A new, automated, four-colour interphase FISH approach for the simultaneous detection of specific aneuploidies of diagnostic and prognostic significance in high hyperdiploid ALL

In hyperdiploid acute lymphoblastic leukaemia (ALL), the simultaneous occurrence of specific aneuploidies confers a more favourable outcome than hyperdiploidy alone. Interphase (I) FISH complements conventional cytogenetics (CC) through its sensitivity and ability to detect chromosome aberrations in non-dividing cells. To overcome the limits of manual I-FISH, we developed an automated four-colour I-FISH approach and assessed its ability to detect concurrent aneuploidies in ALL. I-FISH was performed using centromeric probes for chromosomes 4, 6, 10 and 17. Parameters established for automatic nucleus selection and signal detection were evaluated (3 controls). Cut-off values were determined (10 controls, 1000 nuclei/case). Combinations of aneuploidies were considered relevant when each aneuploidy was individually significant. Results obtained in 10 ALL patients (1500 nuclei/patient) were compared with those by CC. Various combinations of aneuploidies were identified. All clones detected by CC were observed by I-FISH. I-FISH revealed numerous additional abnormal clones, ranging between 0.1% and 31.6%, based on the large number of nuclei evaluated. Four-colour automated I-FISH permits the identification of concurrent aneuploidies of prognostic significance in hyperdiploid ALL. Large numbers of cells can be analysed rapidly by this method. Owing to its high sensitivity, the method provides a powerful tool for the detection of small abnormal clones at diagnosis and during follow up. Compared to CC, it generates a more detailed cytogenetic picture, the biological and clinical significance of which merits further evaluation. Once optimised for a given set of probes, the system can be easily adapted for other probe combinations.

Big brother is watching you: eavesdropping to resolve family conflicts

Adult animals can eavesdrop on behavioral interactions between potential opponents to assess their competitive ability and motivation to contest resources without interacting directly with them. Surprisingly, eavesdropping is not yet considered as an important factor used to resolve conflicts between family members. In this study, we show that nestling barn owls (Tyto alba) competing for food eavesdrop on nestmates' vocal interactions to assess the dominance status and food needs of opponents. During a first training playback session, we broadcasted to singleton bystander nestlings a simulated vocal interaction between 2 prerecorded individuals, 1 relatively old (i.e., senior) and 1 younger nestling (i.e., junior). One playback individual, the "responder," called systematically just after the "initiator" playback individual, hence displaying a higher hunger level. To test whether nestlings have eavesdropped on this interaction, we broadcasted the same prerecorded individuals separately in a subsequent playback test session. Nestlings vocalized more rapidly after former initiators' than responders' calls and they produced more calls when the broadcasted individual was formerly a junior initiator. They chiefly challenged vocally juniors and initiators against whom the likelihood of winning a vocal contest is higher. Owlets, therefore, identified the age hierarchy between 2 competitors based on their vocalizations. They also memorized the dynamics of competitors' previous vocal interactions, and used this information to optimally adjust signaling level once interacting with only 1 of the competitor. We conclude that siblings eavesdrop on one another to resolve conflicts over parental resources.

Effects of victimization on the belief in a just world in four ex-Yugoslavian countries

Levels of support for just world beliefs among young adults (N = 598) from four ex-Yugoslavian countries-Bosnia and Herzegovina, Croatia, the former Yugoslav Republic of Macedonia, and Slovenia-were compared, taking into account victimization experiences and the general belief in a just world. Being a victim affected an individual's belief in a just world in the two less economically favored contexts: Victims of exclusion in Macedonia and victims of war in Bosnia and Herzegovina were less likely to believe in a just world than non-victims. These victimization variables partly explained why the mean scores of these two countries were less than those of the two others. A deleterious effect of cumulative negative events on belief in a just world was identified, in parallel with a lower endorsement of the belief when the first victimization occurred more recently.

The Four Different Types of Internal Hernia Occurring After Laparascopic Roux-en-Y Gastric Bypass Performed for Morbid Obesity: Are There Any Multidetector Computed Tomography (MDCT) Features Permitting Their Distinction?

BACKGROUND: Four different types of internal hernias (IH) are known to occur after laparoscopic Roux-en-Y gastric bypass (LRYGBP) performed for morbid obesity. We evaluate multidetector row helical computed tomography (MDCT) features for their differentiation. METHODS: From a prospectively collected database including 349 patients with LRYGBP, 34 acutely symptomatic patients (28 women, mean age 32.6), operated on for IH immediately after undergoing MDCT, were selected. Surgery confirmed 4 (11.6%) patients with transmesocolic, 10 (29.4%) with Petersen's, 15 (44.2%) with mesojejunal, and 5 (14.8%) with jejunojejunal IH. In consensus, 2 radiologists analyzed 13 MDCT features to distinguish the four types of IH. Statistical significance was calculated (p < 0.05, Fisher's exact test, chi-square test). RESULTS: MDCT features of small bowel obstruction (SBO) (n = 25, 73.5%), volvulus (n = 22, 64.7%), or a cluster of small bowel loops (SBL) (n = 27, 79.4%) were inconsistently present and overlapped between the four IH. The following features allowed for IH differentiation: left upper quadrant clustered small bowel loops (p < 0.0001) and a mesocolic hernial orifice (p = 0.0003) suggested transmesocolic IH. SBL abutting onto the left abdominal wall (p = 0.0021) and left abdominal shift of the superior mesenteric vessels (SMV) (p = 0.0045) suggested Petersen's hernia. The SMV predominantly shifted towards the right anterior abdominal wall in mesojejunal hernia (p = 0.0033). Location of the hernial orifice near the distal anastomosis (p = 0.0431) and jejunojejunal suture widening (p = 0.0005) indicated jejunojejunal hernia. CONCLUSIONS: None of the four IH seems associated with a higher risk of SBO. Certain MDCT features, such as the position of clustered SBL and hernial orifice, help distinguish between the four IH and may permit straightforward surgery.

Young infants' triangular communication with their parents in the context of maternal postpartum psychosis: Four case studies

With increasing data on the dynamics of normative couples as they transition to parenthood and become a triad, the need for greater understanding of the impact of parental psychopathology on this transition has become clear. The goal of the current article is to begin exploring this area that has received little attention to date, by describing case examples from a study of clinical families as they transitioned to parenthood. Four representative cases were selected from a pool of 13 mother-father-baby triads, for whom the mother had been hospitalized conjointly with her infant due to a psychotic episode during the postpartum period. The families were observed as part of a clinical consultation that included a semistructured play paradigm known as the Lausanne Trilogue Play (LTP; E. Fivaz-Depeursinge, & A. Corboz-Warnery, 1999). Interactions were scored using standardized measures as well as clinical impressions. All families from the clinical sample were noted to struggle and frequently failed to achieve the goals of play. The impact on the infants in terms of their developing sense of self as well as their defensive strategies in this context are discussed, with clinical implications explored.

Detection of four Plasmodium species in blood from humans by 18S rRNA gene subunit-based and specific real-time PCR assays

Résumé : Un nombre croissant de cas de malaria chez les voyageurs et migrants a été rapporté. Bien que l'analyse microscopique des frottis sanguins reste traditionnellement l'outil diagnostic de référence, sa fiabilité dépend considérablement de l'expertise de l'examinateur, pouvant elle-même faire défaut sous nos latitudes. Une PCR multiplex en temps réel a donc été développée en vue d'une standardisation du diagnostic. Un ensemble d'amorces génériques ciblant une région hautement conservée du gène d'ARN ribosomial 18S du genre Plasmodium a tout d'abord été conçu, dont le polymorphisme du produit d'amplification semblait suffisant pour créer quatre sondes spécifiques à l'espèce P. falciparum, P. malariae, P. vivax et P. ovale. Ces sondes utilisées en PCR en temps réel se sont révélées capables de détecter une seule copie de plasmide de P. falciparum, P. malariae, P. vivax et P. ovale spécifiquement. La même sensibilité a été obtenue avec une sonde de screening pouvant détecter les quatre espèces. Quatre-vingt-dix-sept échantillons de sang ont ensuite été testés, dont on a comparé la microscopie et la PCR en temps réel pour 66 (60 patients) d'entre eux. Ces deux méthodes ont montré une concordance globale de 86% pour la détection de plasmodia. Les résultats discordants ont été réévalués grâce à des données cliniques, une deuxième expertise microscopique et moléculaire (laboratoire de Genève et de l'Institut Suisse Tropical de Bâle), ainsi qu'à l'aide du séquençage. Cette nouvelle analyse s'est prononcé en faveur de la méthode moléculaire pour tous les neuf résultats discordants. Sur les 31 résultats positifs par les deux méthodes, la même réévaluation a pu donner raison 8 fois sur 9 à la PCR en temps réel sur le plan de l'identification de l'espèce plasmodiale. Les 31 autres échantillons ont été analysés pour le suivi de sept patients sous traitement antimalarique. Il a été observé une baisse rapide du nombre de parasites mesurée par la PCR en temps réel chez six des sept patients, baisse correspondant à la parasitémie déterminée microscopiquement. Ceci suggère ainsi le rôle potentiel de la PCR en temps réel dans le suivi thérapeutique des patients traités par antipaludéens. Abstract : There have been reports of increasing numbers of cases of malaria among migrants and travelers. Although microscopic examination of blood smears remains the "gold standard" in diagnosis, this method suffers from insufficient sensitivity and requires considerable expertise. To improve diagnosis, a multiplex real-time PCR was developed. One set of generic primers targeting a highly conserved region of the 18S rRNA gene of the genus Plasmodium was designed; the primer set was polymorphic enough internally to design four species-specific probes for P. falciparum, P. vivax, P. malarie, and P. ovale. Real-time PCR with species-specific probes detected one plasmid copy of P. falciparum, P. vivax, P. malariae, and P. ovale specifically. The same sensitivity was achieved for all species with real-time PCR with the 18S screening probe. Ninety-seven blood samples were investigated. For 66 of them (60 patients), microscopy and real-time PCR results were compared and had a crude agreement of 86% for the detection of plasmodia. Discordant results were reevaluated with clinical, molecular, and sequencing data to resolve them. All nine discordances between 18S screening PCR and microscopy were resolved in favor of the molecular method, as were eight of nine discordances at the species level for the species-specific PCR among the 31 samples positive by both methods. The other 31 blood samples were tested to monitor the antimalaria treatment in seven patients. The number of parasites measured by real-time PCR fell rapidly for six out of seven patients in parallel to parasitemia determined microscopically. This suggests a role of quantitative PCR for the monitoring of patients receiving antimalaria therapy.

Metaphyseal chondromatosis combined with D-2-hydroxyglutaric aciduria in four patients.

We report four patients who presented with a severe form of metaphyseal chondromatosis in association with D-2-hydroxyglutaric aciduria (D-2-HGA). All patients showed splaying columns of irregular ossification defects with bulbous metaphyses of the long tubular bones, as well as remarkable involvement of the short tubular and flat bones. The vertebral bodies revealed platyspondyly with irregular, stippled endplates. D-2-HGA has been described as a neurometabolic disorder manifesting a broad range of impairment in mental and motor development. Although hydroxyglutaric acid was excreted in high amounts in the urine of all four patients described herein, no significant neurologic abnormalities were evident. This unusual combination of characteristic skeletal and metabolic abnormalities has rarely been reported. Thus, our report will facilitate the recognition of this distinctive entity, and we suggest that a urine organic acid screening be obtained in patients who present with generalized enchondromatosis.

Androgenetic alopecia: identification of four genetic risk loci and evidence for the contribution of WNT signaling to its etiology.

The pathogenesis of androgenetic alopecia (AGA, male-pattern baldness) is driven by androgens, and genetic predisposition is the major prerequisite. Candidate gene and genome-wide association studies have reported that single-nucleotide polymorphisms (SNPs) at eight different genomic loci are associated with AGA development. However, a significant fraction of the overall heritable risk still awaits identification. Furthermore, the understanding of the pathophysiology of AGA is incomplete, and each newly associated locus may provide novel insights into contributing biological pathways. The aim of this study was to identify unknown AGA risk loci by replicating SNPs at the 12 genomic loci that showed suggestive association (5 × 10(-8)<P<10(-5)) with AGA in a recent meta-analysis. We analyzed a replication set comprising 2,759 cases and 2,661 controls of European descent to confirm the association with AGA at these loci. Combined analysis of the replication and the meta-analysis data identified four genome-wide significant risk loci for AGA on chromosomes 2q35, 3q25.1, 5q33.3, and 12p12.1. The strongest association signal was obtained for rs7349332 (P=3.55 × 10(-15)) on chr2q35, which is located intronically in WNT10A. Expression studies in human hair follicle tissue suggest that WNT10A has a functional role in AGA etiology. Thus, our study provides genetic evidence supporting an involvement of WNT signaling in AGA development.

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.

Performance comparison of an active matrix flat panel imager, computed radiography system, and a screen-film system at four standard radiation qualities.

Four standard radiation qualities (from RQA 3 to RQA 9) were used to compare the imaging performance of a computed radiography (CR) system (general purpose and high resolution phosphor plates of a Kodak CR 9000 system), a selenium-based direct flat panel detector (Kodak Direct View DR 9000), and a conventional screen-film system (Kodak T-MAT L/RA film with a 3M Trimax Regular screen of speed 400) in conventional radiography. Reference exposure levels were chosen according to the manufacturer's recommendations to be representative of clinical practice (exposure index of 1700 for digital systems and a film optical density of 1.4). With the exception of the RQA 3 beam quality, the exposure levels needed to produce a mean digital signal of 1700 were higher than those needed to obtain a mean film optical density of 1.4. In spite of intense developments in the field of digital detectors, screen-film systems are still very efficient detectors for most of the beam qualities used in radiology. An important outcome of this study is the behavior of the detective quantum efficiency of the digital radiography (DR) system as a function of beam energy. The practice of users to increase beam energy when switching from a screen-film system to a CR system, in order to improve the compromise between patient dose and image quality, might not be appropriate when switching from screen-film to selenium-based DR systems.

Revising the Cannabis Use Disorders Identification Test (CUDIT) by means of Item Response Theory.

Cannabis use among adolescents and young adults has become a major public health challenge. Several European countries are currently developing short screening instruments to identify 'problematic' forms of cannabis use in general population surveys. One such instrument is the Cannabis Use Disorders Identification Test (CUDIT), a 10-item questionnaire based on the Alcohol Use Disorders Identification Test. Previous research found that some CUDIT items did not perform well psychometrically. In the interests of improving the psychometric properties of the CUDIT, this study replaces the poorly performing items with new items that specifically address cannabis use. Analyses are based on a sub-sample of 558 recent cannabis users from a representative population sample of 5722 individuals (aged 13-32) who were surveyed in the 2007 Swiss Cannabis Monitoring Study. Four new items were added to the original CUDIT. Psychometric properties of all 14 items, as well as the dimensionality of the supplemented CUDIT were then examined using Item Response Theory. Results indicate the unidimensionality of CUDIT and an improvement in its psychometric performance when three original items (usual hours being stoned; injuries; guilt) are replaced by new ones (motives for using cannabis; missing out leisure time activities; difficulties at work/school). However, improvements were limited to cannabis users with a high problem score. For epidemiological purposes, any further revision of CUDIT should therefore include a greater number of 'easier' items.

Perfusion and diffusion MRI of glioblastoma progression in a four-year prospective temozolomide clinical trial.

PURPOSE: This study was performed to determine the impact of perfusion and diffusion magnetic resonance imaging (MRI) sequences on patients during treatment of newly diagnosed glioblastoma. Special emphasis has been given to these imaging technologies as tools to potentially anticipate disease progression, as progression-free survival is frequently used as a surrogate endpoint. METHODS AND MATERIALS: Forty-one patients from a phase II temolozomide clinical trial were included. During follow-up, images were integrated 21 to 28 days after radiochemotherapy and every 2 months thereafter. Assessment of scans included measurement of size of lesion on T1 contrast-enhanced, T2, diffusion, and perfusion images, as well as mass effect. Classical criteria on tumor size variation and clinical parameters were used to set disease progression date. RESULTS: A total of 311 MRI examinations were reviewed. At disease progression (32 patients), a multivariate Cox regression determined 2 significant survival parameters: T1 largest diameter (p < 0.02) and T2 size variation (p < 0.05), whereas perfusion and diffusion were not significant. CONCLUSION: Perfusion and diffusion techniques cannot be used to anticipate tumor progression. Decision making at disease progression is critical, and classical T1 and T2 imaging remain the gold standard. Specifically, a T1 contrast enhancement over 3 cm in largest diameter together with an increased T2 hypersignal is a marker of inferior prognosis.