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.

Monitoring of posture allocations and activities by a shoe-based wearable sensor.

Monitoring of posture allocations and activities enables accurate estimation of energy expenditure and may aid in obesity prevention and treatment. At present, accurate devices rely on multiple sensors distributed on the body and thus may be too obtrusive for everyday use. This paper presents a novel wearable sensor, which is capable of very accurate recognition of common postures and activities. The patterns of heel acceleration and plantar pressure uniquely characterize postures and typical activities while requiring minimal preprocessing and no feature extraction. The shoe sensor was tested in nine adults performing sitting and standing postures and while walking, running, stair ascent/descent and cycling. Support vector machines (SVMs) were used for classification. A fourfold validation of a six-class subject-independent group model showed 95.2% average accuracy of posture/activity classification on full sensor set and over 98% on optimized sensor set. Using a combination of acceleration/pressure also enabled a pronounced reduction of the sampling frequency (25 to 1 Hz) without significant loss of accuracy (98% versus 93%). Subjects had shoe sizes (US) M9.5-11 and W7-9 and body mass index from 18.1 to 39.4 kg/m2 and thus suggesting that the device can be used by individuals with varying anthropometric characteristics.

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.

Limits on the validity of infinite length assumptions for modelling shallow landslides

The infinite slope method is widely used as the geotechnical component of geomorphic and landscape evolution models. Its assumption that shallow landslides are infinitely long (in a downslope direction) is usually considered valid for natural landslides on the basis that they are generally long relative to their depth. However, this is rarely justified, because the critical length/depth (L/H) ratio below which edge effects become important is unknown. We establish this critical L/H ratio by benchmarking infinite slope stability predictions against finite element predictions for a set of synthetic two-dimensional slopes, assuming that the difference between the predictions is due to error in the infinite slope method. We test the infinite slope method for six different L/H ratios to find the critical ratio at which its predictions fall within 5% of those from the finite element method. We repeat these tests for 5000 synthetic slopes with a range of failure plane depths, pore water pressures, friction angles, soil cohesions, soil unit weights and slope angles characteristic of natural slopes. We find that: (1) infinite slope stability predictions are consistently too conservative for small L/H ratios; (2) the predictions always converge to within 5% of the finite element benchmarks by a L/H ratio of 25 (i.e. the infinite slope assumption is reasonable for landslides 25 times longer than they are deep); but (3) they can converge at much lower ratios depending on slope properties, particularly for low cohesion soils. The implication for catchment scale stability models is that the infinite length assumption is reasonable if their grid resolution is coarse (e.g. >25?m). However, it may also be valid even at much finer grid resolutions (e.g. 1?m), because spatial organization in the predicted pore water pressure field reduces the probability of short landslides and minimizes the risk that predicted landslides will have L/H ratios less than 25. Copyright (c) 2012 John Wiley & Sons, Ltd.

Katepillarista kauppakassiin : product placement suomalaisessa tv-ohjelmatuotannossa

Product placement has become more and more common in Finnish television programmes lately. Product placement, as with the whole of the television industry, is strictly regulated and monitored by law. Surreptitious advertising, sponsorship, cooperative partnerships and product placement are often confused with each other. Partially these activities are interpenetrative. Present legislation doesn't recognise product placement, therefore it doesn't have any specific position in law, thus causing problems. Product placement in domestic tv-programmes is still relatively modest. More extensive activity is perceivable at the movies where the restrictions are considerably more liberal. In the United States, product placement is a part of a production's budget. Pressure to increase financing has grouwn in both Finland and Europe. There has been considerable preparation in advance of a new television directive in the European Union which would allow more liberal advertising and product placement as a part of financing tv-programmes. The proposal for a new directive is currently only on its first round so product placement probably won't become better defined in law in the near future. Finnish television producers were interviewed as part of the research for this thesis, in order to clarify product placement position and usage in domestic televion programmes. Surreptitious advertising, sponsorship, different kinds of cooperative partnerships and the need for guidance were also discussed in the course of the themed interviews. Even though product placement does not currently play a significant part in the financing of a production, there are certainly pressures in that direktion. In the field of television, the legal boundaries of product placement are presently being explored in order to assess its position as a part of budgeting and covering expenses.

Kaupungin ja maaseudun vuorovaikutus alueellisessa kehittämispolitiikassa

In Finland, European Union membership and economic globalisation have changed the position of regions from closed territorial systems to nodes of open international networks. The increasing complexity of cities as globalised knowledge centres and functionally specialised and diversified rural areas, and on the other hand growing disparities between prosperous urban cores and lagging peripheral areas are also essential features in contemporary regional development. These trends have produced new needs to promote mutual dialogue between cities and the countryside in western market economies. Urban-rural interaction is an idea which was developed in the late 1990s within regional policy to pull together these new challenges to regional development and handle cities and the countryside as a whole. The aim of my study is to conceptualise the idea of urban-rural interaction, explain the phenomenon theoretically, clarify past and present urban and rural development and analyse regional policies from the interaction angle. The ultimate purpose is to illustrate the existence and nature of particular interaction policy in a globalising society. The general method is discourse analysis, which I use in three cases: Central Finland, South-Ostrobothnia and South-West Finland. Theoretically I have a two-dimensional approach. On the first hand I use World-System theory to explain how the global economy is moulding urban and rural structures at the regional level. On the other hand I use regime theory to explain local political actions and practises between cities and the countryside under the overlapping pressures deriving from reformulated regional structures and policies.

Adaptation to globalisation in Finland has been carried out by strengthening urban centres. The stress in regional policy has been in urban development. The development of the countryside has mostly been implemented by a separate rural policy. At the end of the 1990s and early 2000s Finnish cities have actually shown themselves to be competitive in global markets. The drawbacks of the new growth centre policy have been the sparse network of prosperous cities and their weak spreading effects, which have hindered comprehensive regional development. Tensions between urban and rural areas have also deepened. In this situation the interaction policy is used as a way of balancing development and moderate conflicts within the regions. From this point of view urban-rural interaction can be seen as a way of tackling the challenges of globalisation.

On the other hand the results emphasise that actors involved in regional development still believe, although the hegemonic discourse is on urban policy, that there are opportunities to stimulate progress in the countryside as well. In the situation where regional authorities control development resources, rural development can be successful only if rural actors manage to establish fruitful relationships with their urban partners. This is also the weakness of the programme-based regional policy. If rural municipalities or other actors are for any reason incapable of building development regimes with cities, the offers of interaction policy will be useless.

The problem of the interaction policy is that the focus and methods of it have so far been rather underdeveloped. In order to improve the efficiency of the interaction policy, further research should concentrate on the social processes which define the position of cities and the countryside as partners of interaction, and practises which promote or prohibit the possibilities of developing the interaction policy. The efforts to define different contents of urban-rural interaction or promote interaction projects should not have such an important role in the future as they have had so far. Instead, the focus of interaction policy should be on questions such as how to manage the political tensions between town and country and how to create a positive atmosphere for regional policy where the needs of urban and rural development are promoted equally.

Financial Markets and Real Ecinomy: Four Essays in International Trade

Financial markets play an important role in an economy performing various functions like mobilizing and pooling savings, producing information about investment opportunities, screening and monitoring investments, implementation of corporate governance, diversification and management of risk. These functions influence saving rates, investment decisions, technological innovation and, therefore, have important implications for welfare. In my PhD dissertation I examine the interplay of financial and product markets by looking at different channels through which financial markets may influence an economy.My dissertation consists of four chapters. The first chapter is a co-authored work with Martin Strieborny, a PhD student from the University of Lausanne. The second chapter is a co-authored work with Melise Jaud, a PhD student from the Paris School of Economics. The third chapter is co-authored with both Melise Jaud and Martin Strieborny. The last chapter of my PhD dissertation is a single author paper.Chapter 1 of my PhD thesis analyzes the effect of financial development on growth of contract intensive industries. These industries intensively use intermediate inputs that neither can be sold on organized exchange, nor are reference-priced (Levchenko, 2007; Nunn, 2007). A typical example of a contract intensive industry would be an industry where an upstream supplier has to make investments in order to customize a product for needs of a downstream buyer. After the investment is made and the product is adjusted, the buyer may refuse to meet a commitment and trigger ex post renegotiation. Since the product is customized to the buyer's needs, the supplier cannot sell the product to a different buyer at the original price. This is referred in the literature as the holdup problem. As a consequence, the individually rational suppliers will underinvest into relationship-specific assets, hurting the downstream firms with negative consequences for aggregate growth. The standard way to mitigate the hold up problem is to write a binding contract and to rely on the legal enforcement by the state. However, even the most effective contract enforcement might fail to protect the supplier in tough times when the buyer lacks a reliable source of external financing. This suggests the potential role of financial intermediaries, banks in particular, in mitigating the incomplete contract problem. First, financial products like letters of credit and letters of guarantee can substantially decrease a risk and transaction costs of parties. Second, a bank loan can serve as a signal about a buyer's true financial situation, an upstream firm will be more willing undertake relationship-specific investment knowing that the business partner is creditworthy and will abstain from myopic behavior (Fama, 1985; von Thadden, 1995). Therefore, a well-developed financial (especially banking) system should disproportionately benefit contract intensive industries.The empirical test confirms this hypothesis. Indeed, contract intensive industries seem to grow faster in countries with a well developed financial system. Furthermore, this effect comes from a more developed banking sector rather than from a deeper stock market. These results are reaffirmed examining the effect of US bank deregulation on the growth of contract intensive industries in different states. Beyond an overall pro-growth effect, the bank deregulation seems to disproportionately benefit the industries requiring relationship-specific investments from their suppliers.Chapter 2 of my PhD focuses on the role of the financial sector in promoting exports of developing countries. In particular, it investigates how credit constraints affect the ability of firms operating in agri-food sectors of developing countries to keep exporting to foreign markets.Trade in high-value agri-food products from developing countries has expanded enormously over the last two decades offering opportunities for development. However, trade in agri-food is governed by a growing array of standards. Sanitary and Phytosanitary standards (SPS) and technical regulations impose additional sunk, fixed and operating costs along the firms' export life. Such costs may be detrimental to firms' survival, "pricing out" producers that cannot comply. The existence of these costs suggests a potential role of credit constraints in shaping the duration of trade relationships on foreign markets. A well-developed financial system provides the funds to exporters necessary to adjust production processes in order to meet quality and quantity requirements in foreign markets and to maintain long-standing trade relationships. The products with higher needs for financing should benefit the most from a well functioning financial system. This differential effect calls for a difference-in-difference approach initially proposed by Rajan and Zingales (1998). As a proxy for demand for financing of agri-food products, the sanitary risk index developed by Jaud et al. (2009) is used. The empirical literature on standards and norms show high costs of compliance, both variable and fixed, for high-value food products (Garcia-Martinez and Poole, 2004; Maskus et al., 2005). The sanitary risk index reflects the propensity of products to fail health and safety controls on the European Union (EU) market. Given the high costs of compliance, the sanitary risk index captures the demand for external financing to comply with such regulations.The prediction is empirically tested examining the export survival of different agri-food products from firms operating in Ghana, Mali, Malawi, Senegal and Tanzania. The results suggest that agri-food products that require more financing to keep up with food safety regulation of the destination market, indeed sustain longer in foreign market, when they are exported from countries with better developed financial markets.Chapter 3 analyzes the link between financial markets and efficiency of resource allocation in an economy. Producing and exporting products inconsistent with a country's factor endowments constitutes a serious misallocation of funds, which undermines competitiveness of the economy and inhibits its long term growth. In this chapter, inefficient exporting patterns are analyzed through the lens of the agency theories from the corporate finance literature. Managers may pursue projects with negative net present values because their perquisites or even their job might depend on them. Exporting activities are particularly prone to this problem. Business related to foreign markets involves both high levels of additional spending and strong incentives for managers to overinvest. Rational managers might have incentives to push for exports that use country's scarce factors which is suboptimal from a social point of view. Export subsidies might further skew the incentives towards inefficient exporting. Management can divert the export subsidies into investments promoting inefficient exporting.Corporate finance literature stresses the disciplining role of outside debt in counteracting the internal pressures to divert such "free cash flow" into unprofitable investments. Managers can lose both their reputation and the control of "their" firm if the unpaid external debt triggers a bankruptcy procedure. The threat of possible failure to satisfy debt service payments pushes the managers toward an efficient use of available resources (Jensen, 1986; Stulz, 1990; Hart and Moore, 1995). The main sources of debt financing in the most countries are banks. The disciplining role of banks might be especially important in the countries suffering from insufficient judicial quality. Banks, in pursuing their rights, rely on comparatively simple legal interventions that can be implemented even by mediocre courts. In addition to their disciplining role, banks can promote efficient exporting patterns in a more direct way by relaxing credit constraints of producers, through screening, identifying and investing in the most profitable investment projects. Therefore, a well-developed domestic financial system, and particular banking system, would help to push a country's exports towards products congruent with its comparative advantage.This prediction is tested looking at the survival of different product categories exported to US market. Products are identified according to the Euclidian distance between their revealed factor intensity and the country's factor endowments. The results suggest that products suffering from a comparative disadvantage (labour-intensive products from capital-abundant countries) survive less on the competitive US market. This pattern is stronger if the exporting country has a well-developed banking system. Thus, a strong banking sector promotes exports consistent with a country comparative advantage.Chapter 4 of my PhD thesis further examines the role of financial markets in fostering efficient resource allocation in an economy. In particular, the allocative efficiency hypothesis is investigated in the context of equity market liberalization.Many empirical studies document a positive and significant effect of financial liberalization on growth (Levchenko et al. 2009; Quinn and Toyoda 2009; Bekaert et al., 2005). However, the decrease in the cost of capital and the associated growth in investment appears rather modest in comparison to the large GDP growth effect (Bekaert and Harvey, 2005; Henry, 2000, 2003). Therefore, financial liberalization may have a positive impact on growth through its effect on the allocation of funds across firms and sectors.Free access to international capital markets allows the largest and most profitable domestic firms to borrow funds in foreign markets (Rajan and Zingales, 2003). As domestic banks loose some of their best clients, they reoptimize their lending practices seeking new clients among small and younger industrial firms. These firms are likely to be more risky than large and established companies. Screening of customers becomes prevalent as the return to screening rises. Banks, ceteris paribus, tend to focus on firms operating in comparative-advantage sectors because they are better risks. Firms in comparative-disadvantage sectors finding it harder to finance their entry into or survival in export markets either exit or refrain from entering export markets. On aggregate, one should therefore expect to see less entry, more exit, and shorter survival on export markets in those sectors after financial liberalization.The paper investigates the effect of financial liberalization on a country's export pattern by comparing the dynamics of entry and exit of different products in a country export portfolio before and after financial liberalization.The results suggest that products that lie far from the country's comparative advantage set tend to disappear relatively faster from the country's export portfolio following the liberalization of financial markets. In other words, financial liberalization tends to rebalance the composition of a country's export portfolio towards the products that intensively use the economy's abundant factors.

Hormonal, global, and regional haemodynamic responses to a vascular antagonist of vasopressin in patients with congestive heart failure with and without hyponatraemia.

The pathophysiological role of an increase in circulating vasopressin in sustaining global and regional vasoconstriction in patients with congestive heart failure has not been established, particularly in patients with hyponatraemia. To assess this further, 20 patients with congestive heart failure refractory to digoxin and diuretics were studied before and 60 minutes after the intravenous injection (5 micrograms/kg) of the vascular antagonist of vasopressin [1(beta-mercapto-beta,beta-cyclopentamethylene-propionic acid), 2-(0-methyl) tyrosine] arginine vasopressin. Ten patients were hyponatraemic (plasma sodium less than 135 mmol/l) and 10 were normonatraemic. In both groups of patients the vascular vasopressin antagonist did not alter systemic or pulmonary artery pressures, right atrial pressure, pulmonary capillary wedge pressure, cardiac index, or vascular resistances. Furthermore, there was no change in skin and hepatic blood flow in either group after the injection of the vascular antagonist. Only one patient in the hyponatraemic group showed considerable haemodynamic improvement. He had severe congestive heart failure and a high concentration of plasma vasopressin (51 pmol/l). Plasma renin activity, vasopressin, or catecholamine concentrations were not significantly changed in response to the administration of the vasopressin antagonist in either the hyponatraemic or the normonatraemic groups. Patients with hyponatraemia, however, had higher baseline plasma catecholamine concentrations, heart rate, pulmonary pressure and resistance, and lower hepatic blood flow than patients without hyponatraemia. Plasma vasopressin and plasma renin activity were slightly, though not significantly, higher in the hyponatraemic group. Thus the role of vasopressin in sustaining regional or global vasoconstriction seems limited in patients with congestive heart failure whether or not concomitant hyponatraemia is present. Vasopressin significantly increases the vascular tone only in rare patients with severe congestive heart failure and considerably increased vasopressin concentrations. Patients with hyponatraemia do, however, have raised baseline catecholamine concentrations, heart rate, pulmonary arterial pressure and resistance, and decreased hepatic blood flow.

Is nurse-measured blood pressure a valid substitute for ambulatory blood pressure monitoring?

BACKGROUND: Because ambulatory blood pressure monitoring (ABPM) is not available everywhere, the objective of the study was to determine whether nurse-measured blood pressure could be an acceptable substitute to ABPM. METHODS: We analyzed the data of 2385 consecutive patients referred to our hypertension clinic for the performance of ABPM. Before ambulatory monitoring was performed, a nurse-measured BP was obtained three times using a Y-tube connecting the sphygmomanometer and the recorder. We compared the mean value of the three nurse-measured blood pressures with that of the 12h daytime ambulatory monitoring, considered as the reference. RESULTS: The difference between the nurse-measured and the ambulatory blood pressure was small but statistically significant, indicating that nurse-measured blood pressure tends to overestimate both diastolic and systolic blood pressure. The difference between the nurse blood pressure and ABPM was greater among treated hypertensive patients than untreated patients. To diagnose hypertension, defined as a blood pressure of over 140/90mmHg by ABPM, the positive predictive value of the nurse blood pressure was 0.81 and the negative predictive value 0.63. However, these predictive values could be improved with less stringent cut-off values of blood pressure. Thus, for a diastolic blood pressure above 100mmHg, the positive predictive value of nurse blood pressure was 0.55 and the negative predictive value 0.91. These figures were relatively similar for previously treated and untreated patients. CONCLUSION: Nurse blood pressure is less accurate than ABPM in diagnosing hypertension, defined as a blood pressure of over 140/90mmHg. It could, however, be an acceptable substitute, especially to exclude people who do not need to be treated, in situations where lower resources require a less rigorous definition of hypertension.

Calcium antagonists as first-line therapy in hypertension: results of the Swiss Isradipine Study. Swiss Hypertension Society

In this study of the efficacy and safety of isradipine as first-line therapy in hypertension, 1,647 patients enrolled; 1,472 completed the 4-week placebo run-in period and began treatment with isradipine at 2.5 mg twice daily for 4 weeks. During placebo, 11% (n = 175) of the 1,647 patients withdrew because of normalization of blood pressure, side effects, noncompliance, violation of the study protocol, side effects from concomitant therapy, or other reasons. During isradipine therapy (n = 1,376), blood pressure decreased from 168 +/- 18/102 +/- 8 mm Hg at the end of the placebo period to 155 +/- 17/94 +/- 9 mm Hg after 2 weeks (p less than 0.001) and 151 +/- 16/92 +/- 9 mm Hg after 4 weeks (p less than 0.001). During active treatment, 6.4% (n = 94) were withdrawn because of flushing, headache, edema, palpitations, gastrointestinal side effects, skin rashes, or other side effects, and two patients because of lack of efficacy. The side effect score in the remaining patients worsened for flushing, remained unchanged for edema, but significantly improved for palpitations, fatigue, dizziness, headache, and nervousness. After 4 weeks, 60% of patients had diastolic blood pressures of less than or equal to 90 mm Hg. Thus, isradipine is effective and safe as first-line therapy in patients with primary hypertension as seen in general practice.

Analysis of susceptibility to human immunodeficiency virus 1 (HIV-1) by comparative genetics

Summary [résumé français voir ci-dessous] From the beginning of the 20th century the world population has been confronted with the human immune deficiency virus 1 (HIV-1). This virus has the particularity to mutate fast, and could thus evade and adapt to the human host. Our closest evolutionary related organisms, the non-human primates, are less susceptible to HIV-1. In a broader sense, primates are differentially susceptible to various retrovirus. Species specificity may be due to genetic differences among primates. In the present study we applied evolutionary and comparative genetic techniques to characterize the evolutionary pattern of host cellular determinants of HIV-1 pathogenesis. The study of the evolution of genes coding for proteins participating to the restriction or pathogenesis of HIV-1 may help understanding the genetic basis of modern human susceptibility to infection. To perform comparative genetics analysis, we constituted a collection of primate DNA and RNA to allow generation of de novo sequence of gene orthologs. More recently, release to the public domain of two new primate complete genomes (bornean orang-utan and common marmoset) in addition of the three previously available genomes (human, chimpanzee and Rhesus monkey) help scaling up the evolutionary and comparative genome analysis. Sequence analysis used phylogenetic and statistical methods for detecting molecular adaptation. We identified different selective pressures acting on host proteins involved in HIV-1 pathogenesis. Proteins with HIV-1 restriction properties in non-human primates were under strong positive selection, in particular in regions of interaction with viral proteins. These regions carried key residues for the antiviral activity. Proteins of the innate immunity presented an evolutionary pattern of conservation (purifying selection) but with signals of relaxed constrain if we compared them to the average profile of purifying selection of the primate genomes. Large scale analysis resulted in patterns of evolutionary pressures according to molecular function, biological process and cellular distribution. The data generated by various analyses served to guide the ancestral reconstruction of TRIM5a a potent antiviral host factor. The resurrected TRIM5a from the common ancestor of Old world monkeys was effective against HIV-1 and the recent resurrected hominoid variants were more effective against other retrovirus. Thus, as the result of trade-offs in the ability to restrict different retrovirus, human might have been exposed to HIV-1 at a time when TRIM5a lacked the appropriate specific restriction activity. The application of evolutionary and comparative genetic tools should be considered for the systematical assessment of host proteins relevant in viral pathogenesis, and to guide biological and functional studies. Résumé La population mondiale est confrontée depuis le début du vingtième siècle au virus de l'immunodéficience humaine 1 (VIH-1). Ce virus a un taux de mutation particulièrement élevé, il peut donc s'évader et s'adapter très efficacement à son hôte. Les organismes évolutivement le plus proches de l'homme les primates nonhumains sont moins susceptibles au VIH-1. De façon générale, les primates répondent différemment aux rétrovirus. Cette spécificité entre espèces doit résider dans les différences génétiques entre primates. Dans cette étude nous avons appliqué des techniques d'évolution et de génétique comparative pour caractériser le modèle évolutif des déterminants cellulaires impliqués dans la pathogenèse du VIH- 1. L'étude de l'évolution des gènes, codant pour des protéines impliquées dans la restriction ou la pathogenèse du VIH-1, aidera à la compréhension des bases génétiques ayant récemment rendu l'homme susceptible. Pour les analyses de génétique comparative, nous avons constitué une collection d'ADN et d'ARN de primates dans le but d'obtenir des nouvelles séquences de gènes orthologues. Récemment deux nouveaux génomes complets ont été publiés (l'orang-outan du Bornéo et Marmoset commun) en plus des trois génomes déjà disponibles (humain, chimpanzé, macaque rhésus). Ceci a permis d'améliorer considérablement l'étendue de l'analyse. Pour détecter l'adaptation moléculaire nous avons analysé les séquences à l'aide de méthodes phylogénétiques et statistiques. Nous avons identifié différentes pressions de sélection agissant sur les protéines impliquées dans la pathogenèse du VIH-1. Des protéines avec des propriétés de restriction du VIH-1 dans les primates non-humains présentent un taux particulièrement haut de remplacement d'acides aminés (sélection positive). En particulier dans les régions d'interaction avec les protéines virales. Ces régions incluent des acides aminés clé pour l'activité de restriction. Les protéines appartenant à l'immunité inné présentent un modèle d'évolution de conservation (sélection purifiante) mais avec des traces de "relaxation" comparé au profil général de sélection purifiante du génome des primates. Une analyse à grande échelle a permis de classifier les modèles de pression évolutive selon leur fonction moléculaire, processus biologique et distribution cellulaire. Les données générées par les différentes analyses ont permis la reconstruction ancestrale de TRIM5a, un puissant facteur antiretroviral. Le TRIM5a ressuscité, correspondant à l'ancêtre commun entre les grands singes et les groupe des catarrhiniens, est efficace contre le VIH-1 moderne. Les TRIM5a ressuscités plus récents, correspondant aux ancêtres des grands singes, sont plus efficaces contre d'autres rétrovirus. Ainsi, trouver un compromis dans la capacité de restreindre différents rétrovirus, l'homme aurait été exposé au VIH-1 à une période où TRIM5a manquait d'activité de restriction spécifique contre celui-ci. L'application de techniques d'évolution et de génétique comparative devraient être considérées pour l'évaluation systématique de protéines impliquées dans la pathogenèse virale, ainsi que pour guider des études biologiques et fonctionnelles

Clinical studies with a vascular vasopressin antagonist.

The effect of circulating arginine vasopressin (AVP) on blood pressure, heart rate, and skin blood flow was assessed in normotensive subjects, mild hypertensive patients, and patients with congestive heart failure, utilizing the specific antagonist of AVP at the vascular receptor level, d(CH2)5Tyr(Me)AVP (5 micrograms/kg i.v.). The renin system of the normal volunteers treated with the AVP antagonist was either intact or acutely blocked with the angiotensin converting-enzyme inhibitor captopril (25 mg p.o.). In some volunteers, the cardiovascular effect of AVP released by Finnish sauna or cigarette smoking was studied. In patients with congestive heart failure, hemodynamic measurements (pressures and cardiac output) were obtained invasively. Acute blockade of AVP vascular receptors produced no cardiovascular effect unless plasma AVP levels were markedly elevated. In our experience, abnormally high circulating AVP appears to be responsible for the decrease in skin blood flow induced by cigarette smoking and to some extent for the maintenance of vascular tone in the rare patients with particularly severe congestive heart failure.