Position of fixed-dose combinations containing an AT(1)-receptor blocker and a thiazide diuretic.

Treatment of hypertension remains a difficult task despite the availability of different types of medications lowering blood pressure by different mechanisms. In order to reach the target blood pressures recommended today combination therapy is required in most patients. The co-administration of two drugs with different impacts on the cardiovascular system markedly increases the antihypertensive effectiveness without altering adversely tolerability. Fixed low-dose combinations are becoming a valuable option not only as second-line, but also as first-line therapy. In this respect the co-administration of thiazide diuretic with an AT(1)-receptor blocker is particularly appealing. The diuretic-induced decrease in total body sodium activates the renin-angiotensin system, thus rendering blood pressure maintenance angiotensin II-dependent. During blockade of the renin-angiotensin system low doses of thiazides generally suffice, allowing the prevention of undesirable metabolic effects. Also, blockade of the AT(1)-receptor, particularly when angiotensin II production is enhanced in response to diuretic therapy, is expected to be beneficial, since angiotensin II seems to contribute importantly to the pathogenesis of cardiovascular and renal complications of hypertension.

Controlled contrast transcranial Doppler and arterial blood gas analysis to quantify shunt through patent foramen ovale.

BACKGROUND AND PURPOSE: A right-to-left shunt can be identified by contrast transcranial Doppler ultrasonography (c-TCD) at rest and/or after a Valsalva maneuver (VM) or by arterial blood gas (ABG) measurement. We assessed the influence of controlled strain pressures and durations during VM on the right-to-left passage of microbubbles, on which depends the shunt classification by c-TCD, and correlated it with the right-to-left shunt evaluation by ABG measurements in stroke patients with patent foramen ovale (PFO). METHODS: We evaluated 40 stroke patients with transesophageal echocardiography-documented PFO. The microbubbles were recorded with TCD at rest and after 4 different VM conditions with controlled duration and target strain pressures (duration in seconds and pressure in cm H2O, respectively): V5-20, V10-20, V5-40, and V10-40. The ABG analysis was performed after pure oxygen breathing in 34 patients, and the shunt was calculated as percentage of cardiac output. RESULTS: Among all VM conditions, V5-40 and V10-40 yielded the greatest median number of microbubbles (84 and 95, respectively; P<0.01). A significantly larger number of microbubbles were detected in V5-40 than in V5-20 (P<0.001) and in V10-40 than in V10-20 (P<0.01). ABG was not sensitive enough to detect a shunt in 31 patients. CONCLUSIONS: The increase of VM expiratory pressure magnifies the number of microbubbles irrespective of the strain duration. Because the right-to-left shunt classification in PFO is based on the number of microbubbles, a controlled VM pressure is advised for a reproducible shunt assessment. The ABG measurement is not sensitive enough for shunt assessment in stroke patients with PFO.

Space-time relatedness and Hamilton's rule for long-lasting behaviors in viscous populations.

Genes affect not only the behavior and fitness of their carriers but also that of other individuals. According to Hamilton's rule, whether a mutant gene will spread in the gene pool depends on the effects of its carrier on the fitness of all individuals in the population, each weighted by its relatedness to the carrier. However, social behaviors may affect not only recipients living in the generation of the actor but also individuals living in subsequent generations. In this note, I evaluate space-time relatedness coefficients for localized dispersal. These relatedness coefficients weight the selection pressures on long-lasting behaviors, which stem from a multigenerational gap between phenotypic expression by actors and the resulting environmental feedback on the fitness of recipients. Explicit values of space-time relatedness coefficients reveal that they can be surprisingly large for typical dispersal rates, even for hundreds of generations in the future.

Combined pulmonary fibrosis and emphysema syndrome in connective tissue disease.

OBJECTIVE: Connective tissue diseases (CTDs) are associated with several interstitial lung diseases. The aim of this study was to describe the recently individualized syndrome of combined pulmonary fibrosis and emphysema (CPFE) in a population of patients with CTD. METHODS: In this multicenter study, we retrospectively investigated data from patients with CTD who also have CPFE. The demographic characteristics of the patients, the results of pulmonary function testing, high-resolution computed tomography, lung biopsy, and treatment, and the outcomes of the patients were analyzed. RESULTS: Data from 34 patients with CTD who were followed up for a mean±SD duration of 8.3±7.0 years were analyzed. Eighteen of the patients had rheumatoid arthritis (RA), 10 had systemic sclerosis (SSc), 4 had mixed or overlap CTD, and 2 had other CTDs. The mean±SD age of the patients was 57±11 years, 23 were men, and 30 were current or former smokers. High-resolution computed tomography revealed emphysema of the upper lung zones and pulmonary fibrosis of the lower zones in all patients, and all patients exhibited dyspnea during exercise. Moderately impaired pulmonary function test results and markedly reduced carbon monoxide transfer capacity were observed. Five patients with SSc exhibited pulmonary hypertension. Four patients died during followup. Patients with CTD and CPFE were significantly younger than an historical control group of patients with idiopathic CPFE and more frequently were female. In addition, patients with CTD and CPFE had higher lung volumes, lower diffusion capacity, higher pulmonary pressures, and more frequently were male than those with CTD and lung fibrosis without emphysema. CONCLUSION: CPFE warrants inclusion as a novel, distinct pulmonary manifestation within the spectrum of CTD-associated lung diseases in smokers or former smokers, especially in patients with RA or SSc.

Geochemical compositions of marine fossils as proxies for reconstructing ancient environmental conditions.

A brief summary is given here about some of the geochemical methodologies that are often used to obtain information from fossils and sediments about the past environment. Such methods are frequently applied in our project in which the formation of Paleogene phosphate sequences in North Africa is investigated. These layers were deposited in shallow marine seas during a period of extreme warm climate with a high CO(2) concentration in the atmosphere. Some of the characteristics of this greenhouse interval are similar to the modern anthropogenic situation hence it is intensively investigated from several aspects by many scientists. Here the geochemical compositions of fossils deposited during this time are discussed, focusing on how the data are obtained and how they could be evaluated in terms of palaeo-environmental conditions.

Use of non-invasive ambulatory blood pressure monitoring to screen for high-risk hypertensive patients.

Blood pressures measured casually by a doctor often differ considerably from those recorded during everyday activities away from the medical environment. In the present study, we compared office and ambulatory recorded pressures in 475 consecutive untreated patients diagnosed hypertensive by physicians. Blood pressure monitored non-invasively during the day was, on average 15/7 mmHg lower than the corresponding office pressures. The difference between office and ambulatory recorded pressure tended to be greatest in those patients with the highest office blood pressure levels, although the relationship between the two types of measurement was too weak (r = 0.50 and 0.38 for systolic and diastolic pressure, respectively) to have any predictive value in the individual patient. Office blood pressures were at least 10 mmHg higher than ambulatory pressures in 62% of patients for systolic and 42% for diastolic pressure. Blood pressure levels recorded during ambulatory monitoring were higher than in the doctor's office for 18% of patients for systolic and 22% for diastolic pressure. Among patients with systolic pressures of between 161 and 180 mmHg or diastolic pressures between 96 and 105 mmHg when facing a doctor, 27 and 37% respectively, showed markedly lower systolic (less than 140 mmHg) or diastolic (less than 90 mmHg) ambulatory recorded pressures. These data therefore indicate that ambulatory blood pressure monitoring may help to identify those truly hypertensive patients who are most likely to benefit from antihypertensive therapy.

Genometric analyses of the organization of circular chromosomes: a universal pressure determines the direction of ribosomal RNA genes transcription relative to chromosome replication.

Selective pressures related to gene function and chromosomal architecture are acting on genome sequences and can be revealed, for instance, by appropriate genometric methods. Cumulative nucleotide skew analyses, i.e., GC, TA, and ORF orientation skews, predict the location of the origin of DNA replication for 88 out of 100 completely sequenced bacterial chromosomes. These methods appear fully reliable for proteobacteria, Gram-positives, and spirochetes as well as for euryarchaeotes. Based on this genome architecture information, coorientation analyses reveal that in prokaryotes, ribosomal RNA (rRNA) genes encoding the small and large ribosomal subunits are all transcribed in the same direction as DNA replication; that is, they are located along the leading strand. This result offers a simple and reliable method for circumscribing the region containing the origin of the DNA replication and reveals a strong selective pressure acting on the orientation of rRNA genes similar to the weaker one acting on the orientation of ORFs. Rate of coorientation of transfer RNA (tRNA) genes with DNA replication appears to be taxon-specific. Analyzing nucleotide biases such as GC and TA skews of genes and plotting one against the other reveals a taxonomic clusterization of species. All ribosomal RNA genes are enriched in Gs and depleted in Cs, the only so far known exception being the rRNA genes of deuterostomian mitochondria. However, this exception can be explained by the fact that in the chromosome of the human mitochondrion, the model of the deuterostomian organelle genome, DNA replication, and rRNA transcription proceed in opposite directions. A general rule is deduced from prokaryotic and mitochondrial genomes: ribosomal RNA genes that are transcribed in the same direction as the DNA replication are enriched in Gs, and those transcribed in the opposite direction are depleted in Gs.

Developing methodologies to allow the robust prediction dynamic context dominated by perturbations

El principal objectiu del projecte era desenvolupar millores conceptuals i metodològiques que permetessin una millor predicció dels canvis en la distribució de les espècies (a una escala de paisatge) derivats de canvis ambientals en un context dominat per pertorbacions. En un primer estudi, vàrem comparar l'eficàcia de diferents models dinàmics per a predir la distribució de l'hortolà (Emberiza hortulana). Els nostres resultats indiquen que un model híbrid que combini canvis en la qualitat de l'hàbitat, derivats de canvis en el paisatge, amb un model poblacional espacialment explícit és una aproximació adequada per abordar canvis en la distribució d'espècies en contextos de dinàmica ambiental elevada i una capacitat de dispersió limitada de l'espècie objectiu. En un segon estudi abordarem la calibració mitjançant dades de seguiment de models de distribució dinàmics per a 12 espècies amb preferència per hàbitats oberts. Entre les conclusions extretes destaquem: (1) la necessitat de que les dades de seguiment abarquin aquelles àrees on es produeixen els canvis de qualitat; (2) el biaix que es produeix en la estimació dels paràmetres del model d'ocupació quan la hipòtesi de canvi de paisatge o el model de qualitat d'hàbitat són incorrectes. En el darrer treball estudiarem el possible impacte en 67 espècies d’ocells de diferents règims d’incendis, definits a partir de combinacions de nivells de canvi climàtic (portant a un augment esperat de la mida i freqüència d’incendis forestals), i eficiència d’extinció per part dels bombers. Segons els resultats dels nostres models, la combinació de factors antropogènics del regim d’incendis, tals com l’abandonament rural i l’extinció, poden ser més determinants per als canvis de distribució que els efectes derivats del canvi climàtic. Els productes generats inclouen tres publicacions científiques, una pàgina web amb resultats del projecte i una llibreria per a l'entorn estadístic R.

Biodiversity and global change in Mediterranean benthic communities: perspectives over large spatial and long temporal scales

Many terrestrial and marine systems are experiencing accelerating decline due to the effects of global change. This situation has raised concern about the consequences of biodiversity losses for ecosystem function, ecosystem service provision, and human well-being. Coastal marine habitats are a main focus of attention because they harbour a high biological diversity, are among the most productive systems of the world and present high anthropogenic interaction levels. The accelerating degradation of many terrestrial and marine systems highlights the urgent need to evaluate the consequence of biodiversity loss. Because marine biodiversity is a dynamic entity and this study was interested global change impacts, this study focused on benthic biodiversity trends over large spatial and long temporal scales. The main aim of this project was to investigate the current extent of biodiversity of the high diverse benthic coralligenous community in the Mediterranean Sea, detect its changes, and predict its future changes over broad spatial and long temporal scales. These marine communities are characterized by structural species with low growth rates and long life spans; therefore they are considered particularly sensitive to disturbances. For this purpose, this project analyzed permanent photographic plots over time at four locations in the NW Mediterranean Sea. The spatial scale of this study provided information on the level of species similarity between these locations, thus offering a solid background on the amount of large scale variability in coralligenous communities; whereas the temporal scale was fundamental to determine the natural variability in order to discriminate between changes observed due to natural factors and those related to the impact of disturbances (e.g. mass mortality events related to positive thermal temperatures, extreme catastrophic events). This study directly addressed the challenging task of analyzing quantitative biodiversity data of these high diverse marine benthic communities. Overall, the scientific knowledge gained with this research project will improve our understanding in the function of marine ecosystems and their trajectories related to global change.

Molecular changes underlying mammalian phenotypic innovation

Mammals are characterized by specific phenotypic traits that include lactation, hair, and relatively large brains with unique structures. Individual mammalian lineages have, in turn, evolved characteristic traits that distinguish them from others. These include obvious anatom¬ical differences but also differences related to reproduction, life span, cognitive abilities, be¬havior. and disease susceptibility. However, the molecular basis of the diverse mammalian phenotypes and the selective pressures that shaped their evolution remain largely unknown. In the first part of my thesis, I analyzed the genetic factors associated with the origin of a unique mammalian phenotype lactation and I studied the selective pressures that forged the transition from oviparity to viviparity. Using a comparative genomics approach and evolutionary simulations, I showed that the emergence of lactation, as well as the appear¬ance of the casein gene family, significantly reduced selective pressure on the major egg-yolk proteins (the vitellogenin family). This led to a progressive loss of vitellogenins, which - in oviparous species - act as storage proteins for lipids, amino acids, phosphorous and calcium in the isolated egg. The passage to internal fertilization and placentation in therian mam¬mals rendered vitellogenins completely dispensable, which ended in the loss of the whole gene family in this lineage. As illustrated by the vitellogenin study, changes in gene content are one possible underlying factor for the evolution of mammalian-specific phenotypes. However, more subtle genomic changes, such as mutations in protein-coding sequences, can also greatly affect the phenotypes. In particular, it was proposed that changes at the level of gene reg¬ulation could underlie many (or even most) phenotypic differences between species. In the second part of my thesis, I participated in a major comparative study of mammalian tissue transcriptomes, with the goal of understanding how evolutionary forces affected expression patterns in the past 200 million years of mammalian evolution. I showed that, while com¬parisons of gene expressions are in agreement with the known species phylogeny, the rate of expression evolution varies greatly among lineages. Species with low effective population size, such as monotremes and hominoids, showed significantly accelerated rates of gene expression evolution. The most likely explanation for the high rate of gene expression evolution in these lineages is the accumulation of mildly deleterious mutations in regulatory regions, due to the low efficiency of purifying selection. Thus, our observations are in agreement with the nearly neutral theory of molecular evolution. I also describe substantial differences in evolutionary rates between tissues, with brain being the most constrained (especially in primates) and testis significantly accelerated. The rate of gene expression evolution also varies significantly between chromosomes. In particular, I observed an acceleration of gene expression changes on the X chromosome, probably as a result of adaptive processes associated with the origin of therian sex chromosomes. Lastly, I identified several individual genes as well as co-regulated expression modules that have undergone lineage specific expression changes and likely under¬lie various phenotypic innovations in mammals. The methods developed during my thesis, as well as the comprehensive gene content analyses and transcriptomics datasets made available by our group, will likely prove to be useful for further exploratory analyses of the diverse mammalian phenotypes.

Multilateral Trade and Agricultural Policy Reforms in Sugar Markets, September 2005

We analyze the impact of trade liberalization, removal of production subsidies, and elimination of consumption distortions in world sugar markets using a partial-equilibrium international sugar model calibrated on 2002 market data and current policies. The removal of trade distortions alone induces a 27% price increase while the removal of all trade and production distortions induces a 48% increase by 2011/12 relative to the baseline. Aggregate trade expands moderately, but location of production and trade patterns change substantially. Protectionist OECD countries (the EU, Japan, the US) experience an import expansion or export reduction and significant contraction in production in unfettered markets. Competitive producers in both OECD countries (Australia) and non-OECD countries (Brazil, Cuba), and even some protected producers (Indonesia, Turkey), expand production when all distortions are removed. Consumption distortions have marginal impacts on world markets and location of production. We discuss the significance of these results in the context of mounting pressures to increase market access in highly protected OECD countries and the impact on non-OECD countries.

Bidirectional shifts in colony queen number in a socially polymorphic ant population.

The breeding system of social organisms affects many important aspects of social life. Some species vary greatly in the number of breeders per group, but the mechanisms and selective pressures contributing to the maintenance of this polymorphism in social structure remain poorly understood. Here, we take advantage of a genetic dataset that spans 15 years to investigate the dynamics of colony queen number within a socially polymorphic ant species. Our study population of Formica selysi has single- and multiple-queen colonies. We found that the social structure of this species is somewhat flexible: on average, each year 3.2% of the single-queen colonies became polygynous, and conversely 1.4% of the multiple-queen colonies became monogynous. The annualized queen replacement rates were 10.3% and 11.9% for single- and multiple-queen colonies, respectively. New queens were often but not always related to previous colony members. At the population level, the social polymorphism appeared stable. There was no genetic differentiation between single- and multiple-queen colonies at eight microsatellite loci, suggesting ongoing gene flow between social forms. Overall, the regular and bidirectional changes in queen number indicate that social structure is a labile trait in F. selysi, with neither form being favored within a time-frame of 15 years.

Systematic difference between blood pressure readings caused by cuff type.

In this study we determine whether blood pressure readings using a cuff of fixed size systematically differed from readings made with a triple-bladder cuff (Tricuff) that automatically adjusts bladder width to arm circumference and assessed subsequent clinical and epidemiological effects. Blood pressure was measured with a standard cuff or a Tricuff in 454 patients visiting an outpatient clinic in the Seychelles (Indian Ocean). Overall means of within-individual standard cuff-Tricuff differences in systolic and diastolic blood pressures were examined in relation to arm circumference and sex. The standard cuff-Tricuff difference in systolic and diastolic blood pressures increased monotonically with circumference (from 4.7 +/- 0.8/3.2 +/- 0.7 mm Hg for arm circumference of 30 to 31 cm to 10.0 +/- 1.1/8.0 +/- 0.9 mm Hg for arm circumference > or = 36 cm) and was larger in women than men. Multivariate linear regression indicated independent effects of arm circumference and sex. Forty percent of subjects with a diastolic blood pressure of > or = 95 mm Hg measured with a standard cuff had values less than 95 mm Hg measured with a Tricuff. Extrapolation to the entire population of the Seychelles decreased the prevalence of blood pressure greater than or equal to 160/95 mm Hg by 11.5% and 24.0% in men and women, respectively, aged 35 to 64 years. The age-adjusted effect of body mass index on systolic and diastolic blood pressures decreased twofold using blood pressure readings made with a Tricuff instead of a standard cuff.(ABSTRACT TRUNCATED AT 250 WORDS)

The concentration of foreigners in French schools: interaction effects in place?

This paper explores the existence of negative peer-group pressures derived from the concentration of foreigners in French lower secondary schools. Using different dependent variables (number of years spent in lower secondary education, grades in 4th ‘and 3rd year and track election in upper secondary schooling) the analyses indicate that the much disputed existence of significant and negative effects of the concentration of foreign students in schools depends on the method used for the estimation. If we assume that the concentration of foreigners is a random and exogenous process, then the multivariate analyses confirm negative interactions. If, on the contrary, we question the assumption that this contextual information is not end the result of prior sorting mechanisms of individuals across social spaces, the concentration of foreigners has no statistical impact on attainment.

Diagnosis and treatment of resistant hypertension.

Hypertension resistant to lifestyle interventions and antihypertensive medications is a common problem encountered by physicians in everyday practice. It is most often defined as a blood pressure remaining ≥ 140/90 mmHg despite the regular intake of at least three drugs lowering blood pressure by different mechanisms, one of them being a diuretic. It now appears justified to include, unless contraindicated or not tolerated, a blocker of the renin-angiotensin system and a calcium channel blocker in this drug regimen, not only to gain antihypertensive efficacy, but also to prevent or regress target organ damage and delay the development of cardiorenal complications. A non-negligible fraction of treatment-resistant hypertension have normal "out of office" blood pressures. Ambulatory blood pressure monitoring and/or home blood pressure recording should therefore be routinely performed to identify patients with true resistant hypertension, i.e. patients who are more likely to benefit from treatment intensification.