Changes in vitamin A intake following the social marketing of red palm oil among children and women in Burkina Faso

This paper focuses on changes in vitamin A (VA) intakes as part of the evaluation of a pilot project on social marketing of red palm oil (RPO) as a VA supplement for mothers and children in central-north Burkina Faso. The objectives of the 30-month project are to demonstrate the feasibility and effectiveness of introducing RPO in non-consuming areas. RPO is collected from women in the South-West region and it is sold in project sites by village volunteers. RPO is promoted by community workers trained in persuasive communication and social marketing. The target population is free to buy and consume RPO. Evaluation design includes data collected at onset, then 12 and 24 months later, from the same sample of 210 mothers and their children randomly selected in seven project sites. Children were 1 to 3 years old at onset. Blood samples were collected at baseline from mothers and children for serum retinol determination by HPLC. VA intakes are estimated by a semi-quantitative food frequency questionnaire, using the conventional beta-carotene to retinol conversion factors and the newly revised lower factors. VA deficiency is a major public health problem in the area: 64% of mothers and 85% of children had serum retinol concentrations < 0,70 mumol/l at baseline. VA came mainly from plant foods, particularly fruits and dark green vegetables which provided more than 90% of the dietary VA at onset of the project. Mean vitamin A intakes are low. We found 138 106 mug ER for the children and 302 +/- 235 microg ER for the mothers with conventional factors and 64 +/- 58 microg ER and 133 +/- 162 microg ER, respectively, with the revised factors. One year later, one third of respondents had consumed RPO in the previous week, and it supplied around 56% of the VA intake of children and 67% of mothers (36% and 46% respectively for the whole group). VA intakes were significantly increased at 510 +/- 493 microg ER and 801 +/- 913 microg ER for the children and their mothers respectively (347 +/- 443 microg ER and 568 +/- 803 microg ER respectively, with the revised factors). Analyzing serum retinol and dietary data collected at baseline, it was found that VA intakes < 62,5% of safe level of intake were highly sensitive to low serum retinol (< 0,70 micromol/l) and using revised conversion factors to assess total VA intake slightly enhanced sensitivity. The proportion of mothers and children at risk of inadequate VA intake changed from nearly 100% at baseline to 60% one year later. The results show that promoting RPO (and other VA rich foods) was effective in improving VA intakes. This improvement will hopefully be sustained and even further enhanced during the remaining 12 months of the project, after which repeated measurement of serum retinol and VA intakes will allow the actual impact of the project to be truly assessed.     

Cyclosporins: structure-activity relationships for the inhibition of the human FPR1 formylpeptide receptor

The human formylpeptide receptor (FPR) is a seven-transmembranous G-protein-coupled receptor (7TM-GPCR) for chemotactic peptides of bacterial origins, possibly involved in the recruitment and activation of neutrophils in various inflammatory diseases of mucosal epithelia. Mutational analyses suggest that interactions of formylated peptides with FPR occur on the outer exoplasmic leaflet/domains of the plasma membrane. The immunosuppressive and antifungal antibiotic cyclic undecapeptide cyclosporin A (CsA; cyclo-[MeBmt(1)-Abu(2)-MeGly(3)-MeLeu(4)-Val(5)-MeLeu(6)-Ala(7)-D-Ala(8)-MeLeu(9)-MeLeu(10)-MeVal(11)]) and some tested analogues such as [Ala(2)]-CsA, [Thr(2)]-CsA, [Val(2)]-CsA, and [Nva(2)]-CsA were able of inhibiting the binding of formylpeptides to the FPR, with [D-MeVal(11)]-CsA (CsH) being much more active than the other analogues. CsH is devoid of immunosuppressive and antifungal activities, and its large potency for human FPR inhibition is of inverse agonism origin. Formylpeptide binding to FPR-expressing cells does not only induce chemotaxis; it also causes a rapid release of granule enzymes in the extracellular medium, allowing the easy monitoring of any inhibition of FPR function "in vivo" (with intact live cells). With such an assay, CsH was confirmed to be the most potent FPR inhibitory cyclosporin, although a far related immunosuppressive cyclosporin analogue, FR901459 ([Thr(2), Leu(5), Leu(10)]-CsA), was found to display a high FPR inhibitory activity (FPR-InhA). To establish structure-activity relationships (SAR) for FPR function inhibition, 59 cyclosporins were now studied by this standardized assay (with differentiated human leukemic cell line HL-60 as FPR-expressing cells and with N-acetyl-beta-D-glucosaminidase release as read-out). These SAR confirmed the low FPR-InhA of classical cyclosporins, where such activity was only seldom found: the most active ones ([Thr(2), Ile(5)]-CsA, [aMeIle(11)]-CsA, and [MeAla(11)]-CsA) remained 3-10-fold less potent than CsH. In contrast, the SAR disclosed that N(10)-desmethylated cyclosporins were particularly prone to display a large FPR-InhA: their most potent one was a [Thr(2), Gly(3), Leu(5), D-Hiv(8), Leu(10)]-CsA, found to be only 2-4-fold less active than [D-MeVal(11)]-CsA (CsH), with which it shows six differences out of 11 residues. Because the free conformations of both CsH and N(10)-desmethylated cyclosporins differ from those of "classical" (N(10)-methylated, [L-MeVal(11)]-using) cyclosporins, these potent FPR inhibitory cyclosporins probably bind to FPR pharmacophores for which classical cyclosporins show little affinity. Moreover, because the conformations of the N(10)-desmethylated cyclosporins widely differ from the CsH one, they probably bind to different pharmacophores on the FPR molecules.     

In-vitro transfer of nitazoxanide across the intestinal epithelial barrier

Nitazoxanide is a thiazolide compound that exhibits antimicrobial properties against helminths, protozoa, anaerobic bacteria and also Helicobacter pylori. The mucosal diffusion of this new drug has not been studied. The aim of this study was to examine the transport of radiolabelled nitazoxanide across the epithelial barrier according to the mode (mucosal or serosal) of drug administration. HT29-19A intestinal epithelial cells, grown as monolayers on microporous filters, were used as an epithelial model. In a short-term (100 min) transport study, the apical to basal and the basal to apical transport of nitazoxanide across the monolayers was studied in an Ussing chamber. In a long-term (24 h) study, the transport of the drug and its intracellular accumulation were studied in filter-grown epithelial monolayers kept in culture plates. In the short-term transport study, both the apical and basal fluxes achieved a steady state after 70 min and there was no significant difference between the apical to basal (3991+/-1001 ng h(-1) cm(-2)) and the basal to apical (4246+/-856 ng h(-1) cm(-2)) nitazoxanide fluxes. In the long-term transport study, after apical or basal drug application, a gradual increase in the drug concentration in the opposite compartment was noted, which reached similar values for apical and basal fluxes (2497+/-125 and 2309+/-81 ng mL(-1), respectively) after 24 h. Moreover, a rapid, although transitory, intracellular accumulation of nitazoxanide was observed at 10 min after apical (299+/-25 ng/10(6) cells) and basal (124+/-10 ng/10(6) cells) drug application, but decreased thereafter. There is an important transepithelial transport of nitazoxanide across the digestive epithelial monolayer with a rapid intracellular accumulation of the drug. No difference between the apical to basal and basal to apical fluxes of the drug was observed, suggesting that both topical and systemic modes of action of this antibiotic are successful.     

Efficient synthesis of the benzo[a]pyrene metabolic adducts of 2'-deoxyguanosine and 2'-deoxyadenosine and their direct incorporation into DNA

A new and efficient method is described for the synthesis in gram quantities of the benzo[a]pyrene (B[a]P) metabolic adducts of 2'-deoxyguanosine (dG) and 2'-deoxyadenosine (dA) substituted, respectively, at the N(2)- and N(6)- positions. When the racemic form of the tris(benzoyloxy)amine 5 (related to the notoriously carcinogenic epoxydiol 2) is coupled with the bromoinosine derivative 6 by means of a Buchwald-Hartwig reaction, the expected pair of diastereomers, 7 and 8, is obtained in high (combined) yield. Selective deblocking of this mixture then gave cleanly the pair of diastereomers 9. These were used in the synthesis of a series of DNA oligomers via their 5'-O-DMT-3'-O-phosphoramidites (10) using standard automated methods. Coupling efficiencies were 94-98% at the point of introduction of the xeno-2'-deoxynucleoside, and in all cases the mixtures of the two diastereomeric oligomers (DMT-off stage) were easily separated by HPLC. By a similar sequence of reactions beginning with 5 and the protected 6-bromopurine 2'-deoxynucleoside 11, it was possible with equal efficiency to introduce the N(6)-modified diastereomers (16) of dA into oligomeric DNA. Circular dichroism measurements were used to establish the fundamental configurations at the xeno-2'-deoxynucleoside site for each of the oligomers. Mass spectral data in both the dG and the dA series confirmed the presence of the xeno-2'-deoxynucleoside in the oligomers. This was complemented by enzymatic degradation of one of the oligomers from each of the series. In both of these cases, after HPLC separation, circular dichroism measurements on the reisolated xenonucleoside also confirmed its presence in the oligomer.     

Genotoxic mechanism for the major acrolein-derived deoxyguanosine adduct in human cells

Acrolein, widely distributed in the environment and also produced endogenously, forms deoxyguanosine adducts in DNA. The genotoxicity of the major acrolein-dG adduct, 8alpha and 8beta isomers of 3H-8-hydroxy-3-(beta-D-2'-deoxyribofuranosyl)-5,6,7,8-tetrahydropyrido[3,2-a]purine-9-one (gamma-OH-PdG), and the model adduct, PdG, which lacks the hydroxy group of gamma-OH-PdG, was investigated in human cells. The adducts were site-specifically incorporated into a SV40/BK origin-based shuttle vector. Estimated efficiencies of translesion DNA synthesis were 73% for gamma-OH-PdG and 25% for PdG when compared with dG control. Gamma-OH-PdG was marginally miscoding (T and G-->A base substitutions in HeLa and xeroderma pigmentosum complementation group A (XP-A) and variant (XP-V) cells. There was no significant difference in the miscoding frequency when the adduct was inserted in the leading or lagging strand. PdG was more miscoding than gamma-OH-PdG by inducing targeted base substitutions (G-->T, A, or C) at a frequency of 7.5% in XP-A cells. Thus, the authentic major adduct, gamma-OH-PdG, is less blocking to DNA synthesis and less miscoding than the model adduct, PdG.     

Allelic variants of the human glutathione S-transferase P1 gene confer differential cytoprotection against anticancer agents in Escherichia coli

The polymorphic human GSTP1 gene locus encodes proteins that differentially metabolize electrophilic substrates, including, many chemotherapeutic agents used in clinical cancer therapy. In this study, we used XL1-Blue MRF strain, transformed with phagemid expression vectors carrying cDNAs of three GSTP1 alleles, to investigate the cytoprotective abilities of the different GSTP1 alleles against four clinically active anticancer agents, namely, carboplatin, cisplatin, thiotepa, and 4-hydroperoxyifosfamide. Following induction of protein expression with isopropyl-beta-d-thiogalactoside, the cells were treated with each drug for 3 h (1 h for 4-hydroperoxyifosfamide). Surviving fractions were determined and used to compute a cytoprotective factor for each allele against each drug. The results showed all the GSTP1 alleles to be cytoprotective, albeit, to different degrees. For cisplatin and carboplatin, the allele was most protective, with CPs of 5.58 and 3.76, respectively, compared with 1.21 and 1.61 for and 2.50 and 2.79 for. In contrast, protection against thiotepa was highest for the allele, with a cytoprotective factor of 1.56, compared to 1.32 for and 1.1 for. For 4-hydroperoxyifosfamide, the CP for and was the same, 1.45, compared with 1.18 for. These data demonstrate significant differences in the ability of the different GSTP1 alleles to protect against the cytotoxicity of electrophilic anticancer agents. The level of protection differs significantly between different GSTP1 alleles, and between different anticancer agents. The optimized prokaryotic system described provides a useful and rapid tool for pharmacogenetic analysis of the effects of genes on drug sensitivity.     

IDEC-131. IDEC/Eisai

IDEC, in collaboration with Eisai, is developing IDEC-131 (E6040), a humanized monoclonal antibody (mAb) against CD154, the ligand for CD40 also called CD40L or gp39, for the potential treatment of several autoimmune diseases. IDEC-131 is based on technology that IDEC licensed from Dartmouth Medical School where researchers demonstrated the biological effects of the anti-CD154 antibody in animal models of autoimmunity. In January 2001, phase II trials in psoriasis and idiopathic thrombocytopenic purpura (ITP) were initiated. By january 2002, a phase II trial in Crohn's disease was also ongoing. A pilot, multicenter, multiple-dose phase I trial in moderate-to-severe psoriasis was initiated in January 2001. This trial was ongoing in January 2002. IDEC, in collaboration with Dartmouth Medical School had also initiated a phase I trial in multiple sclerosis by March 1999. IDEC-131 was also previously being developed for systemic lupus ezythematosus (SLE), although no further development for this indication has been reported since the disclosure of disappointing phase II results in April 2000. Analysts at Morgan Stanley predicted in February 2002, that the product would be launched in 2005, with sales of US $25 million, rising to US $75 million in 2006.     

Adverse childhood experiences and self-reported liver disease: new insights into the causal pathway

OBJECTIVE: To examine the relationship of adverse childhood experiences (ACEs), including abuse, neglect, and forms of household dysfunction, to the risk of liver disease by assessing the role of risk behaviors, such as substance abuse and high-risk sexual activity, as mediators of the ACEs-liver disease relationship. METHODS: Retrospective cohort study data were collected from 17 337 adult health plan members through a survey. Logistic regression adjusted for age, sex, race, and education was used to estimate the strength of the ACEs-liver disease relationship and the impact of the mediators in this relationship. RESULTS: Each of 10 ACEs increased the risk of liver disease 1.2 to 1.6 times (P<.001). The number of ACEs (ACE score) had a graded relationship to liver disease (P<.001). Compared with persons with no ACEs, the adjusted odds ratio of ever having liver disease among persons with 6 or more ACEs was 2.6 (P<.001). The ACE score also had a strong graded relationship to risk behaviors for liver disease. The strength of the ACEs-liver disease association was reduced 38% to 50% by adjustment for these risk behaviors, suggesting they are mediators of this relationship. CONCLUSIONS: The ACE score showed a graded relationship to the risk of liver disease that appears to be mediated substantially by behaviors that increase the risk of viral and alcohol-induced liver disease. Understanding the effect of ACEs on the risk of liver disease and development of these behaviors provides insight into causal pathways, which may prove useful in the prevention of liver disease.