Hypercalcemia and 13-cis-retinoic acid in post-consolidation therapy of neuroblastoma.

We report 19 episodes of hypercalcemia in three children treated with 13-cis-retinoic acid (13-cis-RA) as a post-consolidation therapy for high-risk neuroblastoma. There was no concomitant overload in 13-cis-RA blood levels. Blood calcium fell after arrest of 13-cis-RA intake. Half dosage retinoid treatment resumption did not prevent the recurrence of hypercalcemia. Concomitant biological values showed massive bone resorption. Hence, hypercalcemia seemed not secondary to 13-cis-RA overload but rather to inter-individual variability in its interaction with bone metabolism. Current guidelines in case of hypercalcemia are to reduce 13-cis-RA dosage. Instead we propose to maintain the therapeutic dosage, but to shorten the duration of courses.

Liposomal retinoic acids modulate asthma manifestations in mice.

Signaling of all-trans retinoic acid (ATRA) through nuclear retinoid acid (RA) receptors regulates several biological functions in airway epithelial cells, eosinophils, and immune cells, yet its impact on different in vivo aspects of pulmonary allergic reaction remains elusive. We compared the effect of a treatment with liposomally encapsulated ATRA (Lipo-ATRA) in a mouse model of ovalbumin (OVA)-induced T helper (Th) 2-type responses and airway remodeling. Daily intraperitoneal injections of 10 mg/kg Lipo-ATRA, at the time of each of the 2 systemic sensitizing injections, increased OVA-induced Immunoglobulin E synthesis, bronchoalveolar lavage (BAL) eosinophilia, and accumulation of IL-5, transforming-growth factor beta1, fibronectin, eotaxin/chemokine (C-C motif) ligand 11 (eotaxin/CCL11) and regulated upon activation, normal T expressed and secreted chemokine (C-C motif) ligand 5. In contrast, Lipo-ATRA, administered during each of the 4 intranasal OVA challenges, did not affect these variables. Regardless of the treatment regimen, Lipo-ATRA augmented mucin levels in BAL fluid and reduced lung total collagen content. In vitro incubation of mouse splenocytes or purified spleen cluster of differentiation (CD) 4-positive T lymphocytes, with ATRA, increased, respectively, OVA- and anti-CD 3 antibody-induced IL-4 and IL-5 production and inhibited IFNgamma release. These findings demonstrate that, when given during systemic sensitization, Lipo-ATRA exacerbates allergic immune and inflammatory responses, most likely by promoting Th2 development.

Site specific changes of redox metabolism in adipose tissue of obese Zucker rats.

Adipose tissues are differently involved in lipid metabolism and obesity according to their type and location. Increasing reports stress on the impact of redox metabolism on obesity and metabolic syndrome. The aim of this work is to investigate the site-specific redox metabolism in three different adipose tissues and its changes occurring in obesity. We analysed enzymatic and non-enzymatic parameters, and focused on the reduced/oxidized glutathione and coenzyme Q couples. In lean compared with obese non-diabetic Zucker rats, interscapular brown fat seems well protected against oxidative stress and epididymal adipose tissue shows a more reduced glutathione redox state, associated with a higher susceptibility to lipophilic oxidative stress than inguinal adipose tissue. Epididymal adipose tissue redox metabolism significantly differs from inguinal one by its limited redox metabolism adaptation. Our results demonstrate site-specific managements of reactive oxygen species metabolism in obese Zucker rats. These results are not consistent with the classic deciphering of inflammatory situation and produce a new conception of the redox parameters implication in the development of the metabolic syndrome.

Reference range for micronutrients and nutritional marker proteins in cord blood of neonates appropriated for gestational ages.

BACKGROUND: Reference values of numerous micronutrients at different gestational ages (GA) have not been yet reported based on large series. AIMS: This study aimed to establish the reference range for zinc, copper, selenium, vitamin A, vitamin E, retinol binding protein, transthyretin, albumin, transferrin and ceruloplasmin in neonates and to give the profiles according to gestational age. STUDY DESIGN: A total of 510 infants appropriate for gestational age were included in the study. The determinations were done using the serum cord blood of 262 term and 248 preterm infants (gestational age of 37 to 42 and 26 to 36 weeks, respectively). RESULTS: All nutrients correlated significantly with birth weight and gestational age but different patterns were highlighted. Vitamin A, retinol binding protein and prealbumin showed a triphasic pattern with a cut-off at about 36 to 39 weeks. In this period, these parameters rised significantly (P<0.001). Albumin and selenium showed a biphasic pattern with a significant positive correlation (P<0.001) between weeks 26 to 38. Transferrin and ceruloplasmin associated with copper showed a continuous increase with GA (P<0.001). On the opposite, zinc and vitamin E decreased. Zinc showed a biphasic pattern with a significant negative correlation (P<0.001) between the 26th to 34th weeks. Vitamin E presented a triphasic pattern with a cut-off at about 32 to 35 weeks (P<0.001). CONCLUSION: The large number of data allow the build-up of reference ranges and charts for the evaluation of micronutrients and proteins in high-risk neonates.

Positive impact of long-term lifestyle change on erythrocyte fatty acid profile after acute coronary syndromes.

BACKGROUND: The outcome of coronary diseases is influenced by lifestyle and diet. Among dietary factors, n-3 polyunsaturated fatty acids reduce mortality from cardiovascular diseases. AIMS: To evaluate the impact of dietary and lifestyle advice by calculation of scores and analysis of plasmatic lipids and the fatty acid composition of erythrocyte membrane phospholipids after 1 year of patient education in 66 patients with acute coronary syndromes. METHODS: The answers given by patients during questioning were transformed into scores (atherosclerosis risk, dietary habits and global scores) at inclusion and after 1 year of follow-up. Classical metabolic risk factors and fatty acid composition of erythrocyte phospholipids were determined at the same time. RESULTS: After 1 year of education, patients improved their different scores, particularly by changing dietary habits. The positive impact was seen in the blood lipid and erythrocyte fatty acid levels: plasma low-density lipoprotein cholesterol and triglyceride concentrations were lowered and n-3 polyunsaturated fatty acid percentages were improved in phospholipids. CONCLUSION: Global score, lipid variables and the nature of the polyunsaturated fatty acids in erythrocyte phospholipids help us to evaluate patients with high coronary artery disease risk and the benefits of long-term dietary and lifestyle advice.

Evaluation of whole antioxidant defenses of human mononuclear cells by a new in vitro biological test: lack of correlation between erythrocyte and mononuclear cell resistance to oxidative stress.

OBJECTIVES: This work aims to evaluate the resistance of mononuclear cells to oxidative stress using a "KRL" test, formerly utilized to evaluate the resistance of erythrocyte to free radicals. METHODS: The "KRL" test evaluates the resistance to lysis of cells treated by free radicals generated under standardized conditions. RESULTS: We defined new analytical parameters (level of radical production, time course, number of cells) to obtain an accurate assay determining the resistance to oxidative stress of mononuclear cells, in comparison to that of erythrocytes. This test allows the evaluation of change in the redox state of mononuclear cells (improved by an antioxidant mix or deteriorated by antimycin A-induced mitochondrial radical overproduction). Interestingly, our data show that the sensitivity of mononuclear cells to oxidative stress is not correlated with the susceptibility of erythrocytes to oxidative stress. CONCLUSIONS: The quantification of the susceptibility of mononuclear cells to oxidative stress gives additional information (in addition to erythrocyte resistance) and could be helpful for patients with chronic inflammation.

Adipose tissue proadipogenic redox changes in obesity.

The role of inflammation and oxidative stress in the development of obesity and associated metabolic disorders is under debate. We investigated the redox metabolism in a non-diabetic obesity model, i.e. 11-week-old obese Zucker rats. Antioxidant enzyme activities, lipophilic antioxidant (alpha-tocopherol, coenzymes Q) and hydrophilic antioxidant (glutathione, vitamin C) contents and their redox state (% oxidized form), were studied in inguinal white fat and compared with blood and liver. The adipose tissues of obese animals showed a specific higher content of hydrophilic molecules in a lower redox state than those of lean animals, which were associated with lower lipophilic molecule content and lipid peroxidation. Conversely and as expected, glutathione content decreased and its redox state increased in adipose tissues of rats subjected to lipopolysaccharide-induced systemic oxidative stress. In these in vivo models, oxidative stress and obesity thus had opposite effects on adipose tissue redox state. Moreover, the increase in glutathione content and the decrease of its redox state by antioxidant treatment promoted in vitro the accumulation of triglycerides in preadipocytes. Taken together and contrary to the emergent view, our results suggest that obesity is associated with an intracellular reduced redox state that promotes on its own the development of a deleterious proadipogenic process.