Clinical and molecular delineation of the 17q21.31 microdeletion syndrome

Background: The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation. Aim: We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome. Results: We estimate the prevalence of the syndrome to be 1 in 16 000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729-41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p< 10(25)). Conclusion: Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.

Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair

Recurrent submicroscopic genomic copy number changes are the result of nonallelic homologous recombination (NAHR). Nonrecurrent aberrations, however, can result from different nonexclusive recombination-repair mechanisms. We previously described small microduplications at Xq28 containing MECP2 in four male patients with a severe neurological phenotype. Here, we report on the fine-mapping and breakpoint analysis of 16 unique microduplications. The size of the overlapping copy number changes varies between 0.3 and 2.3 Mb, and FISH analysis on three patients demonstrated a tandem orientation. Although eight of the 32 breakpoint regions coincide with low-copy repeats, none of the duplications are the result of NAHR. Bioinformatics analysis of the breakpoint regions demonstrated a 2.5-fold higher frequency of Alu interspersed repeats as compared with control regions, as well as a very high GC content (53%). Unexpectedly, we obtained the junction in only one patient by long-range PCR, which revealed nonhomologous end joining as the mechanism. Breakpoint analysis in two other patients by inverse PCR and subsequent array comparative genomic hybridization analysis demonstrated the presence of a second duplicated region more telomeric at Xq28, of which one copy was inserted in between the duplicated MECP2 regions. These data suggest a two-step mechanism in which part of Xq28 is first inserted near the MECP2 locus, followed by breakage-induced replication with strand invasion of the normal sister chromatid. Our results indicate that the mechanism by which copy number changes occur in regions with a complex genomic architecture can yield complex rearrangements.

Short- and long-term anxiogenic effects induced by a single injection of subconvulsant doses of pilocarpine in rats: investigation of the putative role of hippocampal pathways

Behavioral consequences of convulsive episodes are well documented, but less attention was paid to changes that occur in response to subconvulsant doses of drugs. We investigated short- and long-term effects of a single systemic injection of a subconvulsant dose of pilocarpine on the behavior of rats as evaluated in the elevated plus maze. Pilocarpine induced an anxiogenic-like profile 24 h later, and this effect persisted for up to 3 months (% of time spent on open arms at 24 h, control = 35.47 +/- 3.23; pilocarpine 150 = 8.2 +/- 2.6; 3 months, control = 31.9 +/- 5.5; pilocarpine 150 = 9.3 +/- 4.9). Temporary inactivation of fimbria-fornix with lidocaine 4% promoted an anxiolytic-like effect per se, suggesting a tonic control of this pathway on the modulation of anxiety-related behaviors. Lidocaine also reduced the anxiogenic-like profile of animals tested 1 month after pilocarpine treatment (% of time spent on open arms, saline + phosphate-buffered saline (PBS) = 31.7 + 3.7; saline + lidocaine = 54.4 + 4.7; pilocarpine + PBS = 10.3 + 4.1; pilocarpine + lidocaine = 40.1 + 9.1). To determine whether the anxiogenic-like effect was mediated by septal region or by direct hippocampal projections to the diencephalon, the neural transmission of post-commissural fornix was blocked, and a similar reduction in the anxiogenic-like effect of pilocarpine was observed. Our findings suggest that a single systemic injection of pilocarpine may induce long-lasting anxiogenic-like behavior in rats, an effect that appears to be mediated, in part, through a direct path from hippocampus to medial hypothalamic sites involved in fear responses.

Toxoplasma gondii in the peripheral blood of patients with acute and chronic toxoplasmosis

Background and aims Toxoplasmic retinochoroiditis may recur months or years after the primary infection. Rupture of dormant cysts in the retina is the accepted hypothesis to explain recurrence. Here, the authors present evidence supporting the presence of Toxoplasma gondii in the peripheral blood of immunocompetent patients. Methods Direct observation by light microscopy and by immunofluorescence assay was performed, and results were confirmed by PCR amplification of parasite DNA. Results The authors studied 20 patients from Erechim, Brazil, including acute infected patients, patients with recurrent active toxoplasmic retinochoroiditis, patients with old toxoplasmic retinal scars, and patients with circulating IgG antibodies against T gondii and absence of ocular lesions. Blood samples were analysed, and T gondii was found in the blood of acutely and chronically infected patients regardless of toxoplasmic retinochoroiditis. Conclusions The results indicate that the parasite may circulate in the blood of immunocompetent individuals and that parasitaemia could be associated with the reactivation of the ocular disease.

Naturally acquired inhibitory antibodies to Plasmodium vivax Duffy binding protein are short-lived and allele-specific following a single malaria infection

The Duffy binding protein of Plasmodium vivax (DBP) is a critical adhesion ligand that participates in merozoite invasion of human Duffy-positive erythrocytes. A small outbreak of P. vivax malaria, in a village located in a non-malarious area of Brazil, offered us an opportunity to investigate the DBP immune responses among individuals who had their first and brief exposure to malaria. Thirty-three individuals participated in the five cross-sectional surveys, 15 with confirmed P. vivax infection while residing in the outbreak area (cases) and 18 who had not experienced malaria (non-cases). In the present study, we found that only 20% (three of 15) of the individuals who experienced their first P. vivax infection developed an antibody response to DBP; a secondary boosting can be achieved with a recurrent P. vivax infection. DNA sequences from primary/recurrent P. vivax samples identified a single dbp allele among the samples from the outbreak area. To investigate inhibitory antibodies to the ligand domain of the DBP (cysteine-rich region II, DBP(II)), we performed in vitro assays with mammalian cells expressing DBP(II) sequences which were homologous or not to those from the outbreak isolate. In non-immune individuals, the results of a 12-month follow-up period provided evidence that naturally acquired inhibitory antibodies to DBP(II) are short-lived and biased towards a specific allele.

Effect of Age on Outcome of Reduced-Intensity Hematopoietic Cell Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission or With Myelodysplastic Syndrome

Purpose Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) primarily afflict older individuals. Hematopoietic cell transplantation (HCT) is generally not offered because of concerns of excess morbidity and mortality. Reduced-intensity conditioning (RIC) regimens allow increased use of allogeneic HCT for older patients. To define prognostic factors impacting long-term outcomes of RIC regimens in patients older than age 40 years with AML in first complete remission or MDS and to determine the impact of age, we analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Patients and Methods We reviewed data reported to the CIBMTR (1995 to 2005) on 1,080 patients undergoing RIC HCT. Outcomes analyzed included neutrophil recovery, incidence of acute or chronic graft-versus-host disease (GVHD), nonrelapse mortality (NRM), relapse, disease-free survival (DFS), and overall survival (OS). Results Univariate analyses demonstrated no age group differences in NRM, grade 2 to 4 acute GVHD, chronic GVHD, or relapse. Patients age 40 to 54, 55 to 59, 60 to 64, and >= 65 years had 2-year survival rates as follows: 44% (95% Cl, 37% to 52%), 50% (95% Cl, 41% to 59%), 34% (95% Cl, 25% to 43%), and 36% (95% Cl, 24% to 49%), respectively, for patients with AML (P = .06); and 42% (95% Cl, 35% to 49%), 35% (95% Cl, 27% to 43%), 45% (95% Cl, 36% to 54%), and 38% (95% Cl, 25% to 51%), respectively, for patients with MDS (P = .37). Multivariate analysis revealed no significant impact of age on NRM, relapse, DFS, or OS (all P>.3). Greater HLA disparity adversely affected 2-year NRM, DFS, and OS. Unfavorable cytogenetics adversely impacted relapse, DFS, and OS. Better pre-HCT performance status predicted improved 2-year OS. Conclusion With these similar outcomes observed in older patients, we conclude that older age alone should not be considered a contraindication to HCT.

Sediment deformation in Miocene and post-Miocene strata, Northeastern Brazil: Evidence for paleoseismicity in a passive margin

Stratigraphic intervals characterized by varied and complex styles of soft-sediment deformation structures are well preserved in Miocene and Late Pleistocene to Holocene deposits of a sedimentary basin located in Northeastern Brazil. The Miocene strata, represented by the Barreiras Formation, record only brittle structures, including numerous faults and fractures with straight and high angle-dipping planes that are often filled with sands derived from overlying beds. Folds consisting of broad anticlines and synclines are also present in this unit. The late Pleistocene to Holocene deposits, named Post-Barreiras Sediments, contain an indurated sandy package with a large variety of ductile and brittle deformation structures (i.e., massive sandstones with isolated sand fragments and breccias, undulatory strata, sand dykes and diapirs, sinks and bowls, pebbly pockets, plunged sediment mixtures, fitted sand masses, cone-shaped cracks, fault grading and sedimentary enclaves). These features, confined to sharp-based stratigraphic horizons that progressively grade downward into undisturbed deposits, are related to seismic shocks of high surface-wave magnitude (i.e., Ms>5 or 6). Amalgamated seismites suggest that previously formed seismites were affected by subsequent seismic-wave propagation. Seismic waves caused by activity along one, or most likely, several tectonic structures would have propagated throughout the depositional environment, producing laterally extensive seismites. The close proximity to earthquake epicenters would have promoted pervasive re-sedimentation due to pore overpressure, resulting high volumes of massive sandstones and breccia. The similarity between deposits with correlatable strata from many other areas along the Brazilian coast allows raise the hypothesis that the seismic episodes might have affected sedimentation patterns in a large (i.e., extension of several hundreds of kilometers) geographic area. Thus, the modern seismicity recorded along Northeastern Brazil was recurrent during the Quaternary and, perhaps, also in the Pliocene. The estimated high magnitude of the seismic events and the great regional extent of the affected area demonstrate that the Brazilian coast experienced tectonic stress through the last geological episodes of its evolution, which would have favored sediment accumulation and penecontemporaneous re-sedimentation. This geological context is unexpected in a passive margin, inducing to revisit the debate on how active is a passive margin. (C) 2010 Elsevier B.V. All rights reserved.

Alteration of purinergic P2X(4) and P2X(7) receptor expression in rats with temporal-lobe epilepsy induced by pilocarpine

Although ATP and P2X receptor activity have been lately associated with epilepsy, little is known regarding their exact roles in epileptogenesis. Temporal-lobe epilepsy (TLE) in rat was induced by pilocarpine in order to study changes of hippocampal P2X(2), P2X(4) and P2X(7) receptor expression during acute, latent or chronic phases of epilepsy. During acute and chronic phases increased P2X(7) receptor expression was principally observed in glial cells and glutamatergic nerve terminals, suggesting participation of this receptor in the activation of inflammatory and excitotoxic processes during epileptogenesis. No significant alterations of hippocampal P2X(2) and P2X(4) receptor expression was noted during the acute or latent phase when compared to the control group, indicating that these receptors are not directly involved with the initiation of epilepsy. However, the reduction of hippocampal P2X(4) receptor immunostaining in the chronic phase could reflect neuronal toss or decreased GABAergic signaling. (C) 2008 Elsevier B.V. All rights reserved.

La confrontation de la laideur avec la beauté dans lesromans Mercure et Attentat. Une étude sur lareprésentation de la dualité thématique laideur-beautéchez Amélie Nothomb. : "Where there is Quasimodo, there is also Esmeralda." The confrontationbetween ugliness and beauty in the novels Mercure and Attentat. Astudy on the representation of the duality beauty-ugliness in the worksof Amélie Nothomb.

This paper studies one of the recurrent topics of writing found in Amélie Nothomb’snovels: beauty and ugliness. The novels Mercure and Attentat are analyzed in detail,with respect to figures of speech used to describe the extreme physical appearance ofthe protagonists and the role of the duality beauty-ugliness in the advancement of theplot.

The network of intertextual relations in Naipaul's half a life and magic seeds

Esta dissertação mapeia a rede de relações intertextuais em Half a Life (2001) e sua continuação Magic Seeds (2004), os romances mais recentes do Prêmio Nobel de Literatura de 2001, V. S. Naipaul, como contribuição para o estudo da obra do autor. A noção de intertextualidade permeia os estudos literários, e o termo tem sido largamente empregado desde que foi cunhado por Julia Kristeva nos anos sessenta. Desde então as mais variadas, e muitas vezes divergentes, teorias sobre intertextualidade compartilham a idéia de que um texto só adquire significado pleno na interação com outros textos. A abordagem metodológica proposta é baseada na teoria da transtextualidade de Gérard Genette. Esta escolha implica o estudo de intertextos, paratextos, metatextos, arquitextos e hipertextos que constituem a interface entre os dois romances e outros escritos. O nome do protagonista "William Somerset Chandran" constitui o fio que guia o estudo das várias relações transtextuais nos dois romances. A partir do prenome do protagonista – William – este estudo situa os romances no contexto da tradição do Bildungsroman, e argumenta que estes estabelecem uma paródia arquitextual do gênero na medida em que subvertem seu cerne, ou seja, a formação do caráter do protagonista. O nome do meio do protagonista – Somerset – remete à ficcionalização do escritor Somerset Maugham na narrativa, ao mesmo tempo em que esta desmistifica a ótica ocidental sobre o hinduísmo popularizada por Maugham em The Razor's Edge. O sobrenome do protagonista – Chandran – leva ao estudo do conjunto de referências à origem indiana de Naipaul e o papel desta na produção do autor. Este nome se reporta ao romance de Narayan The Bachelor of Arts, cujo protagonista também é nomeado Chandran. Narayan é um escritor de destaque na literatura anglo-indiana e referência recorrente na obra de Naipaul. Os temas de migração e choque cultural apresentados nos dois romances têm sido presença constante na obra de Naipaul. Esta pesquisa mapeia a relação de continuidade entre os dois romances em questão e o conjunto da obra de Naipaul, salientando o papel da ambientação geográfica da narrativa, marcada pela jornada do protagonista através de três continentes. A teoria da transtextualidade é uma ferramenta operacional para a pesquisa, a qual examina a densidade das referências geográficas, históricas e literárias em Half a Life e Magic Seeds, visando aportar elementos para o estudo da produção literária de Naipaul, na medida em que estes romances recentes condensam e revisitam a visão de mundo deste autor.

A comparative study on the "American innocence" issue : Henry Jame's The American and Daisy Miller : a study

Esta dissertação aborda a questão da “inocência americana” em duas obras do escritor norte-americano Henry James, empregando conceitos da Literatura Comparada como base para a análise dos textos escolhidos: The American e Daisy Miller: A Study. Portanto, os conceitos de intertextualidade, influência e alteridade são fundamentais para o estabelecimento das confluências e divergências entre as duas obras. Este trabalho também apresenta uma análise, com base na teoria comparatista da interdisciplinaridade, entre a obra literária Daisy Miller: A Study e o filme Daisy Miller, dirigido por Peter Bogdanovich. O tema recorrente nas obras analisadas, o da “inocência americana”, foi abordado por Henry James em grande parte de sua produção literária, sendo um reflexo de sua própria experiência como o “outro”, bem como de suas observações sobre seus compatriotas, quando confrontados com os valores e tradições vigentes na Europa, no século XIX. James alcançou seu merecido lugar no cânone literário ocidental, graças ao seu estilo incomparável, o qual foi aperfeiçoando durante toda sua carreira e até hoje é parâmetro para escritores contemporâneos.

Optimal exchange rate policy, optimal incomplete taxation and business cycles

Implementation and collapse of exchange rate pegging schemes are recur- rent events. A currency crisis (pegging) is usually followed by an economic downturn (boom). This essay explains why a benevolent government should pursue Þscal and monetary policies that lead to those recurrent currency crises and subsequent periods of pegging. It is shown that the optimal policy induces a competitive equilibrium that displays a boom in periods of below average de- valuation and a recession in periods of above average devaluation. A currency crisis (pegging) can be understood as an optimal policy answer to a recession (boom).

Social entrepreneurship practices and social change In Brazil: a qualitative study in three non-governmental organizations

Social Entrepreneurship (SE) has attracted growing interest from a wide variety of actors over the last 30 years, especially due to a general agreement that it could be an important tool for tackling many of the world’s social ills. In the academic sphere, this growing interest did not translate into a matured field of study. Quite the opposite, a quick look at this literature makes it evident that: SE has been consistently subjected to numerous theoretical discussions and disagreements, especially over the definition of the concept of SE which is often based on a taken-for-granted notion of social change; it has been more systematically investigated in restricted contexts, often leaving aside so called developing/emerging countries like Brazil and especially lacking in-depth qualitative studies; SE literature lags behind SE practices and few studies focus on how SE actually occurs in a daily and bottom-up manner. In order to address such gaps, this thesis examines how social entrepreneurship practices accomplish social change in the context of Brazil. In this investigation I conducted an inductive practice-based, qualitative/ethnographic study in three Non-Governmental Organizations (NGOs) located in different cities in the Brazilian state of São Paulo. Data collection lasted from February 2014 until March 2015 and was mainly done through participant observations and through in-depth unstructured conversations with research participants. Secondary data and documents were also collected whenever available. The participants of this study included a variety of the studied organizations’ stakeholders: two founders, volunteers, employees, donors and beneficiaries. Observation data was kept in fieldnotes, conversations were recorded whenever possible and were later transcribed. Data was analyzed through an iterative thematic analysis. Through this I identified eight recurrent themes in the data: (1) structure; (2) relationship with other organizational actors (sub-themes: relationship with state, relationship with businesses and relationship with other NGOs); (3) beliefs, spirituality and moral authority; (4) social position of participants, (5) stakeholders’ mobilization and participation; (6) feelings; (7) social purpose; and (8) social change. These findings were later discussed under the lens of practice theory, and in this discussion I argue and show that, in the context studied: (a) even though SE embraces a wide variety of different social purposes, they are intertwined with a common notion of social change based on a general understanding and aspiration for social equality; (b) this social change is accomplished in a processual and ongoing manner as stakeholders from antagonistic social groups felt compelled to and participated in SE practices. In answering the proposed research question the contributions of this thesis are: (i) the elaboration a working definition for SE based on its relationship with social change; (ii) providing in-depth empirical evidence which accounts for and explains this relationship; (iii) characterizing SE in the Brazilian context and reflecting upon its transferability to other contexts. This thesis also makes a methodological contribution, for it demonstrates how thematic analysis can be used in practice-based studies.

Social entrepreneurship, microcredit and development challenges: a case study analysis of Banco Pérola

The term “social entrepreneurship” has been attracting growing interest from different sectors in the past years, driven by the possibility of employing business techniques to tackle recurrent social and environmental issues. At the forefront of this global phenomenon is microcredit, seen by many as an effective anti-poverty tool and having the Grameen Bank as its flagship program. While the prospects of social entrepreneurship seem promising, the newness of the concept and its somewhat confusing definition make conditions difficult to analyze this contemporary phenomenon. Therefore, the objective of this study was to discuss the challenges faced by social entrepreneurs and alternatives of development for social businesses through a case study on a Brazilian microcredit institution and inclusive business, Banco Pérola. The case addresses a growing need for case studies designed for teaching in the field of social entrepreneurship. It was focused mainly on understanding the development challenges within Banco Pérola, and built based on interviews carried out with top management, credit officer and clients of the institution, as well as on secondary data collected. An analysis of the case study was performed under a Teaching Notes. As illustrated by the Banco Pérola case, the main difficulties encountered by social entrepreneurs relate to the systematization of processes and creation of operational routines, including for performance evaluation (impact assessment tools); to the capture and management of both financial and human capital; to scaling up the business model and to the need of forging closer and more personal relationships with customers as against in traditional banking practices. In spite of certain limitations, such as the fact that the case might soon become outdated due to the fast-changing environment surrounding Banco Pérola, or the fact that not all relevant stakeholders (e.g. partners) were selected for interviews, the research objective has been achieved and the study can be seen as a contribution to spreading the concept of social entrepreneurship.

Neurobiology and clinical implications of lucid dreaming

Several lines of evidence converge to the idea that rapid eye movement sleep (REMS) is a good model to foster our understanding of psychosis. Both REMS and psychosis course with internally generated perceptions and lack of rational judgment, which is attributed to a hyperlimbic activity along with hypofrontality. Interestingly, some individuals can become aware of dreaming during REMS, a particular experience known as lucid dreaming (LD), whose neurobiological basis is still controversial. Since the frontal lobe plays a role in self-consciousness, working memory and attention, here we hypothesize that LD is associated with increased frontal activity during REMS. A possible way to test this hypothesis is to check whether transcranial magnetic or electric stimulation of the frontal region during REMS triggers LD. We further suggest that psychosis and LD are opposite phenomena: LD as a physiological awakening while dreaming due to frontal activity, and psychosis as a pathological intrusion of dream features during wake state due to hypofrontality. We further suggest that LD research may have three main clinical implications. First, LD could be important to the study of consciousness, including its pathologies and other altered states. Second, LD could be used as a therapy for recurrent nightmares, a common symptom of depression and post-traumatic stress disorder. Finally, LD may allow for motor imagery during dreaming with possible improvement of physical rehabilitation. In all, we believe that LD research may clarify multiple aspects of brain functioning in its physiological, altered and pathological states.