Circulating estrogens and progesterone during primiparous pregnancies and risk of maternal breast cancer.

Pregnancy reduces maternal risk of breast cancer in the long term, but the biological determinants of the protection are unknown. Animal experiments suggest that estrogens and progesterone could be involved, but direct human evidence is scant. A case-control study (536 cases and 1,049 controls) was nested within the Finnish Maternity Cohort. Eligible were primiparous women who delivered at term a singleton offspring before age 40. For each case, two individually matched controls by age (±6 months) and date of sampling (±3 months) were selected. Estradiol, estrone and progesterone in first-trimester serum were measured by high-performance liquid chromatography tandem mass spectrometry and sex-hormone binding globulin (SHBG) by immunoassay. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. In the whole study population there was no association of breast cancer with any of the studied hormones. In analyses stratified by age at diagnosis, however, estradiol concentrations were positively associated with risk of breast cancer before age 40 (upper quartile OR, 1.81; CI, 1.08-3.06), but inversely associated with risk in women who were diagnosed ≥age 40 (upper quartile OR, 0.64; CI, 0.40-1.04), p(interaction) 0.004. Risk estimates for estrone mirrored those for estradiol but were less pronounced. Progesterone was not associated with risk of subsequent breast cancer. Our results provide initial evidence that concentrations of estrogens during the early parts of a primiparous pregnancy are associated with maternal risk of breast cancer and suggest that the effect may differ for tumors diagnosed before and after age 40.

Predictive ability of an early diagnostic guess in patients presenting with chest pain; a longitudinal descriptive study.

ABSTRACT: BACKGROUND: The intuitive early diagnostic guess could play an important role in reaching a final diagnosis. However, no study to date has attempted to quantify the importance of general practitioners' (GPs) ability to correctly appraise the origin of chest pain within the first minutes of an encounter. METHODS: The validation study was nested in a multicentre cohort study with a one year follow-up and included 626 successive patients who presented with chest pain and were attended by 58 GPs in Western Switzerland. The early diagnostic guess was assessed prior to a patient's history being taken by a GP and was then compared to a diagnosis of chest pain observed over the next year. RESULTS: Using summary measures clustered at the GP's level, the early diagnostic guess was confirmed by further investigation in 51.0% (CI 95%; 49.4% to 52.5%) of patients presenting with chest pain. The early diagnostic guess was more accurate in patients with a life threatening illness (65.4%; CI 95% 64.5% to 66.3%) and in patients who did not feel anxious (62.9%; CI 95% 62.5% to 63.3%). The predictive abilities of an early diagnostic guess were consistent among GPs. CONCLUSIONS: The GPs early diagnostic guess was correct in one out of two patients presenting with chest pain. The probability of a correct guess was higher in patients with a life-threatening illness and in patients not feeling anxious about their pain.

Measuring and Explaining the Increase of Travel Distance : A Multilevel Analysis Using Repeated Cross Sectional Travel Surveys

We want to shed some light on the development of person mobility by analysing the repeated cross-sectional data of the four National Travel Surveys (NTS) that were conducted in Germany since the mid seventies. The above mentioned driving forces operate on different levels of the system that generates the spatial behaviour we observe: Travel demand is derived from the needs and desires of individuals to participate in spatially separated activities. Individuals organise their lives in an interactive process within the context they live in, using given infrastructure. Essential determinants of their demand are the individual's socio-demographic characteristics, but also the opportunities and constraints defined by the household and the environment are relevant for the behaviour which ultimately can be realised. In order to fully capture the context which determines individual behaviour, the (nested) hierarchy of persons within households within spatial settings has to be considered. The data we will use for our analysis contains information on these three levels. With the analysis of this micro-data we attempt to improve our understanding of the afore subsumed macro developments. In addition we will investigate the prediction power of a few classic sociodemographic variables for the daily travel distance of individuals in the four NTS data sets, with a focus on the evolution of this predictive power. The additional task to correctly measure distances travelled by means of the NTS is threatened by the fact that although these surveys measure the same variables, different sampling designs and data collection procedures were used. So the aim of the analysis is also to detect variables whose control corrects for the known measurement error, as a prerequisite to apply appropriate models in order to better understand the development of individual travel behaviour in a multilevel context. This task is complicated by the fact that variables that inform on survey procedures and outcomes are only provided with the data set for 2002 (see Infas and DIW Berlin, 2003).

Circulating insulin-like growth factor-I in pregnancy and maternal risk of breast cancer.

BACKGROUND: Elevated serum concentrations of insulin-like growth factor (IGF)-1 have been associated with increased risk of breast cancer. Previously, we reported a similar association in samples obtained during pregnancy. The current study was conducted to further characterize the association of IGF-1 during pregnancy with maternal breast cancer risk. METHODS: A case-control study was nested within the Finnish Maternity Cohort. The study was limited to primiparous women less than 40 years of age, who donated blood samples during early (median, 12 weeks) pregnancy and delivered a single child at term. Seven hundred and nineteen women with invasive breast cancer were eligible. Two controls (n = 1,434) were matched to each case on age and date at blood donation. Serum IGF-1 concentration was measured using an Immulite 2000 analyzer. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI).RESULTS: No significant associations were observed between serum IGF-1 concentrations and breast cancer risk in both the overall analysis (OR 1.08 (95% CI 0.80-1.47) and in analyses stratified by histological subtype, lag-time to cancer diagnosis, age at pregnancy or age at diagnosis.CONCLUSIONS: There was no association between IGF-1 and maternal breast cancer risk during early pregnancy in this large nested case-control study.Impact:Serum IGF-1 concentrations during early pregnancy may not be related to maternal risk of breast cancer.

Disease in the dark: molecular characterization of Polychromophilus murinus in temperate zone bats revealed a worldwide distribution of this malaria-like disease.

For a better understanding of the complex coevolutionary processes between hosts and parasites, accurate identification of the actors involved in the interaction is of fundamental importance. Blood parasites of the Order Haemosporidia, responsible for malaria, have become the focus of a broad range of studies in evolutionary biology. Interestingly, molecular-based studies on avian malaria have revealed much higher species diversity than previously inferred with morphology. Meanwhile, studies on bat haemosporidian have been largely neglected. In Europe, only one genus (Polychromophilus) and two species have been morphologically described. To evaluate the presence of potential cryptic species and parasite prevalence, we undertook a molecular characterization of Polychromophilus in temperate zone bats. We used a nested-PCR approach on the cytochrome b mitochondrial gene to detect the presence of parasites in 237 bats belonging to four different species and in the dipteran bat fly Nycteribia kolenatii, previously described as being the vector of Polychromophilus. Polychromophilus murinus was found in the four bat species and in the insect vector with prevalence ranging from 4% for Myotis myotis to 51% for M. daubentoni. By sequencing 682 bp, we then investigated the phylogenetic relationships of Polychromophilus to other published malarial lineages. Seven haplotypes were found, all very closely related, suggesting the presence of a single species in our samples. These haplotypes formed a well-defined clade together with Haemosporidia of tropical bats, revealing a worldwide distribution of this parasite mostly neglected by malarial studies since the 1980s.

Tools in pharmacovigilance in psychiatry: therapeutic drug monitoring, pharmacogenetic tests and drug-drug interactions databases

SUMMARYIn order to increase drug safety we must better understand how medication interacts with the body of our patients and this knowledge should be made easily available for the clinicians prescribing the medication. This thesis contributes to how the knowledge of some drug properties can increase and how to make information readily accessible for the medical professionals. Furthermore it investigates the use of Therapeutic drug monitoring, drug interaction databases and pharmacogenetic tests in pharmacovigilance.Two pharmacogenetic studies in the naturalistic setting of psychiatric in-patients clinics have been performed; one with the antidepressant mirtazapine, the other with the antipsychotic clozapine. Forty-five depressed patients have been treated with mirtazapine and were followed for 8 weeks. The therapeutic effect was as seen in other previous studies. Enantioselective analyses could confirm an influence of age, gender and smoking in the pharmacokinetics of mirtazapine; it showed a significant influence of the CYP2D6 genotype on the antidepressant effective S-enantiomer, and for the first time an influence of the CYP2B6 genotype on the plasma concentrations of the 8-OH metabolite was found. The CYP2B6*/*6 genotype was associated to better treatment response. A detailed hypothesis of the metabolic pathways of mirtazapine is proposed. In the second pharmacogenetic study, analyses of 75 schizophrenic patients treated with clozapine showed the influence of CYP450 and ABCB1 genotypes on its pharmacokinetics. For the first time we could demonstrate an in vivo effect of the CYP2C19 genotype and an influence of P-glycoprotein on the plasma concentrations of clozapine. Further we confirmed in vivo the prominent role of CYP1A2 in the metabolism of clozapine.Identifying risk factors for the occurrence of serious adverse drug reactions (SADR) would allow a more individualized and safer drug therapy. SADR are rare events and therefore difficult to study. We tested the feasibility of a nested matched case-control study to examine the influence of high drug plasma levels and CYP2D6 genotypes on the risk to experience an SADR. In our sample we compared 62 SADR cases with 82 controls; both groups were psychiatric patients from the in-patient clinic Königsfelden. Drug plasma levels of >120% of the upper recommended references could be identified as a risk factor with a statistically significant odds ratio of 3.5, a similar trend could be seen for CYP2D6 poor metaboliser. Although a matched case-control design seems a valid method, 100% matching is not easy to perform in a relative small cohort of one in-patient clinic. However, a nested case-control study is feasible.On the base of the experience gained in the AMSP+ study and the fact that we have today only sparse data indicating that routine drug plasma concentration monitoring and/or pharmacogenetic testing in psychiatry are justified to minimize the risk for ADR, we developed a test algorithm named "TDM plus" (TDM plus interaction checks plus pharmacogenetic testing).Pharmacovigilance programs such as the AMSP project (AMSP = Arzneimittelsicherheit in der Psychiatrie) survey psychiatric in-patients in order to collect SADR and to detect new safety signals. Case reports of such SADR are, although anecdotal, valuable to illustrate rare clinical events and sometimes confirm theoretical assumptions of e.g. drug interactions. Seven pharmacovigilance case reports are summarized in this thesis.To provide clinicians with meaningful information on the risk of drug combinations, during the course of this thesis the internet based drug interaction program mediQ.ch (in German) has been developed. Risk estimation is based on published clinical and pharmacological information of single drugs and alimentary products, including adverse drug reaction profiles. Information on risk factors such as renal and hepatic insufficiency and specific genotypes are given. More than 20'000 drug pairs have been described in detail. Over 2000 substances with their metabolic and transport pathways are included and all information is referenced with links to the published scientific literature or other information sources. Medical professionals of more than 100 hospitals and 300 individual practitioners do consult mediQ.ch regularly. Validations with comparisons to other drug interaction programs show good results.Finally, therapeutic drug monitoring, drug interaction programs and pharmacogenetic tests are helpful tools in pharmacovigilance and should, in absence of sufficient routine tests supporting data, be used as proposed in our TDM plus algorithm.RESUMEPour améliorer la sécurité d'emploi des médicaments il est important de mieux comprendre leurs interactions dans le corps des patients. Ensuite le clinicien qui prescrit une pharmacothérapie doit avoir un accès simple à ces informations. Entre autres, cette thèse contribue à mieux connaître les caractéristiques pharmacocinétiques de deux médicaments. Elle examine aussi l'utilisation de trois outils en pharmacovigilance : le monitorage thérapeutique des taux plasmatiques des médicaments (« therapeutic drug monitoring »), un programme informatisé d'estimation du risque de combinaisons médicamenteuses, et enfin des tests pharmacogénétiques.Deux études cliniques pharmacogénétiques ont été conduites dans le cadre habituel de clinique psychiatrique : l'une avec la mirtazapine (antidépresseur), l'autre avec la clozapine (antipsychotique). On a traité 45 patients dépressifs avec de la mirtazapine pendant 8 semaines. L'effet thérapeutique était semblable à celui des études précédentes. Nous avons confirmé l'influence de l'âge et du sexe sur la pharmacocinétique de la mirtazapine et la différence dans les concentrations plasmatiques entre fumeurs et non-fumeurs. Au moyen d'analyses énantiomères sélectives, nous avons pu montrer une influence significative du génotype CYP2D6 sur l'énantiomère S+, principalement responsable de l'effet antidépresseur. Pour la première fois, nous avons trouvé une influence du génotype CYP2B6 sur les taux plasmatiques de la 8-OH-mirtazapine. Par ailleurs, le génotype CYP2B6*6/*6 était associé à une meilleure réponse thérapeutique. Une hypothèse sur les voies métaboliques détaillées de la mirtazapine est proposée. Dans la deuxième étude, 75 patients schizophrènes traités avec de la clozapine ont été examinés pour étudier l'influence des génotypes des iso-enzymes CYP450 et de la protéine de transport ABCB1 sur la pharmacocinétique de cet antipsychotique. Pour la première fois, on a montré in vivo un effet des génotypes CYP2C19 et ABCB1 sur les taux plasmatiques de la clozapine. L'importance du CYP1A2 dans le métabolisme de la clozapine a été confirmée.L'identification de facteurs de risques dans la survenue d'effets secondaire graves permettrait une thérapie plus individualisée et plus sûre. Les effets secondaires graves sont rares. Dans une étude de faisabilité (« nested matched case-control design » = étude avec appariement) nous avons comparé des patients avec effets secondaires graves à des patients-contrôles prenant le même type de médicaments mais sans effets secondaires graves. Des taux plasmatiques supérieurs à 120% de la valeur de référence haute sont associés à un risque avec « odds ratio » significatif de 3.5. Une tendance similaire est apparue pour le génotype du CYP2D6. Le « nested matched case-control design » semble une méthode valide qui présente cependant une difficulté : trouver des patients-contrôles dans le cadre d'une seule clinique psychiatrique. Par contre la conduite d'une « nested case-control study » sans appariement est recommandable.Sur la base de notre expérience de l'étude AMSP+ et le fait que nous disposons que de peux de données justifiant des monitorings de taux plasmatiques et/ou de tests pharmacogénétiques de routine, nous avons développé un test algorithme nommé « TDMplus » (TDM + vérification d'interactions médicamenteuses + tests pharmacogénétique).Des programmes de pharmacovigilances comme celui de l'AMSP (Arzneimittelsicherheit in der Psychiatrie = pharmacovigilance en psychiatrie) collectent les effets secondaires graves chez les patients psychiatriques hospitalisés pour identifier des signaux d'alertes. La publication de certains de ces cas même anecdotiques est précieuse. Elle décrit des événements rares et quelques fois une hypothèse sur le potentiel d'une interaction médicamenteuse peut ainsi être confirmée. Sept publications de cas sont résumées ici.Dans le cadre de cette thèse, on a développé un programme informatisé sur internet (en allemand) - mediQ.ch - pour estimer le potentiel de risques d'une interaction médicamenteuse afin d'offrir en ligne ces informations utiles aux cliniciens. Les estimations de risques sont fondées sur des informations cliniques (y compris les profils d'effets secondaires) et pharmacologiques pour chaque médicament ou substance combinés. Le programme donne aussi des informations sur les facteurs de risques comme l'insuffisance rénale et hépatique et certains génotypes. Actuellement il décrit en détail les interactions potentielles de plus de 20'000 paires de médicaments, et celles de 2000 substances actives avec leurs voies de métabolisation et de transport. Chaque information mentionne sa source d'origine; un lien hypertexte permet d'y accéder. Le programme mediQ.ch est régulièrement consulté par les cliniciens de 100 hôpitaux et par 300 praticiens indépendants. Les premières validations et comparaisons avec d'autres programmes sur les interactions médicamenteuses montrent de bons résultats.En conclusion : le monitorage thérapeutique des médicaments, les programmes informatisés contenant l'information sur le potentiel d'interaction médicamenteuse et les tests pharmacogénétiques sont de précieux outils en pharmacovigilance. Nous proposons de les utiliser en respectant l'algorithme « TDM plus » que nous avons développé.

Increased EBV Reactivation in the Cerebrospinal Fluid of Patients with Early Multiple Sclerosis

Epstein-Barr virus (EBV) has been consistently associated with multiple sclerosis (MS), but whether this virus is a trigger of MS remains undetermined. Recently, EBV-infected B cells recognized by activated CD8_ T cells have been detected in the meninges of autopsied MS patients. In addition, a strong EBV-specific CD8_ T cell response in the blood of patients with MS of recent onset was reported. Here, to further explore the putative relationship between MS and EBV, we assessed the EBV-specific cellular and humoral immune responses in the blood and the cerebrospinal fluid (CSF) of patients with early MS or other neurological diseases, separated into inflammatory (IOND) and non-inflammatory (NIOND) groups. The MS non-associated neurotropic herpesvirus cytomegalovirus (CMV) served as a control. Fifty-eight study subjects were enrolled, including 44 patients (13 with early MS (onset of MS less than one year prior to the assay), 15 with IOND and 16 with NIOND) in the immunological arm of the study. The cellular immune response was investigated using a functional CFSE cytotoxic T lymphocyte (CTL) assay performed with short-term cultured EBV- or CMVspecific effector T cells from the CSF and the blood. The humoral immune response specific for these two viruses was also examined in both the blood and the CSF. The recruitment of a given virusspecific antibody in the CSF as compared to the blood was expressed as antibody indexes (AI). We found that, in the CSF of early MS patients, there was an enrichment in EBV-, but not CMV-specific, CD8_ CTL as compared to the CSF of IOND (P_ 0.003) and NIOND patients (P_0.0009), as well as compared to paired blood samples (P_0.005). Additionally, relative viral capsid antigen (VCA)-, but not EBV encoded nuclear antigen 1 (EBNA1)- or CMV-specific, AI were increased in the CSF of early MS as compared to IOND (P_0.002) or NIOND patients (P_0.008) and correlated with the EBVspecific CD8_ CTL responses in the CSF (rs_0.54, P_0.001). Fourteen additional patients were enrolled in the virological arm of the study: using semi-nested PCR, EBV-encoded nuclear RNA1 (EBER1)-a transcript expressed during all stages of EBV infection-was detected in the CSF of 2/4 early MS, but only 1/6 IOND and 0/4 NIOND patients. Altogether, our data suggest that a reactivation of EBV, but not CMV, is taking place in the central nervous system of patients with MS of recent onset. These data significantly strengthen the link between EBV and MS and may indicate a triggering role of EBV in this disease. This work was supported by grants from the Swiss National Foundation and from the Swiss Society for Multiple Sclerosis.

Plasma leptin levels in men are not related to the development of lipoatrophy during antiretroviral therapy.

OBJECTIVES: To assess the correlations between the hormone leptin and lipoatrophy in HIV-positive, treatment-naive patients on combination antiretroviral therapy (cART). DESIGN: Case-control study nested in a multicentre cohort of HIV-infected adults. Cases were patients that developed lipoatrophy and controls those who did not. PATIENTS AND METHODS: Clinical parameters and plasma leptin determinations were studied in 97 HIV-1-infected, treatment-naive Caucasian men (10 cases and 87 controls) on an unchanged and virologically successful drug regimen with a zidovudine/lamivudine backbone at baseline and after 2 years of cART. The association of plasma leptin levels and the development of lipoatrophy was investigated. RESULTS: Two years of cART was not associated with a change in plasma leptin levels. Plasma leptin levels remained sensible to changes in body mass index. There was no difference in leptin levels between patients who developed lipoatrophy and controls, neither before nor after cART. The only predictor of development of lipoatrophy was a higher age (P = 0.02). CONCLUSIONS: Leptin as measured in plasma is unlikely to play a major role in the genesis of lipoatrophy.

A step-by-step tutorial to use HierFstat to analyse populations hierarchically structured at multiple levels.

The populations of parasites and infectious agents are most of the time structured in complex hierarchy that lies beyond the classical nested design described by Wright's F-statistics (F(IS), F(ST) and F(IT)). In this note we propose a user-friendly step-by-step notice for using recent software (HierFstat) that computes and test fixation indices for any hierarchical structure. We add some tricks and tips for some special data kind (haploid, single locus), some other procedure (bootstrap over loci) and how to handle crossed factors.

Bloodstream infections related to totally implantable venous access port: What is the situation in our hospital?

Port-a-Cath© (PAC) are totally implantable devices that offer an easy and long term access to venous circulation. They have been extensively used for intravenous therapy administration and are particularly well suited for chemotherapy in oncologic patients. Previous comparative studies have shown that these devices have the lowest catheter-related bloodstream infection rates among all intravascular access systems. However, bloodstream infection (BSI) still remains a major issue of port use and epidemiology data for PAC-associated BSI (PABSI) rates differ strongly depending on studies. Also, current literature about PABSI risk factors is scarce and sometimes controversial. Such heterogeneity may depend on type of studied population and local factors. Therefore, the aim of this study was to describe local epidemiology and risk factors for PABSI in adult patients in our tertiary- care university hospital. We conducted a retrospective cohort study in order to describe local epidemiology. We also performed a nested case-control study to identify local risk factors of PABSI. We analyzed medical files of adult patients who had a PAC implanted between January 1st, 2008 and December 31st, 2009 and looked for PABSI occurrence before May 1st, 2011 to define cases. Thirty nine PABSI occurred in this population with an attack rate of 5.8%. We estimated an incidence rate of 0.08/1000 PAC-days using the case-control study. PABSI causative agents were mainly Gram positive cocci (62%). We identified three predictive factors of PABSI by multivariate statistical analysis: neutropenia on outcome date (Odds Ratio [OR]: 4.05; 95% confidence interval [CI]:1.05- 15.66; p=0.042), diabetes (OR: 11.53; 95% CI: 1.07-124.70; p=0.044) and having another infection than PABSI on outcome date (OR: 6.35; 95% CI: 1.50-26.86; p=0.012). Patients suffering from acute or renal failure (OR: 4.26; 95% CI: 0.94-19.21; p=0.059) or wearing another invasive device (OR: 2.99; 95%CI:0.96-9.31; p=0.059) did not have a statistically increased risk for developing a PABSI according to classical threshold (p<0.05) but nevertheless remained close to significance. Our study demonstrated that local epidemiology and microbiology of PABSI in our institution was similar to previous reports. A larger prospective study is required to confirm our results or to test preventive measures.

Shifts in species and phylogenetic diversity between sapling and tree communities indicate negative density dependence in a lowland rain forest

1. As trees in a given cohort progress through ontogeny, many individuals die. This risk of mortality is unevenly distributed across species because of many processes such as habitat filtering, interspecific competition and negative density dependence. Here, we predict and test the patterns that such ecological processes should inscribe on both species and phylogenetic diversity as plants recruit from saplings to the canopy. 2. We compared species and phylogenetic diversity of sapling and tree communities at two sites in French Guiana. We surveyed 2084 adult trees in four 1-ha tree plots and 943 saplings in sixteen 16-m2 subplots nested within the tree plots. Species diversity was measured using Fisher's alpha (species richness) and Simpson's index (species evenness). Phylogenetic diversity was measured using Faith's phylogenetic diversity (phylogenetic richness) and Rao's quadratic entropy index (phylogenetic evenness). The phylogenetic diversity indices were inferred using four phylogenetic hypotheses: two based on rbcLa plastid DNA sequences obtained from the inventoried individuals with different branch lengths, a global phylogeny available from the Angiosperm Phylogeny Group, and a combination of both. 3. Taxonomic identification of the saplings was performed by combining morphological and DNA barcoding techniques using three plant DNA barcodes (psbA-trnH, rpoC1 and rbcLa). DNA barcoding enabled us to increase species assignment and to assign unidentified saplings to molecular operational taxonomic units. 4. Species richness was similar between saplings and trees, but in about half of our comparisons, species evenness was higher in trees than in saplings. This suggests that negative density dependence plays an important role during the sapling-to-tree transition. 5. Phylogenetic richness increased between saplings and trees in about half of the comparisons. Phylogenetic evenness increased significantly between saplings and trees in a few cases (4 out of 16) and only with the most resolved phylogeny. These results suggest that negative density dependence operates largely independently of the phylogenetic structure of communities. 6. Synthesis. By contrasting species richness and evenness across size classes, we suggest that negative density dependence drives shifts in composition during the sapling-to-tree transition. In addition, we found little evidence for a change in phylogenetic diversity across age classes, suggesting that the observed patterns are not phylogenetically constrained.

Combining bone resorption markers and heel quantitative ultrasound to discriminate between fracture cases and control

Rapport de synthèse : L'ostéoporose est reconnue comme un problème majeur de santé publique. Comme il existe actuellement des traitements préventifs efficaces pour minimiser le risque de fracture, il est essentiel de développer des nouvelles stratégies de détection des femmes à risque de fracture. Les marqueurs spécifiques du remodelage osseux dosés dans les urines ainsi que les ultrasons quantitatifs du talon ont été étudiés comme outils cliniques pour prédire le risque fracturaire chez les femmes âgées. Il n'existe cependant que très peu de donnée sur la combinaison de ces deux outils pour améliorer la prédiction du risque de fracture. Cette étude cas-contrôle, réalisée chez 368 femmes âgées de 76 ans en moyenne d'une cohorte suisse de femmes ambulatoires, évalue la capacité discriminative entre 195 femmes avec fracture non-vertébrale à bas traumatisme et 173 femmes sans fractures - de deux marqueurs urinaires de la résorption osseuse, les pyridinolines et les deoxypyridinolines, ainsi que deux ultrasons quantitatifs du talon, le Achilles+ (GE-Lunar, Madison, USA) et le Sahara (Hologic, Waltham, USA). Les 195 patientes avec une fracture ont été choisies identiques aux 173 contrôles concernant Page, l'indice de masse corporel, le centre médical et la durée de suivi jusqu'à la fracture. Cette étude montre que les marqueurs urinaires de la résorption osseuse ont une capacité environ identique aux ultrasons quantitatifs du talon pour discriminer entre les patientes avec fracture non-vertébrale à bas traumatisme et les contrôles. La combinaison des deux tests n'est cependant pas plus performante qu'un seul test. Les résultats de cette étude peuvent aider à concevoir les futures stratégies de détection du risque fracturaire chez les femmes âgées, qui intègrent notamment des facteurs de risque cliniques, radiologiques et biochimiques. Abstract : Summary : This nested case-control analysis of a Swiss ambulatory cohort of elderly women assessed the discriminatory power of urinary markers of bone resorption and heel quantitative ultrasound for non-vertebral fractures. The tests all discriminated between cases and controls, but combining the two strategies yielded no additional relevant information. Introduction : Data are limited regarding the combination of bone resorption markers and heel quantitative bone ultrasound (QUS) in the detection of women at risk for fracture. Methods In a nested case-control analysis, we studied 368 women (mean age 76.213.2 years), 195 with low-trauma non-vertebral fractures and 173 without, matched for age, BMI, medical center, and follow-up duration, from a prospective study designed to predict fractures. Urinary total pyridinolines (PYD) and deoxypyridinolines (DPD) were measured by high performance liquid chromatography. All women underwent bone evaluations using Achilles+ and Sahara heel QUS. Results : Areas under the receiver operating-characteristic curve (AUC) for discriminative models of the fracture group, with 95% confidence intervals, were 0.62 (0.560.68) and 0.59 (0.53-0.65) for PYD and DPD, and 0.64 (0.58-0.69) and 0.65 (0.59-0.71) for Achilles+ and Sahara QUS, respectively. The combination of resorption markers and QUS added no significant discriminatory information to either measurement alone with an AUC of 0.66 (0.600.71) for Achilles+ with PYD and 0.68 (0.62-0.73) for Sahara with PYD. Conclusions : Urinary bone resorption markers and QUS are equally discriminatory between non-vertebral fracture patients and controls. However, the combination of bone resorption markers and QUS is not better than either test used alone.

Association of different lipid measures for atherogenic lipid fractions and risk of coronary events in patients receiving combination antiretroviral therapy: the Swiss HIV Cohort Study

Background: Evidence for a better performance of different highly atherogenic versus traditional lipid parameters for coronary heart disease (CHD) risk prediction is conflicting. We investigated the association of the ratios of sma11 dense low density lipoprotein(LDL)/apoplipoprotein A, aolipoprotein B/apolipoprotein A-I and total cholesterol! HDL-cholesterol and CHD events in patients on combination antiretroviral therapy (cART).Methods: Case control study nested into the Swiss HIV Cohort Study: for each cART-treated patient with a first coronary event between April 1, 2000 and July 31, 2008 (case) we selected four control patients (1) that were without coronary events until the date of the event of the index case, (2) had a plasma sample within ±30 days of the sample date of the respective case, (3) received cART and (4) were then matched for age, gender and smoking status. Lipoproteins were measured by ultracentrifugation. Conditional logistic regression models were used to estimate the independent effects of different lipid ratios and the occurrence of coronary events.Results: In total, 98 cases (19 fatal myocardial infarctions [MI] and 79 non-fatal coronary events [53 definite MIs, 15 possible MIs and 11 coronary angioplasties or bypassesJ) were matched with 392 controls. Cases were more often injecting drug users, less likely to be virologically suppressed and more often on abacavir-containing regimens. In separa te multivariable models of total cholesterol, triglycerides, HDL-cholesterol, systolic blood pressure, abdominal obesity, diabetes and family history of CHD, small dense-LDL and apolipoprotein B were each statistically significantly associated with CHD events (for 1 mg/dl increase: odds ratio [OR] 1.05, 95% CI 1.00-1.11 and 1.15, 95% CI 1.01-1.31, respectively), but the ratiosof small dense-LDLlapolipoprotein A-I (OR 1.26, 95% CI 0.95-1.67), apolipoprotein B/apolipoprotein A-I (OR 1.02, 95% CI 0.97-1.07) and HDL-cholesterol! total cholesterol (OR 0.99 95% CI 0.98-1.00) were not. Following adjustment for HIV related and cART variables these associations were weakened in each model: apolipoprotein B (OR 1.27, 95% CI 1.00-1.30), sd-LDL (OR 1.04, 95% CI 0.99-1.20), small dense-LDLlapolipoprotein A-I (OR 1.17, 95% CI 0.87-1.58), apolipoprotein B/apolipoprotein A-I (OR 1.02, 95% CI 0.97-1.07) and total cholesterolJHDL- cholesterol (OR 0.99, 95% CI 0.99-1.00).Conclusions: In patients receiving cART, small dense-LDL and apolipoprotein B showed the strongest associations with CHD events in models controlling for traditional CHD risk factors including total cholesterol and triglycerides. Adding small dense LDLlapoplipoprotein A-l, apolipoprotein B/apolipoprotein A-I and total cholesterol! HDL-cholesterol ratios did not further improve models of lipid parameters and associations of increased risk for CHD events.

The acquisition of pronouns by French children: A parallel study of production and comprehension

This study examines syntactic and morphological aspects of the production and comprehension of pronouns by 99 typically developing French-speaking children aged 3 years, 5 months to 6 years, 5 months. A fine structural analysis of subject, object, and reflexive clitics suggests that whereas the object clitic chain crosses the subject chain, the reflexive clitic chain is nested within it. We argue that this structural difference introduces differences in processing complexity, chain crossing being more complex than nesting. In support of this analysis, both production and comprehension experiments show that children have more difficulty with object than with reflexive clitics (with more omissions in production and more erroneous judgments in sentences involving Principle B in comprehension). Concerning the morphological aspect, French subject and object pronouns agree in gender with their referent. We report serious difficulties with pronoun gender both in production and comprehension in children around the age of 4 (with nearly 30% errors in production and chance level judgments in comprehension), which tend to disappear by age 6. The distribution of errors further suggests that the masculine gender is processed as the default value. These findings provide further insights into the relationship between comprehension and production in the acquisition process.

Persistence of ultrasound synovitis in patients with rheumatoid arthritis fulfilling the DAS28 and/or the new ACR/EULAR RA remission definitions: results of an observational cohort study.

OBJECTIVE: The primary aim of the study was to evaluate whether rheumatoid arthritis (RA) patients considered to be in remission according to clinical criteria sets still had persisting ultrasound (US) synovitis. We further intended to evaluate the capacity of our US score to discriminate between the patients with a clinically active disease versus those in remission. METHODS: This is an observational study nested within the Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) rheumatoid arthritis cohort. A validated US score (SONAR score) based on a semi-quantitative B-mode and Doppler (PwD) score as part of the regular clinical workup by rheumatologists in different clinical settings was used. To define clinically relevant synovitis, the same score was applied to 38 healthy controls and the 90st percentile was used as cut-off for 'relevant' synovitis. RESULTS: Three hundred and seven patients had at least one US examination and concomitant clinical information on disease activity. More than a third of patients in both DAS28 and ACR/EULAR remission showed significant gray scale synovitis (P=0.01 and 0.0002, respectively) and PwD activity (P=0.005 and 0.0005, respectively) when compared to controls. The capacity of US to discriminate between the two clinical remission groups and patients with active disease was only moderate. CONCLUSION: This observational study confirms that many patients considered to be in clinical remission according the DAS and the ACR/EULAR definitions still have residual synovitis on US. The prognostic significance of US synovitis and the exact place of US in patients reaching clinical remission need to be further evaluated.