An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Group B Streptococcus in the Antenatal Clinic and in the Delivery Room: A Matter of Systematic Attitude

OBJECTIVES: We wanted to evaluate the compliance to the local recommendations, similar to the CDC (Centers for Disease Control and prevention) recommendations launched in 1996, for the prevention of perinatal group B streptococcal (GBS) disease in the clinical practice of a academic maternity and to identify the causes of missed screening and antibiotic prophylaxis. MATERIALS AND METHODS: Retrospective study of 1249 consecutive pregnancies between 1st January and 31th August 2002. The screening methods for GBS colonisation were the culture of rectovaginal swabs collected between 35 and 37 weeks and/or a rapid antigenic screening performed on a vaginal swab collected at the patient's admission for labor. RESULTS: Rate of global screening was very high (97.8%): 28.8% of antenatal screening versus 90.3% during labor. An appropriate antibiotic prophylaxis was administered to only one-third of positive women when the screening was performed at admission to the labor room, whereas two-thirds of GBS-positive women screened between 35 and 37 weeks received their antibiotic prophylaxis. 2.4%o of the newborns were infected and 2.9% were colonized. Among the different risk factors, intrapartum fever was more often associated with maternal GBS colonisation. The observed sensitivity of the rapide antigenic test was 20.4%. CONCLUSION: Compliance to guidelines is sometimes difficult in the clinical practice of an academic maternity. In our hands the rapid test for GBS screening had low sensitivity. The analysis of these data led to introducing a computerized algorithm in our maternity to improve the prevention of perinatal group B streptococcal disease

Hydrolysis of emulsions with different triglycerides and droplet sizes by gastric lipase in vitro. Effect on pancreatic lipase activity

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Digestion and Absorption of Tube-Feeding Emulsions With Different Droplet Sizes and Compositions in the Rat

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Effects of droplet size, triacylglycerol composition, and calcium on the hydrolysis of complex emulsions by pancreatic lipase: an in vitro study

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Preoperative selection of patients with severely impaired left ventricular function for coronary revascularization. Role of low-dose dobutamine echocardiography and exercise-redistribution-reinjection thallium SPECT.

BACKGROUND: Both thallium imaging and low-dose dobutamine echocardiography have been proposed to predict the reversibility of left ventricular (LV) dysfunction in patients with coronary disease. The present study was designed to evaluate whether the use of these techniques during the preoperative assessment of coronary patients with depressed LV function can improve our ability to identify those likely to have improved LV function after surgery. METHODS AND RESULTS: Forty consecutive patients (age, 60 +/- 10 years) with coronary disease and an ejection fraction 5% increase in ejection fraction and > 10 mL decrease in end-systolic volume. Before revascularization, patients with improved postoperative function had smaller end-diastolic volume and less wall motion abnormalities than those with persistent dysfunction. They also showed greater improvement of wall motion score with dobutamine (6.1 +/- 2.4 versus 1.8 +/- 4.2 grades, P < .001) and smaller thallium defect score after exercise (38 +/- 12 versus 47 +/- 14 grades, P = .04). Discriminant analysis selected the improvement in wall motion score with dobutamine and baseline end-diastolic volume as independent predictors of postoperative recovery. Consideration of both parameters allowed prediction of functional outcome in 84% of the patients with and 81% of those without postoperative improvement. CONCLUSIONS: Among the parameters commonly available before surgery in coronary patients with depressed LV function, the maintenance of significant inotropic reserve, the severity of LV remodeling, and the magnitude of the perfusion defect after exercise can predict the reversal of LV dysfunction after revascularization

Relation of exercise capacity to left ventricular systolic function and diastolic filling in idiopathic or ischemic dilated cardiomyopathy

Although exercise intolerance is a cardinal symptom of patients with dilated cardiomyopathy (DC) and heart failure, the factors that limit exercise capacity in these patients remain a matter of debate. To assess the contribution of left ventricular (LV) diastolic filling to the variable exercise capacity of patients with DC, we studied 47 patients (60 +/- 12 years) with DC in stable mild-to-moderate heart failure with a mean LV ejection fraction of 28%. Exercise capacity was measured as total body peak oxygen consumption (VO2) during symptom-limited bicycle (10 W/min) and treadmill (modified Bruce protocol) exercise. LV systolic function and diastolic filling were assessed at rest before each exercise by M-mode, Doppler echocardiography, and radionuclide ventriculography. As expected, treadmill exercise always yielded higher peak VO2 than bicycle exercise (21 +/- 6 vs 18 +/- 5 ml/kg/min, range 12 to 35 and 7 to 30 ml/kg/min, respectively, p <0.001). Both of these VO2 measurements were highly reproducible (R = 0.98). With univariate analysis, close correlations were found between peak VO2 (with either exercise modalities) and Doppler indexes of LV diastolic filling, as well as with the radionuclide LV ejection fraction. Stepwise multiple regression analysis identified 3 nonexercise variables as independent correlates of peak VO2, of which the most powerful was the E/A ratio (multiple r2 = 0.38, p <0.0001), followed by peak A velocity (r2 = 0.54, p <0.0001) and mitral regurgitation grade (r2 = 0.58, p = 0.024). In conclusion, our data indicate that in patients with DC, peak VO2 is better correlated to diastolic filling rather than systolic LV function

Contribution of exercise-induced mitral regurgitation to exercise stroke volume and exercise capacity in patients with left ventricular systolic dysfunction.

BACKGROUND: Functional mitral regurgitation (MR) is common in patients with heart failure and left ventricular (LV) dysfunction, and its severity may vary over time, depending primarily on the loading conditions. Because dynamic changes in the severity of functional MR may affect forward stroke volume, we hypothesized that exercise-induced changes in MR severity influence the stroke volume response of patients with LV dysfunction to exercise, and hence their exercise capacity. METHODS AND RESULTS: Heart failure patients (n=25; mean age 53+/-12 years) with LV dysfunction underwent dynamic bicycle exercise at steady-state levels of 30%, 60%, and 90% of predetermined peak VO2. During each exercise level, right heart pressures, cardiac output, VO2, and MR severity were measured simultaneously. During exercise, MR severity, as evaluated by the ratio of MR jet over left atrium area, increased from 15+/-8% to 33+/-15%. Peak VO2, exercise-induced changes in stroke volume, and those in capillary wedge pressure correlated with the changes in MR (r=-0.55, -0.87, and 0.62, respectively, P<0.01). The changes in MR severity also correlated with those in end-diastolic (r=-0.75, P<0.01) and end-systolic (r=-0.72, P<0.01) sphericity indexes and those in the coaptation distance (r=0.86, P<0.01). CONCLUSIONS: Our data indicate that in patients with LV dysfunction, exercise-induced changes in MR severity limit the stroke volume adaptation during exercise and therefore contribute to limitation of exercise capacity

Evaluation of Allogeneic Bone-Marrow-Derived and Umbilical Cord Blood-Derived Mesenchymal Stem Cells to Prevent the Development of Osteoarthritis in An Equine Model

International audienceOsteoarthritis (OA) is a significant cause of pain in both humans and horses with a high socio-economic impact. The horse is recognized as a pertinent model for human OA. In both species, regenerative therapy with allogeneic mesenchymal stem cells (MSCs) appears to be a promising treatment but, to date, no in vivo studies have attempted to compare the effects of different cell sources on the same individuals. The objective of this study is to evaluate the ability of a single blinded intra-articular injection of allogeneic bone-marrow (BM) derived MSCs and umbilical cord blood (UCB) derived MSC to limit the development of OA-associated pathological changes compared to placebo in a post-traumatic OA model applied to all four fetlock joints of eight horses. The effect of the tissue source (BM vs. UCB) is also assessed on the same individuals. Observations were carried out using clinical, radiographic, ultrasonographic, and magnetic resonance imaging methods as well as biochemical analysis of synovial fluid and postmortem microscopic and macroscopic evaluations of the joints until Week 12. A significant reduction in the progression of OA-associated changes measured with imaging techniques, especially radiography, was observed after injection of bone-marrow derived mesenchymal stem cells (BM-MSCs) compared to contralateral placebo injections. These results indicate that allogeneic BM-MSCs are a promising treatment for OA in horses and reinforce the importance of continuing research to validate these results and find innovative strategies that will optimize the therapeutic potential of these cells. However, they should be considered with caution given the low number of units per group

Interleukin-6 (IL-6) and/or Soluble IL-6 Receptor Down-regulation of Human Type II Collagen Gene Expression in Articular Chondrocytes Requires a Decrease of Sp1·Sp3 Ratio and of the Binding Activity of Both Factors to the COL2A1 Promoter

International audienceType II collagen is composed of alpha1(II) chains encoded by the COL2A1 gene. Alteration of this cartilage marker is a common feature of osteoarthritis. Interleukin-6 (IL-6) is a pro-inflammatory cytokine that needs a soluble form of receptor called sIL-6R to exert its effects in some cellular models. In that case, sIL-6R exerts agonistic action. This mechanism can make up for the partial or total absence of membrane-anchored IL-6 receptors in some cell types, such as chondrocytes. Our study shows that IL-6, sIL-6R, or both inhibit type II collagen production by rabbit articular chondrocytes through a transcriptional control. The cytokine and/or sIL-6R repress COL2A1 transcription by a -63/-35 sequence that binds Sp1.Sp3. Indeed, IL-6 and/or sIL-6R inhibit Sp1 and Sp3 expression and their binding activity to the 63-bp promoter. In chromatin immunoprecipitation experiments, IL-6.sIL-6R induced an increase in Sp3 recruitment to the detriment of Sp1. Knockdown of Sp1.Sp3 by small interference RNA and decoy strategies were found to prevent the IL-6- and/or sIL-6R-induced inhibition of COL2A1 transcription, indicating that each of these Sp proteins is required for down-regulation of the target gene and that a heterotypic Sp1.Sp3 complex is involved. Additionally, Sp1 was shown to interact with Sp3 and HDAC1. Indeed, overexpression of a full-length Sp3 cDNA blocked the Sp1 up-regulation of the 63-bp COL2A1 promoter activity, and by itself, inhibits COL2A1 transcription. We can conclude that IL-6, sIL-6R, or both in combination decrease both the Sp1.Sp3 ratio and DNA-binding activities, thus inhibiting COL2A1 transcription