A Multi-Center Phase II Study (SAKK 36/06) of Single Agent Everolimus (RAD001) In Patients with Relapsed or Refractory Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) accounts for 6% of all B-cell lymphomas and remains incurable for most patients. Those who relapse after first line therapy or hematopoietic stem cell transplantation have a dismal prognosis with short response duration after salvage therapy. On a molecular level, MCL is characterised by the translocation t[11;14] leading to Cyclin D1 overexpression. Cyclin D1 is downstream of the mammalian target of rapamycin (mTOR) kinase and can be effectively blocked by mTOR inhibitors such as temsirolimus. We set out to define the single agent activity of the orally available mTOR inhibitor everolimus (RAD001) in a prospective, multi-centre trial in patients with relapsed or refractory MCL (NCT00516412). The study was performed in collaboration with the EU-MCL network. Methods: Eligible patients with histologically/cytologically confirmed relapsed (not more than 3 prior lines of systemic treatment) or refractory MCL received everolimus 10 mg orally daily on day 1 - 28 of each cycle (4 weeks) for 6 cycles or until disease progression. The primary endpoint was the best objective response with adverse reactions, time to progression (TTP), time to treatment failure, response duration and molecular response as secondary endpoints. A response rate of ≤ 10% was considered uninteresting and, conversely, promising if ≥ 30%. The required sample size was 35 pts using the Simon's optimal two-stage design with 90% power and 5% significance. Results: A total of 36 patients with 35 evaluable patients from 19 centers were enrolled between August 2007 and January 2010. The median age was 69.4 years (range 40.1 to 84.9 years), with 22 males and 13 females. Thirty patients presented with relapsed and 5 with refractory MCL with a median of two prior therapies. Treatment was generally well tolerated with anemia (11%), thrombocytopenia (11%), neutropenia (8%), diarrhea (3%) and fatigue (3%) being the most frequent complications of CTC grade III or higher. Eighteen patients received 6 or more cycles of everolimus treatment. The objective response rate was 20% (95% CI: 8-37%) with 2 CR, 5 PR, 17 SD, and 11 PD. At a median follow-up of 6 months, TTP was 5.45 months (95% CI: 2.8-8.2 months) for the entire population and 10.6 months for the 18 patients receiving 6 or more cycles of treatment. Conclusion: This study demonstrates that single agent everolimus 10 mg once daily orally is well tolerated. The null hypothesis of inactivity could be rejected indicating a moderate anti-lymphoma activity in relapsed/refractory MCL. Further studies of either everolimus in combination with chemotherapy or as single agent for maintenance treatment are warranted in MCL.

Lengua familiar y conocimiento de la lengua escolar en Cataluña al finalizar la Educación Infantil = Home Language and Knowledge of the School Language in Catalonia at the end of Nursery School

La infancia extranjera se escolariza en Cataluña en un programa de cambio de lengua del hogar a la escuela. Las investigaciones afirman que este alumnado tarda un mínimo de seis años en equiparar sus habilidades lingüístico-cognitivas con sus pares autóctonos, no así las habilidades conversacionales, las cuales se adquieren antes de los dos años de residencia. Sin embargo, no existen estudios sobre los efectos de la escolarización en el parvulario del alumnado alófono, así como de su lengua familiar, en relación con la adquisición de la lengua escolar. El artículo es un estudio comparativo de la adquisición del catalán de 567 autóctonos y 434 alófonos, al final del parvulario, en 50 escuelas de Cataluña que escolarizan a alumnado de origen extranjero. Las lenguas del alumnado autóctono son el catalán, el castellano y el bilingüismo catalán-castellano y las lenguas del alumnado alófono son el árabe, el soninké y el castellano. Los factores utilizados más relevantes han sido el nivel socioprofesional y educativo de las familias, el tiempo de residencia y el momento de escolarización del alumnado, el porcentaje de alumnado catalanohablante y de alumnado alófono en el aula y el contexto sociolingüístico del centro escolar. Los resultados muestran que el alumnado autóctono sabe más catalán que el alumnado alófono, pero las diferencias desaparecen respecto a algunos factores, de los cuales los más relevantes son los relacionados con las características del alumnado de las aulas. La lengua familiar del alumnado alófono no incide en sus resultados

Looking for orders of magnitude : five essays in trade and the environment and economic geography

General Summary Although the chapters of this thesis address a variety of issues, the principal aim is common: test economic ideas in an international economic context. The intention has been to supply empirical findings using the largest suitable data sets and making use of the most appropriate empirical techniques. This thesis can roughly be divided into two parts: the first one, corresponding to the first two chapters, investigates the link between trade and the environment, the second one, the last three chapters, is related to economic geography issues. Environmental problems are omnipresent in the daily press nowadays and one of the arguments put forward is that globalisation causes severe environmental problems through the reallocation of investments and production to countries with less stringent environmental regulations. A measure of the amplitude of this undesirable effect is provided in the first part. The third and the fourth chapters explore the productivity effects of agglomeration. The computed spillover effects between different sectors indicate how cluster-formation might be productivity enhancing. The last chapter is not about how to better understand the world but how to measure it and it was just a great pleasure to work on it. "The Economist" writes every week about the impressive population and economic growth observed in China and India, and everybody agrees that the world's center of gravity has shifted. But by how much and how fast did it shift? An answer is given in the last part, which proposes a global measure for the location of world production and allows to visualize our results in Google Earth. A short summary of each of the five chapters is provided below. The first chapter, entitled "Unraveling the World-Wide Pollution-Haven Effect" investigates the relative strength of the pollution haven effect (PH, comparative advantage in dirty products due to differences in environmental regulation) and the factor endowment effect (FE, comparative advantage in dirty, capital intensive products due to differences in endowments). We compute the pollution content of imports using the IPPS coefficients (for three pollutants, namely biological oxygen demand, sulphur dioxide and toxic pollution intensity for all manufacturing sectors) provided by the World Bank and use a gravity-type framework to isolate the two above mentioned effects. Our study covers 48 countries that can be classified into 29 Southern and 19 Northern countries and uses the lead content of gasoline as proxy for environmental stringency. For North-South trade we find significant PH and FE effects going in the expected, opposite directions and being of similar magnitude. However, when looking at world trade, the effects become very small because of the high North-North trade share, where we have no a priori expectations about the signs of these effects. Therefore popular fears about the trade effects of differences in environmental regulations might by exaggerated. The second chapter is entitled "Is trade bad for the Environment? Decomposing worldwide SO2 emissions, 1990-2000". First we construct a novel and large database containing reasonable estimates of SO2 emission intensities per unit labor that vary across countries, periods and manufacturing sectors. Then we use these original data (covering 31 developed and 31 developing countries) to decompose the worldwide SO2 emissions into the three well known dynamic effects (scale, technique and composition effect). We find that the positive scale (+9,5%) and the negative technique (-12.5%) effect are the main driving forces of emission changes. Composition effects between countries and sectors are smaller, both negative and of similar magnitude (-3.5% each). Given that trade matters via the composition effects this means that trade reduces total emissions. We next construct, in a first experiment, a hypothetical world where no trade happens, i.e. each country produces its imports at home and does no longer produce its exports. The difference between the actual and this no-trade world allows us (under the omission of price effects) to compute a static first-order trade effect. The latter now increases total world emissions because it allows, on average, dirty countries to specialize in dirty products. However, this effect is smaller (3.5%) in 2000 than in 1990 (10%), in line with the negative dynamic composition effect identified in the previous exercise. We then propose a second experiment, comparing effective emissions with the maximum or minimum possible level of SO2 emissions. These hypothetical levels of emissions are obtained by reallocating labour accordingly across sectors within each country (under the country-employment and the world industry-production constraints). Using linear programming techniques, we show that emissions are reduced by 90% with respect to the worst case, but that they could still be reduced further by another 80% if emissions were to be minimized. The findings from this chapter go together with those from chapter one in the sense that trade-induced composition effect do not seem to be the main source of pollution, at least in the recent past. Going now to the economic geography part of this thesis, the third chapter, entitled "A Dynamic Model with Sectoral Agglomeration Effects" consists of a short note that derives the theoretical model estimated in the fourth chapter. The derivation is directly based on the multi-regional framework by Ciccone (2002) but extends it in order to include sectoral disaggregation and a temporal dimension. This allows us formally to write present productivity as a function of past productivity and other contemporaneous and past control variables. The fourth chapter entitled "Sectoral Agglomeration Effects in a Panel of European Regions" takes the final equation derived in chapter three to the data. We investigate the empirical link between density and labour productivity based on regional data (245 NUTS-2 regions over the period 1980-2003). Using dynamic panel techniques allows us to control for the possible endogeneity of density and for region specific effects. We find a positive long run elasticity of density with respect to labour productivity of about 13%. When using data at the sectoral level it seems that positive cross-sector and negative own-sector externalities are present in manufacturing while financial services display strong positive own-sector effects. The fifth and last chapter entitled "Is the World's Economic Center of Gravity Already in Asia?" computes the world economic, demographic and geographic center of gravity for 1975-2004 and compares them. Based on data for the largest cities in the world and using the physical concept of center of mass, we find that the world's economic center of gravity is still located in Europe, even though there is a clear shift towards Asia. To sum up, this thesis makes three main contributions. First, it provides new estimates of orders of magnitudes for the role of trade in the globalisation and environment debate. Second, it computes reliable and disaggregated elasticities for the effect of density on labour productivity in European regions. Third, it allows us, in a geometrically rigorous way, to track the path of the world's economic center of gravity.

Impacts of deforestation on water balance components of a watershed on the Brazilian East Coast

The Brazilian East coast was intensely affected by deforestation, which drastically cut back the original biome. The possible impacts of this process on water resources are still unknown. The purpose of this study was an evaluation of the impacts of deforestation on the main water balance components of the Galo creek watershed, in the State of Espírito Santo, on the East coast of Brazil. Considering the real conditions of the watershed, the SWAT model was calibrated with data from 1997 to 2000 and validated for the period between 2001 and 2003. The calibration and validation processes were evaluated by the Nash-Sutcliffe efficiency coefficient and by the statistical parameters (determination coefficient, slope coefficient and F test) of the regression model adjusted for estimated and measured flow data. After calibration and validation of the model, new simulations were carried out for three different land use scenarios: a scenario in compliance with the law (C1), assuming the preservation of PPAs (permanent preservation areas); an optimistic scenario (C2), which considers the watershed to be almost entirely covered by native vegetation; and a pessimistic scenario (C3), in which the watershed would be almost entirely covered by pasture. The scenarios C1, C2 and C3 represent a soil cover of native forest of 76, 97 and 0 %, respectively. The results were compared with the simulation, considering the real scenario (C0) with 54 % forest cover. The Nash-Sutcliffe coefficients were 0.65 and 0.70 for calibration and validation, respectively, indicating satisfactory results in the flow simulation. A mean reduction of 10 % of the native forest cover would cause a mean annual increase of approximately 11.5 mm in total runoff at the watershed outlet. Reforestation would ensure minimum flows in the dry period and regulate the maximum flow of the main watercourse of the watershed.

Mass movement characterization using a reflexion and refraction seismic survey with the sloping local base level concept

This study proposes a new concept for upscaling local information on failure surfaces derived from geophysical data, in order to develop the spatial information and quickly estimate the magnitude and intensity of a landslide. A new vision of seismic interpretation on landslides is also demonstrated by taking into account basic geomorphic information with a numeric method based on the Sloping Local Base Level (SLBL). The SLBL is a generalization of the base level defined in geomorphology applied to landslides, and allows the calculation of the potential geometry of the landslide failure surface. This approach was applied to a large scale landslide formed mainly in gypsum and situated in a former glacial valley along the Rhone within the Western European Alps. Previous studies identified the existence of two sliding surfaces that may continue below the level of the valley. In this study. seismic refraction-reflexion surveys were carried out to verify the existence of these failure surfaces. The analysis of the seismic data provides a four-layer model where three velocity layers (<1000 ms(-1), 1500 ms(-1) and 3000 ms(-1)) are interpreted as the mobilized mass at different weathering levels and compaction. The highest velocity layer (>4000 ms(-1)) with a maximum depth of similar to 58 m is interpreted as the stable anhydrite bedrock. Two failure surfaces were interpreted from the seismic surveys: an upper failure and a much deeper one (respectively 25 and 50 m deep). The upper failure surface depth deduced from geophysics is slightly different from the results obtained using the SLBL, and the deeper failure surface depth calculated with the SLBL method is underestimated in comparison with the geophysical interpretations. Optimal results were therefore obtained by including the seismic data in the SLBL calculations according to the geomorphic limits of the landslide (maximal volume of mobilized mass = 7.5 x 10(6) m(3)).

Graph theory reveals dysconnected hubs in 22q11DS and altered nodal efficiency in patients with hallucinations.

Schizophrenia is postulated to be the prototypical dysconnection disorder, in which hallucinations are the core symptom. Due to high heterogeneity in methodology across studies and the clinical phenotype, it remains unclear whether the structural brain dysconnection is global or focal and if clinical symptoms result from this dysconnection. In the present work, we attempt to clarify this issue by studying a population considered as a homogeneous genetic sub-type of schizophrenia, namely the 22q11.2 deletion syndrome (22q11.2DS). Cerebral MRIs were acquired for 46 patients and 48 age and gender matched controls (aged 6-26, respectively mean age = 15.20 ± 4.53 and 15.28 ± 4.35 years old). Using the Connectome mapper pipeline (connectomics.org) that combines structural and diffusion MRI, we created a whole brain network for each individual. Graph theory was used to quantify the global and local properties of the brain network organization for each participant. A global degree loss of 6% was found in patients' networks along with an increased Characteristic Path Length. After identifying and comparing hubs, a significant loss of degree in patients' hubs was found in 58% of the hubs. Based on Allen's brain network model for hallucinations, we explored the association between local efficiency and symptom severity. Negative correlations were found in the Broca's area (p < 0.004), the Wernicke area (p < 0.023) and a positive correlation was found in the dorsolateral prefrontal cortex (DLPFC) (p < 0.014). In line with the dysconnection findings in schizophrenia, our results provide preliminary evidence for a targeted alteration in the brain network hubs' organization in individuals with a genetic risk for schizophrenia. The study of specific disorganization in language, speech and thought regulation networks sharing similar network properties may help to understand their role in the hallucination mechanism.

The cAMP response element binding protein-2 (CREB-2) can interact with the C/EBP-homologous protein (CHOP).

cAMP response element binding protein-2 (CREB-2) is a basic leucine zipper (bZIP) factor that was originally described as a repressor of CRE-dependent transcription but that can also act as a transcriptional activator. Moreover, CREB-2 is able to function in association with the viral Tax protein as an activator of the human T-cell leukemia virus type I (HTLV-I) promoter. Here we show that CREB-2 is able to interact with C/EBP-homologous protein (CHOP), a bZIP transcription factor known to inhibit CAAT/enhancer-dependent transcription. Cotransfection of CHOP with CREB-2 results in decreased activation driven by the cellular CRE motif or the HTLV-I proximal Tax-responsive element, confirming that CREB-2 and CHOP can interact with each other in vivo.

Factors affecting Hg (II) adsorption in soils from the Rio Negro basin (Amazon)

Mercury (II) adsorption studies in top soils (top 10 cm) from the Rio Negro basin show this process depends strongly on some selected parameters of the aqueous phase in contact with the soils. Maximum adsorption occurred in the pH range 3.0-5.0 (>90%). Dissolved organic matter shows an inhibitory effect on the availability of Hg (II) to be adsorbed by the soils, whereas a higher chloride content of the solution resulted in a lower adsorption of Hg (II) at pH 5.0. Soils with higher organic matter content were less affected by changes in the salinity. An increase in the initial Hg (II) concentration increased the amount of Hg (II) adsorbed by the soil and decreased the time needed to reach equilibrium. A Freundlich isotherm provided a good model for Hg (II) adsorption in the two types of soil studied. The kinetics of Hg (II) adsorption on Amazonian soils showed to be very fast and followed pseudo-second order kinetics. An environmental implication of these results is discussed under the real scenario present in the Negro River basin, where acidic waters are in contact with a soil naturally rich in mercury.

Nursing Ethics Education in Finland from the Perspective of Codes of Ethics

The purpose of this study was to analyze nursing ethics education from the perspective of nurses’ codes of ethics in the basic nursing education programmes in polytechnics in Finland with the following research questions: What is known about nurses’ codes in practice and education, what contents of the codes are taught, what teaching and evaluation methods are used, which demographic variables are associated with the teaching, what is nurse educators’ adequacy of knowledge to teach the codes and nursing students’ knowledge of and ability to apply the codes, and what are participants’ opinions of the need and applicability of the codes, and their importance in nursing ethics education. The aim of the study was to identify strengths and possible problem areas in teaching of the codes and nursing ethics in general. The knowledge gained from this study can be used for developing nursing ethics curricula and teaching of ethics in theory and practice. The data collection was targeted to all polytechnics in Finland providing basic nursing education (i.e. Bachelor of Health Care). The target groups were all nurse educators teaching ethics and all graduating nursing students in the academic year of 2006. A total of 183 educators and 214 students from 24 polytechnics participated. The data was collected using a structured questionnaire with four open-ended questions, designed for this study. The data was analysed by SPSS (14.0) and the open-ended questions by inductive content analysis. Descriptive statistics were used to summarize the data. Inferential statistics were used to estimate the differences between the participant groups. The reliability of the questionnaire was estimated with Cronbach’s coefficient alpha. The literature review revealed that empirical research on the codes was scarce, and minimal in the area of education. Teaching of nurses’ codes themselves and the embedded ethical concepts was extensive, teaching of the functions of the codes and related laws and agreements was moderate, but teaching of the codes of other health care professions was modest. Issues related to the nurse-patient relationship were emphasised. Wider social dimensions of the codes were less emphasized. Educators’ and students’ descriptions of teaching emphasized mainly the same teaching contents, but there were statistically significant differences between the groups in that educators assessed their teaching to be more extensive than what students had perceived it had been. T he use of teaching and evaluation methods was rather narrow and conventional. However, educators’ and students’ descriptions of the used methods differed statistically significantly. Students’ knowledge of the codes and their ability to apply them in practice was assessed as mediocre by educators and by students themselves. Most educators assessed their own knowledge of the codes as adequate to teach the codes, as did most of the students. Educators who regarded their knowledge as adequate taught the codes more extensively than those who assessed their knowledge as less adequate. Also students who assessed their educators’ knowledge as adequate perceived the teaching of the codes to be more extensive. Otherwise educators’ and students’ demographic variables had little association with their descriptions of the teaching. According to the participants, nurses need their own codes, and they are also regarded as applicable in practice. The codes are an important element in nursing ethics education, but their teaching needs development. Further research should focus on the organization of ethics teaching in the curricula, the teaching process, and on the evaluation of the effectiveness of ethics education and on educators’ competence. Also the meaning and functions of the codes at all levels of nursing deserve attention. More versatile use of research methods would be beneficial in gaining new knowledge.

Metsäsääntely Suomessa ja Venäjällä. Näkökulmia kestävään metsätalouteen

Sustainability is the aim of forest management and forest regulation in many countries. Accordingly, forest management has been steered towards more environmentally friendly methods and new regulatory instruments have been introduced. At the same time, wood trade and forest industry have become a global business. Even if the importance of national forest legislation has not decreased, it has been widely acknowledged that national regulation of forest management is no longer sufficient. The movement of goods does not acknowledge boundaries, even though most negative environmental and social consequences stay in the country of origin of wood and other raw materials. As a partial solution to this dilemma, different kinds of regulations have been developed. Various forest certification schemes and wood trade regulation in the EU (995/2010) are examples of efforts to prevent illegal logging and unsustainable forestry. The Finland-based forest industry is to a varying extent dependent on wood trade from Russia. Especially in the 1990‟s, ethical questions concerning import of wood from Russian old growth forests near the Finnish border were widely discussed. Consequently, forest industry enterprises have developed systems to trace the origin of wood and to buy certified wood from Russia. The aim of the research has been to evaluate Finnish and Russian forest regulations in order to investigate what kind of forest management these regulations enhance, and to what extent ecologically sustainable forest management has been integrated into different forms of regulation. I have examined Finnish and Russian forest regulation in four separate articles based on the topics of the Russian Forest Code, forest certification and other voluntary forest protection measures in Russia, Finnish forest certification and Finnish forest legislation. One objective has been to analyse the roles voluntary forest certification plays in promoting sustainable forest management in different countries. In my research, I have mainly concentrated on ecological sustainability and protection of biodiversity, although other aspects of sustainable forest management have been touched upon in different articles. In the following I shall conclude the findings of my research. When the current Russian Forest Code (2006) was being adopted, the main emphasis was not on ecological issues, but on reorganizing forest governance. The role of ecological requirements was even slightly diminished during the legislative reform. There are, nevertheless, still stipulations aiming at ecological sustainability, such as the division of forests into different forest management categories and various protection zones. In 2000, FSC forest certification arrived in Russia, at present covering already 28 million hectares of forests. The PEFC scheme is now in use as well, but to a much lesser extent. If properly implemented, Russian forest certification schemes clearly improve the level of ecological and social sustainability of forestry in Russia. Certification criteria, however, are partly in conflict with the Russian forest legislation and certified enterprises have been forced to pay fines or to negotiate with forest authorities. This clearly indicates that even if Russian forest legislation has otherwise been liberalized to a certain extent, some significant paternalism still exists. Voluntary, hands-on biodiversity protection measures are not valued, and they are not part of the official protection policies as in many other countries. However, there have been some regional solutions to this dilemma. In the Republic of Karelia forest authorities have approved a set of forest biodiversity protection rules created by a local NGO and a forest industry enterprise. By following these local rules, an enterprise can avoid fines for protection measures. The current Finnish Forest Act was adopted in 1996. It brought forest legislation into a new era as some ecological aspects were integrated into forest legislation. The various soft-law forest management recommendations further increased the level of biodiversity protection. My evaluation of the overall legitimacy of the Finnish forest legislation and forest management paradigm revealed, however, several problematic issues. As part of this study I analysed the history of the current forest management paradigm. This analysis revealed the path dependency which still hinders the protection of biodiversity and clearly decreases the general legitimacy of forest management. Due to several historical reasons only even-structured forest management based on clear cuts has for decades been officially approved in Finland. Due to increasing demands of forest owners the legislation is finally being revised. Yet, the official approval of uneven-structured forest management would not be enough to fully improve ecological, social and cultural legitimacy. The latest ecological theories and knowledge of endangered species should be taken into account in the on-going reform of forest legislation as well as the modernisation. Forest legislation is one of the very few spheres of Finnish environmental legislation where openness and participation are still considered a threat. The first Finnish forest certification scheme, PEFC, was established in 2000. It now covers more than 20 million hectares, about 95% of the forests in Finland. PEFC Finland does not require a higher level of biodiversity protection than the recommendations by Tapio (the Development Centre for Forestry), but certification has unified forest management practices and requires more protection measures than mere forest legislation. The study suggests that in Finland PEFC has not functioned as an instrument which would substantially improve the level of forest management. Rather it has supported the status quo of the forest sector. While the ecological and social responsibility of Finland-based forest corporations was one impetus for this research, I want to conclude that there are problems related to forest legislation and non-state regulation in both Finland and Russia. If an enterprise buying wood from Russia buys only certified wood, and carefully avoids wood coming from high conservation value forests that are either ecologically or socially valuable, it can be claimed to be as sustainably produced as in Finland. However, there must be continuous scrutiny of the circumstances. In Russia, the level of the compliance of certification criteria varies considerably, and there are vast unprotected invaluable forest areas. The utilisation of these areas should not be based on short-sighted decisions or lack of consensus among stakeholders.

Competitive ability of corn in coexistence with goosegrass

Competition between plants is one of the main interferences that occurs in agricultural systems and accounts for significant crop yield reductions. The aim of this study was to assess the competitive ability of corn in coexistence with the weed species Eleusine indica. The experiments were conducted in a greenhouse, in the growing season 2010/2011, and were arranged in a completely randomized design with four replications. The experimental units consisted of plastic pots with a volumetric capacity of 8 L. Treatments were arranged in a replacement series with five proportions of corn plants and weed: 100:0, 75:25, 50:50, 25:75, and 0:100, respectively, with a constant population of eight plants per pot, at the end of each treatment. The competitiveness analysis was conducted through diagrams applied to the replacement series experiment and competitiveness index, and the variables evaluated were root, shoot, and total dry mass, and plant height. When in equal proportions, corn showed competitive ability equivalent to goosegrass in relation to the variables shoot, root, and total dry mass. Goosegrass was more competitive than the crop in relation to plant height.

A randomized crossover clinical study showing that methylphenidate-SODAS improves attention-deficit/hyperactivity disorder symptoms in adolescents with substance use disorder

Our objective was to evaluate the effectiveness of a long-acting formulation of methylphenidate (MPH-SODAS) on attention-deficit/hyperactivity disorder (ADHD) symptoms in an outpatient sample of adolescents with ADHD and substance use disorders (SUD). Secondary goals were to evaluate the tolerability and impact on drug use of MPH-SODAS. This was a 6-week, single-blind, placebo-controlled crossover study assessing efficacy of escalated doses of MPH-SODAS on ADHD symptoms in 16 adolescents with ADHD/SUD. Participants were randomly allocated to either group A (weeks 1-3 on MPH-SODAS, weeks 4-6 on placebo) or group B (reverse order). The primary outcome measures were the Swanson, Nolan and Pelham Scale, version IV (SNAP-IV) and the Clinical Global Impression Scale (CGI). We also evaluated the adverse effects of MPH-SODAS using the Barkley Side Effect Rating Scale and subject reports of drug use during the study. The sample consisted of marijuana (N = 16; 100%) and cocaine users (N = 7; 43.8%). Subjects had a significantly greater reduction in SNAP-IV and CGI scores (P < 0.001 for all analyses) during MPH-SODAS treatment compared to placebo. No significant effects for period or sequence were found in analyses with the SNAP-IV and CGI scales. There was no significant effect on drug use. MPH-SODAS was well tolerated but was associated with more severe appetite reduction than placebo (P < 0.001). MPH-SODAS was more effective than placebo in reducing ADHD symptoms in a non-abstinent outpatient sample of adolescents with comorbid SUD. Randomized clinical trials, with larger samples and SUD intervention, are recommended.

Defensive responses to threat scenarios in Brazilians reproduce the pattern of Hawaiian Americans and non-human mammals

A former study with scenarios conducted in Hawaii has suggested that humans share with non-human mammals the same basic defensive strategies - risk assessment, freezing, defensive threat, defensive attack, and flight. The selection of the most adaptive strategy is strongly influenced by features of the threat stimulus - magnitude, escapability, distance, ambiguity, and availability of a hiding place. Aiming at verifying if these strategies would be consistent in a different culture, 12 defensive scenarios were translated into Portuguese and adapted to the Brazilian culture. The sample consisted of male and female undergraduate students divided into two groups: 76 students, who evaluated the five dimensions of each scenario and 248 medical students, who chose the most likely response for each scenario. In agreement with the findings from studies of non-human mammal species, the scenarios were able to elicit different defensive behavioral responses, depending on features of the threat. "Flight" was chosen as the most likely response in scenarios evaluated as an unambiguous and intense threat, but with an available route of escape, whereas "attack" was chosen in an unambiguous, intense and close dangerous situation without an escape route. Less urgent behaviors, such as "check out", were chosen in scenarios evaluated as less intense, more distant and more ambiguous. Moreover, the results from the Brazilian sample were similar to the results obtained in the original study with Hawaiian students. These data suggest that a basic repertoire of defensive strategies is conserved along the mammalian evolution because they share similar functional benefits in maintaining fitness.

Delta sleep instability in children with chronic arthritis

The objective of the present study was to evaluate the expression of a cyclic alternating pattern (CAP) in slow wave sleep (SWS) in children with the well-defined chronic syndrome juvenile idiopathic arthritis (JIA). Twelve patients (9-17 years of age), 7 girls, with JIA were compared to matched controls by age, pubertal stage and gender. After one night of habituation in the sleep laboratory, sleep measurements were obtained by standard polysomnography with conventional sleep scoring and additional CAP analyses. The sleep parameters of the JIA and control groups were similar for sleep efficiency (91.1 ± 6.7 vs 95.8 ± 4.0), sleep stage in minutes: stage 1 (16.8 ± 8.5 vs 17.8 ± 4.0), stage 2 (251.9 ± 41 vs 262.8 ± 38.1), stage 3 (17.0 ± 6.0 vs 15.1 ± 5.7), stage 4 (61.0 ± 21.7 vs 77.1 ± 20.4), and rapid eye movement sleep (82.0 ± 27.6 vs 99.0 ± 23.9), respectively. JIA patients presented nocturnal disrupted sleep, with an increase in short awakenings, but CAP analyses showed that sleep disruption was present even during SWS, showing an increase in the overall CAP rate (P < 0.01). Overall CAP rate during non-rapid eye movement sleep was significantly higher in pediatric patients who were in chronic pain. This is the first study of CAP in pediatric patients with chronic arthritis showing that CAP analyses can be a powerful tool for the investigation of disturbance of SWS in children, based on sleep EEG visual analysis.