18341859 [PubMed - indexed for MEDLINE]

Role of the Clp system in stress tolerance, biofilm formation, and intracellular invasion in Porphyromonas gingivalis.

J Bacteriol. 2008 Feb;190(4):1436-46

Authors: Capestany CA, Tribble GD, Maeda K, Demuth DR, Lamont RJ

Clp proteases and chaperones are ubiquitous among prokaryotes and eukaryotes, and in many pathogenic bacteria the Clp stress response system is also involved in regulation of virulence properties. In this study, the roles of ClpB, ClpC, and ClpXP in stress resistance, homotypic and heterotypic biofilm formation, and intracellular invasion in the oral opportunistic pathogen Porphyromonas gingivalis were investigated. Absence of ClpC and ClpXP, but not ClpB, resulted in diminished tolerance to high temperatures. Response to oxidative stress was not affected by the loss of any of the Clp proteins. The clpC and clpXP mutants demonstrated elevated monospecies biofilm formation, and the absence of ClpXP also enhanced heterotypic P. gingivalis-Streptococcus gordonii biofilm formation. All clp mutants adhered to gingival epithelial cells to the same level as the wild type; however, ClpC and ClpXP were found to be necessary for entry into host epithelial cells. ClpB did not play a role in entry but was required for intracellular replication and survival. ClpXP negatively regulated the surface exposure of the minor fimbrial (Mfa) protein subunit of P. gingivalis, which stimulates biofilm formation but interferes with epithelial cell entry. Collectively, these results show that the Clp protease complex and chaperones control several processes that are important for the colonization and survival of P. gingivalis in the oral cavity.

PMID: 18065546 [PubMed - indexed for MEDLINE]

A transposase-independent mechanism gives rise to precise excision of IS256 from insertion sites in Staphylococcus epidermidis.

J Bacteriol. 2008 Feb;190(4):1488-90

Authors: Hennig S, Ziebuhr W

The mobile element IS256 causes phase variation of biofilm formation in Staphylococcus epidermidis by insertion and precise excision from the icaADBC operon. Precise excision, i.e., removal of the target site duplications (TSDs) and restoration of the original DNA sequence, occurs rarely but independently of functional transposase. Instead, the integrity of the TSDs is crucial for precise excision. Excision increased significantly when the TSDs were brought into closer spatial proximity, suggesting that excision is a host-driven process that might involve most likely illegitimate recombination.

PMID: 18065530 [PubMed - indexed for MEDLINE]

Binding site determinants for the LysR-type transcriptional regulator PcaQ in the legume endosymbiont Sinorhizobium meliloti.

J Bacteriol. 2008 Feb;190(4):1237-46

Authors: MacLean AM, Anstey MI, Finan TM

LysR-type transcriptional regulators represent one of the largest groups of prokaryotic regulators described to date. In the gram-negative legume endosymbiont Sinorhizobium meliloti, enzymes involved in the protocatechuate branch of the beta-ketoadipate pathway are encoded within the pcaDCHGB operon, which is subject to regulation by the LysR-type protein PcaQ. In this work, purified PcaQ was shown to bind strongly (equilibrium dissociation constant, 0.54 nM) to a region at positions -78 to -45 upstream of the pcaD transcriptional start site. Within this region, we defined a PcaQ binding site with dyad symmetry that is required for regulation of pcaD expression in vivo and for binding of PcaQ in vitro. We also demonstrated that PcaQ participates in negative autoregulation by monitoring expression of pcaQ via a transcriptional fusion to lacZ. Although pcaQ homologues are present in many alpha-proteobacteria, this work describes the first reported purification of this regulator, as well as characterization of its binding site, which is conserved in Agrobacterium tumefaciens, Rhizobium leguminosarum, Rhizobium etli, and Mesorhizobium loti.

PMID: 18055594 [PubMed - indexed for MEDLINE]

Juzen-taiho-to, an herbal medicine, activates and enhances phagocytosis in microglia/macrophages.

Tohoku J Exp Med. 2008 May;215(1):43-54

Authors: Liu H, Wang J, Sekiyama A, Tabira T

Microglia are the main resident immunocompetent and phagocytic cells in the central nervous system (CNS). Activated microglia could play phagocytic roles as well as mediate inflammatory processes in the CNS. Involvement of activated microglia in the pathogenesis has been demonstrated in several neurological diseases including Alzheimer's disease (AD). Juzen-taiho-to (JTT), a traditional herbal medicine, has been reported to have effects on activating immune responses and phagocytosis. So far, little is known about the effects of this Kampo formulation JTT on microglia and in AD. In this report, we studied the effects of JTT on the activation and phagocytic functions of mouse microglia and bone marrow-derived macrophages (BMM). JTT could activate microglia, which was confirmed by the prominent morphological change and increased surface expression of an activation marker CD11b. In addition, JTT was revealed to induce microglial proliferation, and enhance microglial phagocytosis of, without eliciting an excessive production of nitric oxide. Furthermore, when mice were administrated with JTT in vivo, their BMM showed more effective phagocytosis of fibrillar Abeta(1-42). These findings implicate the therapeutic potential of JTT in AD and other neurological diseases accompanied by microglial activation.

PMID: 18509234 [PubMed - indexed for MEDLINE]

A systematic review of natural health product treatment for vitiligo.

BMC Dermatol. 2008;8:2

Authors: Szczurko O, Boon HS

BACKGROUND: Vitiligo is a hypopigmentation disorder affecting 1 to 4% of the world population. Fifty percent of cases appear before the age of 20 years old, and the disfigurement results in psychiatric morbidity in 16 to 35% of those affected. METHODS: Our objective was to complete a comprehensive, systematic review of the published scientific literature to identify natural health products (NHP) such as vitamins, herbs and other supplements that may have efficacy in the treatment of vitiligo. We searched eight databases including MEDLINE and EMBASE for vitiligo, leucoderma, and various NHP terms. Prospective controlled clinical human trials were identified and assessed for quality. RESULTS: Fifteen clinical trials were identified, and organized into four categories based on the NHP used for treatment. 1) L-phenylalanine monotherapy was assessed in one trial, and as an adjuvant to phototherapy in three trials. All reported beneficial effects. 2) Three clinical trials utilized different traditional Chinese medicine products. Although each traditional Chinese medicine trial reported benefit in the active groups, the quality of the trials was poor. 3) Six trials investigated the use of plants in the treatment of vitiligo, four using plants as photosensitizing agents. The studies provide weak evidence that photosensitizing plants can be effective in conjunction with phototherapy, and moderate evidence that Ginkgo biloba monotherapy can be useful for vitiligo. 4) Two clinical trials investigated the use of vitamins in the therapy of vitiligo. One tested oral cobalamin with folic acid, and found no significant improvement over control. Another trial combined vitamin E with phototherapy and reported significantly better repigmentation over phototherapy only. It was not possible to pool the data from any studies for meta-analytic purposes due to the wide difference in outcome measures and poor quality ofreporting. CONCLUSION: Reports investigating the efficacy of NHPs for vitiligo exist, but are of poor methodological quality and contain significant reporting flaws. L-phenylalanine used with phototherapy, and oral Ginkgo biloba as monotherapy show promise and warrant further investigation.

PMID: 18498646 [PubMed - indexed for MEDLINE]

Betel nut chewing is associated with hypertension in Taiwanese type 2 diabetic patients.

Hypertens Res. 2008 Mar;31(3):417-23

Authors: Tseng CH

Betel nut chewing is associated with oral cancers and diabetes. This study investigated whether betel nut chewing could be associated with hypertension in Taiwanese patients with type 2 diabetes mellitus (T2DM). The data of a total of 81,226 (37,226 men and 44,000 women) patients with T2DM obtained from a cross-sectional telephone survey in a national sample of diabetic patients in Taiwan were analyzed. Hypertension was defined by a positive history or reported systolic blood pressure>or=140 mmHg and/or diastolic blood pressure>or=90 mmHg. Analyses were performed in separate sexes with consideration paid to the potential confounding effects of age, diabetic duration, body mass index and smoking. The prevalences of betel nut chewing in men and women were 20.4% and 1.1%, respectively. Betel nut chewing was more common in the younger age groups of the male sex. The multivariate-adjusted odds ratios for hypertension in chewers vs. non-chewers were 1.067 (1.007-1.131) and 1.897 (1.534-2.346) for men and women, respectively. In multiple linear regression, although no adjustment was made for the use of antihypertensive agents, betel nut chewing was significantly associated with blood pressure, with regression coefficients of 0.958+/-0.163 (SEM) for systolic and 0.441+/-0.108 for diastolic blood pressure in men; and the respective values for women were 1.805+/-0.618 and 1.198+/-0.393. In conclusion, betel nut chewing was significantly associated with hypertension in Taiwanese patients with T2DM and the association was stronger in women.

PMID: 18497460 [PubMed - indexed for MEDLINE]

TRPA1 is a major oxidant sensor in murine airway sensory neurons.

J Clin Invest. 2008 May;118(5):1899-910

Authors: Bessac BF, Sivula M, von Hehn CA, Escalera J, Cohn L, Jordt SE

Sensory neurons in the airways are finely tuned to respond to reactive chemicals threatening airway function and integrity. Nasal trigeminal nerve endings are particularly sensitive to oxidants formed in polluted air and during oxidative stress as well as to chlorine, which is frequently released in industrial and domestic accidents. Oxidant activation of airway neurons induces respiratory depression, nasal obstruction, sneezing, cough, and pain. While normally protective, chemosensory airway reflexes can provoke severe complications in patients affected by inflammatory airway conditions like rhinitis and asthma. Here, we showed that both hypochlorite, the oxidizing mediator of chlorine, and hydrogen peroxide, a reactive oxygen species, activated Ca(2+) influx and membrane currents in an oxidant-sensitive subpopulation of chemosensory neurons. These responses were absent in neurons from mice lacking TRPA1, an ion channel of the transient receptor potential (TRP) gene family. TRPA1 channels were strongly activated by hypochlorite and hydrogen peroxide in primary sensory neurons and heterologous cells. In tests of respiratory function, Trpa1(-/-) mice displayed profound deficiencies in hypochlorite- and hydrogen peroxide-induced respiratory depression as well as decreased oxidant-induced pain behavior. Our results indicate that TRPA1 is an oxidant sensor in sensory neurons, initiating neuronal excitation and subsequent physiological responses in vitro and in vivo.

PMID: 18398506 [PubMed - indexed for MEDLINE]

[Clinical cases in medical mycology. Case no. 31]

Rev Iberoam Micol. 2008 Mar;25(1):62-4

Authors: Negroni R, Arechavala AI, Maiolo E, Bianchi MH, Santiso G, Garro S, Orduna T

PMID: 18338933 [PubMed - indexed for MEDLINE]

[Use of kenaf fibre in the elaboration of specific substrates for Pleurotus ostreatus (Jacq. ex Fr.) Kummer cultivation]

Rev Iberoam Micol. 2008 Mar;25(1):57-61

Authors: Pardo Giménez A, Perona Zamora MA, Pardo Núñez J

In this study, the viability of the kenaf fibre use, alone or combined with cereal straw, vine shoots and olive mill dried waste, in the elaboration of specific substrates for the cultivation of Pleurotus ostreatus (Jacq. ex Fr.) Kummer, second mushroom in importance cultivated in Spain, is described. Furthermore, three different methods of preparation of the substrate have been considered in order to obtain selectivity for the growth and later fruiting of Pleurotus sporophore. As for the production parameters, the best results have been provided by the substrates that combined kenaf with straw and with vine shoots, being unfavourable the substrates based in just kenaf or combined with olive mill dried waste. As for the treatment applied to the materials, the immersion in water alone and subsequent pasteurization and thermophilic conditioning, together with the semi-anaerobic fermentation, has been favoured in front of the immersion in water with fungicide and later pasteurization.

PMID: 18338932 [PubMed - indexed for MEDLINE]

A seed and feed model for the formation of Candida albicans biofilms under flow conditions using an improved modified Robbins device.

Rev Iberoam Micol. 2008 Mar;25(1):37-40

Authors: Ramage G, Wickes BL, López-Ribot JL

A variety of manifestations of Candida albicans infections are associated with the formation of biofilms on the surface of biomaterials. In order to maintain their niche these adherent populations need to withstand the continuous bathing action of physiological fluids (saliva, blood), which also provide water and nutrients to the fungal cells. Thus, it was the aim of this study to examine and further characterize the development of C. albicans biofilms under shear forces and a flow of replenishing nutrients, emulating the conditions that fungal cells would normally encounter within the host. An improved modified Robbins device (MRD) was designed to hold six poly methyl methacrylate (PMMA) plugs of 25 mm in diameter. A "seed and feed" model of biofilm formation was then implemented for which the apparatus was initially seeded with a C. albicans cell suspension to allow initial adhesion of fungal cells to the biomaterial. Following this initial step, sterile medium was then pumped through the MRD at a constant flow rate. Scanning electron microscopy (SEM) and confocal scanning laser microscopy (CSLM) demonstrated a high degree of heterogeneity associated with the structure of biofilms formed under flowing conditions using the MRD. In addition, these biofilms displayed a complex three dimensional architecture and increased production of exopolymeric material.

PMID: 18338926 [PubMed - indexed for MEDLINE]