Medicinal plants containing pyrrolizidine alkaloids in the New Kreuterbuch by Leonhart Fuchs (1543).

In mid-16 th century, three scientific books have been edited, which have been a real sensation, each one in its own scientific field. The first one, published in Nürnberg by Nikolaus Kopernikus, named: "De Revolutionibus Orbium Celestium Libri VI" put the sun in the center of the universe, and takes the human being out of the middle of the world. The second one, published in Basel by Andreas Vesalius: "De Humani Corporis Fabrica", describes the anatomy of the human body and the third one, also published in Basel by Leonhart Fuchs, was named "New Kreuterbuch". It shows woodcuts of the most important medicinal plants of its time along with botanical descriptions and therapeutic uses. This book emerged as one of the most influential botanical works of the 16 th century and is still interesting. Here, we used it to investigate which medicinal plants of the Early Modern times contained pyrrolizidine alkaloids. In total, 15 species were identified.

The Self-Administered Rheumatoid Arthritis Disease Activity Index (RADAI) is Less Accurate than DAS28-CRP as a Disease Activity Measure in Pregnancy.

OBJECTIVE: Disease Activity Score 28 (DAS28)-using the C-reactive protein (CRP) level has been validated to determine disease activity in rheumatoid arthritis (RA) patients during pregnancy. A self-administered questionnaire like Rheumatoid Arthritis Disease Activity Index (RADAI) has practical advantages over DAS28-CRP, and in this study, we aimed to validate the RADAI for use during pregnancy. METHODS: Patients were derived from a prospective cohort on RA and pregnancy (Pregnancy-induced Amelioration of Rheumatoid Arthritis study). To validate the RADAI as a disease activity measure, the disease course over time and the disease activity states were compared with the DAS28-CRP. Furthermore, the RADAI was compared with DAS28-CRP in predicting fertility and pregnancy outcomes. Finally, to test construct validity, correlation of both RADAI and DAS28-CRP with a biomarker (galactosylation of immunoglobulin G [IgG]) were determined and compared. RESULTS: In total, 269 patients were analyzed in this study. Mean RADAI scores showed a great decline in disease activity in the first trimester compared with DAS28-CRP (mean RADAI, -1.13; mean, DAS28-CRP, -0.04). Correlations between DAS28-CRP and RADAI scores were moderate to good (0.44 < ρ < 0.71). Agreement in disease states was low (0.26 < κ < 0.51). Time to pregnancy was different between disease states according to DAS28-CRP (P = 0.03), but not according to RADAI (P = 0.56). Only DAS28-CRP could predict birthweight (DAS28-CRP ß-0.17, P = 0.04; RADAI ß-0.09, P = 0.10). Both DAS28-CRP and RADAI were associated with galactosylation of IgG at specific time points, but only change in DAS28-CRP was correlated with change in galactosylation of IgG from preconception to pregnancy. CONCLUSION: The RADAI could not be validated as a disease activity measure during pregnancy. DAS28-CRP remains the gold standard of measuring disease activity in pregnancy.

Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) controls adipogenesis in obesity in mice and in humans.

AIMS/HYPOTHESIS: Extracellular matrix reorganisation is a crucial step of adipocyte differentiation and is controlled by the matrix metalloproteinase-tissue inhibitor of matrix metalloproteinase (TIMP) enzyme system. We therefore sought to define the role of TIMP1 in adipogenesis and to elucidate whether upregulation of TIMP1 in obesity has direct effects on adipocyte formation. METHODS: TIMP1 protein levels and mRNA were measured in lean and obese mice with a focus on levels in adipose tissue. We also analysed the effect of recombinant murine TIMP1 on adipogenesis, adipocyte size and metabolic control in vitro and in vivo. RESULTS: TIMP1 levels were increased in the serum and adipose tissue of obese mouse models. Recombinant murine TIMP1 inhibited adipocyte differentiation in 3T3-L1 as well as in subcutaneous primary pre-adipocytes. Conversely, neutralising TIMP1 with a specific antibody enhanced adipocyte differentiation. In vivo, injection of recombinant TIMP1 in mice challenged with a high-fat diet led to enlarged adipocytes. TIMP1-treated mice developed an impaired metabolic profile with increased circulating NEFA levels, hepatic triacylglycerol accumulation and accelerated insulin resistance. Altered glucose clearance in TIMP1-injected mice was due to changes in adipose tissue glucose uptake, whereas muscle glucose clearance remained unaffected. CONCLUSIONS/INTERPRETATION: TIMP1 is a negative regulator of adipogenesis. In vivo, TIMP1 leads to enlarged adipocytes in the state of overnutrition. This might contribute to the detrimental metabolic consequences seen in TIMP1-injected mice, such as systemic fatty acid overload, hepatic lipid accumulation and insulin resistance.

Sublingual immunotherapy in youngsters: adherence in a randomized clinical trial.

BACKGROUND: Adherence is essential for effective treatment. Although several trials on the efficacy of sublingual immunotherapy (SLIT) in youngsters have been published, few contain data on medication intake. OBJECTIVE: We aimed to quantify adherence both to study protocol and medication intake as well as to identify factors that may influence adherence to SLIT in youngsters with rhinoconjunctivitis. METHODS: Two hundred and four youngsters (6-18 years) with hayfever participated in a randomized controlled trial and used grass pollen extract or placebo for 2 years. The primary outcome of the trial was the mean daily total rhinoconjunctivitis symptom score in the second grass pollen season. Participants having completed the follow-up were considered adherent to the study protocol. Adherence to medication intake was assessed by weighing the study medication. Participants who completed the follow-up and used > or = 80% of the prescribed medication were considered adherent to medication intake. Patient-, disease- and treatment-related factors were analysed. RESULTS: One hundred and fifty-four youngsters completed the study. The main reason for discontinuation was the inability to take medication according to schedule. Drop-outs were older, had more difficulty following the medication instructions and their overall evaluation of the treatment effect was lower. The number and reasons for drop-out did not differ between treatment groups. In total, 77% of the participants was adherent to medication intake. Self-reported adherence was 99%. Non-adherent participants experienced more severe symptoms before the trial. Symptom scores did not differ between adherent and non-adherent participants. In adherent as well as non-adherent participants, no difference was found between verum and placebo group with respect to symptom scores. CONCLUSION: Adherence to both study protocol and medication intake was good. Drop-out was affected by age, evaluation of the treatment effect and medication instructions. Non-adherence to medication intake was influenced by the severity of the disease before the trial. The ineffectiveness of SLIT could not be explained by non-adherence.

Bronchodilating effects of cumulative doses of formoterol from a novel multi-dose inhaler (Airmax).

The bronchodilating properties of formoterol from a novel multi-dose inhaler, Airmax 6 microg and from a single-dose dry powder inhaler Foradil Aeroliser 12 microg were investigated in 31 adult asthmatics with FEV1 > or = 60% predicted and a reversibility > or = 12%. Patients received on a single day four doses of formoterol: cumulative dose 6, 12, 24 and 48 microg from Airmax, or 12, 24, 48 and 96 microg from Aeroliser. The mean FEV1 (SD) from baseline to 1 h after the final cumulative dose increased by 0.81 l from 2.62 (0.58) to 3.43 l (0.70) with Airmax and by 0.85 l from 2.65 (0.60) to 3.5 l (0.68) with Aeroliser. All 90% CIs for all four dose comparisons were within the equivalence range +/- 0.11. There was a higher incidence of hypokalaemia and hyperglycaemia at highest doses during treatment with the Aeroliser than with Airmax. In conclusion, formoterol delivered from Airmax provides a dose-dependent bronchodilating effect which is similar to that obtained by Aeroliser, at double the dose.

Housing and care of monkeys and apes in laboratories: adaptations allowing essential species-specific behaviour.

During the last two decades an increasing amount of attention has been paid to the housing and care of monkeys and apes in laboratories, as has been done with the housing and care of other categories of captive animals. The purpose of this review is to develop recommendations for adaptations of housing and care from our knowledge of the daily behavioural activity of monkeys and apes in natural conditions and in enriched laboratory conditions. This review deals mainly with adaptations of daily housing and care with respect to behaviour, and it is restricted to commonly-used species: Callitrichidae (Callitrix jacchus, Saguinus oedipus); Cebidae (Aotus trivirgatus, Saimiri sciureus, Cebus apella); Cercopithecidae (Macaca fascicularis, M. mulatta, M. nemestrina, M. arctoides, Chlorocebus aethiops, Papio hamadryas, P. cynocephalus); Pongidae (Pan troglodytes).

Determination of pyrrolizidine alkaloids in senecio species by liquid chromatography/thermospray-mass spectrometry and liquid chromatography/nuclear magnetic resonance spectroscopy.

A new method using direct on-line coupling between HPLC, MS and (1 )H-NMR was developed for the detection and identification of pyrrolizidine alkaloids (PAs) in crude extracts of Senecio species. The PAs present in the extracts were separated on a C-18 reversed-phase column with an alkaline acetonitrile-water gradient. Molecular weight information of each peak was obtained by LC/MS and specific fragments were recorded by complementary MS/MS experiments. In order to distinguish isomeric structures of PAs, complementary LC/ (1)H-NMR analyses were performed in both on-flow and stop-flow modes with alkaline acetonitrile-D (2)O and methanol-D (2)O as mobile phases. This approach led to the identification of the known PAs of S. vulgaris; retrorsine, seneciphylline, and senecionine. The method was also applied for the analysis of African Senecio species: S. mariettae and S. venosus. Retrorsine was identified as the main PA in both species. Detection of the PAs in small amounts was achieved by LC/MS. Higher amounts of extracts (mg) had to be injected to obtain good quality on-flow LC/ (1)H-NMR.

Generation and characterization of monoclonal antibodies against the pyrrolizidine alkaloid retrorsine.

Monoclonal antibodies against retrorsine were established using a retrorsine-hemisuccinate::bovine-thyroglobuline conjugate as antigen for immunization. In competitive enzyme-linked immunoassays the specificity of the obtained antibodies was tested with 20 different pyrrolizidine alkaloids. Among these the alkaloids acetylgynuramine, gynuramine, integerrimine, neoplatyphylline, platyphylline, rosmarinine, senecionine, and seneciphylline were able to bind the antibody. There was no cross-reactivity with the alkaloids senkirkine, angeloyl-heliotridine, heliotridine, axillarine, anacrotine, monocrotaline, madurensine, otosenine, retronecine, tussilagine, triangularine, and jacoline as well as with seneciphylline N-oxide. From this antigen spectrum it can be concluded that besides the necic structure itself the dominant and discriminative epitope consists of the exocyclic ethylidene group of the various diesters.

Persistent neophobic behaviour in monkeys: A habit or a trait?

Studies on the effects of rearing conditions on behavioural development showed that most monkeys reared with surrogate mothers persistently avoided a big novel object (paper bag) whereas most monkeys reared by natural mothers would approach it. Conditioned fear and conditioned avoidance, observational learning, and lack of support by the mothers' presence could be excluded as possible causes; we established that the high incidence of phobic behaviour in surrogate-reared groups was caused by deprivation of maternal care. Results of further studies showed that the avoidance was not restricted to the object the Ss had been exposed to in infancy; monkeys still avoiding the bag at 2 years also avoided other big novel objects. Some researchers have found differences in the neurobiological status between surrogate-reared monkeys and mother-reared monkeys. However, the results of our experiments showed that both types of rearing condition produced avoiders as well as non-avoiders. The question under discussion here is whether avoidance of novelty is a habit or a trait. The relative importance of features of surrogates versus real mothers, characteristics of infants and differences in mothering style is discussed.

Tussilagine and isotussilagine: two pyrrolizidine alkaloids in the genus arnica1.

In flowerheads of ARNICA MONTANA, A. CHAMISSONIS ssp. FOLIOSA, A. AMPLEXICAULIS, and A. SACHALINENSIS, traces of the non-toxic pyrrolizidine alkaloids tussilagine and isotussilagine were detected. Their identity was unambiguously confirmed by direct comparison (TLC, GC, GC/MS) with the authentic samples.

Isogravacridonchlorine: a potent and direct acting frameshift mutagen from the roots of Ruta graveolens.

The furanoacridone alkaloid isogravacridonchlorine has been isolated from the roots of Ruta graveolens, the structure was elucidated by spectroscopic means. Its mutagenic activity and mode of action was characterized without as well as with metabolic activation using different Salmonella typhimurium strains.

[Studies on the effect of an alkaloid extract of Symphytum officinale on human lymphocyte cultures]. / Wirkung eines Alkaloidextraktes von Symphytum officinale auf menschliche Lymphocytenkulturen.

An alkaloid extract of Symphytum officinale was investigated for its chromosome-damaging effect in human lymphocytes in vitro. In concentrations of 1.4 micrograms/ml and 14 micrograms/ml the alkaloids had no effect, in concentrations of 140 micrograms/ml and 1400 micrograms/ml the alkaloids induced sister chromatid exchanges (SCE) as well as chromosome aberrations. Additionally, the influence of rat liver enzymes (S9) was tested. The SCE-inducing capacity and the clastogenic effect of Symphytum alkaloids was increased by simultaneous application of S9-Mix.