The Medi-RIVAGE study: reduction of cardiovascular disease risk factors after a 3-mo intervention with a Mediterranean-type diet or a low-fat diet.

BACKGROUND: Epidemiologic studies link Mediterranean-type diets to a low incidence of cardiovascular disease; however, few dietary intervention studies have been undertaken, especially in primary prevention. OBJECTIVES: In the Mediterranean Diet, Cardiovascular Risks and Gene Polymorphisms (Medi-RIVAGE) study, the effects of a Mediterranean-type diet (Med group) or a low-fat diet (low-fat group) on risk factors were evaluated in 212 volunteers (men and women) with moderate risk factors for cardiovascular disease. DESIGN: After the 3-mo dietary intervention, changes in many risk factors were evaluated. Dietary questionnaires and plasma nutritional markers were used to test compliance. RESULTS: Although the dietary goals were only partially reached, changes in dietary habits were observed in both groups (n = 169): protein, carbohydrate, and fiber intakes increased and fat quality (decreased saturated fat and increased monounsaturated or polyunsaturated fat) improved. BMI, total and triacylglycerol-rich lipoprotein (TRL) cholesterol, triacylglycerols, TRL triacylglycerols, apolipoproteins A-I and B, insulinemia, glycemia, and the homeostasis model assessment score were significantly lower after 3 mo. The reductions in total cholesterol, triacylglycerols, and insulinemia remained significant after adjustment for BMI. There was a trend for a diet-by-time interaction for LDL cholesterol (P = 0.09). Our data predicted a 9% reduction in cardiovascular disease risk with the low-fat diet and a 15% reduction with this particular Mediterranean diet. CONCLUSION: After a 3-mo intervention, both diets significantly reduced cardiovascular disease risk factors to an overall comparable extent.

Glycemic and insulinemic meal responses modulate postprandial hepatic and intestinal lipoprotein accumulation in obese, insulin-resistant subjects.

BACKGROUND: Exacerbated postprandial lipemia is a risk factor for cardiovascular disease and is linked to insulin status. Limited data on the effect of dietary carbohydrate on postprandial lipoprotein accumulation are available. OBJECTIVE: We tested the hypothesis that dietary carbohydrates with different glucose availability alter postprandial lipoprotein metabolism differently in obese, insulin-resistant subjects. DESIGN: After an overnight fast, 9 subjects with central obesity and insulin resistance but normal triacylglycerolemia randomly ingested 2 test meals with comparable amounts of fat (28-29 g) and digestible carbohydrate (91-94 g) but with different quantities of slowly available glucose (SAG) in cereal products (17 or 2 g SAG/100 g for biscuits and wheat flakes, respectively). Blood samples were collected before and for 6 h after meal intakes. RESULTS: The postmeal 0-2-h areas under the curve (AUCs) for glycemia and insulinemia were significantly lower (P < 0.05) after the biscuit meal than after the flakes meal. Plasma triacylglycerol concentrations increased significantly after the flakes meal but not after the biscuit meal (1.5-fold higher 0-6-h AUC for the flakes meal). Apolipoprotein B-100 concentrations in the triacylglycerol-rich lipoprotein fraction increased significantly 2 h after the flakes meal but not after the biscuit meal (3-fold higher 0-6-h AUC for the flakes meal). Apolipoprotein B-48 concentrations increased (P < 0.05) 4 h after the flakes meal but not after the biscuit meal (2.3-fold higher 0-6-h AUC for the flakes meal). CONCLUSION: Mixed meals containing slowly digestible carbohydrate that induces low glycemic and insulinemic responses reduce the postprandial accumulation of both hepatically and intestinally derived triacylglycerol-rich lipoproteins in obese subjects with insulin resistance.

Decreased stroma adhesion capacity of CD34+ progenitor cells from mobilized peripheral blood is not lineage- or stage-specific and is associated with low beta 1 and beta 2 integrin expression.

Molecular mechanisms leading to mobilization of hematopoietic cells from bone marrow (BM) to peripheral blood (PB) involve modulation of adhesion molecule expression on these cells that probably result in changes in adhesion capacity to the microenvironment. However, it is not clear whether these changes involve different stages or lineages of progenitor cells. In this study, we compared the capacity of mature and immature clonogenic progenitor cells from granulocyte colony-stimulating factor (G-CSF)-mobilized PB and normal BM CD34+ cells to adhere to complete marrow stroma. This functional capacity was assessed concurrently with molecular expression on CD34+ cells of integrins VLA-4 (alpha 4/beta 1), VLA-5 (alpha 5/beta 1), and LFA-1 (alpha L/beta 2) by interindividual (between mobilized PB and normal BM) and intraindividual (between mobilized PB and steady-state BM and PB in the same patient) analysis. The proportion of adherent clonogenic progenitor cells was significantly lower in PB than in BM, not only for total progenitor cells but also for mature and immature progenitor cells, and the difference was found for granulocytic and particularly for erythroid lineages. The lower adhesion capacity of PB CD34+ cells to stroma was associated with decreased expression (signal/noise MFI ratio) of integrin alpha 4, beta 1, alpha L, and beta 2 chains whereas that of alpha 5 chain did not differ from BM cells with the lowest expression level. Similar differences in integrin expression levels were also found between mobilized PB and steady-state BM CD34+ cells in the same patient except for the alpha L chain. Moreover, we demonstrated for the first time a strong positive correlation between mobilizing capacity and expression levels on mobilized CD34+ cells for the LFA-1 alpha L chain but not for VLA-4 or VLA-5. In conclusion, the decreased adhesion capacity of mobilized PB progenitor cells to stroma involves different maturation stages and different lineages. This is associated with down-regulation of integrins VLA-4 and LFA-1, but mobilizing capacity appears positively correlated with LFA-1 levels.

Molecular and fluorescence in situ hybridization analysis of a 10;11 rearrangement in a case of infant acute monocytic leukemia.

Fluorescence in situ hybridization (FISH) analysis in a case of infant acute monocytic leukemia M5 revealed a complex rearrangement between chromosomes 10 and 11, leading to the disruption of the MLL gene. Using two painting probes for chromosomes 10 and 11 and a specific probe for the MLL gene localized on 11q23, we observed a paracentric inversion of the 11q13-q23 fragment translocated to 10p12. Molecular analysis showed that AF10 localized on 10p12 was the fusion partner gene of MLL in this rearrangement (10;11). This report underlined the usefulness of FISH and molecular techniques in identifying complex rearrangements.

Quantitative and qualitative analysis of the human primitive progenitor cell compartment after autologous stem cell transplantation.

The aim of this study was to examine whether the severe prolonged deficiency in marrow clonogenic progenitor cells reported after autologous stem cell transplantation (ASCT) is associated with impairment of the primitive progenitor cell compartment. We performed Dexter-type marrow cultures and limiting dilution assays with CD34(+) cells from patients 1 year and/or later after autografting with peripheral blood stem cells for non-Hodgkin's lymphoma (NHL). Flow cytometric analysis was used to assess the CD38 antigen expression and apoptotic state (7-ADD(-)/annexin-V(+) cells) of the CD34(+) cell population. We found a dramatic decrease in both clonogenic progenitor cell production and frequency of long term culture-initiating cells (LTC-IC) in all the patients tested at 1 year, even in those displaying normal progenitor cell frequency. Surprisingly, the clonogenic capacity of each LTC-IC was not increased. Flow cytometric analysis of the CD34(+) cell population confirmed this quantitative defect, with a reduction in the CD38(dim/neg) cell population but no increase in apoptosis. This defect did not improve over time up to 4 years after transplantation. In addition, qualitative abnormalities were revealed, demonstrated by decreased CD34 antigen expression, together with impaired differentiating properties of LTC-IC toward erythroid lineage at 1 year. This study indicates that both quantitative and qualitative abnormalities of the primitive progenitor cell compartment are a constant feature up to 4 years after autologous stem cell transplantation.

Frequency and differentiation capacity of circulating LTC-IC mobilized by G-CSF or GM-CSF following chemotherapy: a comparison with steady-state bone marrow and peripheral blood.

OBJECTIVE: The present study was designed to compare directly the frequency of circulating LTC-IC and E-LTC-IC mobilized in peripheral blood (PB) after chemotherapy supported by either G-CSF (PB-G) or GM-CSF (PB-GM) in comparison to steady-state bone marrow (BM) and PB (PB-ST) values in the same patients. MATERIALS AND METHODS: Long-term cultures (LTC) were performed from 20 patients with malignant lymphoma at saturating cell concentrations to assess bulk progenitor cell production and by limiting dilution assay (LDA) to measure both frequency of LTC-IC and their proliferative and differentiation capacities. RESULTS: While CFC production in bulk LTC was higher at weeks 3-5 with PB-G than with PB-GM samples, week-5 LTC-IC and week-10 LTC-IC (E-LTC-IC) frequencies were not different using a LDA. However, the number of CFC derived from a single LTC-IC was higher in PB-G patients than in PB-GM patients (p = 0.01). Interestingly, the frequency of LTC-IC per 1 x 10(5) MNC in mobilized PB positively correlated with one-year marrow progenitor cell recovery, in contrast to the number of autografted CD34(+) cells and CFU-GM per kg. CONCLUSION: Both G-CSF and GM-CSF resulted in similar increases in LTC-IC and E-LTC-IC in PB at comparable levels to those present in BM. However, the differentiation capacity of LTC-IC was higher after mobilization with G-CSF than with GM-CSF, suggesting qualitative differences in LTC-IC mobilized with these growth factors.

Genetic polymorphisms and lipoprotein responses to diets.

While human diets have markedly evolved since their origin, the human genome has only marginally changed. Nevertheless, polymorphisms of common genes are widespread. It has been substantiated that most major diseases (including cardiovascular disease, diabetes, obesity and cancers) result from the interaction between genetic susceptibility and environmental factors, including diet. In the field of lipoprotein metabolism and cardiovascular disease several gene polymorphisms for key proteins, such as apoproteins (apo) E, B, A-IV and C-III, LDL receptor, microsomal transfer protein (MTP), fatty acid-binding protein (FABP), cholesteryl ester transfer protein (CETP), lipoprotein lipase and hepatic lipase, have been identified and linked to variable responses to diets. We are carrying out an intervention study (RIVAGE) in Marseille dedicated to investigating the interactions between diets (Mediterranean or low-fat types v. standard Western type), risk factors for cardiovascular disease and gene polymorphisms in about 300 patients randomized into two groups over periods of 3 and 12 months. Some data obtained in about 100 patients after 3 months of dietary change are available. Among single nucleotide polymorphisms (SNP) already studied (apoE (epsilon2, epsilon3, epsilon4), apoB (-516C/T), apoC-III (SstI), apoA-IV (Ser347Thr), MTP (-493G/T), intestinal FABP (Ala54Thr), CETP (TaqIB) and hepatic lipase (-480C/T)), some SNP showed interactions with diets in relation to changes in particular variables after 3 months on the dietary regimens. This was the case for apoE and LDL-cholesterol and triacylglycerols, apoA-IV and LDL-cholesterol, MTP and LDL-cholesterol, intestinal FABP and triacylglycerols. These data provide evidence of the interaction between some SNP and the metabolic response to diets.