Survey of 243 ART patients having made a final disposition decision about their surplus cryopreserved embryos: the crucial role of symbolic embryo representation.

STUDY QUESTION: In couples who have chosen and confirmed the fate of surplus frozen embryos, which factors influence their decision, with a special emphasis on their symbolic representation of the embryo(s)? SUMMARY ANSWER: Embryo representation and gamete donation use significantly influence the fate of surplus cryopreserved embryos. WHAT IS KNOWN ALREADY: Previous studies report difficulties for couples to decide whether or not to continue storing their frozen embryo(s) and different factors have been already highlighted which influence their decision, including embryo conceptualization, information and support provided by the medical institution, quality of embryo(s) and life events. Little is known, however, about couples who definitely decided to stop their parental project and finalized the process of decision-making about the fate of their cryopreserved embryo(s). STUDY DESIGN, SIZE, DURATION: This prospective study was conducted over a period of 3 years (2007-2010) and included IVF/ICSI patients with surplus frozen embryos, who made a final embryo disposition decision. Among the 280 eligible IVF/ICSI patients, 247 agreed to participate in the study. According to the available options, 91 persons chose to 'stop cryopreservation', 77 chose donation to 'research' and 48 'embryo donation' to infertile couples. Furthermore, 31 participants who chose embryo donation for a parental project were refused by the center as not compatible with their mandatory medical conditions. Among them, 27 participants then selected donation to research as a new option and were included in a fourth group: 'donation to research after Refusal of Embryo Donation for parental project' or 'research-RED' (n = 27). Four participants chose 'stop cryopreservation', however, given the small number of subjects this latter group was not included in the analysis. In all, 243 participants who made a final choice concerning the fate of their cryopreserved embryos were included in this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were sent a letter of invitation to a semi-structured interview of 30 min with a psychologist. Interviews were conducted separately for each partner, including a questionnaire with a common part and a specific part, according to the chosen option, and allowing a quantitative evaluation. A multivariate logistic regression model was used to assess the link between their embryo representation and their decision about their embryos' fate. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for age, gender, gamete donation, number of children and the different embryo representations, a choice to 'stop cryopreservation' is more frequent if the embryo is represented as a child [odds ratio (OR) adjusted = 3.29, 95% confidence interval (CI) = 1.62-6.66], P = 0.0009. Representing the embryo as a project prompts patients to choose 'donation to research' [OR adjusted = 3.76, 95% CI = 1.56-9.06], P = 0.0032. Respondents are more likely to choose 'embryo donation' if they represent the embryo as a potential person [OR adjusted = 3.77, 95% CI = 1.45-9.80], P = 0.0064. Furthermore, patients who benefited from gamete donation are ∼10 times more likely to donate their embryos to another couple [OR adjusted = 10.62, 95% CI = 3.99-28.30], P < 0.0001. For more than half the participants (57%) the decision-making was easy, however, deciding to stop cryopreservation was significantly more difficult than choosing research or embryo donation (P < 0.0001). LIMITATIONS, REASONS FOR CAUTION: Socio-economic status, moral and religious affiliations are known to influence the choice of couples but analyzing these factors was not an aim of the present study. WIDER IMPLICATIONS OF THE FINDINGS: When couples definitely decide to stop their parental project, the embryo symbolic representation remains the main factor that influences the fate of their frozen embryo(s). Moreover, this representation can evolve when influenced by external events and information provided. In order to support patients who are making this difficult decision, it could be helpful to explore this symbolic representation early in the IVF/ICSI procedure, before surplus embryo freezing, as a new tool enhancing the accuracy of counseling. STUDY FUNDING/COMPETING INTERESTS: this study was supported by a grant from the 'Agence de la biomedicine (ABM)', the national regulatory ART agency, under the authority of the French Ministry of Health. The authors have no conflict of interest to declare.

Immunogenicity and safety of the influenza A H1N1v 2009 vaccine in cancer patients treated with cytotoxic chemotherapy and/or targeted therapy: the VACANCE study.

BACKGROUND: Influenza vaccination is recommended to cancer patients undergoing chemotherapy, but vaccine coverage remains low. During the 2009 influenza pandemic, French recommendations were to vaccinate immunocompromised patients with two doses of adjuvanted vaccine. This study aimed to evaluate vaccine immunogenicity in cancer patients receiving chemotherapy. PATIENTS AND METHODS: VACANCE is a prospective open-label study that evaluated the immunogenicity and safety of two doses of AS03A-adjuvanted H1N1v vaccine in cancer patients receiving cytotoxic and/or targeted therapies. Serum haemagglutination-inhibited antibody titres against influenza A H1N1v were measured at days 1, 21, and 42, to estimate the proportion of participants with antibody titres ≥ 1 : 40 [seroprotection rate (SPR)], the efficacy of seroconversion, and factors that increased the geometric mean titre. RESULTS: Sixty-five patients were included. At baseline, 5% of patients had vaccine strain titres of specific haemagglutination inhibition antibodies that were ≥ 1 : 40. After one and two doses of vaccine, SPRs were 48% and 73%, respectively, and seroconversion rates were 44% and 73%, respectively. Vaccine-related adverse events were mild to moderate. CONCLUSIONS: A single dose of AS03-adjuvanted A/H1N1 vaccine triggered a low immune response in cancer patients on chemotherapy depending on their treatment type and frequency. Two doses are needed for these cancer patients.

The effect of ursodesoxycholic acid on duodenal adenomas in familial adenomatous polyposis: a prospective randomized placebo-control trial.

AIM: Duodenal adenomas occur in about 90% of patients with familial adenomatous polyposis (FAP) and are the second cause of death of patients who have had a prophylactic proctocolectomy. Studies suggest that biliary acids have a role in the development of duodenal adenomas. The aim of this study was to evaluate the impact of ursodesoxycholic acid (UDCA) on duodenal adenoma formation in patients with FAP. METHOD: A randomized, double-blinded, placebo-controlled study was carried out of 71 patients (20-65 years) who already had a restorative proctocolectomy. Subjects received either 10 mg/kg of UDCA orally per day or a placebo tablet for 24 months. The Spigelman severity score was determined after duodenal axial and lateral view endoscopy at 12 and 24 months. RESULTS: At 2 years 55 patients had completed the entire period of treatment. At the end of the follow-up period, nine (25%) patients in the UDCA group and seven (20%) in the placebo group had a decrease in the Spigelman score (P = 0.6142). Patients receiving UDCA had no side-effects (0%) compared with four (14%) in the placebo group (P = 0.0392). CONCLUSION: UDCA had no effect on the development of duodenal adenomas in FAP patients (NCT: 00134758).

TNFSF15 polymorphisms are associated with susceptibility to inflammatory bowel disease in a new European cohort.

OBJECTIVES: Inflammatory bowel disease (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), is a complex genetic disorder. Tumor necrosis factor (ligand) superfamily, member 15 (TNFSF15) has been previously identified as a susceptibility gene for CD in Japanese and UK cohorts. This replication study was designed in order to confirm and further validate the role of TNFSF15 in IBD. METHODS: A total of 666 IBD families (corresponding to 2,982 relatives) with European ancestry were genotyped for the rs6478108 and rs7869487 polymorphisms, which define the main TNFSF15 haplotypes previously associated with CD. An association between the main haplotypes and CD, UC and IBD was tested using the Genehunter TDT and Unphased statistics. Caspase recruitment domain 15 (CARD15)/TNFSF15 interaction and genotype/phenotype correlations were also studied. RESULTS: The previously reported "high-risk" haplotype (A) was associated with IBD (P=0.001) (OR=1.25 (1.05-1.50)) and CD (P=0.02) (OR=1.31 (1.03-1.67)) whereas the "protective" (B) haplotype was significantly less transmitted to IBD and CD patients. No interaction between CARD15 and TNFSF15 was detected. We also failed to define a clinical subgroup of CD patients specifically associated with TNFSF15 haplotype A. CONCLUSIONS: This study confirms that TNFSF15 or a closely linked gene is involved in the genetic predisposition to CD.

Periodontopathogens antibodies and major adverse events following an acute myocardial infarction: results from the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI).

BACKGROUND: Periodontopathogens antibodies have been shown to be associated with primary myocardial events, but little is known regarding their impact on major adverse events after a prior acute myocardial infarction (AMI). The present prospective study evaluates the association between antibody levels of 4 periodontopathogens and the risk of all-cause death or non-fatal myocardial infarction (MI) at 1 year in 975 patients admitted for acute ST segment or non-ST segment elevation MI in French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI), a nationwide French survey. METHODS: Multiserotype ELISAs were performed to assess levels of IgG and IgA against Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Prevotella intermedia and Tannerella forsythia. RESULTS: Adjusted HRs indicate the lack of association between IgG-anti-Po. gingivalis levels (0.96 (0.78 to 1.18)), IgA-anti-Po. gingivalis levels (1.13 (0.90 to 1.42)) and the risk of all-cause death or non-fatal MI at 1 year. Additionally, no significant association was found between the occurence of an event at 1 year and immunoglobulins levels against the others periodontopathogens. CONCLUSIONS: The present data indicate that circulating levels of periodontopathogens antibodies are not associated with an increased risk of major adverse events in patients with a prior AMI. Studies dealing with bacterial and clinical data are needed to assess the role of oral health in comprehensive cardiac rehabilitation programmes.

Ionic liquid media resulted in the first asymmetric aminohalogenation reaction of alkenes.

[reaction: see text] The first asymmetric aminohalogenation of functionalized alkenes has been established. The ionic liquid [bmim][BF4] was found to be the only effective media for success as normal organic solvents failed to give any product for this reaction. The reaction is also very convenient to perform by simply mixing the three reactants, cinnamates, N,N-dichloro-p-toluenesulfonamide, and catalyst, together with 4 A molecular sieves at room temperature in [bmim][BF4] in any convenient vial of appropriate size without special protection from inert gases. Good chemical yields (60-72%) and diastereoselectivities (up to 75% de) have been obtained with a good scope of substrates. The resulting individual diastereomers have been cleanly separated via column chromatography. The absolute stereochemistry of the reaction was unambiguously determined by X-ray structural analysis.

Cholesteryl ester transfer protein polymorphisms, statin use, and their impact on cholesterol levels and cardiovascular events.

The association of nonfunctional variants of the cholesteryl ester transfer protein (CETP) with efficacy of statins has been a subject of debate. We evaluated whether three functional CETP variants influence statin efficacy. The effect of CETP genotype on achieved levels of high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), and total cholesterol during statin treatment was estimated by meta-analysis of the linear regression outcomes of three studies (11,021 individuals). The effect of these single-nucleotide polymorphisms (SNPs) on statin response in protecting against myocardial infarction (MI) was estimated by meta-analysis of statin × SNP interaction terms from logistic regression in five studies (16,570 individuals). The enhancer SNP rs3764261 significantly increased HDLc by 0.02 mmol/l per T allele (P = 6 × 10(-5)) and reduced protection against MI by statins (interaction odds ratio (OR) = 1.19 per T allele; P = 0.04). Focusing on functional CETP variants, we showed that in carriers of the rs3764261 T variant, HDLc increased more during statin treatment, and protection against MI by statins appeared to be reduced as compared with those in noncarriers.

Effect of paraoxonase-1 polymorphism on clinical outcomes in patients treated with clopidogrel after an acute myocardial infarction.

Paraoxonase-1 (PON1) Q192R polymorphism was recently suggested to determine per se clopidogrel response on major cardiovascular events (MACEs). We assessed the impact of PON1, CYP2C19, and ABCB1 polymorphisms on MACE in clopidogrel-treated acute myocardial infarction (AMI) patients (N = 2,210), including those undergoing percutaneous coronary intervention (PCI) (n = 1,538). PON1 polymorphism was not associated with increased risk of in-hospital death and MACEs at 1 year (adjusted hazard ratio (HR) 1.03, 95% confidence interval (CI) 0.66-1.61 and adjusted HR 0.77, 95% CI 0.42-1.41 for QQ versus RR in all and PCI patients, respectively). The presence of two CYP2C19 loss-of-function (LOF) alleles was associated with the risk of in-hospital death and MACEs at 1 year in the overall population (adjusted odds ratio (OR) 3.67, 95% CI 1.05-12.80 and adjusted HR 1.96, 95% CI 1.08-3.54) and in PCI patients (adjusted OR 6.87, 95% CI 2.52-18.72 and adjusted HR 3.06, 95% CI 1.47-6.41). Unlike CYP2C19 polymorphism, PON1 (Q192R) polymorphism is not a major pharmacogenetic contributor of clinical response to clopidogrel in AMI patients.

Strategy for detecting susceptibility genes with weak or no marginal effect.

Most human diseases result from complex interactions among multiple genes that yield weak or modest effects. Despite the growing awareness of the importance of gene-gene interactions, the paradigm of detectable effects of individual variants remains the cornerstone of genome association studies with tagSNPs. The interactive effect of two variants is only tested once the individual effect of one variant is detected. Both genes, however, may have at the same time a weak (or even no) marginal effect but an important effect through their interaction. In such a situation, current approaches may fail to detect variants having a crucial role in the causal chain. Here, we propose a new strategy: the 2-locus TDT. It allows the detection of the involvement of two genes without individual effect. Our strategy simultaneously uses information on biallelic candidate polymorphisms in two genes M and N. We first estimate the relative marginal penetrances of the genotype at each locus and of the joint (two-locus) genotype and then we test for the interactive effect of the two genes using a likelihood ratio test. We show that our approach has good power to detect the effect of two genes in situations for which a locus-by-locus strategy would have been unsuccessful. At a time where genome-wide association studies are fashionable, we think it is important to consider the strategy of studying good candidate pathways with our approach.

Vicinal diamino functionalities as privileged structural elements in biologically active compounds and exploitation of their synthetic chemistry.

The chemistry, synthetic routes and medicinal properties of vicinal diamines and imidazolines are discussed. Synthetic routes towards chemically and pharmaceutically important molecules containing vicinal diamine functionality are discussed in detail. This mini review article covers the new developments of diamine chemistry between 2000 and 2005.

A catalytic reaction of alkynes via multiple-site functionalization.

The first multiple-site activation of alkynes with amine/halogen functionalities has been established. The reaction was performed by treating alkyne with N,N-dichlorobenzenesulfonamide at 80 degrees C in the presence of palladium acetate catalyst. A new mechanism was proposed which involves the novel formation of beta-halovinyl palladium and pi-allylpalladium species. Excellent regio- and stereoselectivities were achieved with the absolute structure determined by X-ray structural analysis.