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OBJECTIVE: There is a paucity of studies on the impact of maternal body mass index (BMI) on macronutrient content of human milk colostrum (HMC). The objective of this study was to compare macronutrient content of HMC in healthy women of term infants in relation to their BMI. We hypothesized that mother habitus influences human milk colostrum content. METHOD: Colostrum was collected from 109 healthy mothers of hospitalized healthy term infants divided into four prepregnancy BMI groups: 12 underweight, 59 normal weight, 20 overweight, and 18 obese women between 24 and 72 h after birth. Macronutrient content was measured using mid-infrared spectroscopy. RESULTS: There were no significant differences in macronutrients between the BMI groups. We performed four separate stepwise backward multiple regression analyses taking into account fat, carbohydrate, protein or energy content as dependent variables and maternal BMI, parity, gestational age, infant gender, maternal age, maternal education, mode of delivery and time postdelivery. In these analyses, fat, carbohydrate and energy content were not related to maternal BMI, while protein content was significantly and positively correlated with BMI (P=0.008) and negatively correlated with gestational age (P=0.004) and time postdelivery (P<0.001). Colostrum carbohydrate content was positively correlated with parity. Colostrum fat and energy content were negatively correlated with maternal age and positively correlated with parity. CONCLUSION: Most macronutrient and energy content of colostrum are unaffected by prepregnancy maternal BMI, with the exception of protein content that is positively related to maternal BMI.

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Children with autism spectrum conditions (ASC) experience difficulties recognizing others' emotions and mental states. It has been shown that serious games (SG) can produce simplified versions of the socio-emotional world. The current study performed a cross-cultural evaluation (in the UK, Israel and Sweden) of Emotiplay's SG, a system aimed to teach emotion recognition (ER) to children with ASC in an entertaining, and intrinsically motivating way. Participants were 6-9 year olds with high functioning ASC who used the SG for 8-12 weeks. Measures included face, voice, body, and integrative ER tasks, as well as parent-reported level of autism symptoms, and adaptive socialization. In the UK, 15 children were tested before and after using the SG. In Israel (n = 38) and Sweden (n = 36), children were randomized into a SG or a waiting list control group. In the UK, results revealed that 8 weeks of SG use significantly improved participants' performance on ER body language and integrative tasks. Parents also reported their children improved their adaptive socialization. In Israel and Sweden, participants using the SG improved significantly more than controls on all ER measures. In addition, parents in the Israeli SG group reported their children showed reduced autism symptoms after using the SG. In conclusion, Emotiplay's SG is an effective and motivating psycho-educational intervention, cross-culturally teaching ER from faces, voices, body language, and their integration in context to children with high functioning ASC. Local evidence was found for more generalized gains to socialization and reduced autism symptoms.

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OBJECTIVE: Fibroblasts are sentinel cells that could serve as intermediaries in the immune reaction in the inflammatory process. In this work, we investigate the action of the muscarinic agonist carbachol (CARB) on the expression and function of nitric oxide synthase (NOS) and cyclooxygenase (COX) in fibroblasts under normal or inflammatory conditions. METHODS: The normal fibroblast cell line, 3T3, from NIH swiss mouse embryo, was used. The inflammatory milieu was mimicked with lipopolysaccharide (LPS) (10 ng/ml) plus interferon gamma (IFNgamma) (0.5 ng/ml). Nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production were measured by Griess reagent and radioimmunoassay, respectively. NOS, COX, and nuclear transcription factor kappa B (NF-kappaB) were studied by Western blot. RESULTS: CARB increased NO synthesis by 57 +/- 5%, while a 150 +/- 10% increase in NO liberation was triggered by LPS plus IFNgamma treatment. CARB added to LPS plus IFNgamma potentiated NO synthesis by 227 +/- 19%. CARB also upregulated NOS1 protein expression via NF-kappaB activation. In addition CARB and LPS plus IFNgamma stimulated PGE(2) synthesis by 72 +/- 9 and 42 +/- 4%, respectively, while CARB added to LPS plus IFNgamma treated cells produced a synergism in PGE(2) liberation (130 +/- 12%) via COX-2. CONCLUSION: Activation of muscarinic acetylcholine receptors can mimic mild inflammatory conditions or can deepen pre-existing inflammation, establishing a fine-tuned set-up on fibroblasts that in turn could be alerting the immune system.

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Nitric oxide (NO) is a toxic molecule of the immune system which contributes to the control of microbial pathogens. Additional functions of NO in innate and adaptive immunity have recently been described; these functions include the modulation of the cytokine response of lymphocytes and the regulation of immune cell apoptosis. In addition to direct microbicidal actions, NO has immunoregulatory effects relevant to the control of infections. In turn, infected macrophages and macrophage-regulating lymphocytes may undergo apoptosis during infection by Salmonella spp. In this work we investigated the ability of attenuated strains of Salmonella enterica serovar Enteritidis with different protective capacities to induce intestinal inducible nitric oxide synthase (iNOS) and apoptosis in Peyer's patches (PP) in mice. Results showed that the intestinal iNOS activity correlated with increased apoptosis in PP. Furthermore, the ability to induce intestinal NO production and apoptosis within the first few hours after immunization seemed to correlate with the protective capacity of mutant E/1/3 of S. enterica serovar Enteritidis. It was found that nonprotective mutant C/2/2, which was unable to induce intestinal NO production, also failed to induce apoptosis in PP. Moreover, aminoguanidine treatment at the time of immunization resulted in inhibition of the NO production and apoptosis induced by protective mutant E/1/3 and completely abolished protection against challenge. These results suggest that the induction of iNOS in the intestinal mucosa by attenuated mutant E/1/3 of S. enterica serovar Enteritidis at the time of immunization is necessary to generate a protective immune response.

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The non-obese diabetic (NOD) mouse model of autoimmune sialadenitis offers the possibility of studying the L-arginine/nitric oxide signaling pathway in salivary glands in basal and neurotransmitter-stimulated conditions and, thus, of analyzing the neural control of the secretory process in the target organ. The purpose of this study was to explore putative alterations in the activity and expression of nitric oxide synthase (NOS) in submandibular glands of NOD mice in relation to parotid glands and unrelated tissues. Here we report that NOD mice with incipient signs of secretory dysfunction presented a marked decrease in basal and vasoactive intestinal peptide (VIP)-stimulated NOS activity and a differential expression of NOS I in submandibular glands compared to control BALB/c mice. Similar alterations in NOS I were found in parotid glands but not in brain or spleen of NOD mice. No differences between NOD and controls appeared in NOS II and NOS III expression in any of the tissues studied.

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Cardiac tissue from autoimmune myocarditis mice was studied to evaluate the expression and biological activity of mRNA encoding H(1) receptor and iNOS. BALB/c inbred mice were immunized with heart protein and sacrificed at 20, 45 and 50 days post immunization. Heart contractility studies and RT-PCR assays were performed. Heart from autoimmune myocarditis mice show mRNA iNOS-related dysfunction with a decrease in heart contractility. This effect was accompanied with an increase production of cyclic GMP and was improved by treating autoimmune mice with an inhibitor of iNOS activity. In addition, autoimmune myocardium expressed an active histamine H(1) receptor mRNA coupled to phospholipase C. The activation of H(1) receptor by ThEA stimulated both phosphoinositide hydrolysis and heart contractility. Normal myocardium did not expressed neither iNOS mRNA nor H(1) receptor mRNA. In conclusions: the development of autoimmune cardiac dysfunction was associated with the expression of iNOS mRNA, cyclic GMP accumulation and the expression of an active histamine H(1) receptor mRNA with increase production of inositol phosphates. These protein emergence during the course of autoimmune myocarditis may be involved a distinct compensatory mechanism operating in this disease.

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This study reports the expression of the ubiquitous 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene (PFKFB3) (PFK-2/FBPase-2) in different stages of rat brain development. Northern blot and RT-PCR analysis demonstrated that ubiquitous PFK-2/FBPase-2 is expressed in rat brain from embryonic to adult life and shows a transient increase 1 day before birth, coincident with the maximum concentration of Fru-2,6-P(2) and PFK-2 activity. The levels of brain PFK-2/FBPase-2 gene expression as well as the enzymatic activity and the concentration of Fru-2,6-P(2) appear to be remarkably constant during adult life, without significant differences in the brain hippocampus, cortex, cerebellum or striatum areas.

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The antiviral activity of Sanicula europaea L. extracts against human parainfluenza virus type 2 (HPIV-2) was examined. The extract prepared from the leaves of the plant and a fraction separated from the crude extract with gel filtration chromatography were found to inhibit HPIV-2 replication without any toxic effect on Vero cells. The acidic fraction obtained from the crude extract of S. europaea leaves was found to be the most active fraction with plaque inhibition assay at non-cytotoxic concentrations. Unfortunately, antiviral activity was not detected in the molecules purified from the crude ethanol extract of Sanicula leaves.

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Many sesquiterpene lactones (SLs) possess considerable anti-inflammatory activity. They inhibit the transcription factor NF-kappaB by selectively alkylating its p65 subunit probably by reacting with cysteine residues. Here we assayed 28 sesquiterpene lactones for their ability to inhibit NF-kappaB. The majority of the potent NF-kappaB inhibitors possess two reactive centers in form of an alpha-methylene-gamma-lactone group and an alpha,beta- or alpha,beta,gamma,delta-unsaturated carbonyl group. Based on computer molecular modelling we propose a molecular mechanism of action, which is able to explain the p65 selectivity of the SLs and the observed correlation of high activity with alkylant bifunctionality. A single bifunctional SL molecule can alkylate the cysteine residue (Cys 38) in the DNA binding loop 1 (L1) and a further cysteine (Cys 120) in the nearby E' region. This cross link alters the position of tyrosine 36 and additional amino acids in such a way that their specific interactions with the DNA become impossible. We also created a model for monofunctional SLs.

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The aerial parts of Tanacetum argenteum subsp. canum var. canum (Compositae) afforded six guaianolides, five of them (2-6) being new: flabellin (1), epoxyflabellin (2), Delta3(4)-15-oxo-flabellin (3), Delta3(4)-15-hydroxydihydroflabellin (4), 11alpha-dihydroflabellin (5), and 11beta-dihydroflabellin (6). The structures of the compounds were elucidated by spectral methods including NMR (1H NMR, COSY, APT, HETCOR, NOE) and X-ray diffraction, as well as by some chemical reactions.

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This study reports the expression of inducible nitric oxide synthase (NOS) in heart from autoimmune myocarditis mice associated with an alteration in their contractile behavior. By mean of the production of [U-14C]citrulline from [U-14C]arginine and immunoblot assay, the expression of iNOS was demonstrated in autoimmune atria that was normally absent. The iNOS activity decreased with administration of dexamethasone and in mice treated with monoclonal anti-interferon-gamma antibody (anti-IFN-gamma mAb). The inhibitors of protein kinase C activity (staurosporine) but not calcium/calmodulin (trifluoperazine) attenuated the iNOS activity. Moreover, autoimmune atria presented contractile alterations (lower values of dF/dt than control). The in vivo treatment with inhibitors of NOS activity or anti-IFN-gamma mAb or dexamethasone improved the contractile activity of autoimmune atria with no change in the contractility of normal atria. The results suggest that the infiltrative cells in myocarditis heart have a potential role in cardiac dysfunction by production of IFN-gamma and subsequent expression of iNOS, that in turn alter the contractile behavior of the heart. The data indicate that cytokines induced activation of L-arginine nitric oxide pathway in myocarditis atria leading to contractile dysfunction.

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Extracts from the aerial parts of Sanicula europaea L. were investigated for their anti-HIV activity, and the 50% ethanolic extract was shown to exhibit the highest activity. A new triterpene saponin glycoside, 21 beta-(angeloyloxy)-3-O-[beta-D-arabinopyranosyl(1-->4)-beta- D-glucopyranosyl (1-->3)-beta-D-glucuronopyranosyl propyl ester]-3 beta,15,16,22 alpha,28 beta-pentahydroxy-delta(12)-oleanene, saniculoside N (1), in addition to the known phenolic acids, rosmarinic acid (2), and caffeic acid (3) were isolated as major components. Rosmarinic acid was established as the principal active substance.

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The roots of Ononis spinosa subsp. leiosperma (Leguminosae) afforded a new glycoside, spinonin (1), possessing a novel skeleton, in addition to the known isoflavonoid glycoside, ononin [7beta-(glucosyloxy)formononetin] (2) and the known pterocarpan, 7-demethoxy-7-D-(glucosyloxy)homopterocarpin (3). The structure of the new isolate was elucidated by spectral methods including 1H and 13C NMR, COSY, APT, HETCOR, HMBC, NOESY, CD, FABMS, HRMS, EIMS, CIMS, and some chemical reactions. Spinonin was inactive against a number of human cancer cell lines and HIV-1 reverse transcriptase. The compounds 1 and 3 showed weak activity against Pseudomonas aeruginosa, whereas 2 was active against beta-hemolytic Streptococcus.

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Experimental autoimmune myocarditis obtained in mice by immunization with heart antigens is characterized by the presence of lymphomononuclear infiltrates in atria and ventricles. Here we show the ability of soluble factors released by immune cells from mice immunized with heart antigens to decrease heart contractility in a similar way to a muscarinic agonist. These effects appear to be mediated by IFN-gamma since all of them could be blocked by an anti-IFN-gamma monoclonal antibody. Moreover, the negative inotropic effect induced by immune cell-conditioned media was blocked by atropine, confirming previous findings that IFN acts as a muscarinic agonist on isolated atria. The role of locally released cytokines and especially of IFN-gamma was also evaluated in infiltrated autoimmune myocarditis hearts; thus, the addition of monoclonal anti-IFN-gamma antibody reversed the decreased contractility characteristics of this model. We conclude that IFN released both systemically and locally by autoreactive T cells may contribute to the impaired cardiac function in this experimental model of autoimmune myocarditis.

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In this paper, we demonstrated that the production of PGE2 by CD8+ T lymphocytes through muscarinic cholinergic receptor (mAChR) activation of lymphocytes from mice acutely infected with nonlethal Trypanosoma cruzi CA-1 strain could enhance resistance to infection. Treatment in vivo with either atropine or cyclooxygenase inhibitors enhanced mortality rates and parasitemia of mice infected with T. cruzi CA-1 strain. The mechanism by which CD8+ T lymphocytes released PGE2 appears to involve the activation of the cells by circulating IgG present in mice infected with T. cruzi CA-1 strain. Binding of these antibodies to mAChR on CD8+ T lymphocytes triggered the release of large amounts of PGE2. The results point to a role of serum antibodies against mAChR in the protection of T. cruzi infection. The prostanoid acting as an immunomodulator contributed to the maintenance of the chronic course of experimental Chagas disease.

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Ten sesquiterpene lactones and one sesquiterpene isolated from Tanacetum praeteritum subsp. praeteritum: 1 alpha, 6 alpha -dihydroxyisocostic acid methyl ester (2), 1 alpha-hydroxy-1-deoxoarglanine (3), douglanin (5), santamarin (6), reynosin (7), 1-epitatridin B (8), ludovicin A (10), armexin (12), armefolin (13), armexifolin (14), and 3 alpha-hydroxyreynosin (15) were tested against the human lung carcinoma cell line GLC4 and the colorectal cancer cell line COLO 320 as well as against the bacteria Bacillus subtilis, Staphylococcus aureus, Proteus mirabilis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus, beta-hemolytic Streptococcus, and the yeast Candida albicans. In addition, two germacranolides tatridin A (16) and tamirin (17) were included in the study. All compounds showed cytotoxic activity (IC50 = 124 microM) but most of them were not effective in the antimicrobial tests.

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We have previously shown that myocardium from experimental autoimmune myocarditis expresses H1 receptors not present in normal mice heart. ThEA acting via H1 receptors, augments cyclic AMP production in atria from autoimmune myocarditis mice without any effect on atria from control mice. Addition of mepyramine before ThEA caused cyclic AMP levels to fall to a level similar to basal, confirming the H1 receptor participation. Histamine at low concentrations mimicked the ThEA action on H1 receptor-stimulation of cyclic AMP production by autoimmune myocardium. The fact that the inhibition of phospholipase C blocked the cyclic AMP stimulation by ThEA, supports the assumption that this action is secondary to receptor-mediated hydrolysis of phosphoinositides, generating some oxidative metabolites (IP3-DAG), which in turn may be responsible for the cyclic AMP effect. So, the inhibition of protein kinase C and calcium/calmodulin partially prevented the stimulatory action of ThEA on cyclic AMP levels in autoimmune myocardium, suggesting that both pathways are implicated in this effect. Data shows that the stimulation of H1 receptors by specific agonist in atria from autoimmune myocarditis mice, augments the cyclic AMP, requiring the hydrolysis of phosphoinositide cycle. The role of this cyclic AMP augmentation in myocardium from autoimmune myocarditis mice, will provide a basis to assess the role of this second messenger as an important factor in the regulation and/or modulation of the physiological behaviour of the heart in the course of autoimmune myocarditis.

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This review regards the main functional characteristics of hearts subjected to an autoimmune response, focusing especially on the role of T lymphocytes and autoantibodies in the development of cardiac dysfunction. Evidence of a strong association in the onset and time-course of immune response and cardiac dysfunction is presented and the results are viewed comparatively with myocarditis models induced by heart, parasite or virus inoculation. Cardiac damage is evaluated regarding various aspects, namely histologic, immunologic, biochemical, pharmacologic, physiologic. Finally, the model, for its characteristics of resulting from an autoimmune response against the heart with functional consequences, has proved its usefulness to study neuroimmune interaction, mainly the immune to nervous direction, as autoantibodies and T cell-derived factors have a role in cardiac failure.

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This review regards the main functional characteristics of hearts subjected to an autoimmune response, focusing especially on the role of T lymphocytes and autoantibodies in the development of cardiac dysfunction. Evidence of a strong association in the onset and time-course of immune response and cardiac dysfunction is presented and the results are viewed comparatively with myocarditis models induced by heart, parasite or virus inoculation. Cardiac damage is evaluated regarding various aspects, namely histologic, immunologic, biochemical, pharmacologic, physiologic. Finally, the model, for its characteristics of resulting from an autoimmune response against the heart with functional consequences, has proved its usefulness to study neuroimmune interaction, mainly the immune to nervous direction, as autoantibodies and T cell-derived factors have a role in cardiac failure.

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Hearts from mice hyperimmunized with cardiac tissue were studied to evaluate the expression and biological activity of muscarinic cholinergic receptors and immunoglobulin G deposits along the immunization period. Mice were sacrificed at 10 day intervals from the first injection up to day 100. Simultaneously, the activity of autoantibodies against muscarinic receptors on normal hearts was also examined in sera. Hearts with autoimmune myocarditis showed a muscarinic receptor-related dysfunction, with an impaired response to exogenous muscarinic agonists and a significant reduction in muscarinic binding sites, both effects being maximum at 40-50 days post-immunization. In addition, serum or immunoglobulin G from mice with myocarditis were able to interact with muscarinic acetylcholine receptors displaying a partial agonist effect. Autoimmune sera and immunoglobulin G reduced heart contractility while inhibited 3H-QNB binding to cardiac acetylcholine receptors in a concentration dependent manner showing the highest effects at days 40-50 and decreased progressively thereafter. The development of muscarinic receptor-related cardiac dysfunction may be associated with the presence of circulating antibodies having muscarinic receptor activity. These studies are of relevance to clinical conditions such as Chagas' disease, where immunological processes involving the cholinergic system are considered to cause cardiomyopathy.

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