Prevalence of Vitamin A Deficiency in Pregnant and Lactating Women in the Republic of Congo

Vitamin A status in a sample of pregnant and lactating women living in several representative regions of Congo was assessed and compared between August and September 2004. This survey was conducted using a randomized two-stage cluster-sampling method with stratification on 90 clusters, each consisting of at least 15 women. Vitamin A status was determined in a total of 1,054 individuals, using the impression cytology with transfer (ICT) test, the modified relative dose response test (MRDR test) on dried blood spots (DBS), and clinical examination to detect signs of xerophthalmia. The clinical criterion defining vitamin A deficiency was the presence of active xerophthalmia (Bitot's spots [X1B]), active corneal disease), and/ or night blindness (XN stage). The prevalence of clinical signs of stage XN and X1B xerophthalmia in the Republic of Congo was found to be 16% and 19% respectively. The prevalence of clinical signs (X1B) was greater in the rural north than in urban areas, with a gradient running from urban (5%) to rural area (33%); 27% of all the ICT tests showed that the subjects were suffering from vitamin A deficiency. The deficiency rates were significantly higher (p<0.001) in urban surroundings (Brazzaville) than in the rural northern regions. The biochemical MRDR test showed the presence of vitamin A deficiency ( 650.06) in 26% of the mothers in Brazzaville compared to 6% in the town of Kouilou; 44% of the women had retinol levels of <10 \ub5g/dL in the rural north whereas these percentages were significantly lower in the urban areas surveyed (chi-square=62.30, p<0.001). A significant correlation was found to exist (p<0.001) between the ICT test and the MRDR test on DBS. In the population as a whole, 30% of the mothers suffering from malarial attack had abnormally low MRDR levels ( 650.06) compared to no malaria. The results of the present study confirm that vitamin A deficiency is a serious public-health issue in pregnant and lactating mothers in the Republic of Congo

In Vivo Activation of cAMP Signaling Induces Growth Arrest and Differentiation in Acute Promyelocytic Leukemia

Differentiation therapy for acute myeloid leukemia uses transcriptional modulators to reprogram cancer cells. The most relevant clinical example is acute promyelocytic leukemia (APL), which responds dramatically to either retinoic acid (RA) or arsenic trioxide (As2O3). In many myeloid leukemia cell lines, cyclic adenosine monophosphate (cAMP) triggers growth arrest, cell death, or differentiation, often in synergy with RA. Nevertheless, the toxicity of cAMP derivatives and lack of suitable models has hampered trials designed to assess the in vivo relevance of theses observations. We show that, in an APL cell line, cAMP analogs blocked cell growth and unraveled As2O3-triggered differentiation. Similarly, in RA-sensitive or RA-resistant mouse models of APL, continuous infusions of 8-chloro-cyclic adenosine monophosphate (8-Cl-cAMP) triggered major growth arrest, greatly enhanced both spontaneous and RA- or As2O3-induced differentiation and accelerated the restoration of normal hematopoiesis. Theophylline, a well-tolerated phosphodiesterase inhibitor which stabilizes endogenous cAMP, also impaired APL growth and enhanced spontaneous or As2O3-triggered cell differentiation in vivo. Accordingly, in an APL patient resistant to combined RA–As2O3 therapy, theophylline induced blast clearance and restored normal hematopoiesis. Taken together, these results demonstrate that in vivo activation of cAMP signaling contributes to APL clearance, independently of its RA-sensitivity, thus raising hopes that other myeloid leukemias may benefit from this therapeutic approach

Dosage rapide par chromatographie phase gazeuse de la kétamine et de la norkétamine chez le rat

La kétamine est un anesthésique dissociatif dérivé de la cyclohexanone, utilisée en médecine humaine et vétérinaire pour induire l'endormissement et le maintenir lors de brèves interventions chirurgicales. Inhibiteur non compétitifdu glutamate au niveau des récepteurs NMDA centraux, la kétamine est rapidement métabolisée en norkétamine, présentant une action pharmacologique, puis en déhydronorkétamine éliminée par voie urinaire après conjugaison. Les effets secondaires (délires, hallucinations) sont recherchés au cours des raves parties. L'accroissement de son utilisation dans un but d'addiction est à l'origine d'un nombre élevé d'intoxications dont certaines mortelles. De nombreuses méthodes chromatographiques en phase gazeuse ont été rapportées utilisant toutes une étape de dérivation et un volume d'échantillon important. Dans ce travail, nous décrivons une méthode de dosage simultané de la kétamine et de la norkétamine par chromatographie phase gazeuse sans dérivation après extraction liquide-liquide. L'ifosfamide est utilisé comme étalon interne. La méthode est linéaire entre 500 et 4000 μg/L La limite de détection est de 160 et 180 μg/L pour la kétamine et la norkétamine, respectivement. La précision intra et inter séries est satisfaisante (< 10 %), de même que l'exactitude (biais < 15 %). Utilisant un volume réduit de prélèvement, cette méthode peut être appliquée à des études pharmacocinétiques chez l 'animal. Pour illustrer cette application, nous décrivons les cinétiques plasmatiques de la kétamine et de la norkétamine chez le rat après perfusion de kétamine à la dose de 70 mg/kg. Les valeurs des principaux paramètres pharmacocinétiques sont également présentées

Prevalence of Vitamin A Deficiency in Pregnant and Lactating Women in the Republic of Congo

Vitamin A status in a sample of pregnant and lactating women living in several representative regions of Congo was assessed and compared between August and September 2004. This survey was conducted using a randomized two-stage cluster-sampling method with stratification on 90 clusters, each consisting of at least 15 women. Vitamin A status was determined in a total of 1,054 individuals, using the impression cytology with transfer (ICT) test, the modified relative dose response test (MRDR test) on dried blood spots (DBS), and clinical examination to detect signs of xerophthalmia. The clinical criterion defining vitamin A deficiency was the presence of active xerophthalmia (Bitot's spots [X1B]), active corneal disease), and/ or night blindness (XN stage). The prevalence of clinical signs of stage XN and X1B xerophthalmia in the Republic of Congo was found to be 16% and 19% respectively. The prevalence of clinical signs (X1B) was greater in the rural north than in urban areas, with a gradient running from urban (5%) to rural area (33%); 27% of all the ICT tests showed that the subjects were suffering from vitamin A deficiency. The deficiency rates were significantly higher (p<0.001) in urban surroundings (Brazzaville) than in the rural northern regions. The biochemical MRDR test showed the presence of vitamin A deficiency (≥0.06) in 26% of the mothers in Brazzaville compared to 6% in the town of Kouilou; 44% of the women had retinol levels of <10 µg/dL in the rural north whereas these percentages were significantly lower in the urban areas surveyed (chi-square=62.30, p<0.001). A significant correlation was found to exist (p<0.001) between the ICT test and the MRDR test on DBS. In the population as a whole, 30% of the mothers suffering from malarial attack had abnormally low MRDR levels (≥0.06) compared to no malaria. The results of the present study confirm that vitamin A deficiency is a serious public-health issue in pregnant and lactating mothers in the Republic of Congo

Concentrations of Tenofovir and Emtricitabine in Saliva: Implications for Preexposure Prophylaxis of Oral HIV Acquisition▿

To prevent acquisition of HIV through oral sex, drugs used for preexposure prophylaxis (Prep) need to diffuse in saliva. We measured tenofovir (TFV) and emtricitabine (FTC) concentrations simultaneously in the plasma and saliva of 41 HIV-infected patients under stable antiretroviral treatment. Mean ratios of saliva/plasma concentration were 3% (±4%) and 86.9% (±124%) for TFV and FTC, respectively. Tenofovir disoproxil fumarate (TDF) should be used in combination with FTC to prevent oral acquisition of HIV

Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation.

International audienceRetinoic acid and arsenic trioxide target the protein stability and transcriptional repression activity of the fusion oncoprotein PML-RARA, resulting in regression of acute promyelocytic leukemia (APL). Phenotypically, retinoic acid induces differentiation of APL cells. Here we show that retinoic acid also triggers growth arrest of leukemia-initiating cells (LICs) ex vivo and their clearance in PML-RARA mouse APL in vivo. Retinoic acid treatment of mouse APLs expressing the fusion protein PLZF-RARA triggers full differentiation, but not LIC loss or disease remission, establishing that differentiation and LIC loss can be uncoupled. Although retinoic acid and arsenic synergize to clear LICs through cooperative PML-RARA degradation, this combination does not enhance differentiation. A cyclic AMP (cAMP)-dependent phosphorylation site in PML-RARA is crucial for retinoic acid-induced PML-RARA degradation and LIC clearance. Moreover, activation of cAMP signaling enhances LIC loss by retinoic acid, identifying cAMP as another potential APL therapy. Thus, whereas transcriptional activation of PML-RARA is likely to control differentiation, its catabolism triggers LIC eradication and long-term remission of mouse APL. Therapy-triggered degradation of oncoproteins could be a general strategy to eradicate cancer stem cells

Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia

International audienceThe β-haemoglobinopathies are the most prevalent inherited disorders worldwide. Gene therapy of β-thalassaemia is particularly challenging given the requirement for massive haemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected haematopoietic stem cells. Compound β$^E$/β$^0$-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas1, 2. The β$^E$-globin allele bears a point mutation that causes alternative splicing. The abnormally spliced form is non-coding, whereas the correctly spliced messenger RNA expresses a mutated β$^E$-globin with partial instability. When this is compounded with a non-functional β$^0$ allele, a profound decrease in β-globin synthesis results, and approximately half of β$^E$/β$^0$-thalassaemia patients are transfusion-dependent. The only available curative therapy is allogeneic haematopoietic stem cell transplantation, although most patients do not have a human-leukocyte-antigen-matched, geno-identical donor, and those who do still risk rejection or graft-versus-host disease. Here we show that, 33 months after lentiviral β-globin gene transfer, an adult patient with severe β$^E$/β$^0$-thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21 months. Blood haemoglobin is maintained between 9 and 10 g dl$^{−1}$, of which one-third contains vector-encoded β-globin. Most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of $HMGA2$ in erythroid cells with further increased expression of a truncated $HMGA2$ mRNA insensitive to degradation by let-7 microRNAs. The clonal dominance that accompanies therapeutic efficacy may be coincidental and stochastic or result from a hitherto benign cell expansion caused by dysregulation of the $HMGA2$ gene in stem/progenitor cell