Uptake of New Lipid-coated Nanoparticles Containing Falcarindiol by Human Mesenchymal Stem Cells.

Nanoparticles are the focus of an increased interest in drug delivery systems for cancer therapy. Lipid-coated nanoparticles are inspired in structure and size by low-density lipoproteins (LDLs) because cancer cells have an increased need for cholesterol to proliferate, and this has been exploited as a mechanism for delivering anticancer drugs to cancer cells. Moreover, depending on drug chemistry, encapsulating the drug can be advantageous to avoid degradation of the drug during circulation in vivo. Therefore, in this study, this design is used to fabricate lipid-coated nanoparticles of the anticancer drug falcarindiol, providing a potential new delivery system of falcarindiol in order to stabilize its chemical structure against degradation and improve its uptake by tumors. Falcarindiol nanoparticles, with a phospholipid and cholesterol monolayer encapsulating the purified drug core of the particle, were designed. The lipid monolayer coating consists of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol (Chol), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE PEG 2000) along with the fluorescent label DiI (molar ratios of 43:50:5:2). The nanoparticles are fabricated using the rapid injection method, which is a fast and simple technique to precipitate nanoparticles by good-solvent for anti-solvent exchange. It consists of a rapid injection of an ethanol solution containing the nanoparticle components into an aqueous phase. The size of the fluorescent nanoparticles is measured using dynamic light scattering (DLS) at 74.1 ± 6.7 nm. The uptake of the nanoparticles is tested in human mesenchymal stem cells (hMSCs) and imaged using fluorescence and confocal microscopy. The uptake of the nanoparticles is observed in hMSCs, suggesting the potential for such a stable drug delivery system for falcarindiol.

Parthenolide in Danish biodynamic and organic milk: A new source of exposure to an allergenic sesquiterpene lactone.

BACKGROUND: The sunflower family of plants (Compositae = Asteraceae) is currently the most allergenic plant family worldwide, according to the number of sensitizing species. Secondary plant metabolites, including the allergenic sesquiterpene lactones present in Compositae plants, may occur in food items either through their presence in, or through contamination of, plant-based raw materials, or through their occurrence in products of non-plant origin. OBJECTIVE: To analyse biodynamic, organic and conventional milk for the presence of the sesquiterpene lactone parthenolide. METHODS: The content of parthenolide in the milk samples was investigated in dichloromethane extracts obtained by liquid-liquid extraction, followed by gas chromatography-mass spectrometry analyses. RESULTS: The concentration of parthenolide was 0.07 ±0.004 ppm in biodynamic milk, 0.05 ±0.002 ppm in organic milk, and not detectable (<0.002 ppm) in conventional milk. CONCLUSIONS: This is the first report of a potent contact allergen in milk. There seems to be an association between the time that the dairy cattle spend grazing and the amount of parthenolide detected. Although the concentration is low, it is estimated to be high enough to elicit dermatitis in the most sensitive persons by direct contact with the milk.

Dietary polyacetylenes, falcarinol and falcarindiol, isolated from carrots prevents the formation of neoplastic lesions in the colon of azoxymethane-induced rats.

Falcarinol (FaOH) and falcarindiol (FaDOH) are found in many food plants of the Apiaceae family. Carrots are a major dietary source of these polyacetylenes. Feeding azoxymethane (AOM)-induced rats with carrots and purified FaOH have previously been shown to inhibit neoplastic transformations in the colon. FaOH and FaDOH have also shown to have a synergistic effect in vitro, resulting in a significant increased cytotoxic activity. Based on these findings the antineoplastic effect of FaOH and FaDOH (purity > 99%) was investigated in the AOM-induced rat model. Twenty rats received rat diet containing 7 µg FaOH per g feed and 7 µg FaDOH per g feed and 20 rats were controls receiving only rat diet. Then carcinogenesis was induced in all 40 rats with the carcinogen AOM. All animals received the designated diet for 2 weeks before AOM induction and continued on the designated diet throughout the experiment. Rats were euthanized 18 weeks after the first AOM injection and macroscopic polyp/cancers were measured, harvested and stained for histology. The difference in sizes of aberrant crypt foci (ACF) were analysed in a Wilcoxon rank sum test, in which the median number of small ACF was 218 in controls and 145 in polyacetylene treated rats (P < 0.001). Fifteen control rats and 8 treated rats had macroscopic tumors (P = 0.027). The number of tumors larger than 3 mm were 6 and 1 in control and treated rats, respectively (P = 0.032). In conclusion dietary supplements with FaOH and FaDOH reduced the number of neoplastic lesions as well as the growth rate of the polyps suggesting a preventive effect of FaOH and FaDOH on the development of colorectal cancer.

Polyacetylenes from carrots (Daucus carota) improve glucose uptake in vitro in adipocytes and myotubes.

A dichloromethane (DCM) extract of carrot roots was found to stimulate insulin-dependent glucose uptake (GU) in adipocytes in a dose dependent manner. Bioassay-guided fractionation of the DCM extract resulted in the isolation of the polyacetylenes falcarinol and falcarindiol. Both polyacetylenes were able to significantly stimulate basal and/or insulin-dependent GU in 3T3-L1 adipocytes and porcine myotube cell cultures in a dose-dependent manner. Falcarindiol increased peroxisome proliferator-activated receptor (PPAR)γ-mediated transactivation significantly at concentrations of 3, 10 and 30 µM, while PPARγ-mediated transactivation by falcarinol was only observed at 10 µM. Docking studies accordingly indicated that falcarindiol binds to the ligand binding domain of PPARγ with higher affinity than falcarinol and that both polyacetylenes exhibit characteristics of PPARγ partial agonists. Falcarinol was shown to inhibit adipocyte differentiation as evident by gene expression studies and Oil Red O staining, whereas falcarindiol did not inhibit adipocyte differentiation, which indicates that these polyacetylenes have distinct modes of action. The results of the present study suggest that falcarinol and falcarindiol may represent scaffolds for novel partial PPARγ agonists with possible antidiabetic properties.

Sunflower seeds as eliciting agents of Compositae dermatitis.

BACKGROUND: Sunflowers may cause dermatitis because of allergenic sesquiterpene lactones (SLs). Contact sensitization to sunflower seeds has also been reported, but the allergens are unknown. OBJECTIVES: To analyse sunflower seeds for the presence of SLs and to assess the prevalence of sunflower sensitization in Compositae-allergic individuals. PATIENTS/MATERIALS/METHODS: Sunflower-sensitive patients were identified by aimed patch testing. A dichloromethane extract of whole sunflower seeds was analysed by liquid chromatography-mass spectrometry and high-performance liquid chromatography. RESULTS: The prevalence of sensitivity to sunflower in Compositae-allergic individuals was 56%. A solvent wash of whole sunflower seeds yielded an extract containing SLs, the principal component tentatively being identified as argophyllin A or B, other SLs being present in minute amounts. CONCLUSIONS: The concentration of SLs on the sunflower seeds is considered high enough to elicit dermatitis in sensitive persons, and it seems appropriate to warn Compositae-allergic subjects against handling sunflower seeds.

Identification of PPARγ Agonists from Natural Sources Using Different In Silico Approaches.

Peroxisome proliferator-activated receptor γ plays an important role in lipid and glucose homeostasis and is the target of many drug discovery investigations because of its role in diseases such as type 2 diabetes. Activation of peroxisome proliferator-activated receptor γ by agonists leads to a conformational change in the ligand-binding domain altering the transcription of several target genes involved in glucose and lipid metabolism, resulting in, for example, facilitation of glucose and lipid uptake and amelioration of insulin resistance, and other effects that are important in the treatment of type 2 diabetes. Peroxisome proliferator-activated receptor γ partial agonists are compounds with diminished agonist efficacy compared to full agonists; however, they maintain the antidiabetic effect of full agonists but do not induce the same magnitude of side effects. This mini-review gives a short introduction to in silico screening methods and recent research advances using computational approaches to identify peroxisome proliferator-activated receptor γ agonists, especially partial agonists, from natural sources and how these ligands bind to the peroxisome proliferator-activated receptor γ in order to better understand their biological effects.

Isomeric C12-alkamides from the roots of Echinacea purpurea improve basal and insulin-dependent glucose uptake in 3T3-L1 adipocytes.

Echinacea purpurea has been used in traditional medicine as a remedy for the treatment and prevention of upper respiratory tract infections and the common cold. Recent investigations have indicated that E. purpurea also has an effect on insulin resistance. A dichloromethane extract of E. purpurea roots was found to enhance glucose uptake in adipocytes and to activate peroxisome proliferator-activated receptor γ. The purpose of the present study was to identify the bioactive compounds responsible for the potential antidiabetic effect of the dichloromethane extract using a bioassay-guided fractionation approach. Basal and insulin-dependent glucose uptake in 3T3-L1 adipocytes were used to assess the bioactivity of extract, fractions and isolated metabolites. A peroxisome proliferator-activated receptor γ transactivation assay was used to determine the peroxisome proliferator-activated receptor γ activating properties of the extract, active fractions and isolated metabolites. Two novel isomeric dodeca-2E,4E,8Z,10E/Z-tetraenoic acid 2-methylbutylamides together with two known C12-alkamides and α-linolenic acid were isolated from the active fractions. The isomeric C12-alkamides were found to activate peroxisome proliferator-activated receptor γ, to increase basal and insulin-dependent glucose uptake in adipocytes in a dose-dependent manner, and to exhibit characteristics of a peroxisome proliferator-activated receptor γ partial agonist.

Screening for bioactive metabolites in plant extracts modulating glucose uptake and fat accumulation.

Dichloromethane and methanol extracts of seven different food and medicinal plants were tested in a screening platform for identification of extracts with potential bioactivity related to insulin-dependent glucose uptake and fat accumulation. The screening platform included a series of in vitro bioassays, peroxisome proliferator-activated receptor (PPAR) γ-mediated transactivation, adipocyte differentiation of 3T3-L1 cell cultures, and glucose uptake in both 3T3-L1 adipocytes and primary porcine myotubes, as well as one in vivo bioassay, fat accumulation in the nematode Caenorhabditis elegans. We found that dichloromethane extracts of aerial parts of golden root (Rhodiola rosea) and common elder (Sambucus nigra) as well as the dichloromethane extracts of thyme (Thymus vulgaris) and carrot (Daucus carota) were able to stimulate insulin-dependent glucose uptake in both adipocytes and myotubes while weekly activating PPARγ without promoting adipocyte differentiation. In addition, these extracts were able to decrease fat accumulation in C. elegans. Methanol extracts of summer savory (Satureja hortensis), common elder, and broccoli (Brassica oleracea) enhanced glucose uptake in myotubes but were not able to activate PPARγ, indicating a PPARγ-independent effect on glucose uptake.

Revelar, compartir y expresar las emociones: efectos sobre la salud y el bienestar / Disclosing, sharing and expressing emotions: effect on the health and well-being

Este artículo examina los efectos de la comunicación de las experiencias emocionales sobre la salud. Primero, se presentan las investigaciones sobre los efectos positivos de la confrontación de hechos traumáticos. Segundo, se exponen los estudios sobre el compartimiento social de las emociones. Estos estudios muestran que hablar sobre los episodios afectivos no disminuye el impacto de los recuerdos emocionales y que al contrario, la falta de recuperación afectiva relacionada con estos episodios se asocia a una necesidad constante de hablar. También se revisa el concepto de alexitimia, como un déficit en la comunicación emocional, y en la dificultad de identificar y describir emociones. Se revisan evidencias que apoyan la idea que la alexitimia puede considerarse como un déficit de la habilidad para procesar y regular cognitivamente las emociones, así como en la capacidad personal de auto-revelación emocional. Se otroga particular cuidado en discutir los complejos resultados de las investigaciones sobre compartir social, desinhibición y alexitimia. Finalmente se revisan los diversos mecanismos explicativos que regulan la expresión e inhibición emocional en la salud y la enfermedad (AU)

Clinical evaluation, dose-finding and acceptability of AERODIOL, the pulsed estrogen therapy for treatment of climacteric symptoms.

S21400 (AERODIOL) is a new intranasal formulation of 17beta-estradiol. It provides a pulsed estrogen therapy that ensures sufficient estrogenisation of tissues to treat estrogen deficiency symptoms, particularly those of the menopause. This multicentric study was designed to determine dose-range, efficacy and acceptability of S21400. One hundred and thirty four women were allocated a daily dose of 100-900 microg for 12 weeks. The doses of 100, 600 and 900 microg were given in two daily administrations, the doses of 200, 300 and 450 microg were given in one and two daily administrations. Oral progestogen was added the last 10-14 days of each cycle of estrogen therapy in all non-hysterectomized women. S21400 showed a dose-effect relationship and provided adequate estrogenisation in more than 80% of patients receiving a dose ranging from 200 to 600 microg daily. Hormonal impregnation was judged sufficient in 23% of women receiving the lowest dose (100 microg). It was often considered excessive for daily doses of 900 microg (36%). After 12 weeks of treatment, efficacy was similar whether the total daily dose was given in one or two administrations. Treatment was well tolerated and accepted, with only minor nasal events (prickling, sneezing). It was perceived by 92% of patients as good or excellent and 81% chose to continue the nasal treatment when it was offered to them. An initial dose of 300 microg per day provides an optimal efficacy/tolerability ratio. In summary, the pulsed estrogen therapy with AERODIOL in one daily administration offers a safe, well accepted and highly effective treatment to alleviate climacteric symptoms. It can be adapted easily to ensure optimal clinical efficacy.

Subjective and autonomic responses to emotion induction in psychopaths.

It has been theorized that psychopaths have a fundamental deficit with respect to emotions (Cleckley, 1941). This study compares psychopaths with control subjects (Hare, 1991) in terms of their physiological and subjective responses to video clips depicting different emotions: joy, fear, anger, sadness, and disgust. Physiological measures assessed cardiovascular, respiratory, electrodermal, electromyographic responding, as well as skin temperature. Subjective measures assessed bodily sensations and subjective emotional appraisal. The principal physiological difference was a lower blood pressure among psychopaths before and during emotional stimulation. Thus, while psychopaths's autonomic base-line may be generally hyporeactive, they do not seem to have any emotion-specific physiological deficit. Globally, the results suggested no specific psychophysiological deficits among psychopaths in a context using daily emotions. Subjective measures also revealed that, compared to control subjects, psychopaths reported less intense bodily sensations during emotional stimulation. There was no difference between the two groups in terms of emotional appraisal.

Keeping Emotional Memories Secret: Health and Subjective Well-being when Emotions are not Shared.

The present study investigated two predictions derived from inhibition theory. It was hypothesized that emotional secrecy has a negative impact on (1) physical and (2) subjective well-being. Also, the study examined whether the relation holds when controlling for negative affectivity (NA), a variable that can be assumed to mediate the relation between emotional secrecy and physical and subjective well-being. Consistent with the hypothesis, emotional secrecy negatively affected physical health. This finding was not explained by NA, which contributed independently to physical health. Contrary to the prediction, emotional secrecy affected life satisfaction but indirectly through the mediating influence of physical health. The implications of these results for future research on emotional secrecy and physical and subjective well-being are discussed.

Effects of lorazepam on film-induced differentiated emotions in healthy volunteers.

We studied the effects of lorazepam, a benzodiazepine, on differentiated emotions in healthy volunteers. In order to induce differentiated emotions, film excerpts were selected on the basis of the type of emotion they induced (fear, anger and for affective tone neutral film). For 6 days (D1 to D6), ten healthy volunteers received lorazepam (1 mg bid) or placebo in a randomized cross-over double-blind trial. During each treatment period, emotional induction occurred on D4, D5 and D6. One film excerpt (fear, anger or neutral) was presented each morning after relaxation. Evaluation was performed before and after each emotional induction and included questionnaires (Differential Emotions Scale and physical activation visual analog scales), and neurophysiological parameters (systolic and diastolic blood pressure, heart rate and norepinephrine levels). Globally, the film excerpts induced the predicted emotions. An analysis of variance was undertaken and revealed a significant effect of lorazepam versus placebo. On the Differential Emotions Scale and during fear induction, lorazepam induced a significantly higher increase in fear, anxiety and disgust emotions than placebo, whereas no effect was observed after anger induction. Lorazepam also induced a significantly higher increase in diastolic and systolic blood pressure with no change in heart rate, and physical activation items ("tears" and "faster breathing") without no significant change in norepinephrine. In conclusion, our results are consistent with an overall increase in emotional reactivity with lorazepam (1 mg bid) as compared to placebo. The pertinence of film-induced differentiated emotions has to be confirmed for clinical pharmacological use.

Psychological and social adjustment after pediatric liver transplantation as a function of age at surgery and of time elapsed since transplantation.

The study assessed psychological and social adjustment to pediatric liver transplantation in 101 patients aged 4-16 years who had undergone transplantation 2-10 years earlier. Each parent completed the Child Behavior Check List (CBCL) independently and answered a transplantation questionnaire assessing psychosocial issues. Most children scored within the normal range for both parts of the CBCL (i.e. Behavioral Problems and Social Competences). The impact of age at transplantation and of time elapsed since transplantation were examined. Earlier transplantation was associated with subsequent higher scores for Aggressive Behavior and Sex Problems, with lower scores for Activities and Competences, and with more parental anxiety concerning their child's health. The longer the time elapsed since transplantation, the more mothers rated high levels on the Somatic complaints, Anxiety/depression, Competence, and Social activity CBCL scales for their child. Parents reported talking more about the transplantation with their children with increasing time following transplantation. This suggests that transplantation remains an important event even after long periods of time from the transplant event. Finally, despite the difficulties encountered, more than 80% of the parents considered the transplantation had been beneficial to their child.

Stereotypes of emotional expressiveness of northerners and southerners: a cross-cultural test of Montesquieu's hypotheses.

Montesquieu argued that residents of warmer climates are more emotionally expressive than those living in cooler ones. More than 2,900 college students from 26 countries completed a brief questionnaire assessing the degree to which they considered Northerners and Southerners within their own countries to be emotionally expressive. In addition, individuals rated themselves on their own degree of expressiveness. In partial confirmation of Montesquieu's hypothesis, it was found that large within-country North-South stereotypes exist. Especially in Old World countries, Northerners are viewed as less emotionally expressive than Southerners. Regression and other analyses revealed that self-ratings of expressiveness were, in fact, related to being from the South and to warmer mean temperatures. Several possible explanations for these effects are discussed.

[Evaluation of antibiotic use: a prospective study in a university hospital center]. / Evaluation de l'utilisation des antibiotiques: une étude prospective dans un centre hospitalier universitaire.

The inappropriate use of antibiotics has been documented by several studies. Most of these studies have been performed in the USA and there is very little data from Europe and Switzerland. A three-month prospective study was carried out at the University Medical Center of Lausanne in the departments of internal medicine, general surgery and traumatology. During this period, 2112 patients were hospitalized among whom 878 received one or more courses of antibiotic therapy: the treatment was given prophylactically in 35% of the cases and therapeutically in the other 65%. A total of 1165 antibiotic prescriptions were evaluated. The administration of the antibiotic was considered to be indicated in 96% of the cases. However, 24% of the prescriptions contained at least one error. 50% of the errors were observed in prophylactic treatments and most were related to the length of administration and the spectrum of the agents. The errors in therapeutic prescription were found mainly in indications for urinary and respiratory tract infections, and were related to the spectrum of the antibiotic and the length of treatment. It was calculated that the inappropriate use of antibiotics accounted for approximately 7% of the total costs of all antibiotics used. We estimated that half of this excess in costs could probably be saved by the introduction of simple corrective measures mainly directed at limiting the duration of administration.